Rosen's Breast Pathology, 4e

Syed A. Hoda, MD Professor Department of Clinical Pathology and Laboratory Medicine Weill Cornell Medical College Attending Pathologist Department of Pathology and Laboratory Medicine New York Presbyterian Hospital/Weill Cornell Medical Center New York, New York Edi Brogi, MD, PhD Professor Department of Clinical Pathology and Laboratory Medicine Weill Cornell Medical College E. Lauder Breast and Imaging Center Director of Breast Pathology Attending Pathologist Department of Pathology Memorial Sloan-Kettering Cancer Center New York, New York

Frederick C. Koerner, MD Associate Professor Department of Pathology Harvard Medical School Associate Pathologist Department of Pathology Massachusetts General Hospital Boston, Massachusetts

Paul P. Rosen, MD Emeritus Professor of Pathology Department of Pathology and Laboratory Medicine Weill Cornell Medical College Cornell University New York, New York

Acquisitions Editor: Ryan Shaw Product Manager: Kate Marshall

Production Product Manager: David Saltzberg Senior Manufacturing Coordinator: Beth Welsh Designer: Stephen Druding Marketing Manager : Dan Dressler Production Service: S4Carlisle Publishing Services

© 2014 by LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER business Two Commerce Square 2001 Market Street Philadelphia, PA 19103 USA LWW.com

Third Edition © 2009 by Lippincott Williams & Wilkins Second Edition © 2001 by Lippincott Williams & Wilkins First Edition © 1997 by Lippincott-Raven

All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. govern- ment employees are not covered by the above-mentioned copyright.

Printed in China

Library of Congress Cataloging-in-Publication Data

Rosen, Paul Peter, author.  Rosen’s breast pathology / Syed A. Hoda, Edi Brogi, Frederick C. Koerner, Paul P. Rosen.—Fourth edition.  p. ; cm.  Breast pathology  Preceded by Rosen’s breast pathology / Paul Peter Rosen. 3rd ed. c2009.  Includes bibliographical references and index.  ISBN 978-1-4511-7653-7 (alk. paper)  I. Hoda, Syed A., author. II. Brogi, Edi, author. III. Koerner, Frederick C., author. IV. Title. V. Title: Breast pathology.  [DNLM: 1. Breast Neoplasms—pathology. WP 870]  RC280.B8  616.99'44907—dc23 2013041071 Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices. However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication. Application of the information in a particular situation remains the professional responsibility of the practitioner. The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of informa- tion relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly impor- tant when the recommended agent is a new or infrequently employed drug. Some drugs and medical devices presented in the publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings. It is the responsibility of the health care provider to ascertain the FDA status of each drug or device planned for use in their clinical practice. To purchase additional copies of this book, call our customer service department at (800) 638-3030 or fax orders to (301) 223-2320. International customers should call (301) 223-2300. Visit Lippincott Williams & Wilkins on the Internet: at LWW.com. Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to 6 pm, EST.

10 9 8 7 6 5 4 3 2 1

Dedication in Prior Editions To my parents, Beate Caspari-Rosen, MD, and George Rosen, MD, and to the ineffable Mary Sue Rosen.

Dedication for the Fourth Edition To the esteemed mentors who led us forth, the patients we serve, and the students to whom we entrust the future of breast pathology.

Instruction in medicine is like the culture of the production of the earth. For our natural disposition is, as it were, the soil; the tenets of our teacher are, as it were, the seed; the instruction in youth is like the planting of the seed in the ground at the proper season…and it is time which imparts strength to all things and brings them to maturity. — From The Law by Hippocrates

CONTR I BUTORS

Elena Brachtel, MD Assistant Professor

Melinda F. Lerwill, MD Assistant Professor

Department of Pathology Harvard Medical School Assistant Pathologist Department of Pathology Massachusetts General Hospital

Department of Pathology Harvard Medical School Assistant Pathologist Department of Pathology Massachusetts General Hospital Boston, Massachusetts

Boston, Massachusetts Edi Brogi, MD, PhD Professor Department of Clinical Pathology and Laboratory Medicine Weill Cornell Medical College E. Lauder Breast and Imaging Center Director of Breast Pathology Attending Pathologist Department of Pathology Memorial Sloan-Kettering Cancer Center New York, New York Adriana D. Corben, MD Assistant Attending Pathologist Department of Pathology Memorial Sloan-Kettering Cancer Center Department of Pathology Harvard Medical School Director of Hematopathology Department of Pathology Massachusetts General Hospital Boston, Massachusetts Syed A. Hoda, MD Professor Department of Clinical Pathology and Laboratory Medicine Weill Cornell Medical College Attending Pathologist Department of Pathology and Laboratory Medicine New York Presbyterian Hospital/Weill Cornell Medical Center New York, New York Frederick C. Koerner, MD Associate Professor New York, New York Judith A. Ferry, MD Associate Professor

Melissa P. Murray, DO Assistant Attending Pathologist Department of Pathology Memorial Sloan-Kettering Cancer Center New York, New York Erika Resetkova, MD, PhD Associate Professor Breast Pathologist and Cytopathologist Department of Pathology M. D. Anderson Cancer Center Houston, Texas

Paul P. Rosen, MD Emeritus Professor of Pathology Department of Pathology and Laboratory Medicine Weill Cornell Medical College Cornell University New York, New York Aysegul A. Sahin, MD Professor Department of Pathology Chief of Breast Pathology Service University of Texas M. D. Anderson Cancer Center Houston, Texas

Yun Wu, MD, PhD Associate Professor Department of Pathology University of Texas Department of Pathology M. D. Anderson Cancer Center Houston, Texas

Department of Pathology Harvard Medical School Associate Pathologist Department of Pathology Massachusetts General Hospital Boston, Massachusetts

vi

Pre face

Not long after I retired from clinical practice in 2010 ­Jonathan W. Pine, Jr, Senior Executive Editor, contacted me about preparing a fourth edition of Breast Pathology . This came as a shock as I had only recently recovered from the ef- fort that produced the third edition and was adjusting to the freedom conferred by retirement. Mr. Pine and I had a very good working relationship in producing the third edition, and being curious to learn what he had in mind, I walked the short distance from my home to the offices of Wolters Kluwer/Lippincott Williams & Wilkins in Philadelphia. As a result of this and subsequent conversations, we arrived at the plan that has given birth to this fourth edition. After writing the initial edition and revising it twice single-handedly, I am honored that my three colleagues and their associates consented to do the heavy lifting that has been necessary to bring this much-improved Fourth ­Edition to completion. The book has benefitted greatly from their many decades of experience in the diagnosis of mam- mary pathology at three of the most prestigious American academic medical centers that are international leaders in the treatment of breast diseases: New York Presbyterian ­Hospital/Weill Cornell Medical College, ­Memorial Hospital for Cancer and Allied Diseases/Memorial Sloan-­Kettering Cancer Center, and Massachusetts General Hospital/­ Harvard Medical School. I have known Syed A. Hoda, MD, for 20 years and worked closely with him for nearly a decade in the Breast Pathology Consultation practice I established at New York Presbyterian Hospital, with the support and encourage- ment of Daniel M. Knowles, Chairman of Pathology and ­Laboratory Medicine. I was very pleased that Syed agreed to serve as Editor, taking responsibility for overseeing the proj- ect and looking after the innumerable details involved in the creation of a book of this scope. Not the least of these tasks was the final stage of uploading the chapter manuscripts and images as required by the publisher. Drs. Hoda, Brogi, and Koerner each undertook the revision of approximately one-third of the book, in some instances with the assistance of their associates. While ad- hering to the basic outline established in prior editions, each chapter has been thoroughly updated to include the most recent information available when the manuscript was com- pleted, as reflected in the substantial number of 2010 to 2013 references cited. In addition to thorough and extensively illustrated descriptions of the surgical pathology and cytol- ogy of the breast, the reader will find comprehensive, de- tailed overviews of the many clinical facets of breast disease, including epidemiology, clinical presentation, diagnostic imaging, molecular/genetic analysis, clinical management, and prognosis. Many new pictures have been added, others have been replaced, and all have been carefully adjusted to

enhance image quality. Chapter 40, titled “Lymphoid and Hematopoietic Neoplasms of the Breast,” was completely rewritten using contemporary diagnostic terminology by Judith A. Ferry, MD, from Massachusetts General Hospital/ Harvard University. In the Introduction to the third edition to this book, I drew attention to the growing recognition that “altered gene expression is fundamental to neoplastic processes” and noted that “the devil is in the details” of how the exceedingly complex system of gene actions becomes disrupted, resulting in the phenotypic changes in cells and tissues employed by pathologists for diagnosis and estimating prognosis. It has become apparent that the situation is even more complex. Some genotypic alterations are linked to specific neoplasms with similar phenotypic appearances, such as the genetic alterations that underlie the diminished or absent expression of adhesion molecules like E-cadherin in lobular carcinoma or the ETV6 – NTRK3 fusion gene that characterizes secretory carcinoma. On the other hand, an increasing number of ge- netic alterations of significance for prognosis and treatment, not readily apparent in the histologic phenotype of neo- plasms, are being discovered by gene expression profiling, and this is leading to an appreciation of unique characteris- tics of individual tumors that may render them susceptible to personalized therapies aimed at these targets. Of particular interest is the discovery that some of the genomic alterations found in mammary carcinomas also occur in carcinomas that arise in other organs such as the uterus and ovaries. In view of the rapid advances being made in the study of the molecular biology of breast carcinoma and the grow- ing intersection of the resultant knowledge with diagnostic pathology, it was deemed important to expand this book by adding Chapter 45, titled “Molecular ­Classification and Test- ing of Breast Carcinoma,” by Drs. Yun Wu and Aysegul A. Sahin from the M. D. Anderson Cancer Center/University of Texas. This chapter provides an introduction to molecular classifications under investigation and predictive molecular tests that are currently used in clinical practice. Data from molecular studies relevant to specific entities can be found in individual chapters. Additional comments about provoca- tive concepts relating to the molecular classification of breast carcinoma that have emerged as a result of gene expression profiling are addressed in a section titled “Molecular versus Morphology for the Classification of Breast Carcinoma: Must It Be Either/Or” in the Introduction. Histopathologic examination will continue to be the primary basis for the diagnostic classification of mammary lesions in the foreseeable future. Molecular advances used in the past two decades to generate alternative classifica- tions have contributed to defining selected prognostic and therapeutic subgroups within the context of the standard

vii

viii

Preface

pathologic phenotypic classification presented in this book. It is possible that the pathology report for a mammary carci- noma in the coming decade will include a secondary classifi- cation based on molecular markers. Ultimately, it is genotype that serves as the basis for phenotype, and the complex, long- term process of unraveling this relationship will benefit from the work of investigators familiar with both aspects of mam- mary disease. Surgical pathologists are uniquely qualified to fill this role and to assimilate these advances into routine diagnostic testing for the benefit of patients. In addition to the extensive revisions and editing of individual chapters by the authors, this book has been

subjected to rigorous scrutiny by the publisher’s excellent staff throughout the production process. The choice of il- lustrations, the references listed, the selection of data cited, and the conclusions expressed reflect the experience and opinions of the editors and authors. I had the extraordi- nary opportunity to read all of the new references as well as to review and edit the manuscripts and pictures of each chapter. I have also substantially revised and updated the Introduction.

Paul P. Rosen, MD

List of Abbreviations A list of the most frequently used abbreviations in this book can be found on page 1351. LEGENDS FOR COVER IMAGES Front Cover Image Legends (clockwise from top left): radial sclerosing lesion with ductal hyperplasia, cribriform DCIS (E-cadherin positive) and LCIS (E-cadherin negative) in a duct, secretory carcinoma, and fluorescence in situ hybrid- ization (FISH) in secretory carcinoma with separated red and green signals indicating a disrupted NTRK3 gene. (Courtesy of Dr. A. John Iafrate and Ms. Clarice Bo-Moon Chang.) Back Cover Image Legends (clockwise from top left): partially infarcted adenomyoepithelioma; metaplastic carcinoma, spindle and squamous type; reaction to contents of a ruptured breast implant; solid papillary carcinoma (arrows indicate fibrovascular cores).

PRE FACE TO THE F I RST ED I T I ON

1997 He will manage to cure best who has foreseen what is to happen from the present state of matters. —Hippocrates 1 The management of diseases of the breast is a multidisci- plinary endeavor dependent on the skill and expertise of an array of clinical specialists. In this complex effort, the im- portance of one or another member of the team for a given patient will vary depending upon the clinical circumstances. At the outset and often at later critical points, an accurate pathologic diagnosis is the crucial element for determining the course of treatment and for estimating prognosis. A thor- ough knowledge of the pathology of the breast is essential for physicians and other medical personnel who take care of patients with breast diseases. Conversely, the pathologist cloistered in a laboratory, out of touch with patient care, will not be able to provide the clinically meaningful information currently expected of practitioners of this specialty. The breast appears structurally and functionally to be relatively uncomplicated, but it is the site of a surprisingly broad array of pathologic alterations, many of which are organ-specific. New entities continue to be identified. Our understanding of breast pathology has been substantially amplified by the application of new technology to this effort. Particularly rapid progress has occurred in the past decade as a result of the availability of immunohistochemistry and in situ hybridization, which have made it possible to observe the tissue-specific and cell-specific localization of molecular and genetic processes associated with physiologic and patho- logic conditions. Yet, it is important not to be blinded by the blizzard of information and to avoid being swept away in the annual flood of “hot topics.” All too often, today’s hot topic becomes tomorrow’s footnote. Ultimately, our understand- ing of breast pathology is remodeled and enriched by the ongoing process of discovery and thoughtful analysis that contributes to a growing body of knowledge composed of many bits of information from innumerable contributors. This vision embodies the precept of Hippocrates, who wrote: But all these requisites belong of old to Medicine, and an origin and way have been found out, by which many and elegant dis- coveries have been made, during a length of time, and others will yet be found out, if a person possessed of the proper ability, and knowing those discoveries which have been made, should proceed from them to prosecute his investigations . 2 This book provides a comprehensive, extensively illus- trated description of breast pathology in a clinical context. Most of the chapters are devoted to specific diseases or disease groupings. The discussion of each topic consists, where rele- vant, of sections detailing clinical presentation and mammog- raphy, epidemiology, gross pathology, microscopic pathology, including electron microscopy and immunohistochemistry,

differential diagnosis, treatment, and prognosis. Several chap- ters deal with broad subjects, such as precancerous breast pa- thology, staging of carcinoma, biologic markers of prognosis, the pathologic effects of therapy, cytologic and needle core di- agnosis, and the pathologic examination of breast specimens. Illustrations have been selected not only to demonstrate the standard appearance of lesions but also to emphasize the heterogeneity represented by variant forms. Following the manner in which the pathologist encounters them in daily practice, many entities are shown as they appear grossly, in whole-mount histologic sections and, finally, at progres- sively higher magnification, amplified with immunohisto- chemistry and other diagnostic procedures. It is my hope that there is no “pathomythology” in this book. A myth is defined as “an idea that forms part of the beliefs of a group or class but is not founded on fact.” 3 Pathomythology is a term I use to describe the persistent repetition of hypotheses relating to pathology that are com- pletely contradicted by existing data. Perpetrators of this activity frequently reinforce their myth by quoting them- selves or other followers of their belief, eschewing facts that can easily be confirmed by direct observation. One example of pathomythology is the seemingly indestructible idea that the carcinomatous cells of mammary Paget disease arise by transformation of squamous cells in the squamous epi- thelium that harbors Paget disease. Intraductal carcinoma, which is the source of these carcinoma cells, is detected in virtually every patient with Paget disease, but the pathomy- thologists rest their case on the very few instances in which duct carcinoma is not discovered. A reasonable explanation for these exceptional cases is offered in this book. Another example of pathomythology is the inaccurate statement that an intraductal component is not found in true medullary carcinoma. Intraductal carcinoma can be found at the pe- riphery of most medullary carcinomas, but the presence or absence of intraductal carcinoma has been shown not to be a criterion for the diagnosis of medullary carcinoma. Despite diligent attention to detail, it is likely that some er- rors of omission or commission have occurred in the prepara- tion of this book. The author is responsible for the selection of references and illustrations, for the citation of data from pub- lished sources, and for conclusions expressed herein, based on his personal experience and his interpretation of the literature. REFERENCES 1. Adams F. The book of prognostics. The genuine works of Hippocrates . Baltimore: The Williams & Wilkins Co., 1939:42. 2. Adams F. On ancient medicine. The genuine works of Hippocrates . Baltimore: The Williams & Wilkins Co., 1939:1–2. 3. Stein J, ed. The Random House dictionary of the English language . New York: Random House, 1973:946. Paul P. Rosen, MD

ix

ACKNOWL EDGMENTS

The majority of the new illustrations in this book were taken from cases seen at the institutions where the Editors and Contributors practice. Thousands of adult women as well as many hundreds of men and children afflicted with breast diseases who cannot be recognized individually are acknowledged for their anonymous contributions to this and prior editions of Rosen’s Breast Pathology . The task of turning the manuscript into a finished book has been a cooperative effort. All of the images were digitally enhanced by Ms. Patricia Kuharic in the Medical Art and Photography Department of Weill Cornell Medical College. Her patient and meticulous attention to detail has made an essential contribution to this book. A sincere thank-you is extended to the office staff of each contributor for their vital

support, and to residents, fellows, and colleagues who may have provided cases or images that made their way into the book. Dr. Dilip Giri is acknowledged for reviewing portions of the manuscript. Drs. Sonal Varma and Timothy D’Alfonso contributed especially instructive illustrative material. After Jonathan Pine took on other responsibilities, Ryan Shaw, Acquisitions Editor, became our liason with the publisher, a role he fulfilled efficiently and cheerfully. The production process was ably overseen by Kate Marshall, Product Manager, who guided us and offered many helpful suggestions that have improved the book.

Syed A. Hoda, MD Paul P. Rosen, MD

x

CONT ENTS

Contributors    vi Preface    vii Paul P. Rosen Preface to the First Edition    ix Paul P. Rosen Acknowledgments    x

15 Medullary Carcinoma    523 Frederick C. Koerner 16 Carcinoma with Metaplasia and Low-Grade Adenosquamous Carcinoma    547 Edi Brogi 17 Squamous Carcinoma    599 Edi Brogi 18 Mucinous Carcinoma    611 Adriana D. Corben, Edi Brogi 19 Apocrine Carcinoma    645 Edi Brogi 20 Mammary Carcinomas with Endocrine Features    667 Edi Brogi 21 Small Cell Carcinoma    679 Frederick C. Koerner 22 Secretory Carcinoma    689 Frederick C. Koerner 23 Mammary Carcinoma with Osteoclast-like Giant Cells    703 Frederick C. Koerner 24 Cystic Hypersecretory Carcinoma and Cystic Hypersecretory Hyperplasia    715 Edi Brogi 25 Adenoid Cystic Carcinoma    725 Edi Brogi 26 Invasive Cribriform Carcinoma    749 Frederick C. Koerner 27 Lipid-Rich Carcinoma    753 Frederick C. Koerner 28 Glycogen-Rich Carcinoma    757 Frederick C. Koerner 29 Invasive Micropapillary Carcinoma    763 Adriana D. Corben, Edi Brogi 30 Paget Disease of the Nipple    775 Elena Brachtel, Frederick C. Koerner 31 Lobular Carcinoma In Situ and Atypical Lobular Hyperplasia    797 Syed A. Hoda 32 Invasive Lobular Carcinoma    855 Syed A. Hoda

Syed A. Hoda Paul P. Rosen Introduction    xiii Paul P. Rosen

1 Anatomy and Physiologic Morphology    1 Syed A. Hoda 2 Abnormalities of Mammary Development and Growth    27 Syed A. Hoda 3 Inflammatory and Reactive Tumors    37 Syed A. Hoda 4 Specific Infections    79 Syed A. Hoda 5 Papilloma and Related Benign Lesions    95 Frederick C. Koerner 6 Myoepithelial Neoplasms    153 Edi Brogi 7 Adenosis and Microglandular Adenosis    183 Edi Brogi 8 Fibroepithelial Neoplasms    213 Edi Brogi 9 Ductal Hyperplasia: Usual and Atypical    271 Syed A. Hoda 10 Precarcinomatous Breast Disease: Epidemiologic, Pathologic, and Clinical Considerations    309 Syed A. Hoda 11 Ductal Carcinoma In Situ     331 Syed A. Hoda 12 Invasive Ductal Carcinoma: Assessment of Prognosis with Morphologic and Biologic Markers    413 Syed A. Hoda 13 Tubular Carcinoma    469 Edi Brogi 14 Papillary Carcinoma    489 Frederick C. Koerner

xi

xii

Contents

33 Unusual Clinical Presentation of Carcinoma    893 Syed A. Hoda 34 Metastases in the Breast from Nonmammary Neoplasms    937 Syed A. Hoda 35 Benign Proliferative Lesions of the Male Breast    957 Melissa P. Murray, Edi Brogi 36 Carcinoma of the Male Breast    971 Melissa P. Murray, Edi Brogi 37 Breast Tumors in Children    993 Edi Brogi 38 Benign Mesenchymal Neoplasms    1019 Melinda F. Lerwill, Frederick C. Koerner 39 Sarcoma    1095 Frederick C. Koerner 40 Lymphoid and Hematopoietic Neoplasms of the Breast    1167 Judith A. Ferry

41 Pathologic Effects of Therapy    1197 Elena Brachtel, Frederick C. Koerner 42 Cutaneous Neoplasms    1217 Frederick C. Koerner 43 The Pathology of Axillary and Intramammary Lymph Nodes    1241 Syed A. Hoda 44 Pathologic Examination of Breast and Lymph Node Specimens, Including Sentinel Lymph Nodes    1263 Syed A. Hoda, Erika Resetkova 45 Molecular Classification and Testing of Breast

Carcinoma    1337 Yun Wu, Aysegul A. Sahin

List of Abbreviations    1351 Index    1353

I NTRODUC T I ON

The Pathologist as a Specialist in Breast Carcinoma Care The development and application of a concept of localized pathology laid the groundwork for modern specialism by providing a number of foci of interest in the field of medicine. Each such focus of interest, that is, a disease or the diseases of an organ or region of the body, provided a nucleus around which could gather the results of clinical and pathological investigation . —From The Specialization of Medicine by George Rosen, MD , 1944. Impressive advances have been made in the past 60 years to detect, treat, and cure breast carcinoma. Major milestones include the development of mammography for early detec- tion, the refinement of image-based needle biopsy of non- palpable lesions, the introduction of computed tomography (CT) and magnetic resonance imaging (MRI) of the breast, the shift from mastectomy to breast conservation therapy for almost all patients, technologic advances in radiotherapy, improved chemotherapy regimens for primary treatment and as an adjuvant modality, the demonstration that anti- estrogenic compounds can inhibit the development and progression of breast carcinoma, the introduction of sentinel lymph node mapping for axillary staging, and technologic advances that make gene expression profiling possible. The growth of medical specialization in the last half of the 20th century has had a profound influence on these accomplish- ments by fostering multidisciplinary clinical practice and research. Specialism in all aspects of medical care has revolution- ized the role of the surgical pathologist. Rather than foster- ing professional independence, specialization in medicine has created circumstances in which the specialist, delivering a limited segment of medical care, is increasingly dependent on the assistance of colleagues who have acquired comple- mentary expertise. This situation is epitomized by the mul- tidisciplinary approach that is now standard for treating breast diseases. Inherent in this circumstance is the expecta- tion that each member of the team is capable of delivering optimal specialty care. A corollary effect is the growing pres- sure for subspecialization in diagnostic pathology in aca- demic centers and in large community hospital centers. This process will be furthered by growing awareness on the part of patients and patient advocacy organizations that accurate and comprehensive pathology diagnosis is fundamental to effective treatment and research in breast diseases. Even when considered in the context of advances in diagnosis that have been facilitated in recent decades by immunohistochemistry and molecular analysis, micro- scopic examination of hematoxylin and eosin–stained tis- sue sections combined with gross inspection remains the most cost-effective diagnostic procedure for breast diseases.

Pathologists generate an important part of the information used for therapeutic decisions. The complex multifacto- rial description of breast pathology now considered to be standard practice has expanded the diagnostic report from a brief one- or two-line statement to a catalog of data that may be several pages in length. Immunohistochemistry makes it possible to determine whether prognostic and therapeutic markers are present by microscopic examination, and these observations are part of the pathologist’s report. The ex- panded role of pathologists in the management of breast dis- eases requires their active participation as part of the clinical care team. Pathologists who diagnose breast specimens need to be aware of how various components of their reports are relevant to treatment decisions. Coincidental with these medical developments has been the growing involvement of patients in making decisions about their treatment. This, in turn, has led to greater pub- lic awareness of the importance of information contained in pathology reports. For the untrained layperson to read and interpret a pathology report, it is necessary to learn and understand a new vocabulary, a daunting task that is not necessarily made easier by the frequently conflicting and unfiltered information available from the Internet. Surgeons, oncologists, and radiotherapists are experts at interpreting pathology reports for their patients and at explaining the significance of the data. Nonetheless, a sub- stantial number of patients with breast diseases want an explanation from the pathologist who issued the report or they seek out another pathologist, often with specialized expertise, for a second-opinion review. In this way, patholo- gists increasingly participate in direct patient care and pa- tient education, a vital public service. Second Opinions in Breast Pathology Surgical pathologists in general practice provide accurate diagnoses for the great majority of the breast specimens they encounter without the assistance of intramural or extramu- ral consultation. Nonetheless, pathology departments that do not have a dedicated breast pathology subsection should have a built-in mechanism for obtaining second opinions internally through conferencing or other quality assurance programs. As evidenced by a number of papers published in recent years, there is growing recognition of the importance of having an intradepartmental peer-review quality assur- ance program in order to minimize diagnostic errors. 1–3 Procedures have been described for internal review shortly after the diagnosis was officially reported 4 and for pre-sign- out review. 5 For detailed discussions of quality assurance issues in surgical pathology, the reader should consult the aforementioned articles and references cited therein.

xiii

xiv

Introduction

In this setting, the individual pathologist or the pathol- ogy group in a department may seek an extramural opinion from an expert consultant. This typically occurs when there is a difference of interpretation among pathologists in an institution or the diagnosis is uncertain after internal re- view. Consultation may also be obtained when the probable diagnosis is one with which there is little or no experience. Another category of consultation results from uncertainty about the diagnosis engendered by a limited or unrepre- sentative sample, poor histologic preparation, or a patho- logic change that appears to be on the borderline between two or more diagnoses. As noted by Leslie et al., 6 “Second opinions in anatomic pathology are an integral part of qual- ity ­practice … frequent consultation between pathologists should be fostered in all practice settings and documented as part of the quality assurance process.” Several studies have demonstrated the important con- tribution to patient care of second opinion pathology consultations, generally in the context of referrals seen at academic centers. A very encouraging aspect of this practice is the high degree to which the primary diagnosis has been confirmed by the consultant. Epstein et al. 7 reported con- cordant diagnoses (carcinoma vs. not carcinoma) in 98.7% of 535 prostatic needle biopsies diagnosed as carcinoma. Nonetheless, the six diagnoses not sustained as carcinoma were critically important for the 1.3% of patients. A cost analysis of these results suggested that the saving in medical expenses for the six patients who did not undergo surgery substantially exceeded the cost of reviewing all 535 biopsies. In a subsequent study of 855 core biopsy samples from the prostate gland seen in consultation, Epstein and colleagues 8 reported a 1.2% rate of unconfirmed carcinomas, a result that was virtually identical to their 1996 study. Among 844 cases confirmed to be carcinoma, unreported perineural invasion was detected in 4.3% and unreported periprostatic invasion was found in 0.5%. A higher rate of discrepancies was found by Abt et al., 9 who compared the original- and second-opinion diagnoses in a broad range of pathology among 777 patients referred to an academic center. Forty-five diagnostic disagreements (6%) were regarded as clinically significant, and overall the level of agreement was 92.1%. Manion et al. 10 reported a study of 5,629 outside pathology cases examined between 2003 and 2006 as part of the University of Iowa Hospitals and Clinics policy that requires “… second opinion pathol- ogy review of pertinent outside material, irrespective of the nature of the specimen or complexity of the case.” Major diagnostic disagreements with the potential to change treat- ment or prognosis were recorded in 132 (2.3%) cases, result- ing in changes in clinical management in 68 (1.2%). The most frequent sites of major disagreements were the female reproductive tract, the gastrointestinal tract, and the skin. The largest study to date of discordant pathology was re- ported by Swapp et al., 11 who reviewed the records of 71,811 cases seen in consultation at the Mayo Clinic between 2005 and 2010. Major disagreements were recorded in 457 (0.6%)

cases. The most frequent sites of discrepant diagnoses were the gastrointestinal tract (17.5%), lymph nodes (16%), and bone/soft tissue (10%). Major disagreements were encoun- tered in 8% of breast cases. Perkins et al. 12 estimated that diagnoses were inaccurate in 2% to 4% of breast carcinoma cases, including mistaking benign for malignant disease or vice versa , over- or underdi- agnoses of invasive carcinoma, or misinterpretation of prog- nostic markers such as human epidermal growth factor/ neu receptor (HER2/ neu ). In a study restricted to breast carci- nomas, Staradub et al. 13 reviewed second-opinion diagnoses on 346 tumors from 340 patients who had been referred to the Sage Comprehensive Breast Program at Northwestern University. Major changes in diagnosis that affected therapy occurred in 30 (7.8%) cases. Among seven discrepant cases with an initial diagnosis of ductal carcinoma in situ (DCIS), the second-opinion diagnosis was benign in one and inva- sive carcinoma in six. Seven other diagnoses were revised from invasive carcinoma to DCIS. Sixteen changes of mar- gin status were documented and in three cases revised mar- gin status coincided with another major change. Within the United States, several factors have contributed to the growing number of pathology consultations. Much of the increase is generated by patients who seek multiple clinical opinions from different physicians and institutions. Some patients are primarily concerned with confirmation of their diagnosis, and one or more consultations may be obtained directly from pathologists for this reason alone. The involvement of patients is epitomized by a ­January 17, 2012, Wall Street Journal article titled “What If the Doctor Is Wrong?,” 14 which recounts the story of a 47-year-old woman with abdominal tumors. Based on initial tissue samples, it was thought that she had a rare form of ovarian carcinoma. When the patient consulted a major cancer cen- ter, further studies led to a diagnosis of lymphoma. In addition to consultations initiated by pathologists seeking opinions from their colleagues, surgeons, medical oncologists, and other physicians generate some consulta- tions. The review of “outside” pathology slides should be mandatory whenever a patient is referred to a physician for consultation or treatment at an institution other than the one where the primary diagnosis was rendered, 15 a policy referred to by one author as “the pathologist’s preventive medicine.” 16 The office of the physician seeing a patient in consultation should inform the patient of the necessity of obtaining pathology material for review in a timely manner before the office visit. A policy and procedures should be established for guiding the patient through this process, in- cluding instructions as to what material is needed and where it should be sent. The importance of a second review should be explained, and the patient should be informed that there will be a charge for this service. Slides sent for consultation, regardless of the reason, must be accompanied by documents that confirm the identity of the specimen with the patient and a copy of the pathology/cytology report for each specimen represented,

xv

Introduction

clearly displaying the name of the patient and the accession number corresponding to the slides and paraffin blocks enclosed. It is unacceptable and substandard practice to withhold the pathology report previously obtained from a consultant or second-opinion institution so as not to “bias” the second review. The pathology report provides essential information such as an index of location(s) of the specimen(s) represented by individual slides, a description of the gross appearance of the specimen(s), clinical informa- tion provided with the specimen, frozen section interpreta- tions, and details of the originating pathologist’s diagnosis. The pathology report must be included even if a final diag- nosis had not been reached. When the slides are sent directly from one laboratory to another in relation to a clinical consultation at the recipient institution, the correspondence should include the name of the clinical physician who is be- ing consulted (if known) and detailed billing information. When more than one consultant is involved, it is vital that all consultants examine the same or equivalent material. A host of new classifications of breast carcinoma have emerged from studies using tissue microarray and gene expression profile technology. 17–23 Some of these molecular- based classification schemes have led to the introduction of testing procedures that assign patients to prognostic catego- ries and predict response to therapy, as discussed in Chapter 45. Some of these tests are being used in clinical practice based on analysis of retrospective data. It will take many years before they are fully validated in prospective clinical trials. As the results of additional gene profiling studies are reported, more classifications will no doubt be developed and promoted for various reasons. The exceptional speed with which the molecular study of breast carcinoma has advanced makes it hazardous to predict circumstances even a few years hence. Nevertheless, the cur- rent situation was perhaps best summarized by Rakha and Ellis 22 in their paper titled “Modern Classification of Breast Cancer: Should We Stick with Morphology or Convert to Molecular Profile Characteristics,” wherein they observed that the “replacement of conventional classification seems unfounded and incorporation of multigene molecular clas- sifiers to conventional BC [breast carcinoma] classification systems seems more realistic and practical to support more effective tailoring of therapy in the future.” In a report titled “Breast Cancer Prognostic Classification in the ­Molecular Era: The Role of Histological Grade,” Rakha et al. 21 con- cluded that “clinical acceptance of these molecular assays will require them to be more than expensive surrogates for established traditional factors such as histological grade.” A study reported by Sotiriou et al. 24 illustrates how results from gene expression profiling can be complementary to Molecular versus Morphology for the Classification of Breast Carcinoma: Must It Be Either/Or?

conventional pathologic data. The investigators developed a scoring system or gene expression grade index based on a 97-gene list that correlated patterns of gene expression with histologic grade. A high gene expression grade index was associated with 86% of grade 3 tumors, and a low index was associated with 91% of grade 1 tumors. The contribu- tion of the gene expression index was greatest among grade 2 carcinomas, in which a high index was associated with a significantly greater risk for recurrence than a low index ( p < 0.001; hazard ratio, 3.61; CI, 2.25 to 5.78). Finally, there are substantial parts of the world where the technology needed to support a molecular-based descrip- tion of breast carcinoma is unavailable. This situation is not likely to change soon and will require the continued use of standard morphology-based diagnostic reporting. It would be wise to observe this rapidly evolving field with a healthy dose of skepticism regarding the likelihood that any of the current molecular-based classification schemes will soon supplant standard pathologic examination as the basis for establishing a diagnosis, estimating prognosis, and for fundamental treatment decisions. At best, molecular data in its current form complement pathologic observa- tions and can “fine tune” therapeutic decisions, especially in intermediate or ambiguous situations. Ever since it was demonstrated in the 1970s and 1980s that mammography screening could detect clinically occult carci- nomas of the breast and reduce breast carcinoma mortality, concern has been expressed that screening results in “over- diagnosis” and “overtreatment” because it identifies indolent lesions that are unlikely to have a fatal outcome and could be left untreated. The issue first came to a head in the late 1970s when the early results of the Breast Cancer ­Diagnosis Demonstration Project (BCDDP) sponsored by the National Cancer Institute (NCI) and the American ­Cancer Society (ACS) were presented. The BCDDP program, inspired by the breast screening initiative carried out by the Health Insur- ance Plan of Greater New York (HIP) in the 1960s, consisted of 29 mammography centers in 27 ­cities across the United States that were created to assess the feasibility of nationwide breast screening by this method. A total of 283,222 women enrolled for five annual screening examinations between 1973 and 1980. The 1977 report revealed that screening on this scale could be accomplished and that clinically occult carcinomas were detected. The program came under fire for leading to “overdiagnosis” and “overtreatment” as evidenced by the large proportion of biopsies from lesions that proved to be benign, the detection of a small number of benign lesions that were misdiagnosed as carcinoma, and treat- ment for “indolent” carcinomas that might not have become clinically apparent in the patient’s lifetime. There was also concern that radiation exposure during screening might DCIS by Any Other Name Is Still Carcinoma

xvi

Introduction

induce carcinomas at a later date, but this proved to be of less concern because in subsequent years, advances in mam- mography technology led to substantially reduced radiation exposure. Many later studies documented the feasibility of mammography screening and also confirmed that it reduced breast carcinoma deaths in the screened populations. 25–30 Encouraged by the success of breast screening and with the availability of suitable tests, screening for the detection of occult tumors in other organs such as the prostate gland and lungs was introduced, again prompting criticisms of “overdiagnosis” and “overtreatment.” 31,32 In this regard, a study that reported a reduction in deaths due to carcinoma of the lung after screening with low-dose CT scans also noted that 96.4% of “positive” screening findings did not prove to be carcinoma, resulting in a large number of diag- nostic procedures that did not benefit these individuals. 33 In March 2012, the NCI sponsored a meeting to once again address concerns that screening results in the “over- diagnosis” of cancer. A report summarizing the conclusions of the participants was published in July, 2013 34 in an article that attracted wide public attention. The authors of the re- port defined “overdiagnosis” as a diagnosis “…which occurs when tumors are detected that, if left unattended, would not become clinically apparent or cause death. Overdiagnosis, if not recognized, generally leads to overtreatment.” It was concluded that “overdiagnosis” most often occurs as a re- sult of screening when clinically asymptomatic, “indolent” cancers are likely to be detected. In this context, the authors defined “cancer” as a disease “…with a reasonable (my ­Italics) likelihood of lethal progression if left untreated.” The word “reasonable” was not defined by the authors, but pre- sumably referred to an unspecified risk that a patient would experience a fatal outcome. The authors also recommended that the word “cancer” should be dropped from what were referred to as “premalig- nant conditions” such as DCIS that should be renamed “in- dolent lesions of epithelial origin” under the acronym IDLE conditions. They suggested that this change would remove the frightening connotation associated with “cancer” and re- duce “overtreatment” by making it easier to recommend less aggressive therapy for “­indolent” lesions. In support of this position, it was argued that not all in situ carcinomas in vari- ous organs progress to an invasive stage if left untreated, as evidenced by the clinical biology of prostatic (PIN) and cer- vical (CIN) neoplasia, and that in some instances (e.g., the prostate gland) the invasive neoplasms that ultimately arise are so indolent that they pose little danger in the lifetime of the patient. A corollary of latter argument was that the cur- rent tendency to manage all in situ carcinomas with equally aggressive treatments results in the overtreatment of some patients who might not have needed the recommended therapy, and may have been harmed by it. Finally, being able to replace costly treatment with observation would reduce healthcare costs. In summary, it was suggested that simply changing the name of a disease would result in important improvements in patient well-being and save money.

Before addressing the foregoing proposal itself, it is nec- essary to comment on a matter of semantics relating to the words “cancer” and “carcinoma” as they were used by the authors of the aforementioned proposal, as well as many other authors cited among the references in this book. The online Merriam Webster Dictionary defines cancer as “a malignant tumor of potentially unlimited growth that ex- pands locally by invasion and systemically by metastasis.” Carcinoma is defined as “a malignant tumor of epithelial origin.” Thus, carcinoma refers to the subset of malignant tumors arising from epithelium, whereas cancer refers to the entire spectrum of malignant tumors, including carci- nomas, sarcomas, lymphomas, leukemias, and malignant neoplasms of the central nervous system. Regrettably, Drs. Esserman, Thompson, and Reid confused these terms throughout their paper. Although they were mainly con- cerned with “overtreatment” relating to screening-detected carcinomas arising at various sites, and pigmented skin le- sions, they repeatedly used the words cancer and carcinoma interchangeably. In the second paragraph of the article, they refer to “breast cancer and prostate cancer” when they ap- pear to mean carcinoma. The authors’ misuse of these terms is best appreciated in the following quotation from one of the summary recommendations: “First, premalignant con- ditions (eg. ductal carcinoma in situ or high-grade prostatic intraepithelial neoplasia) should not be labeled as cancers or neoplasia, nor should the word cancer be in the name.” This recommendation is meaningless because the word “cancer” already does not appear in the names of the cited lesions. It is to be hoped that Drs. Esserman, Thompson, and Reid are not seeking to deny the concept of in situ carci- noma generally, and in the breast specifically, by referring to it as a “premalignant” condition. All invasive carcinomas arise from a preinvasive stage of the disease that develops in the epithelium from which the carcinoma originates. The duration of the preinvasive stage is variable, depending on factors that are largely not known. At the histologic level, the cytologic appearance of in situ carcinoma cells is often indis- tinguishable from that of the invasive carcinoma it has given rise to. Molecular studies have shown a high level of concor- dance in the genetic alterations between these components in a given tumors that consists of DCIS and invasive ductal carcinoma, as discussed in Chapters 11 and 12, as well as Chapters 31 and 32 in the context of lobular carcinoma. Rather than denying the existence of preinvasive carcinoma, what is needed is further study to identify the molecular alterations that endow DCIS (and lobular carcinoma in situ [LCIS]) with the ability to invade and metastasize, as well as changes in the patient’s “resistance” that might enable these events to occur. Turning to the flawed proposal, which, if adopted in its current form, would probably be more harmful than beneficial, it is self-evident that changing the name of a disease would not change the disease itself. Despite some general principles that invasive carcinomas appear to have in common, such as epithelial origin and a preinvasive,