Frozen Section Library: Pancreas (Frozen Section Library, Volume 8)

Frozen Section Library Series Editor Philip T. Cagle, MD Houston, Texas, USA

For further volumes: http://www.springer.com/series/7869

Frozen Section Library: Pancreas

Wendy L. Frankel, MD The Ohio State University Medical Center, Columbus, OH, USA

Daniela M. Proca, MD The Ohio State University Medical Center, Columbus, OH, USA

Including Chapter 2 co-authored by:

Mark Bloomston, MD The Ohio State University Medical Center Columbus, OH, USA

13

Wendy L. Frankel, MD The Ohio State University Medical Center Columbus, OH 43210, USA [email protected]

Daniela M. Proca, MD The Ohio State University Medical Center Columbus, OH 43210, USA [email protected]

ISSN 1868-4157 e-ISSN 1868-4165 ISBN 978-1-4419-7789-2 e-ISBN 978-1-4419-7790-8 DOI 10.1007/978-1-4419-7790-8 Springer New York Dordrecht Heidelberg London © Springer Science+Business Media, LLC 2011 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

To our fathers, Maurice A. Frankel, MD, and Valentin Cojocea, MD, who are both surgeons and serve as our role models Wendy L. Frankel, MD Daniela Proca, MD

Series Preface

For over 100 years, the frozen section has been utilized as a tool for the rapid diagnosis of specimens while a patient is undergoing surgery, usually under general anesthesia, as a basis for making immediate treatment decisions. Frozen section diagnosis is often a challenge for the pathologist who must render a diagnosis that has crucial import for the patient in a minimal amount of time. In addition to the need for rapid recall of differential diagnoses, there are many pitfalls and artifacts that add to the risk of frozen section diagnosis that are not present with permanent sections of fully processed tissues that can be examined in a more leisurely fashion. Despite the century-long utilization of frozen sections, most standard pathology textbooks, both general and subspecialty, largely ignore the topic of frozen sections. Few textbooks have ever focused exclusively on frozen section diagnosis, and those textbooks that have done so are now out-of-date and have limited illustrations. The Frozen Section Library series is meant to provide convenient, user-friendly handbooks for each organ system to expedite use in the rushed frozen section situation. These books are small and lightweight, copiously color illustrated with images of actual frozen sections, highlighting pitfalls, artifacts, and differential diagnosis. The advantages of a series of organ-specific handbooks, in addition to the ease of use and manageable size, are that (1) a series allows more comprehensive coverage of more diagnoses, both common and rare, than a single volume that tries to highlight a limited number of diagnoses for each organ and (2) a series allows more detailed insight by permitting experienced authorities to emphasize the peculiarities of frozen section for each organ system. As a handbook for practicing pathologists, these books will be indispensable aids to diagnosis and avoiding dangers in one of the most challenging situations that pathologists encounter. Rapid

vii

viii

SERIES PREFACE

consideration of differential diagnoses and how to avoid traps caused by frozen section artifacts are emphasized in these handbooks. A series of concise, easy-to-use, well-illustrated handbooks alleviates the often frustrating and time-consuming, sometimes futile, process of searching through bulky textbooks that are unlikely to illustrate or discuss pathologic diagnoses from the perspective of frozen sections in the first place. Tables and charts will provide guidance for differential diagnosis of various histologic patterns. Touch preparations, which are used for some organs such as central nervous system or thyroid more often than others, are appropriately emphasized and illustrated according to the need for each specific organ. This series is meant to benefit practicing surgical pathologists, both community and academic, and pathology residents and fellows and also to provide valuable perspectives to surgeons, surgery residents, and fellows who must rely on frozen section diagnosis by their pathologists. Most of all, we hope that this series contributes to the improved care of patients who rely on the frozen section to help guide their treatment. Houston, TX

Philip T. Cagle Series Editor

Preface

Intra-operative pathology consultation is one of the most difficult areas in diagnostic surgical pathology due to time constraints, tissue and freezing artifacts, and the lack of ancillary studies such as immunohistochemistry. Frozen sections of the pancreas tend to be one of the more challenging areas due to the relatively small number of these cases at most institutions. Additionally, adenocarcinoma and chronic pancreatitis coexist in many cases and can be difficult to distinguish. This monograph, Frozen Section Library: Pancreas, is a volume in the Frozen Section Library Series. The contents are a combination of personal experience and a review of the available literature. Frozen Section Library: Pancreas will provide a concise pictorial compendium to facilitate intra-operative consultations on pancreas specimens. This user-friendly handbook is divided into chapters that emphasize the common questions a pathologist must answer during frozen section examination and will provide guidance for the differential diagnosis of various histologic patterns. A summary of Key Points as well as Pitfalls will be discussed at the end of the chapters. Some of the pitfalls can be avoided by being aware they exist. When possible, ways to avoid pitfalls will be mentioned. The purpose of this book is to aid in the timely frozen section diagnosis of pancreatic lesions by using a broad array of illustrations, which would reinforce one s visual memory, and a condensed text, useful for rapid review of main diagnostic features. Currently, there is no other up-to-date, single-source reference specifically focused on frozen sections of the pancreas. This book, it is hoped, will be a useful tool to practicing surgical pathologists, as well as to pathology residents and fellows. We hope it will facilitate the accurate diagnosis of pancreatic lesions, by not only describing patterns of disease but also helping to understand

ix

x

PREFACE

the expectations of the surgeon and how the diagnosis will help guide intra-operative decisions. Columbus, OH Columbus, OH

Wendy L. Frankel Daniela M. Proca

Acknowledgments

The authors wish to thank Shawn Scully and Brian Rubin for their technical expertise in preparing the figures and Jacqui Lankford for assistance in preparing/editing the text.

xi

Contents

Series Preface . . . . . . . . . . . . . . . . . . . . . . . . . .

vii

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ix

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . .

xi

1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . .

1

2.

Clinical Indications and Surgeons’ Expectations . .

3

3.

The Distinction Between Chronic Pancreatitis and Adenocarcinoma . . . . . . . . . . . . . . . . . . . Criteria of Malignancy in Frozen Section . . . . . . . . Other Tumor-like Lesions . . . . . . . . . . . . . . . . . .

9 12 23

Variants of Pancreatic Adenocarcinoma and Pancreatic Intraepithelial Neoplasia . . . . . . . Variants of Adenocarcinoma . . . . . . . . . . . . . . . . Pancreatic Intraepithelial Neoplasia (PanIN) . . . . . .

29 29 35

5.

Cystic Lesions in the Pancreas . . . . . . . . . . . . . Non-Neoplastic Cysts . . . . . . . . . . . . . . . . . . . . Neoplastic Cysts . . . . . . . . . . . . . . . . . . . . . . .

43 45 46

6.

Other Pancreatic Tumors . . . . . . . . . . . . . . . . .

55

7.

Secondary Tumors and Miscellaneous Lesions Involving the Pancreas . . . . . . . . . . . . .

63

Metastases, Resectability, and Margins . . . . . . . . Metastasis and Resectability . . . . . . . . . . . . . . . . Margin Assessment . . . . . . . . . . . . . . . . . . . . .

73 73 80

4.

8.

xiii

xiv

CONTENTS

Suggested Reading . . . . . . . . . . . . . . . . . . . . . . .

89

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

93

Chapter 1

Introduction

Frozen sections of the pancreas are performed for tumor confirmation and to assess resectability and margin status. Accurate frozen section diagnoses are important to help guide the surgical procedure. Diagnostic difficulties in pancreatic frozen sections are related to technical and morphological factors, with the main problematic differential diagnosis being between chronic pancreatitis and duct adenocarcinoma. Most of the histologic features useful in frozen sections are similar to those useful in small biopsies, but the diagnosis is more challenging due to frozen artifacts and time constraints. A diagnosis that may be straightforward in large and well-fixed sections may be challenging in small samples with artifact. The majority of specimens sent for frozen section analysis consist of small portions of tissue, rather than whole resection specimens. Therefore, the focus of this monograph will be on the histologic features most useful in these specimens. There are instances when the surgeon takes a patient to the operating room based upon the clinicoradiographic diagnosis of pancreatic carcinoma without tissue confirmation. The use of endoscopic ultrasound-guided fine needle aspiration analysis has increased the number of cases that have definitive pre-operative diagnoses, but cases still remain unconfirmed prior to surgery. Since chronic pancreatitis frequently surrounds malignant lesions in the pancreas, a diagnosis of chronic pancreatitis should not preclude a pancreatic resection for a clinically suspicious mass in a patient with resectable disease. It is acceptable to surgeons to have up to 10% of pancreatic resections for suspected malignancy contain benign processes, many times forms of chronic pancreatitis.

1 W.L. Frankel, D.M. Proca, Frozen Section Library: Pancreas, Frozen Section Library 8, DOI 10.1007/978-1-4419-7790-8_1, © Springer Science+Business Media, LLC 2011

2

FROZEN SECTION LIBRARY: PANCREAS

Frozen sections for the intra-operative assessment of pancreatic lesions are helpful in many cases. Large centers have reported the accuracy of pancreatic frozen sections ranging from 80 to 90%. The false-negative rates range from 1.6 to 30% (where all deferrals were counted as false negatives) and the false-positive rate is very low, limited to a few cases in individual large studies. Therefore, the positive predictive value for a diagnosis of pancreatic cancer is nearly 100% and the negative predictive value is less but remains excellent.

Chapter 2

Clinical Indications and Surgeons’ Expectations Wendy L. Frankel1 and Mark Bloomston2 1

Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, USA, [email protected] 2 Department of Surgery, The Ohio State University Medical Center, Columbus, OH, USA

The primary goal of all frozen section analysis is to help determine the best treatment during the operative procedure. In order to accomplish this goal, it is vital to have an understanding of the surgeons’ expectations and his/her likely response to a stated diagnosis. This perspective may help determine what the more conservative response would be in a given situation. We may want to favor the diagnosis that would stop a major resection or defer to permanents, rather than making a diagnosis that would prompt the resection in a diagnostically difficult case. Depending on the question and site of the biopsy (pancreatic lesion or metastatic site), a “malignant” diagnosis may either prompt resection or stop the procedure. We typically assume the expected response for each case is either “malignant” or “benign,” but there are circumstances where that is not the most helpful answer. At times, a more appropriate response would be to describe what is present, i.e., the description of an epithelial lining in a cystic lesion is more helpful than merely stating “benign.” The finding of an epithelial lining will prompt resection of the cyst, rather than drainage for a pseudocyst. In contrast, the diagnosis of “benign” could be misunderstood by the surgeon as no tumor present; this may not be the

3 W.L. Frankel, D.M. Proca, Frozen Section Library: Pancreas, Frozen Section Library 8, DOI 10.1007/978-1-4419-7790-8_2, © Springer Science+Business Media, LLC 2011

4

FROZEN SECTION LIBRARY: PANCREAS

case if a low-grade mucinous epithelial lining was identified (suggesting the possibility of a mucinous cystic tumor). Mistakes can be made by not focusing on the most important question and not understanding how the response could alter treatment. An experienced surgeon does not typically take a patient to the operating room to establish a diagnosis, but to treat the presumed diagnosis. The surgeon is already relatively confident of the diagnosis from the clinical and radiologic features (Table 2.1) or pre-operative tissue or cytologic diagnosis. In some cases, there is a pre-operative diagnosis of chronic pancreatitis from a core biopsy or fine needle aspirate. Fibrosis and inflammation frequently surround tumors, so a “benign” biopsy or cytology diagnosis does not preclude a pancreatic resection in the proper clinical setting. This perspective is important and explains why, in the face of a benign frozen section diagnosis, a surgeon may proceed with a Whipple resection in a clinically resectable patient

TABLE 2.1 Clinical and demographic features useful in the differential diagnosis of pancreatic neoplasms.

Gender/age

Clinical presentation

Serous cystadenoma Ductal adenocarcinoma Intraductal papillary mucinous neoplasm Mucinous cystic neoplasm Neuroendocrine tumor Solid pseudopapillary Acinar cell carcinoma

F>M, older

Pain, mass

M>F, older

Jaundice, pain, weight loss Pain, exocrine loss Usually head, cystic/intraductal, mucin at ampulla at ERCP Pain, mass Usually tail, cystic

Pancreatoblastoma

M>F, children

M>F, older

Mostly F, middle age M=F, variable F>M, young adults M>F, older

Radiologic findings Usually body/tail, cystic Usually head, solid

Endocrine hypersecretion Pain, mass

Solid

Jaundice rare, some with fat necrosis and polyarthralgia Pain, mass

Solid

ERCP, endoscopic retrograde cholangiopancreatography.

Solid/cystic

Solid

CLINICAL INDICATIONS AND SURGEONS’ EXPECTATIONS

5

who can tolerate a major procedure. There is, however, some variation among surgeons’ comfort in proceeding with resection without a confirmed diagnosis. This is not only due to patient age and health, but the experience of the surgeon. Many experienced surgeons will not request frozen sections for confirmation of malignancy, but only use frozen sections for unusual findings at surgery, to evaluate close margins, or to diagnose a liver lesion or other possible metastatic lesions. Determining the resectability of a tumor may require correlation between the frozen section diagnosis and the surgeon’s clinical impression during laparotomy. Frozen sections may be used at different decision points during surgery. Fig. 2.1 shows commonly asked intra-operative questions and the typical responses of the surgeon to frozen section diagnoses. Prior to laparotomy, the initial determination of resectability and assessment of the patient’s ability to undergo a major resection have already been made. Since most surgeons take a resectable patient with a presumed pancreatic malignancy to the operating room planning on a pancreas resection, the most important initial surgical decision is the determination of metastasis and resectability. If metastatic carcinoma is present outside of the area typically included in the resection field, the resection will be aborted. Therefore, the diagnosis of a lesion in a distant lymph node, liver, or peritoneum is important for the decision to resect. If there are no obvious metastases, the following step is dependent upon local assessment of resectability. Usually this has been determined prior to surgery using radiologic studies, but sometimes palpation during surgery reveals previously unidentified arterial encasement or direct spread beyond the pancreas. If the tumor is technically resectable and the surgeon is confident in the diagnosis of carcinoma, he/she generally resects without frozen section. If the surgeon is less confident, a frozen section may be sent to pathology to confirm the malignant diagnosis, and confirmation will lead to a resection. A benign, deferred, or non-diagnostic response may prompt more tissue to be sent for additional frozen sections. In the case of a technically unresectable tumor, tissue confirmation is necessary for chemo/radiation therapy. A bypass of the pancreatic, biliary, and gastrointestinal tract may be performed depending on the clinical necessity. In most cases a diagnosis of “malignant” or “benign” is sufficient for the surgeon, but at times, a tumor does not show features of a typical adenocarcinoma. In these cases, the diagnosis of “malignant” or “benign” may not be enough. The tumor type suspected on frozen section may impact the surgical procedure. For

6

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 2.1 The surgical response to frozen section diagnosis of pancreatic lesions and possible metastatic sites. After opening the abdomen, the surgeon determines if there are metastases (not seen on pre-operative evaluation) that would preclude the operation. Frozen sections may be requested at this point to help guide therapy. If there is no intra-operative evidence of metastasis, the decision to proceed with the resection will be based upon the assessment of technical resectability. If the tumor is not resectable, frozen section may be necessary to confirm the diagnosis of carcinoma prior to beginning chemo/radiation therapy. If the tumor is resectable, frozen section may be used to confirm carcinoma (if not previously confirmed on biopsy or fine needle aspiration) prior to resection.

example, neuroendocrine tumor suggested during intra-operative consultation allows surgical resection despite the presence of distant metastases; an unsuspected lymphoma in the pancreas likely precludes surgical resection, which would have been otherwise performed for the diagnosis of adenocarcinoma. If a pancreatic lesion is diagnosed on frozen as suspicious for metastasis from another site, it will likely still be resected, if possible. However, it may be helpful to suggest possible sites of origin so they can be investigated during the operative procedure.

CLINICAL INDICATIONS AND SURGEONS’ EXPECTATIONS

7

In summary, frozen sections of the pancreas are useful in diagnosing pancreatic mass lesions, determining the presence of metastases, and evaluating the margins of resection. Some less common types of pancreatic tumors can be suggested by intraoperative consultation, possibly affecting the surgical procedure.

Chapter 3

The Distinction Between Chronic Pancreatitis and Adenocarcinoma

Tumor-like lesions in the pancreas include any non-neoplastic pancreatic lesion that has the gross appearance of a mass. If diagnosed at frozen section, many of these lesions do not require a major procedure. However, some cases may still require a resection to exclude an adjacent malignancy. The final diagnosis is usually not made until the pancreas is widely sampled on the resection specimen. Examples of tumor-like lesions, include “pseudotumoral” forms of chronic pancreatitis, granulomatous inflammation, malakoplakia, other very rare infectious lesions, and noninflammatory lesions (hamartoma, heterotopic spleen). Some pancreatectomies performed with the pre-operative clinical diagnosis of carcinoma will prove to be non-neoplastic by pathologic examination. Chronic inflammatory lesions are the leading cause and among these, chronic pancreatitis (such as autoimmune or paraduodenal) is most important. Autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis) is characterized by periductal sclerosis and infiltration by lymphocytes and plasma cells and granulocytic epithelial lesions with secondary destruction of the ducts and venulitis. It usually involves the head of the pancreas and the distal bile duct. Paraduodenal (groove) pancreatitis is thought to be a form of alcoholic chronic pancreatitis that mimics periampullary carcinoma due to the selective involvement of the region of papilla minor. Histologic features of chronic pancreatitis that are helpful when seen in a frozen section include preservation of normal lobular architecture with irregular loss of acini, duct alterations,

9 W.L. Frankel, D.M. Proca, Frozen Section Library: Pancreas, Frozen Section Library 8, DOI 10.1007/978-1-4419-7790-8_3, © Springer Science+Business Media, LLC 2011

10

FROZEN SECTION LIBRARY: PANCREAS

chronic inflammation, and fibrosis. Duct alterations include dilatation, cyst formation, calcifications, and inspissated secretions (Fig. 3.1). Duct epithelial changes include mucinous or squamous metaplasia, papillary hyperplasia, atrophy, and slight nuclear enlargement and mild variation in nuclear size (Fig. 3.2). Pseudohyperplasia of the islets of Langerhans due to atrophy of the exocrine pancreas and aggregation of residual islets may give the erroneous impression of a neuroendocrine tumor. Clusters of islets in atrophic chronic pancreatitis can be seen in proximity to small nerve fascicles, and even pseudoperineural invasion by neuroendocrine cells has been described and should not be overcalled on a frozen section (Fig. 3.3).

FIGURE 3.1 Chronic pancreatitis. (a) The pancreas has fairly normal lobular architecture with some dilated ducts, acinar atrophy, and fibrosis. (b) Dilated ducts with fairly regular contours are shown.

CHRONIC PANCREATITIS AND ADENOCARCINOMA

11

FIGURE 3.2 Duct epithelial changes in chronic pancreatitis. (a) These ducts contain mucinous metaplasia (pancreatic intraepithelial neoplasia-1) (arrow) and are beneath an islet (arrowhead). (b) There is minimal nuclear enlargement without variation in size in this frozen section. (c) Mild nuclear variation in size is seen in this area.

12

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 3.3 Islet pseudohyperplasia in chronic pancreatitis. (a) Nests of neuroendocrine cells are conglomerated in an area where there are no acini or ducts. (b) Higher power image of nests of neuroendocrine cells in a frozen section from a pancreas with chronic pancreatitis. (c) Islets (arrowhead) are prominent near a nerve (arrow) in this frozen section. (d) Permanent section from a resection specimen in a case of chronic pancreatitis showing pseudoperineural invasion by neuroendocrine cells.

One of the biggest challenges for a surgical pathologist is to distinguish chronic pancreatitis from ductal adenocarcinoma on a frozen section. There are many criteria that help with the differential diagnosis, but few are absolute. Some histologic features useful in permanent sections have not been found to be as useful in frozen sections, such as nuclear hyperchromasia. CRITERIA OF MALIGNANCY IN FROZEN SECTION Multiple histologic features can be assessed to distinguish malignant from benign lesions. In 1981, Hyland et al. proposed the histologic features most helpful in differentiating malignant versus benign lesions on frozen sections. They described major and minor criteria useful for the diagnosis of ductal adenocarcinoma derived from a review of 64 frozen sections. Major criteria were present in all malignant cases and not seen in benign cases and minor criteria were diagnostically useful, but present less often

CHRONIC PANCREATITIS AND ADENOCARCINOMA

13

and less reproducible between observers. The three “major criteria” for malignancy were nuclear size variation of at least 4:1, disorganized duct distribution, and partial ducts (Fig. 3.4). The “minor criteria” included large irregular nucleoli, necrotic debris, epithelial mitoses, and perineural invasion (Fig. 3.5). In addition, the presence of infiltrating, severely atypical single cells and desmoplasia represent other helpful features of malignancy on a frozen section. Glands adjacent to muscular arteries and within fat are other features useful in the diagnosis of malignancy (Fig. 3.6). Lipomatosis (secondary to aging, obesity, type II diabetes) may cause fat infiltration of the pancreas but ducts usually are accompanied by acini or islets.

FIGURE 3.4 Major criteria for malignancy. (a) This tumor shows nuclear atypia and size variation of greater than 4:1. (b) Haphazard and disorganized ducts are present in this frozen section. (c) Partial ducts are seen at high power. (d) Single cell infiltration and partial ducts are shown in this frozen section.

14

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 3.4 Major criteria for malignancy (continued)

CHRONIC PANCREATITIS AND ADENOCARCINOMA

15

FIGURE 3.5 Minor criteria for malignancy. (a) There are large nucleoli (arrow) in some atypical cells in this image. (b) Necrotic debris is present within the malignant glands. (c) Occasional epithelial mitoses are present in these glands (arrow). (d) Perineural invasion is not commonly seen in frozen sections, but when present is helpful, as shown in this figure.

16

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 3.5 Minor criteria for malignancy (continued)

CHRONIC PANCREATITIS AND ADENOCARCINOMA

17

FIGURE 3.6 Additional features of malignancy useful in a frozen section. (a) Desmoplasia and single cell infiltration are seen in this tumor. (b) Glands are seen adjacent to muscular arteries. (c) Glands are present in direct opposition to fat without acini or islets.

The approach we have found most useful when evaluating pancreas frozen sections is to initially scan the slide on low power to get a general idea of the architecture. In chronic pancreatitis, there is retention of the lobular distribution of the ducts rather than haphazard, irregular ducts that may be angulated and incomplete in adenocarcinoma (Fig. 3.7). At higher power, cytologic features can then be evaluated and include pleomorphism, nuclear crowding and stratification, high nuclear to cytoplasmic ratio (nuclei are up to three times the size of a lymphocyte), significant variation in nuclear size (at least 4:1), prominent nucleoli, and mitoses (Fig. 3.8). Figure 3.9 shows an example of this approach. Some cases remain difficult and an “atypical” diagnosis or deferral may be indicated (Fig. 3.10). The surgeon may submit additional frozen sections of the lesion and some are diagnostic. However, many surgeons will proceed with resection without a definitive diagnosis if they are clinically suspicious. Table 3.1 compares features most useful in distinguishing adenocarcinoma from chronic pancreatitis in frozen sections.

18

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 3.7 Low power comparison between chronic pancreatitis and adenocarcinoma. (a and b) These frozen sections from chronic pancreatitis show retention of the lobular architecture. (c and d) These frozen sections from adenocarcinoma show haphazard and irregular glands with loss of lobular architecture.

CHRONIC PANCREATITIS AND ADENOCARCINOMA

19

FIGURE 3.7 Low power comparison between chronic pancreatitis and adenocarcinoma (continued)

20

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 3.8 Higher power comparison between chronic pancreatitis and adenocarcinoma. (a) This case of chronic pancreatitis shows fairly rounded glands without nuclear atypia. (b) Rounded glands are present with slight nuclear variability in size. (c) This adenocarcinoma contains irregular glands with necrotic debris, nuclear atypia, and variation in size. (d) The malignant glands contain atypical cells with variation in nuclear size.

CHRONIC PANCREATITIS AND ADENOCARCINOMA

21

FIGURE 3.9 Evaluation of frozen section using the approach of scanning on low power for lobular architecture and then assessing cytologic features at higher power. (a) The lobular architecture appears mainly intact with one area that appears somewhat altered (arrow). The diagnosis is unclear at this power. (b) High-power image showing clear-cut malignant features including irregular glandular contours, nuclear atypia with fourfold variation in nuclear size.

22

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 3.10 Challenging examples. (a) A few glands show slightly irregular contours in this frozen section. Nuclear atypia is present with variation in size but not fourfold (arrow). There were no other definitive features of malignancy, and this frozen section was called “atypical but favor benign.” The pancreatic resection was performed given the clinical suspicion for malignancy. Straightforward adenocarcinoma was found in the resection specimen that was much more pleomorphic than the area shown. (b) This frozen section shows rounded glandular contours with some nuclear enlargement (arrow) and mild variation in size. The frozen section was called “atypical but favor benign,” and the resection proceeded given the clinical suspicion for malignancy. Chronic pancreatitis was diagnosed in the resection specimen. (c) The lobular architecture is mainly intact but there are some dilated slightly irregular glands in this frozen section. (d) This high-power image of the previous figure shows the most cytologically atypical glands in the area. The glands show a rounded contour, but cells are atypical. No definitive criteria of malignancy were seen. The diagnosis was “atypical, defer,” and the resection proceeded based upon clinical suspicion. Adenocarcinoma was clearly seen in the area of the frozen section on permanent and deeper sections.

CHRONIC PANCREATITIS AND ADENOCARCINOMA

23

TABLE 3.1 Frozen section differential: duct adenocarcinoma versus chronic pancreatitis.

Glandular architecture Glands in fat/adjacent to arteries Nuclei Nucleoli Necrosis Mitoses Perineural invasion

Adenocarcinoma

Chronic pancreatitis

Haphazard, irregular, incomplete lumen ±

Lobular, round, smooth contours –

Variability ≥ 4:1 Prominent, may be multiple ± ± ±

<3:1 ± – – –

OTHER TUMOR-LIKE LESIONS Other tumor-like lesions are rarely encountered in frozen sections; however, they should be considered. Accessory (heterotopic) spleen may form a well-defined nodule within the tail of the pancreas and could be clinically mistaken for a neuroendocrine tumor. Lipomatous pseudohypertrophy can cause enlargement of the pancreas, clinically mimicking a tumor. Nodular lymphoid hyperplasia (pseudolymphoma) may form well-defined nodules composed of hyperplastic lymphoid tissue. Rarely, foreign-body deposits, malakoplakia, fungal or mycobacterial infections, as well as granulomatous inflammation (infectious or sarcoidal) may give the clinical impression of tumor. Inflammatory pseudotumor is a heterogeneous group of lesions occurring in various organs, histologically characterized by fibroblastic and myofibroblastic proliferation with inflammatory infiltrate. Hamartomas consist of irregularly arranged mature pancreatic elements admixed with stromal tissue. Heterotopic pancreas represents a congenital anomaly consisting of pancreatic tissue with no anatomic or vascular connection with the pancreas. It consists mainly of exocrine pancreas; endocrine pancreas is seen less often. Heterotopic pancreas may be seen in the second part of the duodenum, and large foci may cause obstructive symptoms, mimicking tumor. Since it may consist predominantly of ductal elements, the possibility of adenocarcinoma may be considered, but lack of atypia is useful for the diagnosis. Adenomyomatous hyperplasia of the ampulla of Vater may be the cause of obstructive jaundice, but absence of significant atypia can

24

FROZEN SECTION LIBRARY: PANCREAS

help exclude adenocarcinoma. It is important to recognize conditions that form pseudotumors in the pancreas so they can be distinguished from ductal adenocarcinomas and other malignant tumors. Normal anatomy at the ampulla can cause confusion at the time of frozen sections. Non-neoplastic periampullary glands can be seen in smooth muscle and can mimic invasion. Key Points: • Benign features (Fig. 3.11): ➢ Lobular architecture, round, uniform ducts ➢ Absence of significant nuclear size variation, necrosis, and

mitosis

FIGURE 3.11 Key points – benign clues. (a) Lobular architecture is present with regular and fairly uniform ducts. (b) The ducts are rounded with no significant variation in nuclear size and no atypia.

CHRONIC PANCREATITIS AND ADENOCARCINOMA

25

• Malignant features (Fig. 3.12): ➢ Haphazard pattern of ducts with desmoplastic reaction ➢ Incomplete lumina, cribriforming, single atypical cells ➢ Significant variation in nuclear size (at least 4:1) ➢ Necrotic intra-luminal debris, prominent nucleoli, and

mitosis ➢ Perineural and vascular invasion ➢ “Naked” ducts in extrapancreatic fat ➢ Ducts adjacent to blood vessels

FIGURE 3.12 Key points – malignant clues. (a) This frozen section shows irregular ducts, desmoplasia, and absence of a lobular pattern. (b) There are incomplete lumina, single atypical cells, and significant variation in nuclear size. (c) Ducts are present in extrapancreatic fat. (d) Ducts are seen adjacent to a muscular artery.

• Chronic pancreatitis frequently surrounds adenocarcinoma (Fig. 3.13)

26

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 3.13 Key point – chronic pancreatitis frequently surrounds adenocarcinoma. (a) Chronic pancreatitis (arrow) is present surrounding adenocarcinoma (arrowhead). (b) A malignant gland (arrowhead) is seen adjacent to chronic pancreatitis (arrow).

Pitfalls (Fig. 3.14): • Neuroendocrine pseudohyperplasia can be confused with neoplasm ➢ Be

aware that this is commonly seen in chronic pancreatitis

• Crushed/cauterized, benign ducts, acini, and islets with nuclear hyperchromasia can simulate malignant cells ➢ Pay attention to architecture and location ➢ Deeper sections may be helpful ➢ If there is too much crush/cautery artifact, defer and ask

for more tissue

CHRONIC PANCREATITIS AND ADENOCARCINOMA

27

FIGURE 3.14 Pitfall – crushed/cauterized, benign ducts, acini, and islets can simulate malignant cells. (a) Glands with thermal artifact may appear irregular in shape, and the nuclei may be hyperchromatic and pseudostratified simulating invasive cancer. (b) Crushed benign ducts and acini may appear atypical and irregular. (c) Cauterized islets can appear atypical and be confused with nests of malignant cells.

Chapter 4

Variants of Pancreatic Adenocarcinoma and Pancreatic Intraepithelial Neoplasia

Ductal adenocarcinoma is the most common primary malignant neoplasm of the pancreas, representing more than 90% of the exocrine pancreatic tumors. Variants of ductal adenocarcinoma can mimic involvement by the pancreas from other tumors (pancreatic and metastatic). VARIANTS OF ADENOCARCINOMA Variants of ductal adenocarcinoma have characteristic histologic features, such as signet ring cells, pools of mucin, osteoclast-like giant cells, or medullary features. Although it is not necessary to diagnose these variants at the time of frozen section, their recognition may be helpful to avoid confusion with other lesions, particularly to distinguish metastatic lesions from primary pancreatic tumors. Adenosquamous carcinoma is a rare variant and is composed of adenocarcinoma and squamous carcinoma (Fig. 4.1). Occasionally, only the squamous component may be seen at frozen section. Colloid or mucinous carcinoma can occur in a tumor arising in the pancreas (Fig. 4.2) and it can be seen in association with the mucin-producing cystic tumors that will be described in Chap. 5. At frozen section, pools of mucin with scant malignant-appearing cells may be seen (Fig. 4.3). The presence of mucin only, or mucin admixed with inflammation, should not be regarded as diagnostic of malignancy (Fig. 4.4).

29 W.L. Frankel, D.M. Proca, Frozen Section Library: Pancreas, Frozen Section Library 8, DOI 10.1007/978-1-4419-7790-8_4, © Springer Science+Business Media, LLC 2011

30

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 4.1 Adenosquamous carcinoma. There are nests of squamous cells (arrow) and glands (arrowhead).

FIGURE 4.2 Colloid carcinoma. Pools of mucin and rare atypical glands (arrow) are present in this pancreatic tumor.

ADENOCARCINOMA AND PANCREATIC INTRAEPITHELIAL NEOPLASIA

31

FIGURE 4.3 Colloid carcinoma. Nests of malignant cells are seen within a pool of mucin.

FIGURE 4.4 Mucin with inflammatory cells. Pools of mucin with inflammatory cells can be seen in chronic pancreatitis with obstruction or in an intraductal papillary mucinous neoplasm with mucin extravasation. Mucin with muciphages does not suffice for a diagnosis of mucinous carcinoma.

At times, signet ring cells may raise the differential diagnosis of a primary gastrointestinal carcinoma metastatic or directly extending into the pancreas (Fig. 4.5). Medullary carcinomas with a syncytial growth pattern and pushing borders rarely occur primarily in the pancreas. Foamy gland adenocarcinoma is a well-differentiated ductal adenocarcinoma with pale microvesicular cytoplasm and subtle nuclear abnormalities, which can be confused with benign ducts with mucinous metaplasia (pancreatic intraepithelial neoplasia-1) (Fig. 4.6). The characteristic features of this variant are easiest

32

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 4.5 Signet ring cell carcinoma. Signet ring cells (arrow) are present in this tumor. They can be seen in primary pancreatic tumors and do not necessarily suggest a metastatic tumor.

FIGURE 4.6 Foamy gland adenocarcinoma. There is minimal cellular atypia in this pattern of adenocarcinoma. The malignant gland shown could be confused with a duct containing pancreatic intraepithelial neoplasia-1.

to appreciate on permanent sections, where the abundant foamy cytoplasm with apical condensation is more obvious. The malignant diagnosis can be suspected at frozen section by architectural clues such as location in peri-pancreatic fat or adjacent to a muscular artery. Clear cell carcinoma can be seen in the pancreas and raises the differential diagnosis with a metastatic renal cell carcinoma, a solid variant of a serous adenoma, and clear cell neuroendocrine tumor (Fig. 4.7).

ADENOCARCINOMA AND PANCREATIC INTRAEPITHELIAL NEOPLASIA

33

FIGURE 4.7 Clear cell carcinoma. (a) Nests of cells with clear cytoplasm are seen in this frozen section. (b) The cells are rounded and contain small hyperchromatic nuclei and abundant clear cytoplasm.

The large duct type of adenocarcinoma contains dilated and ectatic glands with epithelial cells that may focally resemble benign dilated ducts. Some of these tumors have fairly bland cytologic features. The presence of some smaller haphazard ducts, cribriforming, an invasive pattern, intra-luminal necrotic debris, and abnormal glandular location is helpful on a frozen section (Fig. 4.8). Lobular-type adenocarcinoma consists of cords of malignant cells, similar to the “Indian file” pattern seen in breast cancer (Fig. 4.9). More conventional ductal adenocarcinoma is usually associated, but not always sampled at the time of frozen section.

FIGURE 4.8 Large duct pattern of adenocarcinoma. (a) These ectatic and dilated glands look somewhat similar to large benign ducts, but have irregular contours and surrounding desmoplasia. (b) The cells are fairly bland, but the glands are adjacent to a muscular artery (arrow).

34

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 4.9 Lobular pattern of adenocarcinoma. (a) Cords of malignant cells raise the differential with metastatic lobular carcinoma from the breast. (b) A single file arrangement of the tumor cells can be seen focally in pancreatic adenocarcinoma.

Poorly differentiated carcinomas of the pancreas consist of malignant cells that may be epithelioid, spindled, or mixed (Fig. 4.10). These tumors may be confused with a metastasis or direct extension from another site. Undifferentiated carcinoma with osteoclast-like giant cells is composed of multinucleated, osteoclast-like giant cells that are of histiocytic origin and are mixed with severely atypical neoplastic mononuclear cells (Fig. 4.11).

FIGURE 4.10 Poorly differentiated carcinoma. Poorly differentiated pancreatic carcinoma can be difficult to distinguish from sarcoma, melanoma, or lymphoma.

ADENOCARCINOMA AND PANCREATIC INTRAEPITHELIAL NEOPLASIA

35

FIGURE 4.11 Undifferentiated carcinoma with osteoclast-like giant cells. (a) Frozen section of osteoclast-like giant cells in the background of high-grade malignant cells. (b) The multinucleated giant cells contain bland nuclei while the admixed malignant cells appear pleomorphic.

PANCREATIC INTRAEPITHELIAL NEOPLASIA (PanIN) The nomenclature for PanIN defines potential precursor ductal lesions in the pancreas and is supported by morphological, clinical, and molecular findings. This nomenclature subsumes an array of previously described duct lesions including mucinous and papillary metaplasias and hyperplasias. PanIN-1A consists of ducts lined by flat, columnar mucinous epithelium. In PanIN-1B, similar appearing epithelium is organized into small tufts. PanIN-2 lesions exhibit distinct nuclear abnormalities including elongation, hyperchromasia, and stratification. PanIN-3 frequently demonstrates micropapillary architecture, cribriforming, mitotic figures, and

36

FROZEN SECTION LIBRARY: PANCREAS

severe nuclear abnormalities, including enlargement and hyperchromasia, loss of polarity, and prominent nucleoli. PanIN-1 is common in reactive and benign lesions as well as in adenocarcinoma (Fig. 4.12). PanIN-2 and PanIN-3 are more frequently seen in duct adenocarcinoma supporting the neoplastic nature of these lesions (Fig. 4.13). Glands with high-grade PanIN can be mistaken for invasive adenocarcinoma (Fig. 4.14). Table 4.1 summarizes features useful at frozen section for this distinction.

FIGURE 4.12 PanIN-1. This duct contains tall columnar cells without atypia.

FIGURE 4.13 PanIN-2 and PanIN-3. (a) This duct contains cells with atypical nuclei and likely represents moderate dysplasia (PanIN-2). (b) This duct shows high-grade dysplasia and is considered PanIN-3.

ADENOCARCINOMA AND PANCREATIC INTRAEPITHELIAL NEOPLASIA

37

FIGURE 4.14 Comparison between invasive carcinoma and PanIN. (a) The frozen section shows adenocarcinoma with irregular glands, necrotic debris, and desmoplasia. (b) High-grade PanIN is shown in this duct which has a rounded contour. (c) PanIN (arrowhead) with adjacent invasive adenocarcinoma (arrow) is seen in this frozen section. (d) Higher power image of the intraductal dysplasia. (e) Higher power image of the invasive adenocarcinoma.

38

FROZEN SECTION LIBRARY: PANCREAS

TABLE 4.1 Frozen section differential: duct adenocarcinoma versus PanIN.

Adenocarcinoma Glandular architecture Glandular location Single cells, clusters Dysplasia Necrosis

Haphazard, incomplete Next to muscular arteries, within fat ± + ±

Pancreatic intraepithelial neoplasia Lobular, round Associated with acini – ± –

Key Points (Fig. 4.15): • Variants of adenocarcinoma can be seen and may mimic metastasis

FIGURE 4.15 Key Points. (a) This image shows PanIN-1 with surrounding acini. (b) PanIN-3 is present in this duct.

ADENOCARCINOMA AND PANCREATIC INTRAEPITHELIAL NEOPLASIA

39

• Low-grade PanIN is frequently seen in the benign and malignant pancreas and is not important to diagnose at the time of frozen section • Moderate/high-grade PanIN is frequently seen in the background of the malignant pancreas Pitfalls (Fig. 4.16): • Many tumors can show malignant spindled cells ➢ Diagnose a high-grade tumor and give a differential

including high-grade adenocarcinoma and sarcoma among others • Many tumors can contain clear cytoplasm ➢ The differential includes primary adenocarcinoma and

neuroendocrine tumor as well as metastatic renal cancer • Invasive adenocarcinoma can be confused with intraductal dysplasia ➢ Ducts with dysplasia maintain lobular architecture and

rounded contours

40

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 4.16 Pitfalls. (a) Adenocarcinoma of the pancreas with clear cell features can mimic a metastatic renal cell carcinoma. (b) The irregular contours of this adenocarcinoma with large glands help distinguish it from a high-grade intraductal lesion (PanIN-3 or intraductal papillary mucinous carcinoma). (c) This frozen section shows large rounded glands that architecturally could be confused with intraductal dysplasia. The necrotic debris and desmoplasia help in the distinction. (d) PanIN-2 and PanIN-3 (arrow) are frequently seen adjacent to invasive adenocarcinoma (arrowhead). It is not necessary to diagnose these intraductal lesions in addition to the adenocarcinoma at frozen section. However, if they are seen at a resection margin without invasive adenocarcinoma, the diagnosis should be made.

ADENOCARCINOMA AND PANCREATIC INTRAEPITHELIAL NEOPLASIA

FIGURE 4.16 Pitfalls (continued)

41

Chapter 5

Cystic Lesions in the Pancreas

The pre- and intra-operative diagnosis of cystic pancreatic lesions is important since the management and prognosis varies between different lesions. The majority of pancreatic cystic lesions are pseudocysts that do not require major surgical resections. Fig. 5.1

FIGURE 5.1 Surgical management of cystic lesions of the pancreas in response to the frozen section diagnosis. There are two main intraoperative options for treatment of cystic pancreatic lesions: drainage and resection. Drainage is performed for pseudocysts and resection for possible neoplasms. The key frozen section finding is whether or not the cyst has an epithelial lining. Pseudocysts do not contain an epithelial lining and are treated by drainage. If an epithelial lining is identified, the lesion will likely be resected and final diagnosis made with additional permanent sections.

43 W.L. Frankel, D.M. Proca, Frozen Section Library: Pancreas, Frozen Section Library 8, DOI 10.1007/978-1-4419-7790-8_5, © Springer Science+Business Media, LLC 2011

Mucin

Variable Fibrosis

+ Mucinous, columnar Papillae

IPMN

Mucin

Variable Ovarian type

+ Mucinous, columnar Flat

MCN

Clear, serous

None Collagenized

Flat

+ Cuboidal, flat

SMA

Necrotic, hemorrhagic

Little Little Typical for tumor

Present

±

± ± Typical for tumor Typical for tumor

Ad

SPN

NET

Degenerative change in other tumors

IPMN, intraductal papillary mucinous neoplasm; MCN, mucinous cystic neoplasm; SMA, serous microcystic adenoma; NET, neuroendocrine tumor; SPN, solid pseudopapillary neoplasm; Ad, adenocarcinoma.

Cyst contents

NA

Epithelial architecture Atypia/mitoses Stroma

NA Fibrosis, inflammation Necrotic hemorrhagic

– NA

Epithelial lining Epithelial type

Pseudocyst

TABLE 5.1 Features helpful in distinguishing pancreatic cystic lesions at frozen section.

44 FROZEN SECTION LIBRARY: PANCREAS

CYSTIC LESIONS IN THE PANCREAS

45

shows the typical intra-operative management for cystic lesions in response to frozen section diagnosis. Generally the surgeon submits a portion of the cyst for frozen section, and the tissue should be entirely embedded for intra-operative diagnosis. If the clinical impression of pseudocyst is confirmed, the cyst will be drained rather than resected. If an epithelial lining is identified, the lesion will generally be resected and the final diagnosis made at permanent sections. A diagnosis of “benign” is not entirely helpful, as this does not address the surgeon’s primary question regarding the presence of a pseudocyst. Benign could either mean a pseudocyst, a benign cystic lesion, or benign cystic tumor. Of course, a malignant diagnosis is helpful if malignant features are present. Table 5.1 compares the microscopic features in some of the most common cystic lesions of the pancreas.

NON-NEOPLASTIC CYSTS Pseudocysts represent approximately two-thirds of cystic pancreatic lesions and are more common in patients with episodes of acute or chronic pancreatitis, and secondary to alcohol, obstruction, or trauma. Clinical history and radiological appearance are usually helpful, but not always definitive. Microscopically, a pseudocyst wall has no epithelial lining and is composed of fibroinflammatory tissue, fat necrosis, and adjacent chronic pancreatitis (Fig. 5.2). The possibility of a neoplasm with pseudocyst-like areas should be considered when there is no history suggestive of pancreatitis and the adjacent pancreas does not show features of pancreatitis. Unfortunately, the adjacent pancreas is generally not sampled at frozen section. The identification of an epithelial lining suggests the possibility of a neoplastic cystic lesion. Clinical history and radiologic findings can be helpful if known. Frequent denudation of the epithelial lining in cystic tumors may create confusion with pseudocysts; therefore, extensive sampling of the cyst wall is recommended. The surgeon typically sends a small portion of tissue for frozen section, so complete embedding is usually possible. Para-ampullary duodenal wall cysts (groove pancreatitis) are dilated, partially denuded ducts commonly associated with significant fibroinflammatory changes that occur in the duodenal wall or accessory ampulla. There may be significant atypia mimicking a sarcoma in the stroma adjacent to the cyst. At times, the diagnosis must be deferred to extensive permanent sectioning. Ductal retention cysts are simple cysts with a cuboidal epithelial lining. Congenital cysts, lymphoepithelial cysts, epidermoid

46

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 5.2 Pseudocyst. (a) A fibrotic wall containing chronic pancreatitis and no epithelial lining (arrow). (b) This pseudocyst wall contains inflammatory cells and fibrosis.

cysts in heterotopic spleen, foregut cysts, duodenal diverticula, endometriotic cysts, and infectious cysts are other rare benign nonneoplastic cystic lesions of the pancreas that are rarely seen on a frozen section. NEOPLASTIC CYSTS Serous cystic neoplasms are almost all benign. The gross appearance is very characteristic and gross evaluation is usually adequate if the tumor is sent for intra-operative evaluation in a resection specimen. Tumors are well encapsulated, most are composed of innumerable small cysts, and many contain a central scar. Microscopically, microcystic serous adenoma is composed of numerous small (<2 cm) thin-walled cysts filled with clear fluid and

CYSTIC LESIONS IN THE PANCREAS

47

lined by a single layer of cuboidal cells with clear cytoplasm, small nuclei, and inconspicuous nucleoli (Fig. 5.3). Macrocystic serous adenoma may grossly and radiologically mimic mucin-producing tumors, but histologically they have the same monolayer lining of uniform, cuboidal cells, as seen in the microcystic type. Very rare cases of solid serous adenoma must be distinguished from clear cell neuroendocrine tumor, metastatic renal cell carcinoma, and pancreatic adenocarcinoma with clear cell features. Serous cystadenocarcinomas are very rare and defined by the presence of local invasion or distant metastases, while cytologic features are not very helpful.

FIGURE 5.3 Microcystic serous adenoma. (a) Gross image showing the tumor is well circumscribed and contains innumerable small cysts with a central scar. (b) There are thin-walled cysts of variable size. (c) The cysts are lined by flat/cuboidal cells without atypia.

Mucinous cystic neoplasm (MCN) is a tumor that occurs in middle-aged women, predominantly involves the pancreatic tail and shows no connection with the pancreatic duct. They have a

48

FROZEN SECTION LIBRARY: PANCREAS

mucinous epithelial lining and ovarian-type stroma (Fig. 5.4). Most are non-invasive (with low-, moderate-, and/or high-grade dysplasia), while some contain invasive adenocarcinoma (Fig. 5.5). The epithelial lining can be extensively denuded, but the ovarian-type stroma is generally prominent and helps prevent mistakes, if noted at the time of frozen section. The main differential diagnoses are pseudocysts and other mucin-producing tumors. An MCN misdiagnosed as pseudocyst intra-operatively will be drained rather than resected, leading to severe consequences for the patient. Since the grade of epithelial dysplasia can significantly vary in the same tumor and denudation is common, final assessment of the degree of dysplasia is best done at the time of permanent sectioning of the resection specimen. The frozen section diagnosis of cyst lined by mucinous epithelium is usually adequate.

FIGURE 5.4 Mucinous cystic neoplasm. (a) Cyst lined by mucinous epithelium and adjacent dense ovarian-type stroma. (b) A higher power image showing no to minimal epithelial atypia. (c) Ovarian-type stroma in the wall of a cystic neoplasm which appears more organized than the inflammatory cells and fibrosis in a pseudocyst wall.

CYSTIC LESIONS IN THE PANCREAS

49

FIGURE 5.5 Mucinous cystadenocarcinoma. (a) The cyst is lined by mucinous epithelium and the stroma contains irregular invasive glands. Ovarian-type stroma is difficult to identify, but the important diagnosis is invasive adenocarcinoma; the type of mucinous lesion it arose in is far less important at the time of frozen section. (b) The mucinous epithelial lining shows dysplasia.

Intraductal papillary mucinous neoplasm (IPMN) is a mucinproducing epithelial tumor that grows in the main pancreatic duct and/or its branches and causes ductal dilatation. Extrusion of mucin through the ampulla is seen at endoscopic retrograde cholangiopancreatography. The epithelium in IPMN can be flat or papillary. These tumors range in size from <1 cm to the entire length of the pancreas. Microscopically, IPMN consists of mucinous-type epithelium with variable degrees of atypia (low-, moderate-, and/or high-grade dysplasia). Some IPMNs have associated invasive carcinoma, which can be very focal, and therefore extensive sampling of the resection specimen is necessary to

50

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 5.6 Intraductal papillary mucinous neoplasm (IPMN). (a) Flat mucinous lining with little atypia (low-grade dysplasia). (b) Columnar epithelium lining papillae with little atypia (low-grade dysplasia). (c) The columnar epithelium contains high-grade dysplasia. (d) High power image of high-grade dysplasia. (e) IPMN with invasive carcinoma.

definitively rule out an invasive component (Fig. 5.6). The invasive component can be the typical glandular adenocarcinoma or colloid carcinoma. At the time of frozen section, the diagnosis of mucinous epithelial-lined lesion is usually adequate. Pools of mucin do not necessarily represent invasive carcinoma, but may result from duct rupture and spillage. In order to diagnose colloid/mucinous carcinoma, malignant cells must be identified

CYSTIC LESIONS IN THE PANCREAS

51

TABLE 5.2 Demographic and pathologic differential: mucinous cystic neoplasm (MCN) versus intraductal papillary mucinous neoplasm (IPMN).

Gender Mean age Location in pancreas Communication with pancreatic duct Epithelium Architecture Stroma

Mucinous cystic neoplasm

Intraductal papillary mucinous neoplasm

Mostly female 40’s Tail No

Male > female 60’s Head > tail Yes

Mucinous Flat Ovarian type

Mucinous Papillary Fibrous

floating in the mucin. Table 5.2 compares clinical and pathologic features in IPMN and MCN. The distinction between these tumors can usually be made at the time of frozen section if the patient age, gender, and radiologic findings are known, but this distinction is not usually necessary in a frozen section. Degenerative cystic changes may be encountered in any of the typically solid neoplasms that occur in the pancreas, and therefore one should carefully look for microscopic features characteristic for those tumors. Haphazard, irregular ducts with necrosis and cystic change can be seen in ductal adenocarcinoma. A nested, organoid pattern with uniform nuclei is common in neuroendocrine tumors, and areas of necrosis and hemorrhage associated with drop-out of uniform cells characterize solid pseudopapillary neoplasms. Clinical and radiological information is also useful in differentiating these lesions. At the time of frozen section analysis, a diagnosis of “cystic tumor, defer to permanents” may be adequate. Key Points (Fig. 5.7): • Age/gender, clinical history, and radiographic findings may help suggest diagnosis of cystic lesions • Pseudocyst – lack of epithelial lining • Mucin-producing tumor – mucinous epithelial lining • MCN – middle-aged women, no connection with pancreatic duct, tail, mucinous epithelium, ovarian stroma • IPMN – older men and women, connection with pancreatic duct, head, mucinous epithelium, papillae • Not all cystic lesions are cystic tumors; some are degenerative change and necrosis in typically solid tumors

52

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 5.7 Key points. (a) Lack of epithelial lining in a pseudocyst with a fibrotic and inflamed wall. (b) Mucinous cystic neoplasm with mucinous epithelium supported by dense ovarian-type stroma. (c) Papillae lined by columnar epithelium in an IPMN.

Pitfalls: • A denuded mucinous cystic tumor could look like a pseudocyst at frozen section (Fig. 5.8) ➢ Sample extensively at frozen section; consider freezing all

tissue sent ➢ Pay attention to dense stroma in the wall of a possible

pseudocyst; ask for more tissue or mention the possibility of tumor • Variability in the epithelium of a mucinous cystic tumor could lead to missing high-grade dysplasia or even invasive cancer (Fig. 5.9) ➢ Diagnose mucinous tumor, defer degree of dysplasia, and

invasion until the tumor is extensively sampled at permanent sectioning

CYSTIC LESIONS IN THE PANCREAS

53

FIGURE 5.8 Pitfall – a denuded mucinous cystic tumor could be confused with a pseudocyst at frozen section. (a) This cyst was denuded and no epithelial lining was seen in this frozen section. When the entire lesion was evaluated, mucinous epithelium was identified. The dense stroma may suggest the possibility of a mucinous cystic neoplasm even if no epithelial lining is seen. (b) This frozen section demonstrates a mucinous tumor with detached epithelium. The most important diagnosis in these cases is whether or not there is an epithelial lining; the exact type of tumor, degree of dysplasia, and even invasion can be determined in the resection specimen with permanent sections. (c) The ovarian-type stroma shows organization and is usually denser than inflammation and fibrosis seen in a pseudocyst wall.

54

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 5.9 Pitfall – mucin-producing neoplasms can show various degrees of dysplasia throughout a neoplasm making determination of degree of dysplasia a diagnosis best made with the resection specimen and extensive sampling in permanent sections. (a) IPMN with low-grade dysplasia. (b) IPMN with high-grade dysplasia. (c) IPMN with invasive adenocarcinoma.

Chapter 6

Other Pancreatic Tumors

Although most pancreatic tumors seen at frozen section are adenocarcinomas, occasionally other types of pancreatic neoplasms are present. Table 6.1 compares some of the typically solid pancreatic tumors. Pancreatic neuroendocrine tumor (NET) represents about 2% of pancreatic tumors. Most grow slowly and have a more favorable prognosis than adenocarcinoma. The majority consist of well-differentiated tumors with an organoid pattern and rich vascular network. On frozen section, they show trabeculae, nests, cords, glands, and acini composed of medium-sized cells with eosinophilic cytoplasm and uniform, central nuclei with no nucleoli (Fig. 6.1). Unusual variants such as clear cell, oncocytic, rhabdoid, lipid rich have been described and can cause confusion with other primary or secondary pancreatic tumors. In some cases, there is a known history of endocrine hypersecretion, and the diagnosis is suspected by the surgeon. Other NETs are not suspected pre-operatively, and at frozen section they may just appear as low-grade tumors, not typical of adenocarcinoma (Fig. 6.2). In these cases, the frozen section diagnosis may be “neoplasm present, neuroendocrine is in the differential.” It is important to suggest the possibility of a NET at the time of frozen section because a major resection may still be warranted even in the face of distant metastasis. This is in contrast to adenocarcinoma, where the resection will likely be aborted with the identification of distant metastasis. The other low-grade tumor that most commonly appears similar to a NET at the time of frozen section is a solid pseudopapillary neoplasm (SPN). Definitive distinction may require immunohistochemical stains on the permanent sections.

55 W.L. Frankel, D.M. Proca, Frozen Section Library: Pancreas, Frozen Section Library 8, DOI 10.1007/978-1-4419-7790-8_6, © Springer Science+Business Media, LLC 2011

56

FROZEN SECTION LIBRARY: PANCREAS

TABLE 6.1 Frozen section differential: adenocarcinoma and other cellular predominantly solid pancreatic tumors in adults.

Architecture Cytology

Stroma

Solid pseuAdenocarcinoma Neurodopapillary endocrine neoplasm tumor (low grade) Haphazard Nests, tra- Pseudopapillae glands beculae, acini Hyaline Pleomorphism Lack of globules, atypia, no nuclear nucleoli grooves, no nucleoli Desmoplasia Hyalinized, Degenerative changes, rare hemorrhage, amyloid hyalinized, myxoid

Acinar cell carcinoma

Nests, acini

Eosinophilic cytoplasm, nucleoli, atypia Minimal fibrous stroma

FIGURE 6.1 Pancreatic NET. (a) The tumor is arranged in an organoid, nested pattern. (b) Higher power image showing cells with little cytologic atypia. (c) This tumor shows an acinar arrangement with minimal cytologic atypia.

OTHER PANCREATIC TUMORS

57

FIGURE 6.2 Pancreatic NET. (a) Low-grade neoplasm which does not look like a typical adenocarcinoma. (b) Higher power image with round and regular nuclei with no nucleoli or cytologic atypia.

Solid pseudopapillary neoplasm is a low-grade malignant epithelial tumor that occurs mainly in young women. These tumors contain uniform cells with eosinophilic cytoplasm, occasional cytoplasmic vacuoles, round/oval uniform nuclei with no nucleoli, and frequent longitudinal grooves (Fig. 6.3). Mitoses are rare, pleomorphism exceptional, and degeneration is common. Cells form pseudopapillae, sheets, or may be loosely cohesive. The stroma is inconspicuous, but may be hyalinized or myxoid and the vessels are delicate. Lipofuscin pigment, foam cells, cholesterol crystals, and giant cell reaction may be present. Blood lakes and degeneration are common. The distinction between NET and SPN can sometimes be made at the time of frozen section, particularly when there is a known endocrine syndrome (Fig. 6.4). Definitive diagnosis may require immunohistochemical stains on

58

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 6.3 SPN. (a) A pseudopapillary growth pattern and some degenerative change that may lead to cystic areas (arrow). (b) There may be some myxoid stromal change and the cells are round to oval and fairly uniform without mitotic activity.

the resection specimen, but the possibility can be included in the differential at frozen section. The distinction from NET may not be possible or necessary at frozen section. Acinar neoplasms, defined as tumors with zymogen granules, are very rare and typically occur in older men. The majority of acinar tumors of the pancreas are malignant. Acinar cell carcinomas and cystadenocarcinomas are well circumscribed, with marked cellularity and minimal fibrous stroma. The cells are polarized and have eosinophilic granular cytoplasm, uniform nuclei, and a prominent nucleolus, features sometimes useful in distinguishing these tumors from NET and SPN. At the time of frozen section, the diagnosis of tumor should be made, but the type will likely be deferred until permanent sections and special stains.

OTHER PANCREATIC TUMORS

59

FIGURE 6.4 Comparison between a low-grade NET and SPN. (a) The NET shows a nested architecture. (b) The cells are round without nucleoli and fairly regular in size. (c) A SPN shows a pseudopapillary architecture with some myxoid change in the stroma. (d) The cells in SPN may show longitudinal nuclear grooves, but these are not seen well at frozen section and architectural clues are more useful in the distinction from a NET.

Pancreatoblastoma is a malignant neoplasm that has numerous directions of differentiation showing acinar features as well as squamoid nests. These tumors generally occur in children and present as a palpable mass that is well circumscribed and at least partially encapsulated. Because some pancreatoblastomas occur in adults, squamoid nests may suggest the possibility of this tumor on frozen section of a circumscribed mass that has nested or acinar morphology. Poorly differentiated NET, mixed ductal–neuroendocrine carcinomas, and other pancreatic neoplasms with mixed cell lineage are generally diagnosed on permanent sections, with the help of immunohistochemistry. Key Points (Fig. 6.5): • At the time of frozen section, the most important diagnosis is “tumor present, not typical of adenocarcinoma, NET in the differential.” The tumor type can be deferred to permanents.

60

FROZEN SECTION LIBRARY: PANCREAS

• NET: organoid, nested pattern with uniform cells, no nucleoli, abundant, hyalinized stroma • SPN: young women, degenerative change, pseudopapillae, uniform cells with clear cytoplasm, hyaline globules, oval nuclei with longitudinal grooves • Acinar cell carcinoma: older men, acinar/solid patterns, prominent nucleolus, mitosis • Pancreatoblastoma – children, squamoid nests

FIGURE 6.5 Key points. (a) This NET is arranged in nests and contains fairly round cells with abundant cytoplasm. (b) This SPN shows a pseudopapillary pattern without cytologic atypia.

Pitfalls: • NET with cytologic atypia can be confused with other tumors (Fig. 6.6)

OTHER PANCREATIC TUMORS

61

FIGURE 6.6 Pitfalls – NET with cytologic atypia can mimic other tumors. The nuclear atypia in this case led to the diagnosis of “tumor present, defer type to permanents.” After additional sections and immunohistochemical stains, it was diagnosed as a NET.

➢ Diagnose a tumor and defer the type to permanents

• NET and SPN can be confused at frozen section (Fig. 6.7) ➢ Diagnose a tumor that does not look like a typical adeno-

carcinoma and include both tumors in the differential

FIGURE 6.7 Pitfalls – NET and SPN can be confused. This frozen section shows a low-grade tumor arranged in nests composed of uniform cells without nucleoli. NET and SPN were in the differential at the time of frozen section. The tumor was later diagnosed as SPN with the use of other permanent sections and immunohistochemistry.

Chapter 7

Secondary Tumors and Miscellaneous Lesions Involving the Pancreas

Secondary tumors involving the pancreas (metastatic or by direct extension) may not be treated by surgical resection. They are usually suspected with the proper clinical history and imaging techniques. Tissue confirmation may be obtained through fine needle aspiration or biopsy. In some cases, the diagnosis of a primary pancreatic neoplasm is suspected pre-operatively, and the surgeon may be surprised to be told at the time of frozen section (or post-operatively after the evaluation of permanent sections) that a metastasis is a possibility. The most common secondary tumors involving the pancreas are carcinomas. Gastrointestinal carcinomas are the most likely tumor to involve the pancreas by direct extension, but they can also metastasize to the pancreas. Other carcinomas such as breast, lung, ovary, and kidney may involve the pancreas through lymphatic or hematogenous spread. Usually, the pancreas is diffusely involved, but at times, solitary nodules may be found mimicking a primary pancreatic tumor, particularly when the primary is occult. Metastatic renal cell carcinoma may present as a solitary mass, and its diagnosis may be challenging on a frozen section when the clinical history is not known (Fig. 7.1). Since surgical resection of a solitary metastatic renal cell carcinoma has a relatively good prognosis, resection may be attempted.

63 W.L. Frankel, D.M. Proca, Frozen Section Library: Pancreas, Frozen Section Library 8, DOI 10.1007/978-1-4419-7790-8_7, © Springer Science+Business Media, LLC 2011

64

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 7.1 Metastatic renal cell carcinoma. The tumor consists of cells with clear cytoplasm.

Hematopoietic malignancies can involve the pancreas, the most commonly encountered is non-Hodgkin’s lymphoma (onethird of cases have secondary pancreatic involvement). A diffuse or nodular “blue cell” proliferation may be seen on frozen section analysis in these cases (Fig. 7.2). The differential diagnosis is broad and virtually all solid pancreatic tumors as well as melanoma may be considered. The frozen section diagnosis of a possible hematopoietic malignancy is very important. In these cases, the pancreatic resection will likely be stopped. Many lymphoid neoplasms respond to medical therapy, and resection is not a common approach. The diagnosis of “large cell diffuse malignant neoplasm” is correct, but may not be adequate if the surgeon does not consider a hematopoietic malignancy in the differential. Therefore, to help prevent a mistake by the surgeon, the possibility of a lymphoid/hematologic malignancy should be specifically mentioned. Touch preps may be useful in these cases. It is estimated that up to 9% of patients with melanoma metastatic to the pancreas have no known history of primary skin melanoma. Metastases involving the pancreas may be solitary, occasionally pigmented, and consist of a noncohesive proliferation of epithelioid cells with large round nuclei, and central macronucleoli with moderate cytoplasm (Fig. 7.3). The frozen section diagnosis of “malignant” is usually straightforward, but the specific diagnosis of “melanoma” can be challenging without history, particularly when the tumor contains spindled cells (Fig. 7.4). Benign and malignant mesenchymal tumors can involve the pancreas. Gastrointestinal stromal tumors as well as other

SECONDARY TUMORS AND MISCELLANEOUS LESIONS

65

FIGURE 7.2 Diffuse large cell lymphoma. (a) A diffuse proliferation of cells raises the possibility of a hematologic malignancy, but poorly differentiated carcinoma and melanoma should also be mentioned at the time of frozen section. (b) The cytologic detail is difficult to see in this frozen section, but the cells appear atypical.

sarcomas have been described in the pancreas (Fig. 7.5). The diagnosis of spindle cell and/or epithelioid tumor or proliferation can be made at frozen section and then deferred to permanents. Other, uncommon tumors can be seen in frozen sections from the pancreas and peri-pancreatic tissue and include lymphangioma (Fig. 7.6), hemangioma, extra-adrenal paraganglioma (Fig. 7.7), lipoma, leiomyoma, and neurofibroma. Endometriosis is rarely encountered in the peri-pancreatic tissue (Fig. 7.8), may mimic a cystic neoplasm, and have associated hemorrhage or dense adhesions. Patient age and gender are vital in rendering the correct diagnosis.

66

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 7.3 Metastatic melanoma. Severely atypical epithelioid cells are present, and a malignant neoplasm was diagnosed. The possibility of melanoma should be included in the differential.

FIGURE 7.4 Metastatic melanoma. An atypical spindle cell proliferation was diagnosed at frozen section in this case.

SECONDARY TUMORS AND MISCELLANEOUS LESIONS

67

FIGURE 7.5 Gastrointestinal stromal tumor. (a) This spindle cell tumor involved the pancreas and further classification was deferred at frozen section. (b) A higher power image does not show significant atypia or mitotic activity.

68

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 7.6 Lymphangioma. (a) The frozen section shows poorly oriented and folded fibrotic tissue and lymphoid aggregates; the diagnosis was descriptive only. (b) The permanent section from the frozen tissue showed fibrous tissue containing lymphoid aggregates and lymphocytes with endothelial-lined cystic spaces.

SECONDARY TUMORS AND MISCELLANEOUS LESIONS

69

FIGURE 7.7 Extra-adrenal paraganglioma. (a) The frozen section shows epithelioid cells and was called “neoplasm, defer to permanents.” (b) The permanent section from the frozen section shows a “zellballen” arrangement, and the diagnosis was confirmed with immunohistochemistry.

FIGURE 7.8 Endometriosis. A single gland was identified without stroma or hemosiderin in the peri-pancreatic region. This diagnosis was deferred to permanents but given the young age, female gender, and multiple cystic lesions, endometriosis was considered.

70

FROZEN SECTION LIBRARY: PANCREAS

Key Points (Fig. 7.9): • Age, gender, clinical history, and radiologic findings are helpful when possible • Renal cell carcinoma can metastasize to the pancreas as a solitary lesion • Diffuse, noncohesive single cells suggest hematological malignancy or metastatic melanoma • Metastatic melanoma may contain pigment and nuclear pseudoinclusions

FIGURE 7.9 Key points. (a) There is a proliferation of clear cells with a rich vascular network in this metastatic renal cell carcinoma. (b) Pigment (arrow) and nuclear pseudoinclusions (arrowhead) can be helpful for the diagnosis of melanoma when identified in an atypical epithelioid proliferation.

SECONDARY TUMORS AND MISCELLANEOUS LESIONS

71

Pitfalls (Fig. 7.10): • Many tumors can contain clear cells ➢ Mention

the differential which primarily includes metastatic renal cell carcinoma, clear cell pancreatic adenocarcinoma, and clear cell NET

• Many tumors can contain a diffuse proliferation of cells ➢ Mention the differential including poorly differentiated

adenocarcinoma, lymphoma, and melanoma • Not all brown pigment in a high-grade tumor is melanin – some is hemosiderin

FIGURE 7.10 Pitfall – small lymphocytic lymphoma/chronic lymphocytic leukemia involving the pancreas mimics chronic pancreatitis (a and b). This frozen section showed a dense lymphoid infiltrate that raised the possibility of lymphoproliferative disorder.

Chapter 8

Metastases, Resectability, and Margins

METASTASIS AND RESECTABILITY Liver lesions, enlarged lymph nodes, and suspicious peritoneal nodules may be biopsied in an attempt to diagnose metastatic pancreatic adenocarcinoma and help determine resectability. Small, radiologically inapparent liver metastases are often subcapsular and must be distinguished from benign liver lesions such as bile duct adenoma, bile duct hamartoma (von Meyenburg complex), focal scarring, or reactive bile duct proliferations. Frequently, the frozen section diagnosis of small liver lesions in the setting of a pancreatic mass is an important determinant of the surgical procedure (Fig. 8.1). If ductal adenocarcinoma is found outside of the typical resection zone, pancreaticoduodenectomy is canceled and a palliative bypass procedure may be performed. Bile duct adenomas and hamartomas represent common mimics of metastatic pancreatic adenocarcinoma. These liver lesions commonly occur in a subcapsular location (readily identified intra-operatively) and may be multiple. Bile duct adenomas typically consist of a back-to-back proliferation of tubular glands without atypia. In some cases, there may appear to be more space between glands than typical in a frozen section (Fig. 8.2). Bile duct hamartomas (von Meyenburg complex) consist of branched and elongated glands, many times containing bile (Fig. 8.3). Although both are glandular lesions, they should not show cytologic atypia or mitotic activity. Pancreatic resection should continue as planned when these benign lesions are diagnosed. Metastatic adenocarcinoma typically contains irregular glands with atypia, mitotic activity, and necrosis (Fig. 8.4). Another problematic lesion in this setting is a metastatic NET. This lesion may be confused with a 73 W.L. Frankel, D.M. Proca, Frozen Section Library: Pancreas, Frozen Section Library 8, DOI 10.1007/978-1-4419-7790-8_8, © Springer Science+Business Media, LLC 2011

74

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 8.1 Frozen section diagnosis of possible metastatic sites and the typical surgical response. If metastatic carcinoma is found, the pancreas resection will be aborted unless the tumor is a NET. The pancreas resection will proceed as planned if a benign liver lesion is diagnosed.

METASTASES, RESECTABILITY, AND MARGINS

75

FIGURE 8.2 Bile duct adenoma. (a) A subcapsular proliferation of glands is present in this frozen section. (b) The glands are fairly round and regular with some chronic inflammation and edema. The cells do not show any atypia or mitosis.

76

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 8.3 Bile duct hamartoma. (a) A proliferation of elongated and dilated glands separated by collagen. Some of the glands contain bile. (b) The epithelium is flattened to low cuboidal with no atypia or mitosis.

bile duct adenoma if cytologically bland or an adenocarcinoma if more atypical. In difficult cases, sampling the primary pancreatic tumor, if possible, for comparison may be helpful. A NET may be suggested when nests of uniform cells are seen (Fig. 8.5). The distinction is important, as the surgeon may proceed with pancreatic resection in the face of metastatic NET, but abort resection in case of metastatic adenocarcinoma. Table 8.1 compares features in glandular lesions in the liver useful at frozen section. Additionally, other benign mass-forming lesions can be seen in the liver including granulomas (Fig. 8.6), abscesses, and reactive processes.

METASTASES, RESECTABILITY, AND MARGINS

77

FIGURE 8.4 Metastatic adenocarcinoma to the liver. (a) A subcapsular proliferation of glands with some irregular contours. (b) There is cytologic atypia and occasional mitotic figures (arrow). (c) This area shows necrosis (arrow). The site of origin cannot be determined at frozen section, but in a patient with a pancreatic mass, the tumor is consistent with a pancreas primary.

78

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 8.5 Metastatic pancreas NET to the liver. (a) Subcapsular proliferation of fairly regular cells arranged in nests and glands. (b) The tumor cells are minimally atypical without mitotic figures. The pre-operative presumed pancreas tumor diagnosis was adenocarcinoma. The frozen section was called “atypical” and deferred since there was not enough atypia for a diagnosis of adenocarcinoma and too much architectural atypia (nests not glands) for a diagnosis of bile duct adenoma. The diagnosis of NET was not considered at the time of frozen section, and the Whipple procedure was aborted due to the concern for metastatic adenocarcinoma. After consultation and immunohistochemical staining on the permanent sections, a NET was diagnosed, and a Whipple procedure was performed.

Lymph nodes may be sampled at frozen section, and they should be carefully examined for tumor (Fig. 8.7). If a metastasis is identified in a lymph node away from the area that would be resected in a typical procedure, the resection will likely be aborted. Peritoneal nodules may be sent for frozen section, and

METASTASES, RESECTABILITY, AND MARGINS

79

TABLE 8.1 Frozen section differential: benign ductal liver lesions versus metastatic adenocarcinoma.

Size/number Gland architecture Bile Nuclei Mitoses Mucin

Bile duct adenoma

Bile duct hamartoma

Metastatic adenocarcinoma

<1 cm, single/multiple Regular, tubular

<0.3 cm, multiple Elongated, dilated + Bland − −

Size variable, multiple Haphazard, irregular − Atypical ± ±

− Bland − ±

FIGURE 8.6 Liver granuloma. A hyalinized granuloma is seen in this frozen section of a subcapsular liver nodule.

FIGURE 8.7 Lymph node metastasis. Adenocarcinoma was seen in this nonregional lymph node, and the Whipple procedure was canceled.

80

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 8.8 Metastatic adenocarcinoma involving the peritoneum. (a) Glands are seen within a desmoplastic and inflamed stroma. (b) The glands contain acute inflammation and the epithelial cells are atypical.

a confirmed diagnosis of adenocarcinoma will stop the planned resection (Fig. 8.8). MARGIN ASSESSMENT Resection margins are sent in some cases and most commonly include the bile duct margin and pancreatic margin. The uncinate or retroperitoneal margin is less commonly sampled at frozen section, since it is not usually possible to resect additional tissue, if positive. The bile duct margin may show focal denudation and reactive changes possibly due to stenting (Fig. 8.9). A margin with denuded epithelium is problematic and deeper levels may be useful. At the pancreatic margin, the presence of high-grade dysplasia (PanIN-3) (Fig. 8.10) or invasive carcinoma is usually considered a

METASTASES, RESECTABILITY, AND MARGINS

81

FIGURE 8.9 Stented bile duct margin. (a) The surface mucosa is partially denuded, and the wall of the duct contains a lobular aggregate of glands and inflammation. (b) The epithelium shows reactive change and inflammation.

“positive” margin, and if feasible, additional tissue will be resected. However, it has recently been reported that patient survival is not improved by additional resection of “positive” margins because positive margins are indicative of aggressive tumor biology. A diagnosis of PanIN-1 at the surgical margin should not be made, since there is likely no clinical significance. Cautery artifact can cause difficulty in evaluating margins. Cytologic clues of malignancy may not be as useful in these cases, while architectural clues may be more helpful, such as loss of lobular architecture and location and shape of glands (Fig. 8.11). Frozen sections may be performed to determine the status of resection margins in IPMN. IPMN can extend into smaller ducts,

82

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 8.10 PanIN at the pancreatic margin. Cautery makes it difficult to determine the degree of dysplasia in the duct at the margin, but it is at least moderate and likely high grade (PanIN-3).

FIGURE 8.11 Pancreatic margin containing adenocarcinoma. (a) Cautery artifact severely precludes interpretation at this pancreatic margin. The loss of lobular architecture is concerning for malignancy. (b) The irregular contour of the glands is also helpful in the diagnosis. (c) At high power, more nuclear atypia is seen than can be accounted for from the cautery alone. Fourfold nuclear variation can be identified.

METASTASES, RESECTABILITY, AND MARGINS

83

mimicking PanIN. Although morphologically they may be similar, and both are recognized as precursors of invasive carcinoma, PanIN and IPMN represent two different classes of intraductal neoplasia that may occur independently or may coexist. IPMN is larger (>0.5 cm), grossly visible, and the papillae are typically taller and more complex. However, IPMN involving a branch duct can be similar in size to PanIN and the distinction may not be possible. In either case, the finding of high-grade dysplasia or invasive carcinoma at the pancreatic margin (Fig. 8.12) may prompt additional resection if clinically feasible.

FIGURE 8.12 Pancreatic margin from an IPMN. (a) High-grade dysplasia lines this dilated duct. It may not be possible to distinguish extension of IPMN into smaller ducts from pancreatic intraepithelial neoplasia on microscopic sections. (b) There is invasive adenocarcinoma associated with this dilated duct lined by malignant epithelium. Additional resection was performed given the diagnosis.

Key Points: • Bile duct adenoma contains regular glands without atypia (Fig. 8.13) • Metastatic adenocarcinoma contains irregular glands with atypical nuclei (Fig. 8.13) • Comparison with the primary pancreatic tumor may be helpful in challenging cases • Cauterized malignant glands show useful architectural features such as irregular shape and atypical location (adjacent to artery, in fat or perineural) (Fig. 8.14)

84

FROZEN SECTION LIBRARY: PANCREAS

FIGURE 8.13 Key Point – Comparison of benign versus malignant subcapsular glandular lesion in the liver. (a) The bile duct adenoma shows fairly rounded ducts without cytologic atypia. (b) Metastatic adenocarcinoma contains irregular ducts with atypical cells.

METASTASES, RESECTABILITY, AND MARGINS

85

FIGURE 8.14 Key Point – Cauterized adenocarcinoma can be difficult to diagnose at the pancreatic margin, but architectural clues can be diagnostic. (a) The glands are haphazard. (b) The glands are adjacent to a large muscular artery. (c) Perineural invasion can support the diagnosis of adenocarcinoma even though cytologic detail cannot be evaluated.

86

FROZEN SECTION LIBRARY: PANCREAS

Pitfalls: • Multiple liver lesions in a pancreatic cancer patient are not necessarily malignant ➢ Multiple subcapsular lesions can be seen with bile duct

adenoma or von Meyenburg complex, so careful search for atypia is necessary • Epithelial atypia in a bile duct margin is not always dysplasia ➢ Be aware that stented ducts can show epithelial atypia ➢ A lobular arrangement of small ducts in the wall suggests

a benign process • Cauterized benign pancreas can mimic invasive glands (Fig. 8.15) ➢ Pay attention to architectural features ➢ Compare with the tumor if available ➢ Defer and/or ask for more tissue if necessary

METASTASES, RESECTABILITY, AND MARGINS

87

FIGURE 8.15 Pitfall – Cauterized benign pancreas at the pancreatic margin can mimic adenocarcinoma. (a) These acini appear hyperchromatic and are arranged in elongated nests rather than in acini. (b) Benign islet with adjacent acini (arrow) is shown beneath the adenocarcinoma (arrowhead).

Suggested Reading

Abraham SC, Wilentz RE, Yeo CJ et al (2003) Pancreaticoduodenectomy (Whipple resection) in patients without malignancy. Am J Surg Pathol 27:110–120 Basturk O, Coban I, Adsay NV (2009) Pancreatic cysts: pathologic classification, differential diagnosis, and clinical implications. Arch Pathol Lab Med 133(3):423–438 Bellizzi AM, Frankel WL (2009) Pancreatic pathology: a practical review. Lab Med 40(7):1–10 Bosman FT, Carneiro F, Hruban RH, Theise ND, (eds) (2010) WHO Classification of Tumours of the Digestive System. IARC, Lyon, France. Brugge WR, Lewandrowski K, Lee-Lewandrowski E et al (2004) Diagnosis of pancreatic cystic neoplasm: a report of the cooperative pancreatic cyst study. Gastroenterol 126(5):1330–1336 Campanale RII, Frey CF, Farias R et al (1985) Reliability and sensitivity of frozen-section pancreatic biopsy. Arch Surg 120:183–188 Campbell F, Azadeh B (2008) Cystic neoplasms of the exocrine pancreas. Histopathology 52:539–551 Cioc AM, Ellison CE, Proca DM et al (2002) Frozen section diagnosis of pancreatic lesions. Arch Pathol Lab Med 126(10):1169–1173 Couvelard A, Souvanet A, Kianmanesh R et al (2005) Frozen sectioning of the pancreatic cut surface during resection of intraductal papillary mucinous neoplasms of the pancreas is useful and reliable: a prospective evaluation. Ann Surg 242:774–780 Crippa S, Salvia R, Warshaw AL et al (2008) Mucinous cystic neoplasm of the pancreas is not an aggressive entity. Lessons from 163 resected patients. Ann Surg 247:571–579 Dillhoff M, Yates R, Wall K et al (2009) Intraoperative assessment of pancreatic neck margin at the time of pancreaticoduodenectomy increases likelihood of margin-negative resection in patients with pancreatic cancer. J Gastrointest Surg 13(5):825–830 Furukawa T, Klöppel G, Adsay VN et al (2005) Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study. Virch Arch 447(5):794–799

89 W.L. Frankel, D.M. Proca, Frozen Section Library: Pancreas, Frozen Section Library 8, DOI 10.1007/978-1-4419-7790-8, © Springer Science+Business Media, LLC 2011

90

SUGGESTED READING

Hernandez J, Mullinax J, Clark W et al (2009) Survival after pancreaticoduodenectomy is not improved by extending resections to achieve negative margins. Ann Surg 250(1):76–80 Holaday WJ, Assor D (1974) Ten thousand consecutive frozen sections. A retrospective study focusing on accuracy and quality control. Am J Clin Pathol 61:769–777 Hruban R, Adsay V, Albores-Saavedra J et al (2001) Pancreatic intraepithelial neoplasia. A new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 25(5):579–586 Hruban RH, Pitman MB, Klimstra DS (2007) Tumors of the pancreas. Atlas of tumor pathology, 4th Series, Fascicle 6. Armed Forces Institute of Pathology, Washington, DC Hruban RH, Takaori K, Klimstra DS et al (2004) An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 28(8):977–987 Hyland C, Kheir SM, Kashlan MB (1981) Frozen section diagnosis of pancreatic carcinoma. A prospective study of 64 biopsies. Am J Surg Pathol 5:179–191 Klimstra DS, Pitman MB, Hruban RH (2009) An algorithmic approach to the diagnosis of pancreatic neoplasms. Arch Pathol Lab Med 133(33):454–464 Klimstra DS, Adsay NV (2009) Tumors of the pancreas and ampulla of Vater. In: Odze RD, Goldblum JR, (eds) Surgical pathology of the GI tract, liver, biliary tract and pancreas. Elsevier, Philadelphia, PA, pp 909–960 Klöppel G (2000) Pseudocysts and other non-neoplastic cysts of the pancreas. Sem Diagn Pathol 17(1):7–15 Klöppel G, Adsay NV (2009) Chronic pancreatitis and the differential diagnosis versus pancreatic cancer. Arch Pathol Lab Med 133(3):382–387 Koshmahl M, Pauser U, Peters K et al (2004) Cystic neoplasms of the pancreas and tumor-like lesions with cystic features: a review of 448 cases and a classification proposal. Virch Arch 445(2):168–178 Lechago J (2005) Frozen section examination of liver, gallbladder and pancreas. Arch Pathol Lab Med 129(12):1610–1618 Pai RK, Wilcox R, Noffsinger et al. (2010) Liver, extrahepatic biliary tree, gallbladder, and pancreas. In: Taxy J, Husain A, Montag A, (eds) Biopsy interpretation: the frozen section. Lippincott Williams & Wilkins, Philadelphia, PA, pp 256–268 Proca DM, Ellison EC, Hibbert D et al (2001) Major pancreatic resection for chronic pancreatitis. Arch Pathol Lab Med 125(8):1051–1054 Sharma S, Green KB (2004) The pancreatic duct and its arteriovenous relationship: an underutilized aid in the diagnosis and distinction of pancreatic adenocarcinoma from pancreatic intraepithelial neoplasia. A study of 126 pancreatectomy specimens. Am J Surg Pathol 28(5): 613–620 Tanaka M, Chari S, Adsay VN et al (2006) International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 6:17–32

SUGGESTED READING

91

Traverso LW, Kozarek RA (1997) Pancreaticoduodenectomy for chronic pancreatitis: anatomic selection criteria and subsequent long-term outcome analysis. Ann Surg 226(4):429–435 Wachtel MS, Miller EJ (2005) Focal changes of chronic pancreatitis and duct-arteriovenous relationships: avoiding a diagnostic pitfall. Am J Surg Pathol 29(11):1521–1523 Wenig BM, Heffess CS (2009) Inflammatory, infectious, and other nonneoplastic disorders of the pancreas. In: Odze RD, Goldblum JR, (eds) Surgical pathology of the GI tract, liver, biliary tract and pancreas. Elsevier, Philadelphia, PA, pp 877–907 Yeo CJ, Cameron JL, Sohn TA et al (1997) Six-hundred fifty consecutive pancreaticoduodenectomies in the 1990’s: pathology, complications and outcomes. Ann Surg 226(3):248–257

Index

Note: The letters ‘t’ and ‘f’ followed by the locators represents ‘tables’ and ‘figures’. low power comparison, 12, 18f major criteria, 13f minor criteria, 15f malignant features, 25, 25f pitfalls, 26, 27f tumor-like lesions, examples adenomyomatous hyperplasia, 23–24 hamartomas, 23 heterotopic pancreas, 23 inflammatory pseudotumor, 23 lipomatous pseudohypertrophy, 23 nodular lymphoid hyperplasia, 23 non-neoplastic periampullary glands, 24 Clinical indications and surgeons expectations clinical and demographic features, 4t frozen section diagnosis, 6f malignant/benign diagnosis, 5–6 Congenital cysts, 45 Cystic lesions intra-operative management, 43, 43f IPMN and MCN, clinical and pathologic features, 51t microscopic features, 45, 51t neoplastic cysts degenerative cystic changes, 51 frozen section diagnosis, 48 IPMN, epithelium, 49

A Acinar cell carcinoma, 4t, 56t, 58, 60 Acinar neoplasms, 58 Adenomyomatous hyperplasia, 23–24 Autoimmune pancreatitis, 9 B Benign islet, 87f Bile duct adenomas, 73, 75f, 78f, 79t, 76, 83, 84f C Chronic pancreatitis and adenocarcinoma, distinction benign features, 24, 26f chronic inflammatory lesions, 9 duct adenocarcinoma vs chronic pancreatitis, 23t duct alterations, 9–10, 10f duct epithelial changes, 10, 11f histologic features, 9–10 islets of Langerhans, pseudohyperplasia, 10, 12f malignancy in frozen section, criteria challenging examples, 22f frozen section evaluation, 18f higher power comparison, 13, 16f histologic features proposed by Hyland in 1981, 12

93

94

INDEX

Cystic lesions (Continued) key points, 51, 52f macrocystic serous adenoma, 47 mucinous cystadenocarcinoma, 47, 49f mucinous cystic neoplasm, 47, 48f pitfalls, 52–54, 53f–54f serous cystadenoma, 47, 47f non-neoplastic cysts ductal retention cysts, 45 epithelial lining identification, 45 groove pancreatitis, 45 microscopic features, 44t rare benign lesions, 46 D Duodenal diverticula, 46 E Endometriosis, 65, 69f Endometriotic cysts, 46 Epidermoid cysts, 46 Extra-adrenal paraganglioma, 65, 69f F Foamy gland adenocarcinoma, 31, 32f Foregut cysts, 46 G Gastrointestinal carcinomas, 31, 63 H Hamartomas, 9, 23, 73, 76f, 79t Hemangioma, 65 Heterotopic pancreas, 23 Heterotopic spleen, 9, 23, 46 I Infectious cysts, 46 Intraductal papillary mucinous neoplasm (IPMN), 4t, 29f, 44t, 49–50, 50f, 51t, 52f, 54f, 81–82, 74–75, 83f

IPMN, see Intraductal papillary mucinous neoplasm (IPMN) Islets of Langerhans, 10 L Leiomyoma, 65 Lipoma, 65 Lipomatosis, 13 Lipomatous pseudohypertrophy, 23 Lymphangioma, 65, 68f Lymphoepithelial cysts, 45 M Malakoplakia, 9, 23 Margin assessment cautery artifact, 81 high-grade dysplasia/invasive carcinoma, 80, 83f key points, 83, 84f pancreatic margin containing adenocarcinoma, 80, 82f panIN at pancreatic margin, 80, 82f pitfalls cauterized benign pancreas, 86, 87f lobular arrangement of small ducts, 86 multiple subcapsular lesions, 86 resection margins, 86 stented bile duct margin, 86, 87f uncinate/retroperitoneal margin, 80 MCN, see Mucinous cystic neoplasm (MCN) Medullary carcinomas, 31 Metastases and resectability benign ductal liver lesions vs metastatic adenocarcinoma, 79t bile duct adenomas, 73, 75, 75f bile duct hamartomas, 73, 76f frozen section diagnosis, 73, 74f liver granuloma, 79f lymph node metastasis, 78, 79f

INDEX

metastatic adenocarcinoma involving peritoneum, 73, 77f metastatic adenocarcinoma to the liver, 76, 77f metastatic pancreas endocrine neoplasm to the liver, 76, 78f pancreatic resection, 73 von Meyenburg complex, 73 Metastatic pancreatic adenocarcinoma, 73 Mucinous cystic neoplasm (MCN), 4t, 44t, 47–48, 48f, 51, 51t, 52f–53f N NET, see Pancreatic neuroendocrine neoplasm (NET) Neurofibroma, 65 Nodular lymphoid hyperplasia, 23 Non-Hodgkin’s lymphoma, 64 Nuclear atypia, 13f, 20f–22f, 61f, 82f P Pancreatic adenocarcinoma variants adenosquamous carcinoma, 29, 30f clear cell carcinoma, 32, 33f colloid carcinoma/mucinous noncystic carcinoma, 30f–31f foamy gland adenocarcinoma, 31, 32f large duct pattern, 33, 33f lobular pattern, 33, 34f mucin with inflammatory cells, 29, 31f poorly differentiated carcinomas, 34, 34f signet ring cells, 29, 31, 32f Pancreatic neuroendocrine neoplasm (NET), 55 Pancreatic Intraepithelial Neoplasia (panIN) definition, 35

95

frozen section differential, 38t invasive carcinoma and PanIN, comparison, 35–36, 37f pitfalls, 39, 40f adenocarcinoma of pancreas, 40f frozen section, 40f irregular contours, 40f Pancreatic tumors acinar neoplasms, 58 frozen section differential, 56t key points, 59–60, 60f mitoses, 57 pancreatic NET and SPN, distinction, 55, 59f pancreatoblastoma, 59 solid pseudopapillary neoplasm, 55, 56f Pancreatoblastoma, 4t, 59–60 PanIN, see Pancreatic Intraepithelial Neoplasia (panIN) PanIN-1A, 35, 36f PanIN-1B, 35, 36f PanIN-2, 35–36, 36f, 40f PanIN-3, 36–37, 36f, 38t, 40f, 80, 82f Para-ampullary duodenal wall cysts, 45 Paraduodenal (groove) pancreatitis, 9 Positive margins, 81 Pseudocysts, 3, 43, 43f, 44t, 46f, 48, 48f, 51–52, 52f–53f See also Cystic lesions, non-neoplastic cysts R Resection margins, 40f, 80–81 S Secondary tumors and miscellaneous lesions diffuse large cell lymphoma, 65f endometriosis, 65, 69f extra-adrenal paraganglioma, 69f extra-intestinal gastrointestinal stromal tumor, 64, 67f

96

INDEX

Secondary tumors (Continued) gastrointestinal carcinomas, 63 key points, 70, 70f lymphangioma, 65, 68f metastatic melanoma, 66f metastatic renal cell carcinoma, 63, 64f pitfalls, 60, 61f tissue confirmation, 63

Serous cystadenoma, 4t, 47, 47f Solid pseudopapillary neoplasm (SPN), 44t, 51, 55, 56t, 57–58, 58f–59f, 60–61, 61f SPN, see Solid pseudopapillary neoplasm (SPN) V von Meyenburg complex, 73, 86