Frozen Section Library,Vol.3: Pleura

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Frozen Section Library: Pleura

For other titles published in this series, go to www.springer.com/series/7869

Frozen Section Library: Pleura

Philip T. Cagle, MD Weill Medical College of Cornell University, NY, NY The Methodist Hospital, Houston, TX, USA

Timothy Craig Allen, MD, JD University of Texas Health Science Center at Tyler, Tyler, TX, USA

Dr. Philip T. Cagle Weill Medical College of Cornell University The Methodist Hospital Houston, TX USA [email protected]

Dr. Timothy Craig Allen University of Texas Health Science Center at Tyler Tyler, TX USA [email protected]

ISSN 1868-4157 e-ISSN 1868-4165 ISBN 978-0-387-95985-6 e-ISBN 978-0-387-95986-3 DOI 10.1007/978-0-387-95986-3 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2010921592 © Springer Science+Business Media, LLC 2010 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 my wife, Kirsten Philip T. Cagle To my parents, Oliver and Mildred Allen Timothy Craig Allen

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 consideration of differential diagnoses and how to avoid traps caused by frozen section artifacts are emphasized in these

vii

viii Series Preface 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

Frozen sections are diagnosed by the pathologist while a patient is undergoing surgery, often under general anesthesia, for the purpose of rapid diagnosis, which may be used to make immediate treatment decisions or to confirm that diagnostic tissues have been sampled for further study. As a result, frozen section diagnosis is often a highly demanding situation for the pathologist who must render a diagnosis quickly and is a basis for critical decisions to the surgeon. 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. Most standard pathology textbooks, both general and subspecialty, largely ignore the topic of frozen section. Few textbooks have ever focused exclusively on frozen section diagnosis. The Frozen Section of the Pleura provides a convenient, userfriendly handbook to expedite use when performing intraoperative consultations on pleural specimens. This book is divided into chapters that emphasize the common questions that a pathologist must answer on frozen section examination and the pitfalls associated with those specific diagnoses. The diagnostic issues impacting immediate surgical decision-making are color illustrated and discussed succinctly, including a complex array of primary and secondary neoplasms of the pleura that have overlapping histologic features and the well-known problems of reactive atypia vs. cancer in pleural tissue. As a handbook for practicing pathologists, this book is an indispensible aid to diagnosis and avoiding dangers in one of the most challenging situations that pathologists encounter. Rapid consideration of differential diagnoses and how to avoid traps caused by frozen section artifacts will be readily accessible to the users of this handbook. Tables provide guidance for various categories of differential diagnoses. Currently, there is no other

ix

x Preface up-to-date single-source reference specifically focused on frozen sections of the pleura. This book will be highly valuable to practicing surgical pathologists, both community and academic, and to pathology residents and fellows. The perspectives provided will also be valuable to thoracic surgeons and especially to surgery residents and thoracic surgery fellows who must answer questions about pathology and frozen section on their board examinations. Tyler, TX Houston, TX

Timothy Craig Allen Philip T. Cagle

Contents

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

ix

1. Diffuse Malignant Mesothelioma................................... Introduction........................................................................ Diffuse Malignant Mesothelioma.......................................

1 1 2

2. Metastatic Cancers............................................................

23

3. Other Primary Neoplasms of the Pleura.......................

35

4. Pleuritis and Pleural Plaque...........................................

57

5. Uncommon Nonneoplastic Lesions of the Pleura.......

75

6. Benign Reactive Proliferations vs. Malignancy............

79

Suggested Reading.................................................................. 109 Index.......................................................................................... 111

xi

Chapter 1

Diffuse Malignant Mesothelioma

INTRODUCTION Frozen section of pleural tissue is performed during surgery to confirm that diagnostic tissue has been obtained for permanent section examination and to decide on intraoperative therapy. Benign reactive/inflammatory conditions (infections, plaques, pleuritis of various etiologies), benign neoplasms, primary pleural malignancies, and metastatic cancers may produce overlapping radiologic, clinical, or gross findings. These diverse pleural diseases (1) may cause pleural thickening, nodules or masses observed on imaging studies or grossly by the surgeon, (2) are often accompanied by pleural effusions, and (3) may be asymptomatic or cause difficulty in breathing, chest pain, or other thoracic symptoms, regardless of the etiology. The suspected diagnosis based on clinical context and current imaging modalities often proves correct. However, even the most recent advances in noninvasive diagnosis have limitations. For example, a few cases of malignancy will be negative on positron emission tomography (PET) using 18-fluorodeoxyglucose (FDG), and some benign reactive/inflammatory conditions will be positive. Even when a diagnosis of cancer is correctly rendered on a clinical and radiologic basis, histologic examination may be necessary to determine the type of malignancy involving the pleura. Therefore, even with modern imaging techniques, t he definitive diagnosis of a pleural abnormality often requires tissue samples. Although pleural effusion cytology and transthoracic needle biopsy may provide an accurate diagnosis of a pleural abnormality, larger or more representative tissue samples may be necessary to render a diagnosis in some cases. Frozen section allows the pathologist to guide the surgeon in obtaining adequate samples

1 P.T. Cagle and T.C. Allen, Frozen Section Library: Pleura, Frozen Section Library 3, DOI 10.1007/978-0-387-95986-3_1, © Springer Science + Business Media, LLC 2010

2 Frozen Section Library: PLEURA for diagnosis on permanent section and also provides the surgeon with immediate feedback for intraoperative therapeutic decisions. Therapy at the time of surgery depends in large part on the diagnosis rendered at frozen section: (1) often no additional therapy for reactive/inflammatory conditions (samples may be taken for additional studies such as permanent sections, microbiologic cultures, etc), (2) complete resection for benign neoplasms, localized malignant neoplasms, and solitary metastases, and (3) pleurodesis, pleurectomy, decortication, or possibly more extensive resection for cancer. On occasion, frozen section of the pleura may also be performed for margins of a pleuropneumonectomy/extrapleural pneumonectomy. DIFFUSE MALIGNANT MESOTHELIOMA Although it is the most common primary neoplasm of the pleura, diffuse malignant mesothelioma (DMM) is relatively rare compared with most cancers with about 2,000 new cases in the USA each year. Because of its extremely bleak prognosis with limited treatment options and the potential for compensation to the patient in toxic tort litigation, accurate diagnosis of DMM has great importance despite its comparative uncommonness. There are two primary categories of differential diagnoses for DMM. The first category of differential diagnoses is DMM vs. other types of cancer involving the pleura. The latter includes primary pleural cancers other than DMM and, more commonly, cancers metastatic to the pleura. The histologic features of these differential diagnoses are further discussed in Chaps. 2 and 3. The second category of differential diagnoses is DMM vs. benign reactive/ inflammatory processes that produce mesothelial hyperplasia or granulation tissue that mimics DMM. The problem of distinguishing benign reactive proliferations from malignancy, particularly DMM, is discussed in detail in Chap. 6. DMM arises from mesothelial cells and often spreads as diffuse nodules over serosal membrane surfaces, classically encasing the lung along the pleural surface. DMM may invade or metastasize into underlying or neighboring tissues and sometimes form bulky masses, but their gross distribution along serosal membrane surfaces is an essential feature of their diagnosis. The gross description of the surgeon and the radiologic findings to confirm the characteristic growth patterns of DMM are very important to the diagnosis of DMM. However, metastatic cancers and other primary cancers of the pleura may grow in patterns that mimic the growth pattern of DMM and, therefore, serosal surface distribution by itself is not diagnostic of DMM. Essentially always, the definitive diagnosis of DMM depends on examination of permanent tissue sections, often accompanied

Diffuse Malignant Mesothelioma 3

by confirmatory special studies. DMM has a wide range of histologic patterns that may potentially overlap with the histologic patterns of many other types of cancer. Knowledge of the diverse histologic patterns of DMM at frozen section allows the pathologist to suspect a diagnosis of DMM and better guide the surgeon in obtaining tissue that is satisfactory for confirmatory study on permanent sections and in making immediate decisions regarding pleurodesis, pleurectomy, decortication, or other treatments at the time of surgery. DMM is divided into three major histologic types: epithelioid, sarcomatoid, and mixed (biphasic). The differential diagnosis varies with the histologic type. Epithelioid DMMs are composed of cuboidal, polygonal, or oval cells and include reactive nonneoplastic mesothelial hyperplasia, carcinomas, and other epithelioid malignancies (metastatic or primary to the pleura) in their histologic differential diagnosis. Sarcomatoid DMMs are composed of spindle cells and have as their histologic differential diagnosis fibrous pleuritis and granulation tissue in addition to sarcomas and other spindle cell neoplasms metastatic or primary to the pleura. Mixed or biphasic DMM has both epithelioid and sarcomatoid components and includes reactive pleuritis and biphasic neoplasms in its differential diagnosis. The major histologic types of DMM are further subdivided into histologic variants, which are listed in Table 1.1. These histologic variants have their own specific considerations in their differential diagnoses. Table 1.2 summarizes the DMM histologic patterns that enter into the differential diagnosis of various pleural proliferative lesions, both malignant and benign. In many cases, particularly with certain histologic patterns such as the well-differentiated epithelioid types that resemble mesothelial cells, DMMs are correctly identified or strongly suspected based on their routine histology at frozen section. However, due to the overlap of radiologic, clinical, gross, and histologic features, differentiation of DMM from metastatic cancers often requires evaluation of the permanent sections usually with confirmation by immunostains. Therefore, during procedures to obtain tissue for diagnosis, the pathologist may suggest DMM or a suspicion of DMM, depending on the level of certainty at the frozen section, and advise the surgeon that confirmation of the diagnosis will occur after permanent sections and ancillary studies are reviewed. Pleurodesis or other procedure for malignancy may be performed by the surgeon even if there is a need for the pathologist to confirm the type of malignancy at a later time, provided that a diagnosis of cancer has been made at frozen section (Figs. 1.1–1.26).

4 Frozen Section Library: PLEURA Table 1.1 Histologic variants of diffuse malignant mesothelioma. Epithelioid histologic patterns Solid Well-differentiated (mesothelial cell-like) Poorly differentiated Tubulopapillary Acinar (glandular) Adenomatoid (microglandular)/microcystic Clear cell Deciduoid Adenoid cystic Signet ring Small cell Desmoplastic Sarcomatoid histologic patterns Sarcomatous Fibrous histiocytoma-like Osteosarcomatous Chondrosarcomatous Lymphohistiocytoid Desmoplastic Mixed (biphasic) histologic patterns Miscellaneous histologic patterns Pleomorphic Transitional


Table 1.2 Pleural proliferative lesions and differential diagnosis of diffuse malignant mesothelioma histologic patterns. Pleural proliferative lesion Adenocarcinomas

Differential diagnosis: diffuse malignant mesothelioma histologic patterns Solid well-differentiated (mesothelial cell-like), solid poorly differentiated, tubulopapillary, acinar (glandular), adenomatoid (microglandular)/microcystic, clear cell, deciduoid, adenoid cystic, signet ring, mixed (biphasic) Squamous cell Solid well-differentiated (mesothelial cell-like), carcinomas solid poorly differentiated, clear cell, deciduoid, mixed (biphasic), sarcomatous, pleomorphic, transitional Undifferentiated Solid well-differentiated (mesothelial cell-like), large cell/non-small solid poorly differentiated, clear cell, deciduoid, cell carcinomas pleomorphic, transitional Small cell Small cell carcinomas Sarcomas Sarcomatous, fibrous histiocytoma-like, osteosarcomatous, chondrosarcomatous, lymphohistiocytoid, desmoplastic, solid poorly differentiated, clear cell, deciduoid, mixed (biphasic) Melanoma Solid well-differentiated (mesothelial cell-like), solid poorly differentiated, clear cell, deciduoid, mixed (biphasic), sarcomatous, pleomorphic, transitional Lymphomas Lymphohistiocytoid Benign reactive Solid well-differentiated (mesothelial cell-like), mesothelial tubulopapillary, acinar (glandular), adenohyperplasia matoid (microglandular)/microcystic, mixed (biphasic) Benign fibrous Desmoplastic, sarcomatous, mixed (biphasic) pleuritis

6 Frozen Section Library: PLEURA

Figure 1.1 Frozen section of normal visceral pleura shows connective tissue with anthracotic pigment overlying lung parenchyma. There are inconspicuous flattened nuclei of mesothelial cells occasionally discernable along the pleural surface.


Figure 1.2 Gross of cut surface of lung showing encasing rind-like growth of dense ivory colored DMM along pleural surface and interlobar fissure.


Figure 1.3 Closer view of gross of cut surface of lung with thick dense ivory colored DMM growing along pleural surface and extending into underlying lung parenchyma.


Figure 1.4 Cut surface of wedge biopsy of pleura and lung shows dense tan to ivory colored tumor nodules of DMM with yellow areas of necrosis.

Figure 1.5 Close view of gross of tan to ivory rind of DMM growing over pleural surface.

Figure 1.6 Frozen section of epithelial DMM shows sheets of oval to polygonal cells with vesicular nuclei and conspicuous nucleoli suggestive of a carcinoma. Significant pleomorphism and mitoses are absent.

Figure 1.7 Frozen section of epithelial DMM shows sheets of polygonal cells with abundant cytoplasm, sharp cell borders, vesicular nuclei, and prominent nucleoli resembling a carcinoma.


Figure 1.8 Frozen section of epithelial DMM composed of smaller cells, less abundant cytoplasm, and more crowded, oval nuclei, some of which have conspicuous nucleoli.


Figure 1.9 Frozen section of epithelial DMM shows sheets of cells with vesicular nuclei and prominent, red nucleoli.


Figure 1.10 High power of a tubulopapillary DMM with acinar or tubular structures and papillae lined by epithelioid cells with vesicular nuclei and conspicuous nucleoli. Differential diagnosis includes adenocarcinoma.

Figure 1.11 Low power of papillary DMM with fibrovascular cores lined by epithelioid cells.


Figure 1.12 Medium power of papillary DMM shows myxoid to collagenized fibrovascular cores lined on the surface by epithelioid cells. Papillary adenocarcinoma is in the differential diagnosis.


Figure 1.13 Cribiform pattern of epithelial DMM with complex, back-toback glands. Adenocarcinoma is in the differential diagnosis.


Figure 1.14 Low power of a desmoplastic DMM shows predominantly fibrous tissue infiltrated focally by an epithelioid neoplasm forming acinar or tubular structures.

Figure 1.15 High power of a cellular area of a desmoplastic DMM shows the infiltrative gland-like structures lined by relatively uniform epithelioid cells. Differential diagnosis includes adenocarcinoma metastatic to the pleura.


Figure 1.16 High power of another cellular area of a demsoplastic DMM shows acinar or tubular structures lined by relatively uniform cells with vesicular nuclei and prominent nucleoli.


Figure 1.17 Gland-like spaces of this epithelial DMM are lined by large cells with abundant cytoplasm, vesicular nuclei, and obvious, red nucleoli. Adenocarcinoma would be considered in the differential diagnosis.

Figure 1.18 Epithelial DMM with a component exhibiting clear cytoplasm. The differential diagnosis would include clear cell carcinomas.

Figure 1.19 Deciduoid DMM has copious eosinophilic cytoplasm with sharp cell borders that superficially resembles decidual change.

Figure 1.20 Several signet ring cells with nuclei compressed by cytoplasmic vacuoles are seen in this epithelial DMM.


Figure 1.21 Spindle cells of sarcomatous DMM are seen in slit-like spaces in a desmoplastic region of a mixed (biphasic) DMM. An epithelioid component is also present.

Figure 1.22 Low power of sarcomatous DMM shows fascicles of cytologically atypical spindle cells in a myxoid stroma.


Figure 1.23 Higher power of the same sarcomatous DMM consists of atypical spindle cells in a connective tissue background. The differential diagnosis would include sarcomas and sarcomatous carcinoma.

Figure 1.24 A background of relatively bland large polygonal cells of DMM blends with lymphocytes suggesting an inflammatory process in this lymphohistiocytoid DMM.


Figure 1.25 Low power shows a pleomorphic DMM composed of poorly differentiated cells of varying size and shape. Some cells are very large and bizarre. There is overlying pleural plaque.

Figure 1.26 High power of pleomorphic DMM shows cells of varying size and shape, including some giant cells and cells with multiple nuclei.

Chapter 2

Metastatic Cancers

Metastases to the pleura are much more common than primary cancers of the pleura. Pleural metastases produce pleural effusions and pleural-based nodules or masses or pleural thickening, features that are also produced by primary tumors of the pleura and by reactive processes. Whereas DMMs account for about 1,500 pleural effusions in the USA each year, metastatic cancers account for about 200,000 pleural effusions each year, a ratio of greater than 130 metastatic cancers to 1 DMM. The most frequent metastatic cancers causing pleural effusion are lung carcinoma (about 60,000), breast carcinoma (about 50,000), and lymphoma (about 40,000). The remaining metastatic tumors to the pleura include virtually every known malignancy, including carcinomas from various sites, sarcomas, and melanoma. Table 2.1 summarizes the incidence of primary sites for malignant pleural effusions. Similar to DMM, diagnosis of metastatic cancer is often possible by transthoracic pleural biopsy or pleural effusion cytology, but may require more extensive tissue sampling by thoracotomy or thoracoscopy. In some cases, surgical biopsy may be performed to determine the primary site of a metastasis of unknown origin, and the pathologist must guide the surgeon in obtaining adequate amounts of tissue for a diagnosis on permanent sections. Even if the patient has a known primary cancer, pleural sampling may be necessary to confirm that the pleural thickening or mass does not represent a second primary cancer or a benign process mimicking metastatic malignancy. Frozen section is used to confirm adequate sampling of tissue for permanent sections (including for immunohistochemistry or other special studies if indicated) and to provide information for immediate treatment of metastatic cancer such as


24 Frozen Section Library: PLEURA Table 2.1 Approximate incidence of primary sites for malignant pleural effusions. Lung carcinoma Breast carcinoma Lymphomas Ovarian carcinoma Gastric carcinoma Unknown

36% 25% 10% 5% 2% 7%

Table 2.2 Differential diagnosis of distinctive histopathologic patterns of cancers metastatic to the pleura. Clear cell cancers Clear cell adenocarcinoma or clear cell squamous cell carcinoma Renal cell carcinoma Clear cell carcinoma of the ovary, endometrium, or cervix Clear cell melanoma/clear cell sarcoma of soft parts Adrenal cortical carcinoma Alveolar soft part sarcoma Rare clear cell variants of other cancer types (hepatocellular clear cell variant; clear cell adenocarcinoma of the urinay bladder, etc.) Papillary cancers Papillary adenocarcinoma of the lung (includes micropapillary subtype) Papillary thyroid carcinoma Papillary renal cell carcinoma Papillary serous ovarian carcinoma Papillary endometrial carcinoma and endocervical carcinoma Papillary urothelial (transitional cell) carcinoma Papillary pancreatic adenocarcinoma Papillary breast carcinoma Papillary cholangiocarcinoma Serous papillary adenocarcinoma of the peritoneum Small blue cell cancers Lymphoma Lobular breast carcinoma Small cell carcinoma Carcinoid tumor and atypical carcinoid tumor Melanoma Rhabdomyosarcoma

Metastatic Cancers 25

resection of solitary metastases or pleurodesis for symptomatic pleural effusions. Although final diagnosis of the primary site of a metastasis may have to await permanent sections and possibly special studies such as immunohistochemistry, the pathologist can convey a differential diagnosis to the surgeon at the time of frozen section so that an informed clinical decision can be made. Adenocarcinomas are the most frequent cell type of cancer metastatic to the pleura, including adenocarcinomas of the lung, breast, ovary, stomach, and other sites. Even when a metastasis is of unknown origin, the differential diagnosis for probable primary sites can often be conveyed to the surgeon at the time of frozen section. The differential diagnosis of several distinctive histopathologic patterns of metastatic cancers is given in Table 2.2 (Figs. 2.1–2.16).

Figure 2.1 Gross of wedge biopsy of lung and pleura shows multiple white nodules of metastatic carcinoma involving the pleura. There is adipose tissue attached to the top of the specimen.


Figure 2.2 Low power of frozen section of pleura shows thickened fibrotic pleura containing a cellular nodule.

Figure 2.3 Medium power confirms that the cellular nodule consists of glands within a fibrous stroma.


Figure 2.4 High power shows irregular glands lined by malignant cells consistent with adenocarcinoma metastatic to the pleura.

Figure 2.5 Frozen section of pleural biopsy displays cellular nests within desmoplastic connective tissue.


Figure 2.6 High power reveals that the nests are composed of epithelial cells with irregular nuclei, conspicuous nucleoli, and relatively abundant cytoplasm consistent with a metastatic carcinoma.

Figure 2.7 Low power of frozen section of relatively uniform, bland cells infiltrating in cords in a parietal pleura biopsy.


Figure 2.8 High power discloses cords or single files of relatively small, uniform cancer cells infiltrating into the fat consistent with metastatic breast carcinoma.

Figure 2.9 Medium power of frozen section of papillary carcinoma involving the pleura in patient with metastatic papillary thyroid carcinoma.

Figure 2.10 High power of metastatic prostate carcinoma to the pleura shows nests of cells with relatively uniform round nuclei.

Figure 2.11 High power of clear cell renal cell carcinoma metastatic to the pleura. The cells have oval nuclei with conspicuous nucleoli, clear cytoplasm, and capillaries in the stroma.


Figure 2.12 High power of another pattern of renal cell carcinoma metastatic to the pleura. In this tumor, the cells have granular cytoplasm.


Figure 2.13 Touch preparation performed at the time of frozen section shows discohesive epithelioid-appearing cells with abundant cytoplasm, round to oval nuclei with conspicuous nucleoli, and binucleate cells. This is metastatic melanoma. There is one focus of brown material, representing melanin pigment, but most of the cells are amelanotic.

Figure 2.14 High power of melanoma metastatic to the pleura. The cells have large, vesicular nuclei with large purple nucleoli and only a modest amount of melanin pigment in the cytoplasm.

Figure 2.15 Melanoma metastatic to the pleura, which contains larger amounts of brown melanin pigment in the cytoplasm of the cancer cells than noted in the previous examples.


Figure 2.16 Malignant tumor composed of large, pleomorphic spindle cells involving the pleura. This tumor could represent metastatic sarcoma or metastatic sarcomatous carcinoma.

Chapter 3

Other Primary Neoplasms of the Pleura

All primary neoplasms of the pleura are very rare. As noted in Chap. 1, DMM is the most frequent primary neoplasm of the pleura and only about 2,000 new cases occur per year in the USA. Other primary neoplasms of the pleura may be unfamiliar to the surgeon and pathologist because of the infrequency with which they are encountered, making diagnosis challenging. Since some of these neoplasms are benign or borderline and, even when malignant, are localized, they are often treated and may be cured by complete surgical excision. Therefore, it is often important to differentiate these exceedingly rare neoplasms at frozen section from processes that may not be treatable by resection, including DMM and metastatic cancers on the one hand and reactive or inflammatory diseases on the other. Modern imaging techniques such as high-resolution CT scan show a localized pleural mass for many of these tumors, but imaging may often provide only a differential diagnosis. These rare primary neoplasms of the pleura may potentially be diagnosed by transthoracic pleural biopsy or possibly pleural effusion cytology, but specific diagnosis may require more extensive tissue sampling by thoracotomy or thoracoscopy. Frozen section may be used to determine that adequate samples have been taken for diagnostic purposes. Frozen section diagnosis can guide the surgeon’s decision to do a complete resection by providing a definitive diagnosis of a localized neoplasm or at least excluding processes that are likely to be diffuse or metastatic malignancies or reactive processes. For resections, frozen section can also provide margins for the


36 Frozen Section Library: PLEURA localized tumor. When necessary, final diagnosis of these unfamiliar tumors can be confirmed with permanent sections and immunohistochemistry. Demographic, clinical, and radiographic features of the more commonly encountered rare primary pleural neoplasms are given in Table 3.1, and their gross and histologic features at frozen section are listed in Table 3.2. Solitary fibrous tumor (SFT) is not a common pleural tumor, but it is the most common primary benign tumor of the pleura (Figs. 3.1–3.6). These are well-circumscribed tumors but may cause significant symptoms if they are large because of compression of thoracic organs. Most SFTs are less than 10 cm, but some grow to larger sizes, up to 40 cm. Large SFTs with or without clinical symptoms may be benign, but the pathologist should be aware that large size and presence of clinical symptoms increase the risk that a SFT may be malignant. Malignant solitary fibrous tumors (MSFT) are less often encountered than the benign tumors and take two forms: (1) tumors that have the basic histologic features recognizable as SFT at low power but also display malignant histologic features including pleomorphism, increased mitoses, necrosis, and/or hemorrhage within this SFT pattern and (2) tumors in which frank, poorly differentiated sarcomas arise from the stroma of otherwise benign solitary fibrous tumors. In MSFT with the latter pattern, it is important to sample the sarcoma portion of the tumor (i.e., areas with gross invasion, hemorrhage, or necrosis), not only the benign portion, to recognize that it is malignant at frozen section (Figs. 3.7–3.10). If no area of an SFT is grossly suspicious for malignancy, the surgeon can be advised that, although unlikely, additional sampling of the tumor for permanent sections may reveal malignant areas. As noted, larger tumors have a greater risk of malignancy. Localized malignant mesotheliomas (LMM) are very rare and have histology, immunohistochemistry, and ultrastructure identical to DMM, but occur as well-circumscribed, discrete, solitary nodules and do not spread diffusely over the pleural surface (Figs. 3.11–3.14). As a result, LMM may be successfully surgically excised and, therefore, have a much better prognosis than DMM, although they may recur or metastasize. The gross findings are essential to the diagnosis of LMM. At the time of frozen section, the radiologic information, gross description of the surgeon, and gross examination of the specimen permit the pathologist to differentiate LMM from DMM on the basis of the sharp circumscription. DMM may sometimes have a dominant mass accompanied by diffuse pleural spread, and this gross pattern should be distinguished from a solitary, well-circumscribed LMM.

Imaging/gross features Location 5–10 cm, occasionally larger

Average size

Age range

Gender predilection

Majority Children to Male asymptomatic; eighth dec= female chest pain, ade; average shortness of age in 50s breath; clubbing or hypoglycemia may occur More likely to Generally Male present with middle= female chest pain, aged/older shortness of patients breath, and pleural effusion

Clinical presentation

Prognosis Majority cured by local resection; occasionally recur

(continued)

Malignant Usually localized More likely to Typically May recur locally, solitary mass but may be attached greater than metastasize or fibrous tumor invade adjacent to parietal 10 cm be fatal; pedicle structures; pleura, and negative tumor necrosis, mediastiresection marand hemornum, or gins associated rhage inverted into with better progthe lung nosis Localized WellVisceral 2–15 cm, Mostly asympRange 30s to Male: Half cured by malignant circumscribed, or parietal average 6 cm tomatic; chest 80s with female = 3:2 local resecmesothelioma solitary mass pleura pain, dyspnea, mean age in tion; may malaise, fever, 60s recur locally or and night sweats metastasize

Solitary WellVisceral fibrous tumor circumscribed; pleura (70– usually solitary 80%) > but may be parietal multiple localpleura ized masses

Primary pleural neoplasm

Table 3.1 Demographic, clinical, and radiographic features of more commonly encountered rare primary pleural neoplasms.

Most are localized to circumscribed mass, but some are diffuse over serosal surface; may invade adjacent structures Diffuse pleural thickening with pleural effusion

Primary synovial sarcoma

Primary epithelioid hemangioendothelioma

Generally incidental finding at surgery, not detected radiographically as mass

Diffuse over serosal surface

As mass attached to pleural surface or diffuse over pleural surface

Superficially spreads diffusely over serosal surface; may be confined to local area

Imaging/gross features Location

Welldifferentiated papillary mesothelioma


Table 3.1 (continued)

Diffuse over serosal surface

Multiple small nodules (rarely solitary nodule) from few millimeters to several centimeters over pleural surface Range from 10 cm and sessile; more likely but with increased mitoses (>4 per high to have hemorrhage and necrosis power field), pleomorphism, necrosis, and hemorrhage or may consist of areas of frank sarcoma arising from benign-appearing patterns of solitary fibrous tumor Localized malignant Pedunculated or sessile well-circumscribed Same histologic features as DMM but has mesothelioma mass with firm, off-white to tan cut surface sharply demarcated margins; epithelial pattern most frequent Well-differentiated papillary Diffuse velvety fronds over serosal surface Fibrovascular cores lined by single layer of mesothelioma bland cuboidal mesothelial cells; cores may be edematous or myxoid

Gross features at frozen section


Table 3.2 Gross and histologic features at frozen section of more commonly encountered rare primary pleural neoplasms.

39

Primary synovial sarcoma

Primary epithelioid hemangioen- Diffuse serosal firm thickening or rind dothelioma reminiscent of DMM

Gross features at frozen section

Pedunculated or sessile firm relatively circumscribed mass with hemorrhage and necrosis or diffuse serosal firm thickening or rind reminiscent of DMM


Table 3.2 (continued) Histologic features at frozen section Most pleural primaries are biphasic and consist of well-differentiated cuboidal to columnar epithelium lining gland-like spaces surrounded by homogeneous spindle cells with monomorphic nuclei and pale cytoplasm. Monophasic composed of spindle cell component only. Oval to slightly fusiform epithelioid cells with bland nuclei arranged in sheets, nests, or tubulopapillary patterns that resemble DMM; often with myxoid to hyaline stroma; cells may have intracytoplasmic vacuoles or lumina



41

Figure 3.1 Gross of cut surfaces of a SFT of the pleura that has been cut in half. The cut surface is ivory in color and fibrous in texture. There is a pedicle present at the base of the specimen on your right.

Figure 3.2 Gross of cut surface of another SFT displays firm, off-white fibrous tissue. It is attached by a short pedicle to the pleural surface, which has also been excised as part of a wedge resection of lung and pleura beneath the tumor.


Figure 3.3 Low power of frozen section of SFT reveals pink collagen in the area sampled.

Well-differentiated papillary mesothelioma (WDPM) is a benign or borderline mesothelial neoplasm that occurs as velvety tumor nodules on the surface of serosal membranes, typically spreading superficially with little or no invasion (Figs. 3.15–3.17). Classically, WDPMs occur on the peritoneum of women, but they may also occur on other serosal surfaces, including the pleura in which case they have no predilection for either gender. Although they may be multiple or recurrent, most of these tumors are noninvasive and are cured by surgical excision. Occasionally cases have been reported that these were invasive. Invasion may be noted in WDPMs that have recurred several times over a number of years. These cases may have a worse prognosis. As with LMM, the gross findings are essential to the diagnosis of WDPM. It is important to distinguish true WDPM from a focus of WDPM-like pattern in a DMM. The radiologic, clinical, and gross findings should make the latter diagnosis apparent.


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Figure 3.4 High power of SFT shows area of “patternless pattern of Stout” in which there are thick ropes of virtually acellular collagen. Occasional inconspicuous nuclei are discernable in the slit-like spaces.

Sarcomas in the pleura usually represent metastases from other primary sites. However, rarely sarcomas can occur as primary tumors of the pleura or chest wall. At frozen section, the pathologist will encounter the usual diagnostic features of the specific type of sarcoma. Two rare primary sarcomas of the pleura deserve special mention because they may mimic DMM grossly and histologically. In contrast to primary synovial sarcomas of the lung, which tend to be monophasic sarcomatous tumors, primary pleural synovial sarcomas tend to be biphasic with both epithelial and sarcomatous components, thus imitating biphasic DMM histologically. In addition, primary synovial sarcomas of the pleura may sometimes spread diffusely over the pleural surface like a DMM. More often, synovial sarcomas grow as localized masses and may potentially be amenable to surgical excision. Primary pleural epithelioid hemangioendothelioma spreads diffusely over the pleural surface causing associated symptoms and, thus, mimics DMM clinically, radiographically, and grossly.


Figure 3.5 High power of frozen section of a “cellular pattern” in a SFT is composed of sheets of relatively bland oval to fusiform cells.

In contrast to epithelioid hemangioendotheliomas of the soft tissues and other organs, which are generally considered lowgrade tumors, primary epithelioid hemangioendotheliomas of the pleura are aggressive cancers with poor prognosis. This aggressive clinical course mimics the clinical course of DMM. Epithelioid hemangioendothelioma has a variety of histologic patterns that may resemble DMM, and it may be necessary to wait for permanent sections and immunostains to make a definitive diagnosis (Figs. 3.18–3.21). The pathologist may rarely encounter other primary tumors in the pleura. Malignant neoplasms that may occur as primary pleural tumors or chest wall tumors that involve the pleura in children and/or young adults include pleuropulmonary blastoma, primitive neuroectodermal tumors, and desmoplastic small round cell tumor. Benign neoplasms such as lipomas, Schwannomas, adenomatoid tumors, calcifying fibrous tumors, and desmoid tumors may occur rarely as primary tumors of the pleura and have the same gross and histologic features that they have in their more common nonpleural primary sites. Thymomas that have grown along the pleural surface rather than in the anterior mediastinum may be sampled at frozen section and have the same histologic features as anterior mediastinal thymomas (Figs. 3.22–3.25).


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Figure 3.6 Area of “hemangiopericytoma pattern” in a medium power view of a SFT displays branching, dilated, “staghorn” vessels with small, round to fusiform cells in the adjacent tissue.


Figure 3.7 Gross of a MSFT shows a bulky tumor attached to the pleura of a wedge resection of underlying lung tissue.


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Figure 3.8 Gross of cut surface of a MSFT shows ivory colored fibrous tissue with foci of yellow necrosis.

Figure 3.9 Medium power of this MSFT reveals a “hemangiopericytome pattern” composed of pleomorphic spindle cells admixed with a few “staghorn” vessels.


Figure 3.10 High power of frozen section of a MSFT discloses atypical sarcomatoid cells and multiple mitoses.

Figure 3.11 Gross of LMM shows a circumscribed oval mass sitting on the surface of the visceral pleura in this resection specimen.

Figure 3.12 Cut surface of LMM reveals tan, fleshy tissue.

Figure 3.13 Low power shows the sharp circumscription of the neoplastic cells in the top part of the image of a LMM with a well-demarcated outer rim of connective tissue.

Figure 3.14 At high power, this LMM is composed of epithelial cells with vesicular nuclei and prominent nucleoli that histologically are indistinguishable from many epithelial DMMs.

Figure 3.15 Papillary fronds of a WDPM are attached to the visceral pleural surface of this wedge resection of lung and pleura.

Figure 3.16 WDPM consists of myxoid fibrovascular cores lined by a single row of bland cuboidal cells.


Figure 3.17 High power of a WDPM shows myxoid fibrovascular cores lined on their surface by a single layer of bland cuboidal cells of mesothelial origin with uniform, small, round nuclei.

Figure 3.18 Low power of biphasic synovial sarcoma of the pleura with gland-like spaces lined by relatively bland cuboidal cells surrounded by a monomorphic spindle cell stroma.


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Figure 3.19 High power shows relatively uniform cuboidal cells lining gland-like spaces and a stroma composed of homogeneous spindle cells.

Figure 3.20 Medium power of primary pleural epithelioid hemangioendothelioma consists of nests of epithelioid cells with relatively bland oval nuclei.


Figure 3.21 High power of primary pleural epithelioid hemangioendothelioma shows cells with cytoplasmic vacuoles or lumens embedded in a hyalinized stroma.


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Figure 3.22 Thymomas may occasionally grow primarily along the pleura, mimicking the growth pattern of a DMM. This low power shows a sclerosing thymoma spreading predominantly over the visceral pleura. There are nests of epithelioid cells within the hyalinized fibrous stroma.

Figure 3.23 High power of the nests of epithelioid cells of the thymoma.


Figure 3.24 Low power shows the thick rind of hyalinized stroma with small strands of epithelioid thymoma cells including at the interface with the underlying lung parenchyma.

Figure 3.25 High power shows small nests of epithelioid thymoma cells at the interface with the underlying lung parenchyma.

Chapter 4

Pleuritis and Pleural Plaque

Pleuritis is a reactive process that may or may not include inflammatory cell infiltrates. In the typical frozen section, the patho logist may see fibrinous exudates on the pleural surface (fibrinous pleuritis), organization of the fibrin by granulation tissue (organizing pleuritis), or maturing or mature connective tissue (fibrous pleuritis). Causes of fibrinous and fibrous pleu ritis are listed in Table 4.1. In combination with any of these findings, or as a dominant finding, the pathologist may see lymphocytes, lymphoid aggregates and plasma cells (chronic pleuritis – see Table 4.1), eosinophils (eosinophilic pleuritis – see Table 4.2), or granulomas (granulomatous pleuritis – see Table 4.3). Eosinophilic pleuritis is often the result of air and/or blood in the pleura from any etiology and is commonly seen in specimens from patients with pneumothorax and/or hemotho rax with a wide range of causes. Bacterial infections may produce empyema with neutrophils and leukocytoclastic necrosis with basophilic debris (Figs. 4.1–4.4). On occasion, fibrous tissue may organize into circumscribed, firm, off-white formations on the pleural surface called pleural plaque. Histologically, pleural plaques consist of a distinctive dense, virtually acellular collagen in a basket weave pattern (Fig. 4.5). Pleural plaques may undergo calcification and/or ossification and may occasionally be nodular, appearing as circumscribed, pleuralbased masses on imaging studies. Causes of pleural plaques are listed in Table 4.4. Desmoplastic DMM and the patternless pattern of SFT may potentially enter into the histologic differential diagnosis of pleural plaque on frozen section and may require examination of permanent sections for final diagnosis (Figs. 4.6–4.10).


58 Frozen Section Library: PLEURA Table 4.1 Causes of fibrinous and fibrous pleuritis and chronic pleuritis. Infections Bacteria Mycobacteria Fungus Parasites Viruses Collagen vascular diseases Systemic lupus erythematosus Drug-induced lupus Rheumatoid arthritis Sjogren’s syndrome Thoracic conditions Post surgery Pulmonary infarcts Pneumothorax Trauma Post radiation Gastrointestinal diseases Hepatitis/cirrhosis Pancreatitis Intraabdominal abscess Post abdominal surgery Miscellaneous Drug reactions Vasculitis (Wegener’s granulomatosis, Churg–Strauss syndrome) Sarcoidosis Asbestos exposure Nonspecific Table 4.2 Causes of eosinophilic pleuritis. Pneumothorax including spontaneous pneumothorax Hemothorax Idiopathic Drug reactions Infections (including tuberculosis, certain bacteria, fungus, and parasites) Churg–Strauss syndrome Malignancy Pulmonary embolism Collagen vascular disease

Pleuritis, pleural fibrosis, and pleural plaque may produce pleural thickening and may be associated with pleural effusion, features that might include malignancy in the differential diagnosis of some cases. In addition, pleuritis may produce chest pain

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Table 4.3 Causes of granulomatous pleuritis. Infections (tuberculosis, fungus) Sarcoidosis Wegener’s granulomatosis Foreign body reaction including pleurodesis Collagen vascular diseases including rheumatoid nodule Silicotic nodules

Figure 4.1 Gross of lung specimen shows patchy opaque ivory colored fibrinous and fibrous pleuritis obscuring portion of visceral pleural surface.

and pleural effusion may cause breathing difficulties, which are also symptoms of malignancy. In most cases, modern imaging techniques and the clinical history suggest the correct diagnosis (Figs. 4.11–4.15). The diagnosis and etiology of the pleural lesion may be obtained by transthoracic needle biopsy or from pleural


Figure 4.2 Gross of lung specimen with opaque tan fibrinous and fibrous pleuritis diffusely covering the visceral pleural surface.

effusion cytology, but additional tissue may be required in some cases to rule out malignancy and/or provide tissue for micro biologic culture and otherwise obtain a definitive diagnosis. In addition, the surgeon may treat the patient’s symptoms or prevent recurrent pleural effusion by performing a decortication or pleu rodesis. Most often, the pathologist is asked to perform a frozen section to confirm that adequate tissue has been sampled for diagnosis, render an immediate diagnosis to direct the surgeon’s next steps, and to collect tissue for microbiologic cultures or other special studies if indicated (Figs. 4.16–4.19). One of the most challenging problems with frozen section diagnosis of pleuritis occurs when histologic features of the benign

Figure 4.3 Gross of sectioned lung specimen demonstrates diffuse encase ment of lung by fibrous pleuritis and pleural plaque covering the visceral pleural surface. This specimen grossly resembles the growth pattern of DMM.

Figure 4.4 Gross of cut surface of 3-cm pleural mass excised to rule out cancer. Histologically, the mass consisted of chronic fibrous pleuritis with pleural plaque and calcifications. No malignancy was identified.

Figure 4.5 Gross of pleural plaques excised to rule out malignancy. The plaques are grossly composed of firm, tan-white fibrous tissue. Table 4.4 Causes of pleural plaque. Asbestos exposure Empyema Tuberculosis Rib fractures Hemothorax Thoracic surgery Exposure to nonasbestos fibers (?)

Figure 4.6 Frozen section of fibrinous pleuritis shows bright red-pink strands of amorphous fibrin on the pleural surface and admixed with an edematous stroma.


Figure 4.7 Frozen section of organizing fibrinous pleuritis displays bright red-pink amorphous fibrin at the surface with ingrowth of organizing fibroblasts and fibrous tissue from below.

reactive process mimic malignancy. Differentiation of benign reactive processes from malignancy is discussed in Chap. 6. On occasion, it may not be possible to exclude malignancy on frozen section of pleuritis, and a final diagnosis may need to be deferred for examination of permanent sections (Figs. 4.20–4.25).


Figure 4.8 Higher power of Fig. 4.7 showing surface fibrin with ingrowth of organizing fibroblasts and fibrous tissue from below.

Figure 4.9 As the fibrinous pleuritis organizes into fibrous pleuritis, granulation tissue may be the predominant feature. On this biopsy frozen section, the fibrinous pleuritis has progressed to granulation tissue com posed of fibroblasts, capillaries, inflammatory cells, and myxoid young connective tissue stroma.

Figure 4.10 Higher power of Fig. 4.9 reveals fibroblasts and endothelial cells lining capillaries. The fact that the capillaries are parallel to one another and perpendicular to the pleural surface favors a benign proc ess since an invasive malignancy would be expected to disrupt an orderly arrangement of the capillaries.


Figure 4.11 Frozen section of a mature fibrous pleuritis composed of bundles of mature collagen, which has progressed from an organized acute injury such as fibrinous pleuritis.

Figure 4.12 Higher power of Fig. 4.9 showing bundles of mature collagen and fibrocytes in a mature fibrous pleuritis.


Figure 4.13 High power of frozen section shows an aggregate of lym phocytes in a background of mature fibrous pleuritis in a typical example of chronic pleuritis.

Figure 4.14 Frozen section of a prominent lymphocytic infiltrate in a more cellular example of chronic pleuritis.

Figure 4.15 Plasma cells predominate in this frozen section of a chronic pleuritis from a patient with rheumatoid arthritis.

Figure 4.16 Numerous eosinophils are present in addition to lymphocytes and fibrosis in this frozen section of an eosinophilic pleuritis in a patient with pneumothorax. The pneumocytes lining the underling lung paren chyma show reactive hyperplasia.


Figure 4.17 Noncaseating granuloma of the pleura on frozen section shows round circumscribed aggregate of histiocytes, lymphocytes, and a few multinucleated giant cells.

Figure 4.18 Higher power of another noncaseating granuloma of the pleura with characteristic multinucleated giant cell.


Figure 4.19 Low power of frozen section of pleural plaque and underly ing pleurodesis containing foreign material and foreign body giant cell reaction.


Figure 4.20 High power of Fig. 4.16 shows foreign crystalline material in multinucleated giant cells.

Figure 4.21 The pleurodesis material in Fig. 4.16 is birefringent with polarized light.

Figure 4.22 Low power of rheumatoid nodule of the pleura shows cen tral necrosis and rim of palisading histiocytes. The differential diagnosis includes granulomas.


Figure 4.23 Low power of silicotic nodule of the pleura consists of cen tral whorls of hyalinized collagen surrounded by pigmented macrophages and lymphocytes. This lesion should be differentiated from a hyalinized granuloma.

Figure 4.24 Low power of frozen section of pleural plaque discloses bas ket weave pattern of virtually acellular dense bundles of collagen.


Figure 4.25 High power of this figure reveals the woven pattern of thick mature collagen bundles with scanty, inconspicuous cell nuclei.

Chapter 5

Uncommon Nonneoplastic Lesions of the Pleura

There are several nonneoplastic lesions of the pleura that, although uncommon, should be differentiated from pleural neoplasms. Sclerosing mediastinitis presents as an extensive dense fibrous tissue in the mediastinum that compresses, entraps, and invades chest structures, including pleura, bronchi, and lungs, often grossly mimicking invasive neoplasm (Fig. 5.1). Patients may be of any age, with the greatest frequency in patients in their 40s to 60s. Patients may experience compression of the superior vena cava (superior vena cava syndrome), bronchi, pulmonary hilum, and/or esophagus. Presenting symptoms include cough, dyspnea, hemoptysis, and chest pain. There may be a clinical suspicion of cancer involving the pleura and other structures of the chest including diffuse malignant mesothelioma and lung cancer in the differential diagnosis. The diagnosis typically requires a surgical biopsy, often with frozen section, and the pathologist may feel pressure to diagnose malignancy at the time of frozen section because of the clinical presentation. However, the frozen section will typically show thick ropey collagen with or without a mixed inflammatory infiltrate of lymphocytes, plasma cells, and eosinophils. There is a frequent association with infections, particularly Histoplasma and tuberculosis, and so special stains should be obtained on the permanent sections. Endometriosis and splenosis are rare unexpected findings that may present grossly as pleural nodules suspicious for metastatic malignancy. Endometriosis may be associated with dyspnea and chest pain and, rarely, pneumothorax and pleural effusion at the time of menses (Fig. 5.2). Endometriosis shows foci of endometrial glands and stroma on frozen section, which should not be confused



Figure 5.1 High power of sclerosing mediastinitis shows characteristic thick ropey collagen. Although the clinical presentation may be worrisome for cancer, no malignancy is present. Special stains for Histoplasma and tuberculosis should be performed.

Figure 5.2 Medium power of endometriosis shows endometrial glands and stroma in pleural connective tissue.

Uncommon Nonneoplastic Lesions of the Pleura 77

Figure 5.3 Low power of nodular histiocytic hyperplasia of the pleura shows cellular nodule composed of histiocytes and mesothelial cells.

with a metastatic adenocarcinoma. Splenosis shows splenic tissue at frozen section. In order to correctly diagnose these rare pleural entities at frozen section, the pathologist must be aware that these entities can occur. Nodular histiocytic hyperplasia of the pleura is typically an incidental nodule on the pleural surface that might be sampled by a surgeon during a procedure unrelated to the incidentally discovered nodule (Fig. 5.3). These lesions are composed of nodular proliferations of histiocytes mixed with mesothelial cells and may suggest primary or metastatic neoplasm on frozen section (Fig. 5.4). The pathologist should be aware of the existence of these benign lesions and recognize the bland cytologic features of the histiocytes and admixed mesothelial cells in order to avoid overcalling these nodules as cancer. On the permanent sections, I may suggest primary or metastatic neoplasm on frozen section. Immunostains can help confirm the diagnosis.


Figure 5.4 High power of Fig. 5.3 shows cytologically bland histiocytes admixed with mesothelial cells.

Chapter 6

Benign Reactive Proliferations vs. Malignancy

One of the most frequent questions at frozen section of pleural tissue is whether or not a pleural lesion is benign or malignant. Differentiating benign reactive mesothelial hyperplasia or organizing pleuritis from a malignancy on frozen section may be a more difficult and a more immediately important differential than determining the type of cancer that a patient has on frozen section (Figs. 6.1–6.3). Immediate treatment decisions by the surgeon may depend on the frozen section diagnosis of benign reactive process vs. malignancy as discussed in the “Introduction” of Chap. 1. Conditions associated with benign reactive mesothelial hyperplasia and organizing pleuritis are listed in Table 6.1. As discussed in the “Introduction” of Chap. 1, reactive, inflammatory processes can potentially produce clinical, radiographic, gross, and microscopic features that mimic those of malignancy (Figs. 6.4–6.10). The surface lining of the normal pleura consists of thin, flattened mesothelial cells that are generally inconspicuous. Simple hyperplasia of reactive mesothelium consists of a single row of regularly spaced cuboidal mesothelial cells along the pleural surface, which have relatively bland cytology and sometimes modestly conspicuous nucleoli. In general, simple hyperplasia is not a diagnostic challenge (Figs. 6.11–6.16). On the other hand, a florid benign reactive mesothelial hyperplasia can mimic malignancy in any of a number of ways that are listed in Table 6.2. Indeed, the cells of some DMMs may occasionally be more cytologically bland than the cytologically atypical mesothelial cells of some benign reactive processes. Likewise, a number of architectural features in florid reactive proliferations may mimic malignancy (Figs. 6.17–6.22).



Figure 6.1 Medium power of a frozen section of pleura shows mesothelial cells with mild reactive hyperplasia. The cells are cuboidal, uniform and lined up in a single row along the visceral pleural surface. These cells lack severe cytologic atypia or architectural changes such as nodules, tubules, or papillae. This mild reactive hyperplasia is easily distinguished from malignancy.

Features that favor malignancy on a pleural tissue sample at frozen section are listed in Table 6.3, and features that favor a benign reactive mesothelial hyperplasia are listed in Table 6.4. In difficult cases, unambiguous invasion of tissues such as fat, skeletal muscle, or underlying lung or expansive cellular nodules of tumor should provide the diagnosis on frozen section (Figs. 6.23–6.26). However, in some cases with equivocal features in the tissue submitted for frozen section, it may be necessary to defer diagnosis until permanent sections. Additional pleural tissue may be requested of the surgeon if the original sample provided was a relatively small biopsy. In this situation, a diagnosis of atypical mesothelial hyperplasia (AMH) may be rendered for the frozen section. AMH is a term recommended for profuse mesothelial proliferations that are of uncertain biologic behavior. Many AMHs are probably florid benign reactive hyperplasias, but others are probably DMMs sampled in a noninvasive or equivocally invasive area


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Figure 6.2 This high power of a frozen section with simple hyperplasia of the mesothelium consists of a single row of regularly spaced cuboidal mesothelial cells with very mild reactive cytologic atypia and an occasional nucleolus. In general, this is recognizable as simple hyperplasia. Compare to Fig. 6.27.

(Figs. 6.27–6.29). A diagnosis of AMH may be rendered on frozen section as discussed here, in the hope that permanent sections will provide a more definitive diagnosis. However, it may not be possible to render a more definitive diagnosis than AMH on the permanent sections or in other settings such as biopsies in which no frozen section was obtained. The diagnosis of atypical mesothelial hyperplasia does not rule out nor confirm malignancy. Depending on the clinical suspicion, the patient’s treating doctor may elect to follow the patient, obtain more tissue, or treat the patient.


Figure 6.3 This high power of a frozen section shows slightly more cytologic variation of the reactive mesothelial cells. In addition, there is minimal tufting and stratification of the hyperplastic cells. Tangential cuts may also contribute to the appearance of stratification. A few nucleoli are present. There is no invasion of underlying tissues, no discrete tumor nodules with stromal distension, and no cytologic and architectural atypia that is frankly malignant. A diagnosis of malignancy cannot be made on this pattern, and it represents a slightly more severe hyperplasia than Fig. 6.2. Compare to Fig. 6.27.

Table 6.1 Causes of benign reactive mesothelial hyperplasia and organizing pleuritis. Infections Collagen vascular diseases Pulmonary infarcts Drug reactions Pneumothorax Subpleural lung carcinomas Surgery Trauma Nonspecific


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Figure 6.4 Low power of a florid reactive mesothelial hyperplasia shows high cellularity as well as other features shown at medium power in Fig. 6.5. The high cellularity of this mesothelial proliferation raised concerns of DMM, and a diagnosis of “atypical mesothelial hyperplasia” was made on frozen section (implying florid reactive mesothelial hyperplasia vs. DMM – the final diagnosis could become more definitive on the permanent sections if, for example, invasion is found). On permanent sections, no invasion of underlying tissues, no discrete tumor nodules, and no unequivocally malignant histologic features were observed. Subsequent clinical and radiologic information, including high-resolution CT scan, and follow-up excluded DMM.


Figure 6.5 Medium power of this figure shows reactive mesothelial cells with variation in nuclear size and contour, binucleated cells, prominent nucleoli, multiple nucleoli, and foci of necrosis with neutrophils present. These features combined with the high cellularity were worrisome for DMM and a diagnosis of “atypical mesothelial hyperplasia” was made. On permanent sections, no invasion of underlying tissues, no discrete tumor nodules, and no unequivocally malignant histologic features were observed. DMM was eventually ruled out.


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Figure 6.6 Medium power of Fig. 4.11, a frozen section of mature fibrous pleuritis, shows a group of small, simple tubule-like structures confined to the surface area of the biopsy. The formation of these structures may be seen in benign reactive mesothelial hyperplasia and must be distinguished from tubules of DMM or glands of metastatic adenocarcinoma. In benign reactive mesothelial hyperplasia, the tubules tend to be small and simple and lined by flattened to cuboidal cells lacking frank malignant cytologic features, although they may exhibit benign reactive atypia in some cases. The tubular structures show “zonation” or limitation within the tissue toward the pleural surface rather than deep infiltration through the full thickness of the pleura (Compare this figure and Figs. 4.11–6.19).


Figure 6.7 This high power of an organizing pleuritis shows papillary tufts of benign reactive mesothelial hyperplasia. The benign reactive cells have enlarged vesicular nuclei with prominent nucleoli and form tufts and simple papilla-like structures projecting from the surface mesothelial cells. Architectural structures resembling papillae of tubulopapillary and papillary DMM may be seen in benign reactive mesothelial hyperplasias. The cells lack frank malignant cytologic features, are not associated with invasion or unequivocal tumor nodules, and may lack the robust fibrovascular cores of papillae in DMM.


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Figure 6.8 Benign reactive hyperplastic mesothelial cells entrapped within the fibrin and granulation tissue of an organizing fibrinous pleuritis. The cells show cytologic reactive atypia and some surround “lumens” resembling tubule-like structures. These cells should be interpreted in the overall context of representing only a few cells entrapped in abundant granulation tissue and lacking unequivocal invasion into underlying tissues, frank cytologic features of malignancy or tumor nodules.


Figure 6.9 Benign reactive hyperplastic mesothelial cells entrapped within the granulation tissue of an organizing pleuritis show conspicuous nucleoli and include binucleate cells. Cytologic atypia of the surrounding proliferating fibroblasts and reactive endothelial cells of proliferating capillaries in the granulation tissue may also add to the concerns of possible malignancy, perhaps contributing to the impression of possible invasion. If it is uncertain at the time of frozen section whether the proliferation is benign or malignant, a diagnosis of “atypical mesothelial hyperplasia” can be made and further examination for a more definitive diagnosis made on the permanent sections. Keratin immunostains on permanent sections can help exclude invasion into underlying tissues and also confirm that the fibroblasts and endothelial cells are not cells of DMM or carcinoma.


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Figure 6.10 This group of benign reactive hyperplastic mesothelial cells is entrapped within the granulation tissue of an organizing pleuritis and form a conspicuous gland-like structure. This finding must be interpreted in the context of the overall sample, including the abundant amount of granulation tissue relative to the entrapped cells, which are confined to a zone, usually superficial, within the granulation tissue without invasion into deeper underlying tissues.


Figure 6.11 Entrapment of benign reactive hyperplastic mesothelial cells begins when there is a fibrinous exudate overlying the pleural surface lined by the proliferating reactive mesothelial cells. This medium power of a fibrinous pleuritis shows a layer of fibrin covering the pleural surface, which is lined by cuboidal hyperplastic mesothelial cells with reactive atypia.


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Figure 6.12 Medium power of another example shows a row of reactive hyperplastic mesothelial lining the pleural surface with a superimposed organizing exudate of fibrin and hemorrhage above the pleural surface. As the exudate organizes into granulation tissue and advances to mature fibrous tissue, the reactive mesothelial cells become entrapped between the original pleural surface and the new covering of organized exudates. Eventually, this may create an impression of invasion (“pseudoinvasion”) of the pleural tissue if the entrapment of mesothelial cells by organizing pleuritis is not recognized.


Figure 6.13 Low power shows a linear array of hyperplastic benign mesothelium entrapped between the original pleura below and overlying fibrous tissue from an organized exudate. Although this may initially give an impression of invasion of the pleural tissue, the proliferating cells are confined to this linear array by entrapment and do not infiltrate into surrounding tissues. In this case of florid mesothelial hyperplasia entrapped by organized exudate, there are artifactual clefts giving the impression of tubule-like or gland-like structures and adding to the perception of possible malignancy. However, the “tubules” are simple and round to elongate without branching or cribriforming, lined by cells lacking frank malignant features, and most importantly are confined to the linear zone of entrapment between the original pleural surface and the superimposed organized exudate.


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Figure 6.14 In contrast to the simple tubular or glandular structures sometimes seen in florid benign reactive mesothelial hyperplasias, the tubules of a DMM may be complex and branching as shown in this frozen section of a tubular DMM.


Figure 6.15 This small nodule of proliferating cells might be problematic because the cells are cytologically very bland and, due to the small size of the lesion, invasion of the parietal pleural connective tissue could be ambiguous, possibly representing a tangential cut. There was no identifiable tumor mass on radiology or on gross examination by the surgeon who found several of these tiny firm, ivory-colored “spots” on the pleura. A diagnosis of malignancy is based on focal superficial invasion into the adipose tissue. This represents an early DMM that has not yet formed a bulky or encasing tumor. When present, unequivocal invasion into underlying tissues is the most reliable feature of malignancy in a pleural sample of this type.


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Figure 6.16 High power of this figure shows relatively bland cells of mesothelioma infiltrating around fat cells in a focus of minimal invasion. If necessary, the infiltration of the mesothelial cells into adipose tissue can be confirmed later with keratin immunostains performed on the permanent sections.

Table 6.2 Features of benign reactive mesothelial hyperplasia that may mimic malignancy. High cellularity Cytologic atypia/mitoses Necrosis Papillary excrescences or lumens Entrapment (pseudoinvasion with benign mesothelial cells entrapped in organizing pleuritis)


Figure 6.17 Low power of frozen section of a chest wall and pleura biopsy showed a bland, relatively sparse cellular infiltrate that was equivocal for malignancy. However, it was noted that the skeletal muscle had a focus of separation of muscle fibers by connective tissue.


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Figure 6.18 High power of the focus mentioned in Fig. 6.17 confirms that there are cytologically bland mesothelial cells with associated connective tissue infiltrating the skeletal muscle. This single focus of skeletal muscle invasion is consistent with an invasive DMM.


Figure 6.19 This low power shows a proliferation of relatively bland mesothelial cells along the pleural surface with minimal focal stratification and tufting. There is infiltration of similar cells through the full thickness of the pleural connective tissue. This proliferation of atypical cells through the full thickness of the pleura or lack of zonation contrasts with the zonation (often toward the pleural surface) of entrapped benign reactive mesothelial cells. Although lack of zonation is not as definitive in some cases as unequivocal invasion, it is a finding that supports a diagnosis of malignancy. Tangential cuts or en face cuts of tissue may sometimes mimic lack of zonation, and orientation of the specimen should be taken into account before diagnosing on the basis of lack of zonation.


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Figure 6.20 The presence of a fibrinous or fibrous pleuritis does not exclude a diagnosis of an accompanying DMM. In this low power of a pleural biopsy, the proliferating cells on the lower right represent an epithelial DMM with an overlying organizing fibrinous pleuritis filling the remainder of the field. In this situation, the diagnosis of DMM is made on independent criteria of malignancy discussed in this chapter.


Figure 6.21 There is a row of small clusters of relatively bland mesothelial cells just beneath the surface of the pleura on this frozen section. The cells lack cytologic features of frank malignancy, do not form a discrete nodule, and do not invade underlying tissue in this section. A benign reactive hyperplasia cannot be excluded, and a diagnosis of malignancy cannot be made on this focus of proliferating mesothelial cells. If this proliferation is the only finding, a diagnosis of “atypical mesothelial hyperplasia” can be made.


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Figure 6.22 Elsewhere in the same pleural sample, identical cells are observed infiltrating through the full thickness of the pleura and into the underlying fat. These findings confirm a diagnosis of DMM.

Table 6.3 Histologic features favoring a diagnosis of malignancy over reactive hyperplasia. Unequivocal invasion of underlying tissues Cellular nodules with stromal expansion Cellularity of the atypical cells throughout the full thickness of the pleura (lack of zonation) Unequivocal malignant features of severe pleomorphism, atypical mitoses, etc. Bland necrosis

Table 6.4 Histologic features favoring nonneoplastic entrapment over invasion. Active fibrin deposition with active inflammation Linear arrays of individual cells and small glands Simple nonbranching glands Proliferating mesothelial cells separated by large amounts of stroma


Figure 6.23 Higher power of Fig. 6.22 shows cords and small tubules of bland mesothelial cells infiltrating around and between fat cells, confirming the diagnosis of DMM despite the bland cytology and the lack of malignant features elsewhere in the sample as seen in Fig. 6.21. This example emphasizes the potentially focal nature of diagnostic features, such as invasion, in a pleural sample of an “early” or minimally invasive DMM. Depending on the area sampled at frozen section and the size of the specimen, it may be necessary to defer a more complete sampling of the specimen until permanent sections.


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Figure 6.24 This example of “atypical mesothelial hyperplasia” consists of a florid proliferation of mesothelial cells with focal architectural complexity (tubule-like and papillary structures). There was no gross tumor mass. There is no invasion of underlying tissue or other findings to verify an unequivocal diagnosis of malignancy. A tangential cut of an exuberant benign reactive mesothelial hyperplasia cannot be ruled out.


Figure 6.25 High power of Fig. 6.24 displays proliferating mesothelial cells with modest cytologic atypia consisting of slightly enlarged, vesicular nuclei with conspicuous nucleoli. This example of “atypical mesothelial hyperplasia” was later proven to be a benign reactive hyperplasia.


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Figure 6.26 This proliferation of bland mesothelial cells along the pleural surface includes some clusters of similar cells immediately beneath the surface, which could represent a tangential cut. Since the connective tissue of the pleura is so thin in this section, whether or not the mesothelial cells are approaching the fat because of invasion is questionable. The findings are not conclusive for malignancy in this field and, if this is the only finding, a diagnosis of “atypical mesothelial hyperplasia” can be made. Nearby an unequivocal invasive DMM was present composed of similar cells.


Figure 6.27 This frozen section shows a single row of cuboidal mesothelial cells along the pleural surface. The cells are slightly crowded, but not truly stratified. There are no tubules, no papillae, and no tumor nodules. There is no invasion and no questionable areas of invasion vs. entrapment or tangential cut. The individual cells have bland cytology, round to oval nuclei with smooth contours, modestly conspicuous nucleoli, and very abundant cytoplasm. This is an example of mesothelioma in situ. There was invasive DMM composed of identical cells nearby. Without the knowledge of the unequivocal malignancy nearby, there is no way to know if the cells in Fig. 6.27 are benign or malignant. A diagnosis of mesothelioma in situ cannot, therefore, be made on this field alone. A diagnosis of “atypical mesothelial hyperplasia” can be rendered for this field if other findings from elsewhere in the specimen are not available.


figure 6.28

107

Low power of a discrete cellular nodule within the pleural stroma is a histologic feature that is highly likely to represent a neoplasm. Higher power of this nodule disclosed histologic features of a tubulopapillary DMM. Distinct, obvious cellular nodules with stromal expansion strongly favor a diagnosis of DMM over benign reactive mesothelial hyperplasia.


Figure 6.29 Medium power of a sarcomatous DMM with bland necrosis. Bland necrosis is a “clean” ischemic-type necrosis with no or minimal cellular debris consisting of acellular eosinophilic necrosis sharply demarcated from the surrounding viable neoplasm. It is characteristic of DMM and contrasts with the “dirty” or leukocytoclastic necrosis seen in reactive processes of the pleura, particularly infections. In the latter, basophilic nuclear debris is present, often accompanied by intact and disintegrating neutrophils. Therefore, the presence of bland necrosis is helpful in distinguishing DMM from benign reactive proliferations. So-called “dirty” necrosis may also be seen in cancers, such as adenocarcinoma of the colon.

Index

A Adenocarcinomas, 25, 27 AMH. See Atypical mesothelial hyperplasia Atypical mesothelial hyperplasia (AMH) diagnosis, 80–81 focal architectural complexity, 103 vesicular nuclei, 104 B Benign mesothelial hyperplasia entrapment fibrinous exudate, 90 granulation tissue, 87–89 pseudoinvasion, 91 superimposed exudate, 92 histologic features, 101 vs. malignancy florid, high cellularity, 83 granulation tissue entrapment, 87–89 nuclear size and contour, 84 papillary tufts, 86 tubule-like structures, 85 Biphasic synovial sarcoma, 52 Breast carcinoma, 29 C Chronic pleuritis causes, 58

cut surface, 61 plasma cells, 68 D Diffuse malignant mesothelioma (DMM) connective tissue, 6 deciduoid cells, 19 desmoplastic cells acinar/tubular structures, 16, 17 gland-like structures, 16 differential diagnosis, 2, 5 epithelial cells cribiform pattern, 15 cytoplasm, 18 gland-like spaces, 18 polygonal cells, 10 signet ring cells, 19 vesicular nuclei, 12 histologic types, 3, 4 ivory colored cells rind-like growth, 7 thick dense growth, 8 wedge biopsy, 9 ivory rind cells, 9 mesothelial hyperplasia epithelial, 99 sarcomatous, 108 tubular, 93 papillary cells, fibrovascular cores, 13, 14 pleomorphic cells, 22

111

112 index Diffuse malignant mesothelioma (DMM) (Continued) pleural proliferative lesions, 5 spindle sarcomatous cells connective tissue, 21 desmoplastic region, 20 mesothelial hyperplasia, 108 myxoid stroma, 20 tubulopapillary cells, 13 DMM. See Diffuse malignant mesothelioma E Endometriosis, 75, 76 Eosinophilic pleuritis causes, 58 pneumothorax patients, 68 Epithelial DMM cribiform pattern, 15 cytoplasm, 18 gland-like spaces, 18 mesothelial hyperplasia, 99 polygonal cells, 10 signet ring cells, 19 vesicular nuclei and red nucleoli, 12 Epithelioid hemangioendothelioma biphasic synovial sarcoma, 52 cytoplasmic vacuoles, 54 DMM, 43–44 epithelioid cells, 53 uniform cuboidal cells, 53 F Fibrinous pleuritis amorphous form, 62–63 bacterial infections, 59–61 capillaries, 65 causes, 58 fibroblast ingrowth, 64 granulation tissue, 65 lung diffuse encasement, 61 lymphocytic infiltrate, 67 mature collagen, 66 G Granulomatous pleuritis causes, 59 noncaseating granuloma, 69

I Ivory colored DMM rind-like growth, 7 thick dense growth, 8 wedge biopsy, 9 L Localized malignant mesotheliomas (LMM) cut surface, 49 occurrence, 36 sharp neoplastic cells, 49 M Malignancy mesothelial hyperplasia vs. benign florid, high cellularity, 83 granulation tissue entrapment, 87–89 nuclear size and contour, 84 papillary tufts, 86 tubule-like structures, 85 histologic features, 101 Malignant solitary fibrous tumors (MSFT) cut surface, 47 forms, 36 hemangiopericytome pattern, 47 sarcomatoid cells, 48 Mesothelial hyperplasia AMH diagnosis, 80–81 focal architectural complexity, 103 vesicular nuclei and conspicuous nucleoli, 104 benign entrapment, 87–92 histologic features, 101 vs. malignancy, 83–89 papillary tufts, 86 bland cells cellular nodules, 107 cytologic, 94 fat invasion, 95 focal stratification and tufting, 98 skeletal muscle invasion, 96–97 small clusters, 100

tangential cut, 105 tubules, 102 causes, 82 cytologic variation, 82 DMM sarcomatous, 108 tubular, 93 high cellularity, 83 malignancy vs. benign, 101 histologic features, 101 mature fibrous pleuritis, 85 nuclear size and contour, 84 structure, 79–80 Metastatic cancers bland cells, 28 breast cells, 29 cellular nodule, 26 desmoplastic connective tissue, 27 differential diagnosis, 24 vs. DMM, 23 epithelial cell nests, 28 histopathologic patterns, 24 irregular glands, 27 melanoma, 32, 33 multiple white nodules, 25 papillary cells, 29 pleural effusions, 23, 24 prostate cells, 30 renal cells, 30, 31 sarcomatous cells, 34 Metastatic melanoma, 32, 33 MSFT. See Malignant solitary fibrous tumors N Nonneoplastic pleura endometriosis, 75, 76 features, 101 nodular histiocytic hyperplasia, 77, 78 sclerosing mediastinitis, 75, 76 splenosis, 75–76 P Papillary carcinoma, 13, 14, 29 Pleomorphic DMM, 22 Pleural plaque causes, 62

index

113

collagen, 73–74 foreign crystalline material, 70, 71 Pleuritis chronic causes, 58 cut surface, 61 plasma cells, 68 eosinophilic causes, 58 pneumothorax patients, 68 fibrinous amorphous form, 62–63 bacterial infections, 59–61 capillaries, 65 causes, 58 fibroblast ingrowth, 64 granulation tissue, 65 lung diffuse encasement, 61 lymphocytic infiltrate, 67 mature collagen, 66 granulomatous causes, 59 noncaseating granuloma, 69 rheumatoid nodule, 72 silicotic nodule, 73 Primary pleural neoplasms clinical and histologic features, 37–38 diagnosis, 35–36 epithelioid hemangioendothelioma biphasic synovial sarcoma, 52 cytoplasmic vacuoles, 54 epithelioid cells, 53 uniform cuboidal cells, 53 gross features, 39–40 LMM cut surface, 49 occurrence, 36 sharp neoplastic cells, 50 MSFT bulky tumor, 46 forms, 36 hemangiopericytome pattern, 47 sarcomatoid cells, 48 yellow necrosis, 47 radiographic features, 37–38

114 index Pleuritis (Continued) SFT cellular pattern, 44 collagen, 42–43 cut surface, 41 hemangiopericytoma pattern, 45 size, 36 WDPM myxoid fibrovascular cores, 52 occurrence, 42 papillary fronds, 51 Prostate carcinoma, 30 R Renal cell carcinoma, 30, 31 Rheumatoid pleuritis, 72 S Sarcomatous carcinoma, 34 Sclerosing mediastinitis, 75, 76 SFT. See Solitary fibrous tumor Silicotic pleuritis, 73

Solitary fibrous tumor (SFT) cellular pattern, 44 collagen, 42–43 hemangiopericytoma pattern, 45 size, 36 Spindle sarcomatous DMM connective tissue, 21 desmoplastic region, 20 mesothelial hyperplasia, 108 myxoid stroma, 20 Splenosis, 75–76 T Tubular DMM, mesothelial hyperplasia, 93 W WDPM. See Well-differentiated papillary mesothelioma Well-differentiated papillary mesothelioma (WDPM) myxoid fibrovascular cores, 52 occurrence, 42 papillary fronds, 51

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