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Description

Apply a systematic pattern recognition method to achieve more accurate diagnoses with Practical Breast Pathology: A Diagnostic Approach. Using a practical, pattern-based organization, this volume in the Pattern Recognition series guides you efficiently and confidently through the evaluation of even the most challenging neoplastic and non-neoplastic specimens in breast pathology, and also highlights patterns crucial to radiologic diagnosis.

  • Consult this title on your favorite e-reader with intuitive search tools and adjustable font sizes. Elsevier eBooks provide instant portable access to your entire library, no matter what device you're using or where you're located.

  • Compare specimens to commonly seen patterns, categorize them accordingly, and turn directly to in-depth diagnostic guidance using the unique, pattern-based Visual Index at the beginning of the book.

  • Assess key pathologic and clinical aspects of both neoplastic and non-neoplastic conditions with over 530 high-quality, full-color images that help you evaluate and interpret biopsy samples.

  • Apply the latest techniques and advances in the field, including optimal processing of breast specimens for early detection of breast cancer, the latest molecular diagnosis in breast pathology, and the use of radiology in optimizing detection of breast lesions.
  • Progress logically from the histological pattern, through the appropriate work-up, around the pitfalls, and to the best diagnosis.
  • Find the information you’re looking for quickly and easily with patterns color-coded to specific entities in the table of context and text and key points summarized in tables, charts, and graphs.
  • Review all the information essential for completing a sign-out report: clinical findings, pathologic findings, diagnosis, treatment, and prognosis.
  • View key diagnostic features associated with less common conditions in a visual encyclopedia of unusual patterns at the end of the book.

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Publié par
Date de parution 29 octobre 2012
Nombre de lectures 0
EAN13 9781455733408
Langue English
Poids de l'ouvrage 7 Mo

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Exrait

Practical Breast Pathology
A Diagnostic Approach

Kristen A. Atkins, MD
Associate Professor, Director, Residency Program, Department of Pathology, University of Virginia, Charlottesville, Virginia

Christina S. Kong, MD
Associate Professor, Director, Cytopathology Service, Director, Cytopathology Fellowship, Department of Pathology, Stanford University School of Medicine, Stanford, California
Saunders
Table of Contents
Cover image
Title page
Series page
Copyright
Dedication
Contributors
Series Preface
Preface
Patterns-Based Approach to Diagnosis
Chapter 1: The Normal Breast
Normal Gross Anatomy
Normal Histology
Secondary Changes
Differential Diagnosis
Ancillary Studies
Genetics
Chapter 2: Specimen Processing
Fine Needle Aspiration Biopsy
Needle Core Biopsies
Excisional Biopsy
Margin Specimens
Reexcision Specimens
Mastectomy
Reduction Mammoplasty
Implants
Lymph Nodes
Chapter 3: Basic Breast Radiology
Imaging Evaluation of Patients
Breast Imaging Reporting and Data System
Imaging Characteristics
Biopsy Techniques: Image-Guided Biopsy Methods
Differential Diagnosis
Management after Biopsy
Conclusions
Chapter 4: Surgical Approaches to Breast Lesions
Fine Needle Aspiration Biopsy
Core Needle Biopsy
Fine Needle Aspiration or Core Needle Biopsy of Presumed Axillary Lymph Node
Excisional Biopsy
Lumpectomy
Surgery after Neoadjuvant Therapy
Mastectomy
Sentinel Lymph Node Biopsy
Axillary Dissection
Mesenchymal Lesions
Chapter 5: Juvenile Breast Lesions
Normal Growth and Development
Congenital and Developmental Abnormalities
Endocrine Disorders
Infectious/Inflammatory Lesions
Stroma-Predominant Tumors and Tumor-like Lesions
Fibroepithelial Tumors
Benign Epithelial-Predominant Tumors
Malignant Tumors
Chapter 6: Fibrosing Lesions of the Breast
Fibrocystic Changes
Sclerosing Adenosis
Sclerosing Lymphocytic Lobulitis
Pseudoangiomatous Stromal Hyperplasia
Radial Scar
Fat Necrosis
Chapter 7: Stromal Lesions/Sarcomas (Including Mixed Epithelial/Stromal, Metaplastic [Spindle Cell] Carcinoma, and Vascular)
Fibroadenoma
Phyllodes Tumor
Mammary Myofibroblastoma
Pseudoangiomatous Stromal Hyperplasia
Adenomyoepithelioma
Metaplastic Carcinoma (Spindle Cell/Sarcomatoid Carcinoma)
Hemangioma
Angiosarcoma
Primary Sarcoma Other Than Angiosarcoma
Chapter 8: Intraductal and Intralobular Proliferations
Usual Ductal Hyperplasia
Columnar Cell Lesions
Atypical Ductal Hyperplasia
Atypical Lobular Hyperplasia
Lobular Carcinoma In Situ
Ductal Carcinoma In Situ
Apocrine Lesions
Papillary Lesions
Chapter 9: Invasive Breast Carcinomas
Invasive Ductal Carcinoma, Not Otherwise Specified
Invasive Lobular Carcinoma
Tubular Carcinoma
Tubulolobular Carcinoma
Invasive Cribriform Carcinoma
Invasive Papillary Carcinoma
Invasive Micropapillary Carcinoma
Adenoid Cystic Carcinoma
Medullary Carcinoma
Neuroendocrine Carcinoma
Mucin-Producing Carcinoma
Apocrine Carcinoma
Inflammatory Carcinoma
Secretory Carcinoma
Chapter 10: Cutaneous Lesions of the Breast
Benign Melanocytic Lesions
Atypical Melanocytic Lesions
Paget Disease of the Breast
Cutaneous Involvement of Breast Cancer
Benign Adnexal Tumors
Malignant Adnexal Tumors
Atypical Vascular Lesions
Radiation Dermatitis
Silicone Mastitis
Chapter 11: Sentinel Lymph Nodes
Sentinel Lymph Node Biopsy
Macrometastatic Carcinoma
Micrometastatic Carcinoma
Isolated Tumor Cell Clusters
Chapter 12: Fine Needle Aspiration Cytology
Overview
Fibroadenoma
Fibrocystic Change
Lactational Change
Papillary Neoplasm
Adenocarcinoma
Post-therapeutic Changes
Chapter 13: Special Studies
Prognostic and Predictive Markers
Myoepithelial Markers
Lymphovascular Markers
Epithelial Markers
Markers of Ductal versus Lobular Differentiation
Markers of Breast Differentiation
Gene Expression Profiling
Acknowledgments
Index
Series page
Pattern Recognition Series
Series editors: Kevin O. Leslie and Mark R. Wick
Practical Breast Pathology
Edited by Kristen A. Atkins and Christina S. Kong
Practical Cytopathology
Edited by Matthew Zarka and Barbara Centeno
Practical Dermatopathology
Written by James W. Patterson
Practical Hepatic Pathology
Edited by Romil Saxena
Practical Pulmonary Pathology, Second Edition
Edited by Kevin O. Leslie and Mark R. Wick
Practical Renal Pathology
Edited by Donna J. Lager and Neil A. Abrahams
Practical Soft Tissue Pathology
Edited by Jason L. Hornick
Practical Surgical Neuropathology
Edited by Arie Perry and Daniel J. Brat
Copyright

1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
PRACTICAL BREAST PATHOLOGY: A DIAGNOSTIC APPROACH ISBN: 978-1-4377-0763-2
Copyright © 2013 by Saunders, an imprint of Elsevier Inc.
All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions .
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data
Practical breast pathology : a diagnostic approach / [edited by] Kristen A. Atkins, Christina S. Kong.
p. ; cm.—(Pattern recognition series)
Includes bibliographical references and index.
ISBN 978-1-4377-0763-2 (hardcover : alk. paper)
I. Atkins, Kristen A. II. Kong, Christina S. III. Series: Pattern recognition series.
[DNLM: 1. Breast Diseases. 2. Breast—pathology. WP 840]
618.1′9071—dc23
2012016928
Acquistions Editor: William R. Schmitt
Publishing Services Manager: Pat Joiner-Myers
Project Manager: Marlene Weeks
Designer: Lou Forgione
Printed in China.
Last digit is the print number: 9 8 7 6 5 4 3 2 1
Dedication
This book is dedicated to my husband, Jason, my kids, Cole and Renee, and my parents, Pope and Joan, for their endless support and humor. It is also in honor of my aunts and my best friend who are closer to the subject matter than anyone cares to be, and to the memory of my mother-in-law. And of course to my co-editor, Christina, my far away buddy.

Kristen A. Atkins
To my father for all he has taught me.

Christina S. Kong
Contributors

Kristen A. Atkins, MD
Associate Professor Director, Residency Program Department of Pathology University of Virginia Charlottesville, Virginia

Catherine Barry, DO
Attending Pathologist Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles, California

Gerald J. Berry, MD
Professor Department of Pathology Director, Surgical Pathology Fellowship Stanford University School of Medicine Stanford, California

David R. Brenin, MD
Chief, Breast Surgical Services Co-Director, University of Virginia Breast Center Department of Surgery University of Virginia Health Center Charlottesville, Virginia

Yunn-Yi Chen, MD, PhD
Professor Director, Immunohistochemistry Laboratory Department of Pathology University of California at San Francisco San Francisco, California

Florette K. Gray Hazard, MD
Assistant Professor Director, Pediatric Surgical Pathology Departments of Pathology and Pediatrics Stanford University Stanford, California

Kristin C. Jensen, MD
Assistant Professor Department of Pathology Stanford University School of Medicine Stanford, California; Assistant Service Chief and Associate Director of Cytopathology Veterans Affairs Palo Alto Health Care System Palo Alto, California

Richard L. Kempson, MD
Emeritus Professor Department of Pathology Stanford University School of Medicine Stanford, California

Jonathan M. Kitayama, MD
Department of Pathology Stanford University School of Medicine Stanford, California

Christina S. Kong, MD
Associate Professor Director, Cytopathology Service Director, Cytopathology Fellowship Department of Pathology Stanford University School of Medicine Stanford, California

Teri A. Longacre, MD
Professor Department of Pathology Director, Gynecologic and Breast Pathology Fellowship Stanford University School of Medicine Stanford, California

Amy Ly, MD
Instructor Department of Pathology Harvard Medical School; Associate Pathologist Department of Pathology Brigham and Women’s Hospital Boston, Massachusetts

Jesse K. McKenney, MD
Associate Professor Department of Pathology Stanford University Medical Center Stanford, California

Brandi Tamara Nicholson, MD
Department of Radiology Division of Breast Imaging University of Virginia Health System Charlottesville, Virginia

James W. Patterson, MD
Division of Surgical Pathology and Cytopathology University of Virginia Health System Charlottesville, Virginia

Yan Peng, MD, PhD
Associate Professor Medical Director, Immunohistochemistry Laboratory and Image and In Situ Hybridization Analysis Laboratory Department of Pathology University of Texas Southwestern Medical Center; Department of Pathology Parkland Health and Hospital System Dallas, Texas

William M. Rogers, MD
Department of Anatomic Pathology El Camino Hospital Mountain View, California

Anneke T. Schroen, MD, MPH
Department of Surgery University of Virginia Health System Charlottesville, Virginia

Matt van de Rijn, MD, PhD
Professor Department of Pathology Stanford University Medical Center Stanford, California
Series Preface

It is often stated that anatomic pathologists come in two forms: “Gestalt”-based individuals, who recognize visual scenes as a whole, matching them unconsciously with memorialized archives, and criterion-oriented people, who work through images systematically in segments, tabulating the results—internally, mentally, and quickly—as they go along in examining a visual target. These approaches can be equally effective, and they are probably not as dissimilar as their descriptions would suggest. In reality, even “Gestaltists” subliminally examine details of an image, and, if asked specifically about particular features of it, they are able to say whether one characteristic or another is important diagnostically.
In accordance with these concepts, in 2004 we published a textbook entitled Practical Pulmonary Pathology: A Diagnostic Approach (PPPDA). That monograph was designed around a pattern-based method, wherein diseases of the lung were divided into six categories on the basis of their general image profiles. Using that technique, one can successfully segregate pathologic conditions into diagnostically and clinically useful groupings.
The merits of such a procedure have been validated empirically by the enthusiastic feedback we have received from users of our book. In addition, following the old adage that “imitation is the sincerest form of flattery,” since our book came out other publications and presentations have appeared in our specialty with the same approach.
After publication of the PPPDA text, representatives at Elsevier, most notably William Schmitt, were enthusiastic about building a series of texts around pattern-based diagnosis in pathology. To this end we have recruited a distinguished group of authors and editors to accomplish that task. Because a panoply of patterns is difficult to approach mentally from a practical perspective, we have asked our contributors to be complete and yet to discuss only principal interpretative images. Our goal is eventually to provide a series of monographs which, in combination with one another, will allow trainees and practitioners in pathology to use salient morphological patterns to reach with confidence final diagnoses in all organ systems.
As stated in the introduction to the PPPDA text, the evaluation of dominant patterns is aided secondarily by the analysis of cellular composition and other distinctive findings. Therefore, within the context of each pattern, editors have been asked to use such data to refer the reader to appropriate specific chapters in their respective texts.
We have also stated previously that some overlap is expected between pathologic patterns in any given anatomic site; in addition, specific disease states may potentially manifest themselves with more than one pattern. At first, those facts may seem to militate against the value of pattern-based interpretation. However, pragmatically, they do not. One often can narrow diagnostic possibilities to a very few entities using the pattern method, and sometimes a single interpretation will be obvious. Both of those outcomes are useful to clinical physicians caring for a given patient.
It is hoped that the expertise of our authors and editors, together with the high quality of morphologic images they present in this Elsevier series, will be beneficial to our reader-colleagues.

Kevin O. Leslie, MD

Mark R. Wick, MD
Preface
When Mark Wick and Kevin Leslie approached us to edit the breast book for the pattern-based series, we were excited to take on the challenge of putting together a book based on patterns that reflects the way we practice pathology. A pattern-based approach allows an entity to be placed in a general diagnostic category on the basis of assessment from scanning magnification. Then more specific features identified on higher magnification assist in rendering a more definitive diagnosis. Breast pathology lends itself nicely to a pattern-based approach since the basic terminal duct lobular unit is either maintained or lost and the stromal component is normal, increased, or replaced in the majority of the lesions.
We asked all contributing authors to focus on problematic areas and to offer ways to handle cases when the diagnosis is uncertain. This book is written for residents and practicing pathologists, with an emphasis on lesions that have overlapping morphologic patterns. Because benign and malignant breast lesions can often mimic one another, this book is intended to be a lifeline for pathologists when faced with those problematic lesions.
We also included chapters on radiology and breast surgery because understanding the radiographic findings and surgical approach is critical to evaluating breast specimens. The ability to correlate radiographic with pathologic findings is paramount to good patient care. The radiology chapter is organized like a teaching seminar, and we hope the reader will learn a great deal from this easy-to-read chapter.
Documentation of tissue processing is becoming increasingly complicated, with ancillary diagnostics and College of American Pathologists requirements for minimum and maximum fixation times. These requirements, along with guidelines on how much tissue to submit for different specimen types, are addressed in the specimen-processing chapter. Newer molecular assays are also being marketed by commercial laboratories, and the question arises as to whether these assays provide more prognostic information than what is already obtained by testing for estrogen and progesterone receptors and HER2. The chapter on special studies provides an overview of currently available tissue-based assays that are prognostically useful and influence treatment.
We both enjoy the process of taking complex topics and parceling them into understandable pieces. This is in large part due to the influence of our mentor—Dr. Richard Kempson, MD—a master at creating clarity in murky areas. We hope this book delivers useful information to pathologists in a helpful and practical manner.

Acknowledgments
We are grateful to the contributing authors for working with us on this project and for fitting it in with their myriad of responsibilities.
We are also indebted to Norm Cyr and Anet James for their expert assistance with optimizing the photomicrographs and with the creation of illustrations. Norm Cyr is the Digital Image Specialist in the Department of Pathology at Stanford University. Anet James previously held this position and is now living in Natick, MA, where she is freelancing as a Scientific Image Specialist ( www.anetjames.com ). They are both wonderful artists, as can be seen with the illustrations by Norm in Chapters 1 ( Figs. 1-2 and 1-5 ) and 2 ( Fig. 2-4 ), and by Anet in Chapters 2 ( Fig. 2-1 ) and 5 ( Fig. 5-1 ).
A special thank you goes to Peggy Gordon and Nancy Lombardi at P. M. Gordon Associates and William Schmitt at Elsevier for their gentle nudging and shepherding of the project. Without their assistance, this book would never have been completed.

Kristen A. Atkins, MD

Christina S. Kong, MD
Patterns-Based Approach to Diagnosis
A wide variety of lesions can occur in the breast, but the majority can be parceled into a handful of patterns. Given the basic anatomy of the ducts, terminal duct lobular units, and surrounding fat and stroma, recognizing the retention of normal breast compartments versus distortion or complete loss of architecture can aid the pathologist greatly. Needle core biopsies, which are limited samples that offer a narrow view of the process, can be especially challenging, and identifying the pattern can aid the pathologist in placing the sample in the correct diagnostic category. Correlation of the pathology results with the radiographic findings is crucial, particularly for benign diagnoses, requiring the radiologist to assess whether the biopsy definitively accounts for the imaging findings. Using a patterns-based approach assists the pathologist in considering both benign and malignant processes in the differential diagnosis.
Pattern Entities to be Considered Stroma Predominant

Pseudoangiomatous stromal hyperplasia
Scar
Hamartoma
Diabetic mastopathy
Fibrocystic changes
Phyllodes tumor
Metaplastic carcinoma
Fat necrosis
Periductal stromal tumor
Fibromatosis
Solitary fibrous tumor
Spindle cell lipoma Mixed Stroma and Epithelial

Sclerosing adenosis
Radial scar
Fibrocystic changes
Fibroadenoma
Phyllodes tumor
Tubular carcinoma
Metaplastic carcinoma Infiltrative

Sclerosing adenosis
Microglandular adenosis
Carcinomas
Sarcomas
Granular cell tumor
Vascular lesions
Fat necrosis Nodular

Fibroadenoma
Phyllodes tumor
Periductal stromal tumor
Hamartoma
Tubular adenoma
Mucinous carcinoma
Medullary carcinoma
Lymph node Intraductal

Papilloma
Apocrine metaplasia
Hyperplasia
Atypical ductal hyperplasia
Ductal carcinoma in situ
Lactational change
Columnar cell change
Flat epithelial atypia
Clinging carcinoma
Radiation changes Intralobular

Atypical lobular hyperplasia
Lobular carcinoma in situ
Cancerization of the lobules by ductal carcinoma in situ
Collagenous spherulosis
Columnar cell change

Pattern 1 Stroma Predominant


Elements of the pattern: The usual fat and terminal duct lobular units in the breast biopsy are replaced or displaced by spindle cells.
Additional Findings Diagnostic Considerations Chapter/Page Slitlike spaces

Pseudoangiomatous stromal hyperplasia
Vascular lesions Ch5:73; Ch6:90; Ch7:100Ch7:107; Ch10:221 Mitoses easily identified

Phyllodes tumor
Metaplastic carcinoma Ch5:77; Ch7:95Ch7:105; Ch9:152 Interspersed fat

Fibromatosis
Hamartoma
Fat necrosis
Metaplastic carcinoma Ch5:74; Ch7:106Ch5:75; Ch7:94Ch5:70; Ch6:91Ch7:105 Keloid-like collagen

Scar
Fibromatosis
Solitary fibrous tumor
Hyalinized fibroadenoma
Diabetic mastopathy Ch6:89Ch5:74; Ch7:106Ch7:100Ch5:76; Ch7:93Ch5:68; Ch6:89 Periductal lymphocytes

Diabetic mastopathy Ch5:68; Ch6:89

Pattern 2 Mixed Stroma and Epithelial


Elements of the pattern: The normal fat is replaced by spindle cells with interspersed epithelial cells in the form of terminal duct lobular units, isolated ducts, nests of cells, or single epithelial cells.
Additional Findings Diagnostic Considerations Chapter/Page Lobular architecture with maintained terminal duct

Sclerosing adenosis
Fibrocystic change
Diabetic mastopathy Ch6:88; Ch9:151Ch6:87Ch6:89 Distorted, variably sized, elongated ducts

Radial scar
Fibroadenoma
Fibrocystic changes
Sclerosed papilloma
Metaplastic carcinoma Ch6:90Ch5:76; Ch7:93Ch6:87Ch8:140Ch7:105; Ch9:152 Numerous, well formed, small ducts

Fibroadenoma
Tubular adenoma
Tubular carcinoma Ch5:76; Ch7:93Ch5:80Ch6:90; Ch9:165 Tiny, compressed ducts

Sclerosing adenosis Ch6:89; Ch9:151 Single cells

Sclerosing adenosis
Invasive lobular carcinoma
Metaplastic carcinoma Ch6:88; Ch9:151Ch9:157Ch7:105; Ch9:152

Pattern 3 Infiltrative


Elements of the pattern: Single cells and strands of cells percolate through the breast tissue. As opposed to the mixed stroma and epithelial pattern, the stroma is a minor component of the process.
Additional Findings Diagnostic Considerations Chapter/Page Tiny glands

Sclerosing adenosis
Microglandular adenosis
Invasive carcinoma Ch6:88; Ch9:151Ch9:166Ch9:147 Eosinophilic, granular cytoplasm

Invasive carcinoma
Granular cell tumor
Histiocytes of fat necrosis Ch9:201Ch9:161Ch6:91; Ch9:201 Epithelial cell atypia

Carcinomas
Sarcomas Ch9:169Ch7:114 Loss of the terminal duct lobular unit architecture

Microglandular adenosis
Invasive carcinomas Ch9:166Ch9:169

Pattern 4 Nodular


Elements of the pattern: The stroma or epithelial proliferation forms a well-circumscribed nodule. On core biopsy, the interface between the tumor and normal breast tissue may not be apparent if the core consists of tumor only.
Additional Findings Diagnostic Considerations Chapter/Page Condensation of stromal cells under the epithelium

Phyllodes Ch5:77; Ch7:95 Large cystic spaces

Fibroadenoma
Phyllodes Ch5:76; Ch7:93Ch5:77; Ch7:95 Stromal nodules around terminal duct lobular units

Periductal stromal tumor
Fibroadenoma Ch7:96Ch5:76; Ch7:93 Dense collection of lymphocytes

Intramammary lymph node
Medullary carcinoma Ch9:184 Extracellular or stromal mucin

Mucinous carcinoma
Fibroadenoma
Mucocele Ch9:182Ch5:76; Ch7:93Ch9:194 Interspersed fat

Hamartoma Ch5:75; Ch7:94 Numerous ducts

Tubular adenoma
Fibroadenoma
Sclerosing adenosis
Papilloma
Papillary carcinoma Ch5:80Ch5:76; Ch7:93Ch6:88; Ch9:151Ch8:140Ch9:178

Pattern 5 Intraductal


Elements of the pattern: The lesion maintains the contours of the large (terminal) ducts and a surrounding layer of myoepithelial cells.
Additional Findings Diagnostic Considerations Chapter/Page Fibrovascular cores

Papilloma Ch8:140 Distinct cell membranes

Ductal carcinoma in situ
Atypical ductal hyperplasia
Papilloma
Lactational change
Apocrine metaplasia Ch8:135Ch8:127Ch8:142Ch1:6; Ch12:263Ch8:139 Apical snouts

Apocrine metaplasia
Columnar cell change
Flat epithelial atypia Ch8:139Ch8:123Ch8:124 Prominent nucleoli

Apocrine metaplasia
Ductal carcinoma in situ
Lactational change
Flat epithelial atypia Ch8:139Ch8:145Ch1:6; Ch12:263Ch8:124 Vacuolated cytoplasm

Lactational change
Radiation change Ch1:6; Ch12:263Ch1:8 Single layer of cells with marked cytologic atypia

Clinging carcinoma
Radiation atypia Ch8:137Ch1:8 Haphazard “flip-flop” orientation of cells

Papilloma
Usual ductal hyperplasia Ch8:140Ch8:121 Slitlike spaces in the cell clusters

Usual ductal hyperplasia
Atypical ductal hyperplasia
Papilloma Ch8:121Ch8:127Ch8:140

Pattern 6 Intralobular


Elements of the pattern: The normal lobular unit is filled and sometimes expanded by cells or secretions.
Additional Findings Diagnostic Considerations Chapter/Page Filling of lobular units by cells

Atypical lobular hyperplasia
Lobular carcinoma in situ
Cancerization of the lobule by ductal carcinoma in situ Ch8:130Ch8:131Ch8:132 Secretions in the lobule

Collagenous spherulosis
Columnar cell change Ch8:135; Ch9:173Ch8:123
1 The Normal Breast

Jonathan M. Kitayama, MD, Teri A. Longacre, MD

Normal Gross Anatomy
Normal Histology
Menstrual Cycle
Pregnancy and Lactation
Menopause
Male Breast
Secondary Changes
Pregnancy-like (Pseudolactational) Change
Gynecomastia and Gynecomastia-like Change
Radiation
Chemotherapy
Hormonal Effects
Differential Diagnosis
Pregnancy-like Hyperplasia versus Cystic Hypersecretory Lesions
Myoepithelial Cell Prominence versus Lobular Neoplasia
Intraepithelial Clear Cells versus Paget Disease
Toker Cells versus Paget Cells/Disease
Gynecomastoid Changes versus Atypical Ductal Hyperplasia
Atrophy versus Invasive Ductal Carcinoma
Ancillary Studies
Genetics
The human breast is a relatively mutable organ due to the effects of the fluctuating hormonal milieu throughout the female life cycle. Breast parenchymal tissue is normally inactive until puberty but undergoes a series of sequential changes during the menstrual cycle. The tissue reaches its largest growth during pregnancy, at which time it provides a source of nourishment and immunologic protection for the nursing newborn. Ultimately, the breast parenchymal tissue regresses at menopause.
Prior to puberty, breast development is the same in both boys and girls. The human mammary glands begin to develop in the sixth week of gestation, following formation of the bilateral mammary ridges (known as milk lines), which extend from the axilla to the groin. 1, 2 Except for the breast placodes in the midpectus, the majority of the ridges do not develop and ultimately disappear during fetal development. Persistence of these segments gives rise to accessory nipples or ectopic breast tissue, which may develop anywhere along the milk lines, 1, 2 most commonly in the axilla or vulva. 2 The early stages of breast development are largely independent of the influence of sex steroid hormones. Only after the 15th week of gestation is the breast sensitive to testosterone, which triggers formation of the breast bud. Subsequently epithelial columns develop within this mesenchyme, giving rise to the eventual lobules. Myoepithelial cells develop between weeks 23 and 28. 2 The fetal papillary dermis encases the developing cords and gives rise to the fibrous connective tissue. Portions of the mesenchyme eventually differentiate into fat by weeks 20 to 32. In the last 8 weeks, the cords branch and canalize. The epidermis depresses, forming the lactiferous ducts, and the nipple forms by evagination of the mammary pit at the time of birth. Only in the last few weeks of gestation does the mammary gland become responsive to maternal and placental steroid hormones, resulting in secretory changes. With the withdrawal of steroid hormones, colostrum is secreted under the control of prolactin, and the breast buds become enlarged. When the level of steroid hormones such as prolactin decreases secretory activity declines, and the glands regress and remain inactive until puberty. 1, 2
At puberty, the female breast ducts elongate, branch, and develop thickened epithelium under the influence of estrogen ( Fig. 1-1 ). Although lobuloalveolar differentiation and growth are enhanced by insulin, progesterone, and growth hormone, 1 the development of the terminal duct lobular unit (TDLU) is largely driven by estrogen. Besides the ducts, there is an increase in the density of the periductal connective tissue and stromal adipose tissue, also under the influence of estrogen; the latter changes are responsible for the increase in size of the breast. This proliferation and maturation begin in the center of the breast parenchyma and proceed toward the periphery, extending into the axilla. During the menstrual cycles, progesterone promotes lobuloacinar and connective tissue growth. The bulk of breast development occurs during puberty and continues into the third decade. However, only pregnancy induces terminal differentiation of the breasts. 1

Figure 1-1 Adolescent breast has immature terminal duct lobular units with minimal duct branching. Acini develop after puberty.

Normal Gross Anatomy
The breasts are modified skin appendage glands located on the anterior chest wall overlying the pectoralis muscle. They extend from the second to sixth rib vertically and from the sternal edge to the midaxillary line, laterally. The breast tissue lies within the superficial fascia, which is continuous with the fascia superiorly and the superficial abdominal fascia of Cooper inferiorly. Generally, the breast is well demarcated on its deep aspect against the pectoralis muscle, but occasionally accessory tissue can be found extending into the pectoralis and axilla.
The mass of the female breast is influenced by individual body habitus but generally ranges from 30 to 100 grams. In the adult female, the breast is composed of a series of ducts, ductules, and lobuloacinar units that are embedded in a stroma of fibrous and adipose tissue. The bulk of the breast mass is composed of stroma, which varies in its fibrous and adipose components based on body habitus and the age of the individual. For example, the stroma tends to be dense at puberty and gradually becomes more adipocytic with age. 1, 3
The duct lobular system is arranged to form segments or lobules. There are no obvious boundaries or anatomical landmarks to separate the anatomic lobes or segments of the breast. 1 Segments consist of hierarchical branching structures that terminate in the lobules. Below the nipple are the ducts that coalesce to form the lactiferous sinuses, which terminate into the ampullae located below the surface of the nipple. There are 15 to 20 ductal orifices on the nipple surface, suggesting that 20 or so ductal systems or lobules make up the breast. 1, 4 In recent years, this has been a subject of debate; mammary duct injection studies have suggested that there are only 5 to 10 discrete breast ductal systems or segments.
The nipple-areola complex is the circular area of the skin that exhibits increased skin pigmentation and increased sensory nerve endings. The nipple itself is generally elevated from the areola and contains the orifices that open to the skin. Rarely, small hypopigmented macules or papules may be present due to increased numbers of normally occurring Toker cells.

Normal Histology
It is important to recognize and understand the organization and histology of the ductal lobular system because it is often the basis for distinguishing benign from malignant lesions of the breast. 1, 4 In addition, a general knowledge of normal structure informs the distribution of various pathologic abnormalities ( Fig. 1-2 ). The hallmark of the terminal duct lobular system is the bilayered nature of the ductal lobular system. The two-layer system is composed of an inner (luminal) epithelial cell layer, which is involved in producing secretions, and an outer (basal) layer of myoepithelial cells that contract and push out the secretions ( Fig. 1-3 ). Histologically, the luminal epithelial cells are cuboidal to columnar in shape, with pale eosinophilic cytoplasm and uniform oval nuclei. The basal myoepithelial cells are often inconspicuous but may show clear or pale cytoplasm, particularly during the second phase of the menstrual cycle ( Fig. 1-4 ).

Figure 1-2 This schematic of normal female breast duct elements depicts the site of origin for major breast abnormalities discussed in this book. Most hyperplasias (ductal and lobular) arise in the terminal duct lobular unit ( inset ), as do most carcinomas (see Fig. 1-5 ). Because the terminal duct lobular units are concentrated in the deep central portions of the breast, peripheral carcinomas are uncommon. Similarly, duct ectasia, nipple adenoma, and most single solitary papillomas arise within the immediate vicinity of the nipple.

Figure 1-3 A, Intermediate-power view of ducts and acini displaying the typical bilayer cell population: outer, myoepithelial cells and inner, luminal cells. B, High-power view displaying the bilayer cell population of the breast ducts: outer, myoepithelial cells and inner, luminal cells. Secretory snouts may or may not be present. Dense eosinophilic intraluminal material is often seen in the proliferative phase of the menstrual cycle.

Figure 1-4 High-power view showing the variable appearance of myoepithelial cells with clear cytoplasm. This change is most prominent in the secretory phase of the menstrual cycle.
The ductal lobular system is contained and surrounded by a basal lamina composed of type IV collagen and laminin. Beyond the basal lamina, the extralobular ducts are surrounded by fibroblasts and capillaries. Within the stroma, there are elastic fibers, which increase in number with age. The lobule, in combination with the terminal duct, is referred to as the TDLU, which is the structural and functional unit of the breast. The TDLU is responsible for breast secretions during lactation and gives rise to various pathologies including cysts, duct epithelial hyperplasia without/with atypia, and ductal carcinoma ( Fig. 1-5 ). 1, 3

Figure 1-5 Schematic of normal female breast terminal duct lobular unit (TDLU) ( A ), fibrocystic change ( B ), fibroadenoma ( C ), sclerosing adenosis ( D ), intraductal epithelial hyperplasia ( E ), and atypical lobular hyperplasia ( F ), which depicts alterations that occur within the TDLU that are discussed elsewhere in this book. The TDLU is a discrete, rounded, or ovoid structure that is surrounded by more dense fibroconnective tissue (extralobular stroma) than is seen within the TDLU (intralobular stroma). The individual acini are uniform in size and shape and lined by two cell layers—outer myoepithelial and inner epithelial. Alterations in the TDLU (e.g., increased size of acini [cysts], increased intralobular stromal fibrosis with irregular or compressed acini [fibroadenoma or sclerosing adenosis], and increased cell layers [ductal or lobular epithelial proliferation]) are responsible for the majority of pathology in the female breast.
The general arrangement of the lobule consists of a variable number of blind-ending terminal ductules referred to as acini, which are invested in a loose, fibrovascular intralobular stroma (see Fig. 1-5 ; Figs. 1-6 to 1-8 ). Within the stroma, there are variable numbers of inflammatory cells: lymphocytes, plasma cells, macrophages, and mast cells. Intralobular stroma differs from the surrounding interlobular stroma, which is highly collagenized, paucicellular, and contains adipose tissue. The overall size of the lobules and number of acini are variable. Russo and Russo describe four general lobule types ( Table 1-1 ). 5 Type 1 lobules are the most rudimentary and are seen in prepubertal and nulliparous women. These lobules eventually mature into type 2 and 3 lobules, which are characterized by the development of additional alveolar buds. Type 3 lobules are most prevalent in parous and premenopausal women. Type 4 lobules are seen in women who are pregnant or lactating. 1, 2

Figure 1-6 The normal reproductive age female breast contains well-developed terminal duct lobular units that connect with extralobular ducts. The low-power appearance consists of rounded, smoothly contoured lobules set in dense fibrous connective tissue stroma.

Figure 1-7 Low-power view of normal reproductive age terminal duct lobular units with extralobular duct at left.

Figure 1-8 Intermediate-power view of the terminal duct lobular units showing the intralobular ducts and acini. The intralobular stroma is loose and contains scattered mononuclear cells. This is the typical appearance of breast lobules during the proliferative phase of the menstrual cycle.

Table 1-1 Types of Breast Lobules
Both the nipple and areola are covered by keratinizing squamous epithelium, which extends for a short distance down the lactiferous duct ( Fig. 1-9 ). Careful microscopic examination of the nipple epithelium occasionally shows cells with clear to pale cytoplasm; these cells represent Toker cells, which are benign and should not be confused with those found in Paget disease ( Figs. 1-10 and 1-11 ). 6, 7 Toker cells can be found in up to 11% of normal nipples. 1 The distribution of Toker cells is usually limited to the nipple, but they can also be seen in accessory nipples, pubic regions, or anywhere in the milk line distribution. 8

Figure 1-9 Low-power view of the nipple showing keratinizing squamous epithelium, sebaceous glands, and ducts.

Figure 1-10 Intermediate-power view of the nipple with clear cells (Toker cells) located primarily in the basal epidermis.

Figure 1-11 High-power view of scattered nipple clear (Toker) cells.
The ducts in the dermis have a pleated or serrated contour and are surrounded by abundant stroma composed of smooth muscle bundles, collagen, and elastic fibers. While the nipple-areolar complex generally lacks pilosebaceous units and hairs, except at the periphery of the areola, periareolar ducts often form pilosebaceous structures. The dermis contains numerous sebaceous glands, which open directly to the surface of the nipple and areola or into the lactiferous duct. Other glands such as apocrine sweat glands may also be seen in the dermis of the nipple and areola. 1

Menstrual Cycle
The lobules are responsive to hormones during the menstrual cycle and exhibit morphologic changes in both the epithelial and stromal components ( Table 1-2 ). 9 – 11 In brief, the intralobular stroma is dense and cellular in the early follicular phase and becomes looser and more edematous in the late luteal phase. During the follicular phase, the epithelial component is crowded, and cells are poorly oriented with little or no lumina (days 3 to 7). Mitoses are prominent, and the myoepithelial cells are inconspicuous. Progression through the menstrual cycle results in the myoepithelial cells becoming more apparent in the luteal phase (days 15 to 20); in addition, the lumens become more prominent and filled with secretions. In the menstrual phase (days 1 to 3 and 28 to 30), the breast stroma and glands return to baseline. These changes are not as dramatic compared to those seen in pregnancy. 1, 2

Table 1-2 Morphologic Changes during the Menstrual Cycle

Pregnancy and Lactation
Breasts reach full development during pregnancy. During pregnancy, epithelial cell proliferation resumes, with significant increases in the number of lobules and acinar units within each lobule. These changes are largely under the influence of estrogen, progesterone, prolactin, and growth hormone. Other hormones that contribute to the growth process are those produced by the adrenal glands and insulin. The increase in lobular size comes at the expense of the intralobular and extralobular stroma. At the end of the first trimester, the breasts are grossly enlarged with superficial venous dilatation and increased pigmentation of the areola. 1 With each successive pregnancy, there is the recruitment of more and more lobules. 2
Progressing through the second and third trimester, there is continued lobular growth, causing the acinar units to appear monolayered due to the epithelial growth; the myoepithelial cells become increasingly difficult to discern. The epithelial cells become vacuolated, and secretions accumulate in the expanded lumens. Once parturition occurs, the breast shows lactational changes characterized by distention of the lobular acini due to the accumulation of increased secretory material and increased cytoplasmic vacuolization. The luminal epithelial cells have a bulbous or hobnail appearance as they protrude into the lumina, and the myoepithelial cells remain inconspicuous. Breast growth may result in the formation of palpable and radiologically detectable masses as a consequence of localized adenomatous lactational hyperplasias, which may be of concern during pregnancy. These lactational adenomas are detected generally in the third trimester. 2
Once lactation ceases, the lobules involute and return to their normal resting state. The lobules appear irregular and often are infiltrated by lymphocytes and plasma cells.

Menopause
In the postmenopausal period, due to the reduction in estrogen and progesterone, the TDLUs involute and atrophy, resulting in the reduction in size and complexity of the acini. The specialized intralobular stroma is lost, resulting in the reduction in glandular tissue and collagenous stroma with an inverse increase in adipose tissue ( Fig. 1-12 ). At the end of menopause, the remnant TDLUs consist of atrophic acini surrounded by hyalinized connective tissue embedded in adipose tissue with no intralobular stroma (see Fig. 1-12 ; Fig. 1-13 ).

Figure 1-12 A, Low-power view of breast tissue in a postmenopausal female. The lobules are small and atrophic. B, Intermediate-power view of breast tissue in a postmenopausal female depicting isolated, atrophic ducts surrounded by adipose tissue.

Figure 1-13 Breast tissue in a postmenopausal female is characterized by atrophic ducts surrounded by dense fibrous stroma. Note minimal branching.

Male Breast
Like the female breast, the male breast is composed of a nipple and rudimentary branching duct system composed of glandular epithelial elements in a stroma of collagen and adipose tissue. However, in contrast to the female breast, there is no lobule formation. The male breast is susceptible to the same disease entities that occur in the female breast (e.g., invasive carcinoma and carcinoma in situ), although at lower incidences. 1, 3 In addition, the male breast is subject to hypertrophic changes induced by estrogenic hormone stimulation (see “ Gynecomastia and Gynecomastia-like Change ”).

Secondary Changes

Pregnancy-like (Pseudolactational) Change
It is not uncommon for breast lobules to exhibit lactational or even hypersecretory change in the absence of recent pregnancy or lactation, even in the postmenopausal setting. Partial or complete involvement of one or more lobules may be seen ( Fig. 1-14 ). In most instances this change is focal, but in some cases there may be marked clearing of the cytoplasm within acinar cells. Both patterns may be present simultaneously. These foci often contain enlarged, vacuolated, pleomorphic, and hobnail cells that may be confused with neoplastic cells, but nuclear features of malignancy are absent. 12 The voluminous cytoplasm is pale to clear and finely granular or vacuolated ( Fig. 1-15 ). Intraluminal secretions may accumulate and result in distinctive laminated microcalcifications, which can be detected on mammography and thus biopsied. 13 The appearance of these laminated microcalcifications is reminiscent of corpora amylacea in the prostate and lung, Hormonal, antipsychotic, and antihypertensive medications have been associated with lactational change in some patients. 14 In others, it is likely that these focal pregnancy-like changes indicate a selective susceptibility of the mammary glandular tissue to estrogen and represent a normal histologic variant. An underlying occult, endogenous hormonal dysfunction is exceedingly rare. Despite the apparent morphologic and biochemical similarity to lactational change, ultrastructural studies suggest that these pregnancy-like changes represent a combination of both secretory and involutional alterations. 12

Figure 1-14 Low-power view of a breast in a pregnant female showing expanded terminal duct lobular units with luminal secretions and vacuolated cytoplasm. The intralobular stroma is inconspicuous due to terminal duct expansion.

Figure 1-15 Lactational changes are characterized by luminal secretions, vacuolated, slightly frothy cytoplasm, and hobnail nuclei.

Gynecomastia and Gynecomastia-like Change
Gynecomastia typically manifests as a unilateral or bilateral tender palpable breast mass. Mammographically, gynecomastia appears as a triangular soft-tissue density that emanates from the nipples and extends posteriorly. The density has the appearance of normal glandular tissue, and this is largely confirmed on microscopic examination. Varying combinations of stromal or ductular prominence may be seen. The ducts exhibit a characteristic pseudopapillary epithelial proliferation, which may feature hyperchromatic nuclei surrounded by concentric fibrosis; lobular development is absent ( Fig. 1-16 ). The surrounding stroma also exhibits a characteristic basophilic myxoid change. Most cases of gynecomastia in young adolescent boys are considered physiologic or idiopathic and resolve within 6 to 18 months (sometimes 2 years). The etiology is usually postulated as an imbalance between estrogen and androgen, along with issues involving end-organ response to hormonal changes.

Figure 1-16 Gynecomastia. This high-power view shows dilated duct with epithelial proliferation. The luminal contour is irregular due to the hobnail effect of the luminal cells. The stroma surrounding the duct is either slightly myxoid and edematous or fibrotic, as depicted here.
Gynecomastia-like change in the female breast has a similar appearance. 15 Although gynecomastia in the male breast almost always presents as a mass, gynecomastia-like change may be incidental. Ducts with papillary hyperplasia but without lobule formation are seen scattered in a myxoid stroma, occasionally raising the differential diagnosis of intraductal micropapillary carcinoma or atypical ductal hyperplasia ( Fig. 1-17 ). Gynecomastia-like change has been recognized in women with and without a known hormonal imbalance.

Figure 1-17 Atypical duct configurations in gynecomastoid change can be misinterpreted as atypical ductal hyperplasia. The clinical setting, absence of lobular development in the male, and minimal epithelial stratification provide clues to the nature of the process.

Radiation
The long-term effect of radiation on breast tissue evolves over a period of months to years. 16 The range differs among individuals, but the majority develop firmness and/or sclerosis of the breast, which tends to be mild in most cases. Ptosis, which is a natural change of aging, is less pronounced in individuals receiving radiation therapy. Areas under the radiation field will display cutaneous atrophy and telangiectasia ( Fig. 1-18 ). The majority of changes occur in the TDLUs. These changes include collagenization of intralobular stroma and thickening of periacinar and periductular basement membranes, as well as severe atrophy of acinar and ductular epithelium ( Fig. 1-19 ). Cytologic atypia develops in the residual epithelium and myoepithelial cells ( Fig. 1-20 ). The myoepithelial cells are more preserved compared with the epithelial cells ( Fig. 1-21 ). Vacuolization of the cytoplasm can be seen ( Fig. 1-22 ). Within the interlobular stroma, atypical fibroblasts may be apparent. The larger ducts are more resistant to the effects of radiation. 16

Figure 1-18 Radiation change. Skin overlying breast parenchyma is atrophic, and there is stromal fibrosis with dilated vessels.

Figure 1-19 Radiation change. This low-power view of breast parenchyma demonstrates postradiation atrophic lobules and stromal fibrosis.

Figure 1-20 Radiation change. This high-power view of breast parenchyma depicts enlarged nuclei and prominent nucleoli in epithelial and myoepithelial cells. Despite the nuclear enlargement, the overall nuclear-to-cytoplasmic ratio is maintained. Often the cytoplasm is vacuolated.

Figure 1-21 Radiation change. This high-power view of radiated breast parenchyma shows luminal cells with enlarged nuclei and prominent nucleoli but maintained nuclear-to-cytoplasmic ratios.

Figure 1-22 Radiation change. This high-power view of ducts in a radiated breast highlights the cytoplasmic vacuolization of normal duct epithelial cells.
Use of radioactive implants or external boosts may lead to more severe changes in the breast compared with the surrounding areas. Fat necrosis and atypical fibroblasts are seen in the areas closest to the radiation exposure. Radiation-induced vascular changes appear more prominent in the areas of the boost and are characterized by endothelial atypia and myointimal proliferation with vascular sclerosis. The presence of cytologic atypia can present diagnostic challenges, even when the history of radiation treatment is known. 16

Chemotherapy
Chemotherapy treatment can have various effects on the normal breast parenchyma; these are most commonly encountered in the setting of neoadjuvant chemotherapy for locally advanced or inflammatory carcinoma. Histologic findings related to chemotherapy correlate with the extent of clinical response. Changes induced by chemotherapy appear to be similar between the primary tumor and nodal metastases. The most significant alterations are observed in those patients who clinically appear to have complete resolution of tumor.
The most significant change associated with chemotherapy effect is decrease in tumor cellularity. In patients who have responded, the tumor often appears infarcted and necrotic; if sufficient time has elapsed between treatment and biopsy, the degenerated tumor may be absorbed or there may be no residual tumor ( Fig. 1-23 ). In areas of previous tumor infiltration, there is significant architectural distortion characterized by fibrosis, stromal edema, increased vascularity, and a chronic inflammatory infiltrate.

Figure 1-23 Chemotherapy change; a low-power view of an invasive ductal carcinoma with tumor necrosis.
Residual tumor cells may appear unaltered, but in most cases they exhibit cytologic changes reflective of treatment effect. Cells become enlarged and have minute cytoplasmic vacuoles or eosinophilic granules ( Fig. 1-24 ). Nuclei of tumor cells can become enlarged, pleomorphic, and hyperchromatic. The presence of multinucleated cells and the presence of abnormal mitotic figures are classic chemotherapy-related changes ( Fig. 1-25 ). 2, 16, 17

Figure 1-24 Chemotherapy effect; a high-power view of an invasive ductal carcinoma with chemotherapy effect displaying cytoplasmic vacuolization.

Figure 1-25 Chemotherapy effect; a high-power view of an invasive ductal carcinoma with chemotherapy effect displaying cytoplasmic vacuolization and nuclear atypia.
Non-neoplastic breast parenchyma changes are more subtle. The glandular elements undergo atrophy, resulting in a reduction in the number and size of lobules ( Fig. 1-26 ). Cytologic changes do occur in the lobular and ductal epithelial cells ( Fig. 1-27 ).

Figure 1-26 Chemotherapy effect. This low-power view of breast parenchyma depicts lobular atrophy and stromal fibrosis.

Figure 1-27 A, Chemotherapy effect. This intermediate-power view of acini shows prominent cytoplasmic vacuolization of the normal terminal duct luminal epithelial cells. B, This high-power view of acinar structures shows cytoplasmic vacuolization of the normal epithelial cells with low nuclear-to-cytoplasmic ratios.

Hormonal Effects
Estrogens and androgens have various effects on the normal breast parenchyma. Estrogen receptor (ER)–alpha content is higher in parous than in nonparous women and increases with premenopausal age. 18 In general, postmenopausal breast tissue has higher ER-alpha content than premenopausal tissue in the follicle phase of the menstrual cycle. Short-term oral contraceptive use has been associated with lower ER-alpha and progesterone receptor (PR) content. PR expression is lower in postmenopausal breast tissue following combined estrogen and progestin therapy than following estrogen-only therapy.

Differential Diagnosis

Pregnancy-like Hyperplasia versus Cystic Hypersecretory Lesions
Cystic hypersecretory lesions (cystic hypersecretory hyperplasia, cystic hypersecretory atypical hyperplasia, and cystic hypersecretory intraductal carcinoma) typically form a mass. These lesions are characterized by dilated ducts and cysts containing acellular, homogeneous, eosinophilic, colloid-like secretion; the dense secretions create a characteristic retraction artifact with a smooth or scalloped margin from the lining epithelium. 13, 19, 20 Microcalcifications are seldom seen. In contrast, pregnancy-like hyperplasia does not form a palpable mass and lacks colloid secretions. The ducts are not dilated in focal pregnancy-like change (see Fig. 1-14 ). Occasionally, pregnancy-like change may be associated with cystic hypersecretory lesions, and in these cases, cells with pregnancy-like change may line some of the cysts. 2

Myoepithelial Cell Prominence versus Lobular Neoplasia
On occasion, particularly during the secretory phase of the menstrual cycle or following adjuvant radiation or chemotherapy, the myoepithelial cells may take on more abundant, clear cytoplasm in the TDLUs; this increased prominence may suggest a differential diagnosis of lobular neoplasia (see Figs. 1-4 and 1-27 ). However, the myoepithelial cells are not dyshesive, and they are confined to a single layer in the outer compartment of the terminal duct/acinar unit. In some cases, the terminal ducts may appear to be filled, but they are only mildly expanded by this process, which may uniformly affect all ducts but more commonly demonstrates a patchy pattern of involvement.

Intraepithelial Clear Cells versus Paget Disease
Cells with optically clear cytoplasm may at times be quite prominent in the epidermis of the nipple and may simulate Paget disease. In some cases, the latter cells appear to represent pagetoid dyskeratosis, whereas in others, they appear to be a fixation artifact ( Fig. 1-28 ). Despite their mimicry, these cells express high-molecular-weight keratin and can easily be distinguished from Paget cells with the use of judicious immunohistochemistry.

Figure 1-28 A, Low-power view of the nipple epidermis, which shows prominent clear cells. These cells appear to be an artifact of processing but are commonly seen in biopsy and mastectomy specimens. B, On high power, artifactually clear cells have shrunken nuclei with low nuclear-to-cytoplasmic ratios, which are uncharacteristic of Toker cells (see Fig. 1-29 ). Paget disease demonstrates more prominent nucleoli and nuclear atypia (see Fig. 1-31B ).

Toker Cells versus Paget Cells/Disease
Toker cells of the nipple bear a more similar morphologic and immunohistochemical appearance to Paget cells and may pose a significant differential diagnostic challenge when present in increased numbers. In most cases, distinguishing Toker cells from those of Paget disease is based on morphology, because Toker cells lack pleomorphism, prominent nucleoli, and vesicular chromatin. 21 They are typically bland cells with round nuclei and are commonly concentrated along the basal layer ( Fig. 1-29 ). Although both Toker cells and Paget cells have a similar keratin 7 immunoprofile ( Fig. 1-30 ), Paget cells are positive for HER2, whereas Toker cells are not. 22 On occasion, there may be numerous Toker cells within the normal nipple epithelium, but large aggregates of cells with gland formation are diagnostic of Paget disease ( Fig. 1-31 ). The presence of an associated malignancy is also a strong argument for Paget disease.

Figure 1-29 High-power view of the scattered clear (Toker) cells. The nuclei appear rounder and slightly more prominent than the surrounding keratinocytes.

Figure 1-30 Intermediate-power view of epidermis that is stained for CK7 to highlight the Toker cells.

Figure 1-31 A, Intermediate-power view of the epidermis with confluent nests of cells with clear cytoplasm, prominent nucleoli, and nuclear atypia, which are characteristic of Paget disease. B, Paget disease. High-power view of the epidermis with confluent nests of basal cells with clear cytoplasm, prominent nucleoli, and nuclear atypia. Note the gland lumen at bottom right. Contrast with artifactual clear cells (see Fig. 1-28B ) and Toker cells (see Fig. 1-29 ).
Although Toker cells have been considered non-neoplastic, their relationship to Paget disease is uncertain; some investigators postulate that Toker cells may indeed be the precursor cells for Paget disease. 8, 23, 24 Three conditions reinforce this notion: (1) mammary Paget disease that is not associated with an underlying malignancy, (2) extramammary Paget disease that is typically not associated with an underlying malignancy, and (3) rare cases of invasive adenocarcinoma arising from primary Paget disease. Van der Putte and colleagues reported a case of mammary Paget disease arising from Toker cell hyperplasia. 25 Despite the cases of extramammary Paget disease, substantial studies support the direct extension of neoplastic cells derived from carcinomas located deep in the breast parenchyma through the duct system as the underlying cause of Paget disease. 2

Gynecomastoid Changes versus Atypical Ductal Hyperplasia
Gynecomastia and gynecomastia-like changes may simulate atypical ductal hyperplasia due to the pseudopapillary epithelial proliferation and nuclear hyperchromasia, but the periductal stromal edema and concentric fibrosis should suggest the correct diagnosis (see Figs. 1-16 and 1-17 ). Micropapillary ductal carcinoma in situ has more pronounced papillary architecture with bulbous tips.

Atrophy versus Invasive Ductal Carcinoma
Occasionally, atrophic breast tissue may feature ducts set within adipose tissue without apparent preserved lobular architecture or surrounding stroma (see Fig. 1-12 ). These “naked ducts” are distinguished from low-grade invasive carcinoma by adjacent atrophic changes elsewhere in the breast and the absence of a haphazard, irregular infiltrative pattern. Myoepithelial cells are present.

Ancillary Studies
The duct and lobular luminal epithelial cells express low-molecular-weight keratins 7, 8, 18, and 19. 26, 27 Variable expression of casein, gross cystic disease fluid protein-15 (BRST2), and alpha-lactalbumin can also be seen in the mammary epithelium. Myoepithelial cells can be identified with a variety of immunohistochemical stains such as S-100, actin, calponin, smooth muscle actin, myosin heavy chain, and p63, among others ( Figs. 1-32 to 1-34 ). 1, 28 They can also express high-molecular-weight keratins 5/6, 14, and 17. 26, 27, 29

Figure 1-32 The pattern of staining with smooth muscle myosin heavy chain in the normal myoepithelial cells is strong, diffuse, and cytoplasmic.

Figure 1-33 Myoepithelial cells in normal female breast lobules express calponin within the cytoplasm.

Figure 1-34 The myoepithelial cell nuclei are highlighted by p63 stain.
Normal breast ductal and lobular epithelium express ER-alpha and ER-beta and PR ( Figs. 1-35 and 1-36 ). Myoepithelial cells, stromal cells, and endothelial cells also express ER-beta. During the follicular phase of the menstrual cycle, ductal and lobular cells express ER-alpha at a significantly higher level, whereas no significant cyclic changes occur with ER-beta or PR expression. 30 The level of ER-alpha expression varies from 1% to 100% but is generally seen in 1% to 10% of ductal cells and 1% to 25% of lobular epithelial cells. 31, 32 Apocrine cells often do not express hormone receptors but may be strongly positive for HER2. Except in rare instances, overexpression of HER2 is not seen in normal breast tissue.

Figure 1-35 Normal adult female breast luminal epithelial cells express estrogen receptor.

Figure 1-36 Normal adult female breast luminal epithelial cells express progesterone receptor.
Toker cells are positive for CAM5.2, CK7, and EMA but are negative for HER2. Intraepidermal CK7-positive cells may also represent intraepithelial extension of lactiferous duct cells or, possibly, Merkel cells. 6

Genetics
Loss of heterozygosity and allelic imbalance at various chromosomal loci have been reported in histologically normal terminal duct lobular units in women with and without BRCA1 germline mutations. 33 The significance of these genetic alterations is uncertain.

Suggested Readings

Collins LC, Schnitt SJ. Normal breast. In: Mills SE, ed. Histology for Pathologists . Philadelphia: Lippincott Williams & Wilkins; 2007:57–71.
Rosen PP. Rosen’s Breast Pathology . Philadelphia: Lippincott Williams & Wilkins; 2009.

References

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27 Heatley M, Maxwell P, Whiteside C, et al. Cytokeratin intermediate filament expression in benign and malignant breast disease. J Clin Pathol . 1995;48:26–32.
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29 Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res . 2004;10:5367–5374.
30 Boyd M, Hildebrandt RH, Bartow SA. Expression of the estrogen receptor gene in developing and adult human breast. Breast Cancer Res Treat . 1996;37:243–251.
31 Battersby S, Robertson BJ, Anderson TJ, et al. Influence of menstrual cycle, parity and oral contraceptive use on steroid hormone receptors in normal breast. Br J Cancer . 1992;65:601–607.
32 Shaw JA, Udokang K, Mosquera JM, et al. Oestrogen receptors alpha and beta differ in normal human breast and breast carcinomas. J Pathol . 2002;198:450–457.
33 Rennstam K, Ringberg A, Cunliffe HE, et al. Genomic alterations in histopathologically normal breast tissue from BRCA1 mutation carriers may be caused by BRCA1 haploinsufficiency. Genes Chromosomes Cancer . 2010;49:78–90.
2 Specimen Processing

Christina S. Kong, MD, Kristin C. Jensen, MD

Fine Needle Aspiration Biopsy
Needle Core Biopsies
Excisional Biopsy
Margin Specimens
Reexcision Specimens
Mastectomy
Reduction Mammoplasty
Implants
Lymph Nodes

Fine Needle Aspiration Biopsy


General Overview
Fine needle aspiration (FNA) biopsy is a minimally invasive method of obtaining material from palpable and radiographically detected breast lesions by using a small-gauge (23-gauge or less) needle. By moving the needle back-and-forth through the lesion, it is possible to obtain minute fragments of tissue. The technique can be performed with or without aspiration. Material from FNA biopsy is typically used to prepare cytologic smears and can also be made into a formalin-fixed, paraffin-embedded tissue block.

Gross Pathology

Direct Smears
Material from an FNA biopsy can be smeared directly onto a glass slide. Using air in the syringe, the material is expelled from the needle onto the upper third of a slide labeled with two patient identifiers (e.g., patient’s last name, first initial, and date of birth). Using a second slide, the material is then smeared, and the slide can be either immediately fixed in alcohol or allowed to air dry. The best material is frequently in the needle hub. By placing the needle tip into a rubber stopper or holding the needle tip with a hemostat, the material can be quickly flicked out onto a glass slide and made into a smear ( Fig. 2-1 ). It is optimal to prepare both alcohol-fixed and air-dried smears; Papanicolaou-stained fixed smears are useful in the evaluation of nuclear detail, whereas background features such as mucin and stroma are more easily identified on Romanowsky-stained air-dried smears.

Figure 2-1 Fine needle aspiration. The best aspirate material is often in the hub of the needle. This material can be flicked onto a glass slide by placing the needle tip into a rubber stopper or hemostat. With the hub touching the slide, gently lift up the hub with two fingers and let go. The hub hitting the slide causes the material to be expelled. This action should be rapidly repeated several times until all the material is expelled from the hub.

Liquid-Based Preparations
Aspirate material can be rinsed directly into a vial of liquid-based fixative, such as CytoLyt (Hologic, Marlborough, MA) or CytoRich (BD, Franklin Lakes, NJ), which can then be processed into a thin-layer slide. Processing thin-layer samples requires specialized equipment.

Cell Block
Formalin-fixed, paraffin-embedded cell blocks can be prepared from aspirate material and are very useful for cases where special studies for hormone receptor or HER2 status are desired. If the specimen is bloody, it is best to allow the material to clot in the hub of the needle before flicking it out onto a slide and rinsing into formalin (see Fig. 2-1 ). Nonbloody or nonclotted specimens can be rinsed directly into formalin, but multiple visible particles are needed to prepare an adequate cell block. This may require the use of HistoGel or a collodion bag. 1 It is best to use formalin for fixation because most laboratories have validated their prognostic and predictive markers for formalin-fixed, paraffin-embedded material.

Needle Core Biopsies


Definition and Synonyms
Synonyms: TruCut, Mammotome.

General Overview
Breast needle core biopsies are frequently obtained under mammographic or ultrasound guidance but can also be performed with magnetic resonance imaging guidance or without imaging guidance if the nodule is palpable. The target may be either microcalcifications or a mass lesion.

Gross Pathology
Needle core biopsies should be submitted in their entirety, and at least three level sections should be evaluated. It is helpful to align the cores and wrap them in tissue paper before placing in the cassette. The gross description should indicate the number of cores, color, and size.
It is important to know if the needle cores are targeting a mass lesion or microcalcifications. If microcalcifications are targeted, a specimen radiograph should be obtained at the time of the procedure to confirm the presence of microcalcifications. Optimally, cores with calcifications should be separated from those without calcifications either by inking or by placing in a different specimen vial. This allows the cores to be submitted in separate blocks and streamlines histologic evaluation for calcifications. If microcalcifications are not identified on the H&E sections, evaluating additional level sections and looking for calcium oxalate crystals (rhomboid, pale-yellow to clear) under polarized light can be helpful. 2 If microcalcifications are still not seen, it may be necessary to radiograph the paraffin blocks flat and on edge to determine if calcifications are present and, if so, how deep in the block they are located 3 ( Fig. 2-2 ).

Figure 2-2 Paraffin block radiograph. If calcifications are not identified on H&E sections, radiographs of the paraffin block can be helpful in determining whether calcifications are present ( A ) and if so, how deep in the block they are located ( B; block on edge). Arrows indicate the location of calcifications.
Needle core biopsies should be fixed in neutral-buffered formalin for a minimum of 6 hours. If the specimen is fixed in formalin for more than 72 hours, calcifications can leach out and become undetectable on histologic sections. 4 For hormone receptor studies, needle core biopsies should be fixed for at least 6 hours and not longer than 72 hours ( Table 2-1 ). The physician obtaining the sample should record the time the specimen was placed into formalin on the specimen vial or requisition sheet. In general, it is preferable to perform testing for prognostic and predictive markers on needle core biopsy specimens due to essentially immediate fixation and better formalin penetration of a smaller specimen. 5 (See Chapter 13 for additional information on prognostic and predictive markers.)
Table 2-1 ASCO/CAP Guidelines for ER, PR, and HER2 Testing ER and PR HER2 Cold ischemic time ≤1 hour ≤1 hour Formalin fixation time 6–72 hours 6–48 hours * Optimal sample Core needle Resection
ASCO/CAP, American College of Clinical Oncology/College of American Pathologists; ER, estrogen receptor; PR, progesterone receptor.
* More recent studies have suggested that up to 72 hours of fixation is acceptable for HER2 testing.

Excisional Biopsy


Definition and Synonyms

Lumpectomy or tylectomy: excision of a mass lesion with a rim of surrounding normal tissue
Wire-localized biopsy: radiographically placed wire used to identify the location of a mammographically detected mass or microcalcifications; tissue around the wire encompassing the area of interest is excised.
Quadrantectomy: excision of a mass that entails the removal of an entire quadrant of the breast

General Overview
Excisional biopsies encompass both lumpectomies of palpable masses and wire-localized biopsies of radiographically detected microcalcifications or mass lesions. The mass or area of microcalcifications is removed with a surrounding rim of normal tissue.

Gross Pathology

Processing
It is necessary to record the weight, the size of the specimen in three dimensions, and the location of any orienting sutures and localization wire (if present) ( Fig. 2-3 ). The cold ischemic time (interval between tissue removal and placement in formalin) should also be documented. The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines recommend a cold ischemic time of less than 1 hour for specimens used for estrogen receptor, progesterone receptor, and HER2 testing 5, 6 (see Table 2-1 ).

Figure 2-3 Wire-localized biopsy. Excisional biopsy with two localization wires ( A ), which on the specimen radiograph ( B ) are seen to mark separate areas of clustered microcalcifications. A radiopaque clip is adjacent to the wire on the right.
Because excisional biopsies may contain a malignant lesion, it is essential to ink all margins. The specimen may be received oriented or unoriented. Oriented specimens are frequently marked with sutures placed on two perpendicular surfaces (commonly “short superior,” “long lateral”). The location of the sutures should be indicated on the requisition sheet. Together with information regarding the laterality of the specimen, the sutures can be used to identify all six possible margins: superior, inferior, medial, lateral, anterior, and posterior. Although this is the standard of practice, Molina and colleagues found a significant rate of incorrect orientation that ranged from 20% for larger specimens and 78% for small specimens (volume <20 cm 3 ). 7 The most commonly affected sites were the superficial and deep margins. These discrepancy rates emphasize the need for careful attention to orientation, especially for small specimens, which had a significantly higher discrepancy rate. If there is any ambiguity regarding orientation of the specimen, it is necessary to review the case with the surgeon prior to inking and sectioning.
If the specimen is received unoriented, it can be inked completely in black. However, if the specimen is received oriented, it is best to differentially ink the specimen to ensure that the orientation is maintained. One inking method is to use blue ink for the superior surface (“sky is blue”), green for the inferior (“grass is green”), and black for the posterior ( Fig. 2-4 ). The specimen can then be serially sectioned from medial to lateral. Of course, the inking will have to be modified based on the shape of the specimen, but it is important to develop a routine method of inking. If a localization wire is present, it can be helpful to mark the entry point of the wire with a different color of ink. In some cases, the area of interest may be marked by blue dye, but this dye will not be visible on histologic sections, so it is best to mark the area with a permanent tissue dye. Regardless of the method used to mark the radiographic area of interest in wire-localized specimens, a radiograph showing the presence of the targeted lesion should accompany the specimen.

Figure 2-4 Specimen inking. This specimen is inked blue for superior (“sky is blue”), green for inferior (“grass is green”), and black for posterior. After inking, the specimen should be sectioned perpendicular to the long axis and the slices laid out in sequential order.
The specimen should be sliced perpendicular to the long axis (see Fig. 2-4 ). For cases with a high probability of cancer that may require prognostic and predictive markers, immediate gross evaluation, including inking and slicing (at 3- to 5-mm intervals), is suggested for greatest formalin penetration of the tissue sections and for optimal cold ischemic time (≤1 hour). 5 Thinner slices for histology can be obtained after some degree of formalin fixation increases the firmness of the tissue. Alternatively, if tumor is grossly identified, a small section containing tumor and surrounding uninvolved fibrous tissue can be removed and immediately placed in formalin for optimal fixation. The section of tumor used for prognostic and predictive marker analysis should be fixed in neutral-buffered formalin for a minimum of 6 hours. For hormone receptor studies, fixation should not exceed 72 hours. For HER2, recommended maximum fixation time is 48 hours, but more recent studies evaluating this issue have shown no difference in results between 48-hour and 72-hour fixation times 6, 8 – 11 (see Table 2-1 ).
For specimens that are likely to contain cancer but are obtained at an off-site location, bisecting the specimen through the middle and immediately immersing it in adequate amounts of formalin is suggested to initiate formalin fixation. In these cases, it is important to mark the specimen in such a way that orientation is maintained after bisection.
When serially sectioning the specimen, the slices can be laid out in sequential order on an × 11-inch sheet of paper or on a paper towel in a flat container and immersed in adequate amounts of neutral-buffered formalin. The slices will adhere to the paper and, if the specimen is not entirely submitted, the sheet can be rolled up for easy storage and maintenance of orientation. Once sliced, any gross lesions should be fully described (size, color, circumscription, texture, distance from margins, relationship to any localizing wires). If no gross lesion is identified, it is important to note the sections corresponding to the area of abnormality documented on the specimen radiograph. It can also be helpful to radiograph the sliced sections. Laying the sections on sheets of paper facilitates this process. Specimen radiographs performed in pathology should be documented in the gross description. The presence of any radiographic masses, calcifications, localization wires, radiopaque clips, or other markers should be noted ( Fig. 2-5 ).

Figure 2-5 Radiopaque clip. Clips are placed at the time of needle core biopsy to mark the biopsy site. This clip (arrow) marks an area of calcifications.

Sections to Submit
The general rule of thumb should be to submit the entire specimen if it can fit in 10 to 20 cassettes 12, 13 ( Table 2-2 ). For larger specimens, there is a range of opinions about how many cassettes should be submitted to optimize the balance between the detection of a significant lesion and cost-effectiveness. In general, the optimal number of blocks depends more on the percentage of the specimen that is abnormal than on the overall size of the specimen; fewer sections need to be evaluated in cases where more than 50% of the specimen is abnormal than in cases where only 5% to 10% of it is abnormal. 13 If the specimen is not entirely submitted, it is important to indicate in the gross description the percentage of the lesion submitted and the overall percentage of the specimen submitted. The number of cassettes required depends on whether the mass is visible grossly or only radiographically.

Table 2-2 Guidelines for Specimen Sampling

No Mass Lesion.
If no mass lesion is grossly identified, sampling should concentrate on the fibrous areas, because fatty tissue is unlikely to contain significant disease. 13, 16 For mammographically detected lesions, radiographs of the specimen slices can also be very helpful for directing sampling ( Fig. 2-6 ). Recommendations put forth in gross dissection manuals range from submitting 10 cassettes of fibrous tissue, all the tissue if ductal carcinoma in situ (DCIS) is identified on the prior needle core biopsy, all the tissue if it fits in 20 cassettes, the entire specimen for mammographically localized biopsies, or two thirds of the fibrous tissue for palpable mass lesions 12, 14, 17, 18 (see Table 2-2 ).

Figure 2-6 Specimen slices. Obtaining a radiograph of specimen slices laid out on a sheet of paper is especially helpful for directing sampling of specimens removed for calcifications. The insets show unremarkable fatty breast tissue ( A ) with clustered calcifications on the specimen radiograph ( B ).
In one of the few studies that directly address this issue, Schnitt and Wang reviewed 384 consecutive breast biopsies performed for a palpable mass where only fibrofatty tissue was identified on gross examination and the specimen was entirely submitted for histologic examination. The researchers detected atypical hyperplasia or worse in 26 cases, and these findings were present, at least partially, in fibrous tissue in 25 of 26 cases. 13 They saw one case of atypical lobular hyperplasia in fatty tissue only. Further evaluation showed that the balance between cost-effectiveness and lesion detection can be optimized by the initial evaluation of 10 blocks of fibrous tissue. It is apparent that if atypical hyperplasia or worse is identified, then more sections should be taken. Using this method, only one case with a small focus of lobular carcinoma in situ (LCIS) would have been missed.
A follow-up study by Owings and associates examined wire-localized biopsies excised for microcalcifications and showed that sampling should include areas of surrounding fibrous tissue as well as the targeted microcalcifications. 16 Limiting initial sampling to the area of microcalcifications would have missed one case of DCIS and five cases of atypical hyperplasia. Extending sampling to include all fibrous parenchyma would have detected all cases of carcinoma and all but two cases of atypical hyperplasia.
In general, the specimen should be submitted sequentially so that the size of the lesion can be determined from the histologic sections. Also, if atypical hyperplasia or in situ carcinoma is identified on the initial sections, the remainder of the specimen or at least all the fibrous tissue should be submitted for histologic evaluation.

Grossly Visible Mass.
For grossly visible mass lesions, sampling should focus on the lesion and the relationship of the mass to the surrounding normal breast and to the different margins. To determine size, it is helpful to have a full cross section through the largest area of tumor; this may need to be placed into more than one cassette, which can then be reassembled for histologic determination of size ( Fig. 2-7 ). For margins that are less than 2 cm away from the mass, it is necessary to submit perpendicular margins.

Figure 2-7 Cross section of tumor. Blocking in an entire cross section of tumor is useful for determining the size of an invasive carcinoma. This tumor can be submitted in two cassettes. The arrow indicates the prior needle core biopsy site.

Magnetic Resonance Imaging–Directed Biopsies.
For magnetic resonance imaging–directed, wire-localized excisional biopsies, the entire specimen should be submitted. Because MRI relies on gadolinium uptake by the lesion after intravenous injection, it cannot be used to obtain an image of the gross specimen to confirm the presence of the abnormality. Carlson and coworkers evaluated 85 specimens and found that the majority of the 20 malignant cases did not have an abnormality apparent on the specimen radiograph or by gross examination. 19 Ninety-five percent of cases were submitted entirely, and the number of blocks per case ranged from 1 to 37 (median, 13). The study did not address whether malignancy was ever detected in areas of the specimen that grossly or radiographically were consistent with adipose tissue.

Post-treatment Specimen.
It is important to identify the tumor bed and determine the extent of residual tumor. Most patients receiving neoadjuvant therapy have undergone a needle core biopsy for diagnosis. It is helpful if a radiopaque clip is placed at the time of biopsy to mark the tumor site, because in cases of complete response, it can be difficult to identify the tumor bed in the excision specimen. Calcifications can also be useful in identifying the tumor site; they typically remain after therapy. Sahoo and Lester suggest submitting one block of tissue from the tumor bed per centimeter of pretreatment tumor size. 15 If a pathologist identifies no tumor on the initial sections and the tumor bed is small, it is best to submit it entirely. If the residual tumor bed is greater than 5 cm, the M.D. Anderson group recommends submitting at least five representative sections of the largest cross-sectional area. A calculation for determining the residual cancer burden that incorporates the size of the tumor bed, the percent cellularity of the residual tumor, the percentage of carcinoma in situ in the residual tumor, and involvement of lymph nodes has also been proposed by the M.D. Anderson group. 20 However, there are no established guidelines regarding how extensively the tumor bed should be sampled. In the event that residual tumor is identified, the sections should be submitted in a way that the tumor size and distance to margin can be determined.

Margin Specimens


Definition and Synonyms
Synonym: shave margin.

General Overview
Separately submitted margin specimens represent tissue surrounding the lumpectomy or reexcision site. Some surgeons submit all of their true margins as separate specimens, whereas others submit a shave margin in an area where the tumor appears to be transected at or close to the specimen margin. Separately submitted margin specimens can minimize the possibility of incorrectly orienting the specimen based on sutures and have been shown to decrease the need for repeat surgery to obtain adequate margins in breast-conserving therapy. 7, 21

Gross Pathology

Processing
It is necessary to record the size of the specimen in three dimensions as well as the location of any orienting sutures. Margin specimens typically consist of thin strips of tissue with a stitch marking either the true or false margin. It is best to ink the true (new) margin one color and the false (old) margin a different color. A useful mnemonic is “true-blue, false-black.” Although the false margin may be left uninked, it can be difficult to identify the true margin if ink bleeds onto the false margin.

Sections to Submit
In general, it is best to submit all of the tissue in separately submitted margin specimens, because they represent true margins. However, in reality, this is often not practical. Sampling should focus on fibrous areas; fatty tissue is less likely to contain a significant lesion. 13 Lester recommends submitting one section per centimeter of the specimen length and more if the margin evaluation is for DCIS. 14 If the margin evaluation is for DCIS or invasive lobular carcinoma, or if a significant lesion is identified in the initial sections, more of the specimen should be submitted (see Table 2-2 ).

Reexcision Specimens


General Overview
Reexcisions are a form of excisional biopsy where the previous biopsy cavity is excised. Surgeons typically perform them to obtain a larger margin of benign tissue around a previously resected invasive or in situ carcinoma.

Gross Pathology

Processing
It is necessary to record the weight, size of the specimen in three dimensions, and location of any orienting sutures. Because reexcisions are performed to obtain adequate margins around invasive and in situ carcinomas, it is essential to ink the specimen prior to sectioning. (See “ Excisional Biopsy ” for discussion of inking and slicing.) Once the specimen is sectioned, it is essential to record the location and size of the biopsy cavity and distance to the margin. If the initial excision was remote, the biopsy cavity may appear as an area of scarring, and fresh biopsy sites are hemorrhagic with chalky areas of fat necrosis ( Fig. 2-8 ).

Figure 2-8 Biopsy site. The chalky white nodule in the upper portion of the slices represents an area of fat necrosis in a prior biopsy site.

Sections to Submit
The majority of reexcision specimens do not have grossly identifiable tumor. In these cases, it is best to submit the entire specimen if all the tissue can be submitted in 10 to 20 cassettes (see Table 2-2 ). For larger specimens, sampling should concentrate on the biopsy cavity and the relationship of the biopsy cavity to margin. Argani recommends submitting two sections per centimeter of the greatest dimension of the biopsy cavity. 12 Lester recommends at least four sections of the biopsy cavity, two sections of each margin, and one of skin (if present); if the reexcision is for DCIS, submission of all fibrous areas is necessary 14 (see Table 2-2 ).
Abraham and colleagues performed a study to determine the optimal amount of tissue to sample when the reexcision specimen appears grossly benign. 22 By submitting one section per centimeter of maximum tissue dimension, 81% of clinically significant lesions were detected, with a 52% reduction in the number of blocks processed. Two sections per centimeter detected 95% of clinically significant lesions with a 17% reduction in blocks processed. If they considered only lesions that led to major changes in management, they identified 88% of lesions with one section per centimeter and 97% with two sections per centimeter. The decision on how much of the specimen to submit relies on a balance between cost-effectiveness and the detection of lesions that will result in a change, whether major or minor, to the patient’s treatment plan.

Mastectomy


Definition and Synonyms 14, 23

Radical mastectomy: removal of the entire breast, including nipple and skin, with the pectoralis major and minor muscles and complete axillary contents
Modified radical (or extended simple) mastectomy: removal of entire breast, including nipple, skin, and axillary tail, and variable amounts of axillary contents
Simple (or total) mastectomy: removal of breast with nipple and variable amounts of skin but no axillary contents
Prophylactic mastectomy: simple mastectomy performed in a woman at high risk for developing breast carcinoma
Skin-sparing (or subcutaneous) mastectomy: removal of breast tissue without overlying skin or nipple; not used for malignancy

General Overview
Mastectomies are performed for many different reasons, as reflected in the different modifiers used for mastectomies. The intention is to remove the entire breast, but in reality some small amounts of breast tissue may be left behind on the chest wall. In patients with known cancer, mastectomies may be performed either before or after chemotherapy and radiation therapy.

Gross Pathology

Processing
It is necessary to record the weight, the size of the specimen in three dimensions, and the location of any orienting sutures. Measurements and descriptions of the skin ellipse and nipple should also be included. Because mastectomies are typically performed for malignancy, it is essential to ink all margins. The specimen can be oriented by the presence of the axillary tail or an orienting stitch and information regarding laterality. The nipple-areola complex represents the center of the specimen. Three colors of ink are a simple way of maintaining orientation: superior blue (“sky is blue”), inferior green (“grass is green”), and posterior black. The nipple-areola complex should be removed, serially sectioned along the axis perpendicular to the base, and entirely submitted. If an axillary tail is present, it should also be removed and a search for lymph nodes conducted. The specimen can then be serially sectioned at 5- to 7-mm intervals from medial to lateral. The slices can be laid out in sequential order on × 11-inch sheets of paper to maintain orientation, or the skin can be left intact to hold the specimen together. Placing paper towels between the slices can help to accelerate the fixation process. The specimen may be sliced fresh for optimal formalin fixation, but it is often easier to obtain thinner sections for histology after the tissue is firmer with formalin fixation. The cold ischemic time (interval between tissue removal and placement in formalin) should be documented, because the ASCO/CAP guidelines recommend a cold ischemic time of less than 1 hour for specimens used for estrogen receptor, progesterone receptor, and HER2 testing. 5, 6
Once sliced, any gross lesions (i.e., biopsy site, tumor mass) should be fully described: size, color, circumscription, texture, location, and distance from margins. The slices should be carefully examined to determine if more than one lesion is present, and, if so, the location of the lesions in relation to the nipple-areola complex and/or breast quadrant, and in relation to each other should be documented. If radiographs of the sliced sections are obtained, any suspicious densities and calcifications, including the location of the abnormalities, should be described. Any section containing a biopsy clip or marker should be adequately sampled (see Fig. 2-5 ). Specimen radiographs can be especially helpful in evaluating mastectomies for multifocal or multicentric carcinomas, mastectomies for non–mass-forming lesions marked by calcifications, post-treatment mastectomies, and prophylactic mastectomies. It is helpful to submit intervening tissue between two distinct, adjacent masses to determine if the mass is one unusually shaped tumor or two distinct tumors.
If prognostic and predictive markers are required, immediate gross evaluation, including inking and slicing at 5-mm intervals, is recommended for optimal formalin penetration of the specimen slices. If tumor is grossly identified, it is best to remove a representative section and place it immediately into neutral-buffered formalin for a minimum of 6 hours. This section can be used for prognostic and predictive marker analysis. For hormone receptor studies, fixation should not exceed 72 hours. For HER2, the recommended maximum fixation time is 48 hours, but more recent studies evaluating this issue have shown no difference in results between 48-hour and 72-hour fixation times 6, 8 – 11 (see Table 2-1 ).

Sections to Submit
The number of sections to submit depends on the underlying disease and the reason for the mastectomy (see Table 2-2 ). For example, a mastectomy for known malignancy is processed differently than a prophylactic mastectomy.

Mastectomy for Known Malignancy.
Sampling should be directed toward obtaining the information needed for staging and management. When a mass lesion is present, it is generally recommended that two to five sections of tumor be submitted for histologic evaluation of known invasive carcinomas, more for known in situ carcinoma, to look for areas of invasion. 12, 14, 17 The sections should show the junction of tumor with surrounding benign breast parenchyma, relationship to the closest surgical margin (perpendicular margin in a single cross section if tumor is <2 cm from margin), and relationship to skin and/or nipple. If the tumor is small, a complete cross section can be helpful for determining size. 24

Post-treatment Mastectomy.
Obtaining a specimen radiograph can be very helpful in identifying the tumor bed and directing sampling to determine the extent of residual tumor. As discussed previously in the “Excisional Biopsy” section, Sahoo and Lester suggest submitting one block of tissue from the tumor bed per centimeter of pretreatment tumor size. 15 If a clip, area of calcifications, or mass lesion is not identified radiographically or grossly, it is possible to use the location of the tumor as denoted by quadrant or o’clock position and distance from the nipple to direct sampling. However, there are no established guidelines regarding how extensively the tumor bed should be sampled.

Prophylactic Mastectomy.
The clinician should direct sampling toward any gross or radiographic abnormalities. If no abnormalities are detected, it is appropriate to submit one to two sections of fibrous tissue from each quadrant plus a section of the nipple. 14 Small foci of occult invasive and/or in-situ carcinomas are most frequently detected in women with a history of breast cancer undergoing prophylactic mastectomy of the contralateral breast and have been reportedly found in up to 19% of cases. 25, 26

Skin-sparing Mastectomy.
Typically performed for gynecomastia in men, skin-sparing mastectomies are similar to reduction mammoplasty specimens. It is standard to submit two sections of fibrous parenchyma, if no gross abnormalities are detected.

Reduction Mammoplasty


Definition and Synonyms
Synonym: breast reduction.

General Overview
Reduction mammoplasties, which are performed to decrease breast volume, consist of fragments of breast tissue and skin. When performed for therapeutic reasons (weight >300 g), they are typically bilateral. Patients who have undergone lumpectomy for malignancy may have a unilateral reduction mammoplasty of the contralateral breast. The incidence of malignancy in breast reduction specimens is very low—approximately 2 to 4 per 1000 cases. 14

Gross Pathology
The gross description should clearly document the weight and aggregate measurement of the pieces as well as a description and range of size of the fragments. It can be helpful to obtain a specimen radiograph of the aggregated fragments to direct sampling, but this is optional. It is necessary to section all fragments at 5-mm increments and thoroughly examine them for any abnormalities. For standard reduction mammoplasties, two cassettes of tissue, including breast parenchyma and skin, are typically submitted. It is critical that more extensive sampling be performed if the patient has a strong family history or prior personal history of breast cancer. Argani also recommends submitting more sections if the specimen is from an older patient. 12 However, the extent of sampling required in these cases is not defined and is left to the judgment of the prosector.

Implants


Definition and Synonyms

Tissue expander: implant placed under the chest muscles at the time of mastectomy with a port that allows the volume to be adjusted with saline injections
Permanent implant: typically filled with either saline or silicone but can also be filled with oil; used for cosmetic breast enhancement as well as reconstruction after mastectomy

General Overview
Removal of breast implants, composed of saline or silicone, occurs for a variety of reasons, including complications and patient concerns about the safety of silicone implants. Litigation involving breast implants began in 1977, with a patient winning a $170,000 settlement for a ruptured implant, and peaked in 1994, with a large class-action settlement involving several companies, who paid close to $4.25 billion. 27 A report published in 1999 by the Institute of Medicine of the National Academy of Sciences cleared silicone implants of an association with systemic diseases, and many studies have shown that the complications from implants are localized, involving capsular contracture or rupture.

Gross Pathology
Although litigation surrounding breast implants has significantly decreased, it continues to be important to document the implant with a complete gross description and photographs. Because there are currently no national guidelines for how long an implant has to be retained, each laboratory should have a policy specifically addressing retention of implants. If implants are not retained indefinitely, it is prudent to notify patients and treating physicians of the institutional policy.
The gross description of the implant should indicate the size of the specimen in three dimensions and include a description of any identifying marks (e.g., name of manufacturer, size of implant), type of wall (single or double lumen), surface texture, and internal contents (saline, silicone, or oil; color). If the implant is leaking, it is important to identify the source of the leak and to describe the defect carefully. In some cases, the leak may be evidenced only by a tacky surface. Photographs should be taken of any identifying marks and any gross abnormalities ( Fig. 2-9 ). If tissue is adherent to or accompanies the implant capsule, one to two representative sections should be submitted. 12, 14

Figure 2-9 Breast implant. Photographs of implants should document identifying marks and any gross abnormalities (none in this case).

Lymph Nodes


Definition and Synonyms

Axillary dissection: removal of axillary contents; can range from removal of the axillary tail to the full axillary contents
Sentinel lymph node biopsy: removal of one or more lymph node(s) identified by a radioactive tracer or dye as the first lymph node in the lymphatic drainage from the breast

General Overview
Axillary lymph nodes are removed to determine if cancer has spread outside of the breast, and this information plays an important role in breast cancer staging. Sentinel lymph node biopsies are commonly performed at the time of excisional biopsy in patients with invasive carcinomas and high-grade DCIS. If metastatic carcinoma is detected in the sentinel lymph node, then a completion axillary dissection is often performed.

Gross Pathology

Processing
The axillary tail or axillary contents should be carefully dissected for lymph nodes. Small lymph nodes can be submitted whole, but larger ones should be longitudinally sectioned into 2-mm thick sections. If more than one lymph node is placed in a cassette, the lymph nodes should be differentially inked prior to sectioning to ensure that the different lymph nodes can be accurately distinguished on histologic sections. For a complete discussion of sentinel lymph node processing, refer to Chapter 11 .

Sections to Submit
The axillary lymph nodes should be entirely submitted, unless the lymph node is grossly replaced by tumor. 28 In these cases, representative sections should be selected to demonstrate greatest extent of nodal involvement and presence or absence of extracapsular extension.

Suggested Readings

Argani P. Breast. In: Westra WH, Hruban RH, Phelps TH, Isacson C. Surgical Pathology Dissection: An Illustrated Guide . 2nd ed. New York: Springer; 2003:132–140.
Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Arch Pathol Lab Med . 2010;134:907–922.
2011 HER2 testing guidelines and resources: changes to the HER2 testing guideline, clinical notice. http://www.cap.org/apps/cap.portal?_nfpb=true&cntvwrPtlt_actionOverride=%2Fportlets%2FcontentViewer%2Fshow&_windowLabel=cntvwrPtlt&cntvwrPtlt{actionForm.contentReference}=committees%2Fimmunohistochemistry%2Fher2_index.html&_state=maximized&_pageLabel=cntvwr , 2011. Available at
Lester SC. Breast. In: Manual of Surgical Pathology . Philadelphia: Elsevier Saunders; 2010:262–288.
Lester SC, Bose S, Chen YY, et al. Protocol for the examination of specimens from patients with invasive carcinoma of the breast. Arch Pathol Lab Med . 2009;133:1515–1538.
Lester SC, Bose S, Chen YY, et al. Protocol for the examination of specimens from patients with ductal carcinoma in situ of the breast. Arch Pathol Lab Med . 2009;133:15–25.

References

1 Varsegi GM, Shidham V. Cell block preparation from cytology specimen with predominance of individually scattered cells. J Vis Exp . 2009. Department of Pathology. Paper 4 http://digitalcommons.wayne.edu/med_path/4
2 Rosen PP. Pathological assessment of nonpalpable breast lesions. Semin Surg Oncol . 1991;7:257–260.
3 Rebner M, Helvie MA, Pennes DR, et al. Paraffin tissue block radiography: adjunct to breast specimen radiography. Radiology . 1989;173:695–696.
4 Moritz JD, Luftner-Nagel S, Westerhof JP, et al. Microcalcifications in breast core biopsy specimens: disappearance at radiography after storage in formaldehyde. Radiology . 1996;200:361–363.
5 Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Arch Pathol Lab Med . 2010;134:907–922.
6 HER2 testing guidelines and resources: changes to the HER2 testing guideline, clinical notice. http://www.cap.org/apps/cap.portal?_nfpb=true&cntvwrPtlt_actionOverride=%2Fportlets%2FcontentViewer%2Fshow&_windowLabel=cntvwrPtlt&cntvwrPtlt{actionForm.contentReference}=committees%2Fimmunohistochemistry%2Fher2_index.html&_state=maximized&_pageLabel=cntvwr , 2011. Available at
7 Molina MA, Snell S, Franceschi D, et al. Breast specimen orientation. Ann Surg Oncol . 2009;16:285–288.
8 Tong LC, Nelson N, Tsourigiannis J, Mulligan AM. The effect of prolonged fixation on the immunohistochemical evaluation of estrogen receptor, progesterone receptor, and HER2 expression in invasive breast cancer: a prospective study. Am J Surg Pathol . 2011;35:545–552.
9 Redfield SBD, Rezeanu L, Brown AS. Testing the limits: reevaluation of the upper limit of formalin fixation time recommended in the ASCO/CAP HER2 testing guidelines. Mod Pathol . 2011;24:59A.
10 Lowe ACNG, Shintaku IP, Shapourifar-Tehrani S, et al. Effect of ischemic time, fixation time and fixatives on HER-2/neu IHC and FISH results in breast cancer. Mod Pathol . 2011;24:52A.
11 Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol . 2007;25:118–145.
12 Argani P. Breast. In: Westra WH, Hruban RH, Phelps TH, Isacson C. Surgical Pathology Dissection: An Illustrated Guide . 2nd ed. New York: Springer; 2003:132–140.
13 Schnitt SJ, Wang HH. Histologic sampling of grossly benign breast biopsies. How much is enough? Am J Surg Pathol . 1989;13:505–512.
14 Lester SC. Breast. In: Lester LC, ed. Manual of Surgical Pathology . Philadelphia: Elsevier Saunders; 2010:262–288.
15 Sahoo S, Lester SC. Pathology of breast carcinomas after neoadjuvant chemotherapy: an overview with recommendations on specimen processing and reporting. Arch Pathol Lab Med . 2009;133:633–636.
16 Owings DV, Hann L, Schnitt SJ. How thoroughly should needle localization breast biopsies be sampled for microscopic examination? A prospective mammographic/pathologic correlative study. Am J Surg Pathol . 1990;14:578–583.
17 Rosai J. Guidelines for handling of most common and important surgical specimens. In: Rosai J, ed. Rosai and Ackerman’s Surgical Pathology . Philadelphia: Mosby, 2004. 2919–2293
18 Lester SC, Bose S, Chen YY, et al. Protocol for the examination of specimens from patients with ductal carcinoma in situ of the breast. Arch Pathol Lab Med . 2009;133:15–25.
19 Carlson JW, Birdwell RL, Gombos EC, et al. MRI-directed, wire-localized breast excisions: incidence of malignancy and recommendations for pathologic evaluation. Hum Pathol . 2007;38:1754–1759.
20 Residual Cancer Burden Calculator. University of Texas, M.D. Anderson Center; 2011. Available at http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3
21 Huston TL, Pigalarga R, Osborne MP, Tousimis E. The influence of additional surgical margins on the total specimen volume excised and the reoperative rate after breast-conserving surgery. Am J Surg . 2006;192:509–512.
22 Abraham SC, Fox K, Fraker D, et al. Sampling of grossly benign breast reexcisions: a multidisciplinary approach to assessing adequacy. Am J Surg Pathol . 1999;23:316–322.
23 Standardized management of breast specimens recommended by Pathology Working Group, Breast Cancer Task Force. Am J Clin Pathol . 1973;60:789–798.
24 Edge SB, Byrd D, Compton CC, et al. Breast. In AJCC Cancer Staging Manual , 7th ed, New York: Springer; 2010:353.
25 Khurana KK, Loosmann A, Numann PJ, Khan SA. Prophylactic mastectomy: pathologic findings in high-risk patients. Arch Pathol Lab Med . 2000;124:378–381.
26 Leunen K, Drijkoningen M, Neven P, et al. Prophylactic mastectomy in familial breast carcinoma. What do the pathologic findings learn us? Breast Cancer Res Treat . 2008;107:79–86.
27 Spear SL, Parikh PM, Goldstein JA. History of breast implants and the food and drug administration. Clin Plast Surg . 2009;36:15–21. v
28 Lester SC, Bose S, Chen YY, et al. Protocol for the examination of specimens from patients with invasive carcinoma of the breast. Arch Pathol Lab Med . 2009;133:1515–1538.
3 Basic Breast Radiology

Brandi Tamara Nicholson, MD

Imaging Evaluation of Patients
Screening Mammography
Diagnostic Mammography
Ultrasound
Magnetic Resonance Imaging
Breast Imaging Reporting and Data System
Imaging Characteristics
Features of Typically Benign Mass Lesions
Features of Typically Malignant Mass Lesions
Calcification Morphology
Calcification Distribution
Non-masslike Enhancement on Magnetic Resonance Imaging
Biopsy Techniques: Image-Guided Biopsy Methods
Needle Types
Calcifications: A Special Case
Biopsy Site Markers
Accuracy of Core Needle Biopsies
Differential Diagnosis
Masses
Calcifications
Management after Biopsy
Conclusions
Breast biopsies are performed to diagnose or exclude malignancy, typically a primary breast cancer, which is the most common female malignancy, excluding skin cancer. 1 Each year between 2006 and 2012 more than 180,000 new cases of invasive breast cancer and an additional 60,000 cases of in situ breast carcinoma were diagnosed. 2, 3 Approximately 40,000 women die of breast cancer each year. 2, 3 The goal of breast imaging is to detect suspicious lesions in the breast and to allow the performance of safe, image-guided biopsies. From the asymptomatic screening population, approximately 80 women in 1000 will be called back after an original screening mammogram for additional studies. Sixteen of these women will require a biopsy, with cancer ultimately detected in six. 4 Additionally, radiologists need to determine whether the biopsy results are concordant with the imaging finding. Recommendations for follow-up imaging, surgery, or repeat biopsy are determined on the basis of the histology results and the accuracy of the targeted biopsy. The radiologist and pathologist work closely together to determine the cause of the biopsied lesion to ensure appropriate management of the patient. This chapter discusses common breast imaging techniques and findings, expected pathologic results based on imaging appearances, and the importance of radiology-pathology correlation.

Imaging Evaluation of Patients

Screening Mammography
Screening mammograms are performed in asymptomatic women. The American Cancer Society recommends that women 40 years of age and older have annual screening mammograms. Screening prior to 40 years of age is appropriate in women with a strong family history or with other significant risk factors for early breast cancer. A screening examination consists of two views of each breast: craniocaudal (CC) and mediolateral oblique (MLO) ( Figs. 3-1 and 3-2 ). Imaging features suggestive of disease include a neodensity (developing asymmetry or mass on mammography); architectural distortion; calcifications; a mass; or secondary signs of disease such as lymphadenopathy, nipple changes, or skin thickening. When abnormalities are seen on baseline examinations, women are asked to return for additional evaluation.

Figure 3-1 Screening mammogram, craniocaudal ( A ) and mediolateral oblique ( B ) projections, with a focal asymmetry ( circles ).

Figure 3-2 Screening mammogram, craniocaudal ( A ) and mediolateral oblique ( B ) projections, with abnormal calcifications ( circles ).

Diagnostic Mammography
After an abnormal screening examination, the patient returns for a diagnostic workup. This can include a combination of mammography, ultrasound imaging, and physical examination. Diagnostic mammographic views include, but are not limited to, mediolateral, spot compression, and/or magnification views. Spot compression views are obtained when the mammographic finding is suggestive of a mass ( Fig. 3-3 ). 5 Magnification views are obtained when calcifications are seen ( Fig. 3-4 ). 5

Figure 3-3 Diagnostic mammogram of the patient in Figure 3-1 . Spot views in craniocaudal ( A ) and mediolateral oblique ( B ) projections and full mediolateral view ( C ) demonstrate a persistent irregular, ill-defined, equal-density mass in the central posterior third of the breast ( circles ).

Figure 3-4 Diagnostic mammogram of the patient in Figure 3-2 . Magnification views in craniocaudal ( A ) and mediolateral ( B ) projections demonstrate the linear, heterogeneous pleomorphic calcifications in the upper outer left breast ( circles ).
Other indications for a diagnostic mammogram include a palpable mass, skin thickening, nipple discharge, nipple or skin changes, and possible axillary adenopathy. In these cases, the patient presents to the radiologist with a specific complaint that is addressed with mammographic and, usually, ultrasound imaging.

Ultrasound
Ultrasound is used most commonly to assist in the evaluation of suspicious masses. Ultrasound’s largest and primary impact is in determining whether a mass is solid or cystic ( Fig. 3-5 ). 6 It can also characterize a lesion as more likely to be benign or malignant based on its margins, shape, orientation, echogenicity, posterior acoustic features (ability of the sound waves to traverse through the lesion), and boundary (interface with surrounding tissue) ( Figs. 3-6 and 3-7 ). 7 Various combinations of these imaging features correlate with a level of concern for lesions seen.

Figure 3-5 Ultrasound (US) of two patients with breast masses. One patient ( A ) has a solid mass on US demonstrated by an oval, circumscribed, hypoechoic mass ( arrows ), which is most consistent with a fibroadenoma. The second patient ( B ) has a cystic mass demonstrated by an oval, circumscribed, anechoic mass ( arrows ), which is consistent with a simple cyst.

Figure 3-6 Ultrasound images demonstrating the difference between a malignant mass ( A ) and a benign mass ( B ). The first image ( A ) is of an invasive breast cancer. It reveals the suspicious features of an irregular, ill-defined mass ( long arrows ) with shadowing ( arrowheads ) and an echogenic halo ( short arrows ). The second image ( B ) is of a benign fibroadenoma ( arrows ). It reveals benign features, as described in Figure 3-5 .

Figure 3-7 Ultrasound image of the mass depicted in Figures 3-1 and 3-3 . This round, ill-defined mass ( between arrowheads ) has suspicious shadowing ( arrows) consistent with the histology of an invasive ductal carcinoma.
In lesions that require biopsy, ultrasound can be used for guidance ( Fig. 3-8 ). If a lesion is highly suspicious for malignancy or is a known cancer, ultrasound is useful for staging the disease through evaluation of the entire breast and axilla 8 ( Fig. 3-9 ). In a patient with known ipsilateral breast cancer, a lymph node with greater than 2.3 mm of cortical thickness is worrisome for metastatic disease. 9

Figure 3-8 Static ultrasound (US) image of the prefire ( A ) and postfire ( B ) needle position during an US-guided breast biopsy of the lesion depicted in Figures 3-1 , 3-3 , and 3-7 . The mass is noted by its shadowing ( A ), and it is marked with circles ( A and B ).

Figure 3-9 Ultrasound (US) staging of a patient with known invasive breast cancer demonstrates a suspicious axillary lymph node ( A, arrows ). The calipers outline the cortical thickness. US can also be used for image-guided needle biopsy of the lymph node prior to surgery. The patient’s correlative mammogram image also demonstrates the adenopathy ( B, circle ). The primary mass is palpable ( underlies the triangle in B ).

Magnetic Resonance Imaging
Although mammography and ultrasound represent the conventional imaging used to screen and evaluate abnormalities in the breast, magnetic resonance imaging (MRI) is another breast imaging modality. Indications for breast MRI are screening in high-risk patients, implant evaluation, workup of patients with axillary metastasis from unknown primaries with negative conventional imaging, evaluating extent of disease in newly diagnosed cancer patients, assessing response to chemotherapy, and, infrequently, helping resolve diagnostic dilemmas on conventional imaging. 10
Breast MRI uses intravenous contrast for identification of disease. Enhancing lesions, which take up the contrast, demonstrate common morphologies (shapes), enhancement patterns (kinetics and internal characteristics), and margins. Non-masslike areas of enhancement also have typical enhancement features and distributions. Breast MRI is a sensitive test for the detection of breast cancer, with a sensitivity for detecting invasive cancers between 89% and 100% ( Fig. 3-10 ). 11 The specificity ranges from 30% to 89%. 11, 12 If an abnormality is detected on MRI, the patient is often referred for a targeted or “second-look” ultrasound. When a biopsy is indicated, it can be performed with either MRI or ultrasound guidance. If the lesion is visualized with ultrasound and believed to correlate with the MRI finding, ultrasound guidance is feasible.

Figure 3-10 Axial postcontrast T1-weighted breast magnetic resonance imaging (MRI) depicting a typical cancer ( arrows ). The mass is heterogeneously enhancing, has spiculated margins, and is irregular in shape. This MRI scan was performed for staging purposes after the ultrasound-guided biopsy revealed invasive ductal carcinoma.

Breast Imaging Reporting and Data System
The Breast Imaging Reporting and Data System (BI-RADS) lexicon is the vocabulary used in describing all imaging findings and recommendations. 7 The standard lexicon was developed to report masses, calcifications, and associated findings for both conventional imaging and MRI. The nomenclature allows for uniformity in reports, assessments, and recommendations. 13 The main goal of the BI-RADS lexicon is to convey the level of concern and appropriate management regarding a lesion to referring physicians and the pathologists. The BI-RADS assignments also help determine concordance or discordance for biopsy results. There are seven BI-RADS categories, BI-RADS 0 through 6.
BI-RADS 0 is typically used for screening examinations that are incomplete. The patient may need further evaluation of a finding, the radiologist may want prior films for comparison, or the study may be technically inadequate. The screening examinations in Figures 3-1 and 3-2 are BI-RADS 0 studies.
BI-RADS 1 and 2 are used for final assessment of either screening or diagnostic examinations. Both categories imply that the patient has no imaging findings to suggest cancer and that the patient can continue or return to usual screening. BI-RADS 1 means no finding of significance is seen and BI-RADS 2 means the patient has a benign finding.
BI-RADS 3 is used for baseline examinations where there is a benign-appearing mass or calcifications. BI-RADS 3 interpretations have a less than 2% chance of malignancy. 14 – 16 Affected patients are followed closely for 2 to 3 years, often at 6-month intervals, to establish benignity; biopsy is not used. 17 The imaging modality that best identifies and measures the lesion is used on the follow-up examinations for comparison. The most common explanation for a BI-RADS 3 category mass is fibroadenoma (see Figs. 3-5A and 3-6B ). 18, 19 Reasons to sample a BI-RADS 3 lesion include known ipsilateral breast cancer, transplant listing, or per patient request. If the lesion increases in size or the number of calcifications has increased at follow-up, a biopsy is also indicated.
BI-RADS 4 and 5 designations are reserved for lesions that are suspicious for malignancy. BI-RADS 4 lesions are suspicious for cancer, and the reported percentage positivity for malignancy ranges from 2% to 90% ( Figs. 3-11 and 3-12 ). 7 Etiologies for BI-RADS 4 lesions cover a broad range because they include all lesions from those very unlikely to represent malignancy (BI-RADS 3) to those most likely to represent a malignancy (BI-RADS 5). BI-RADS 4 lesions can be further subdivided into 4a, 4b, and 4c, with 4c representing the highest risk. For most BI-RADS 4 lesions, a benign result that explains the imaging appearance and physical examination finding would be considered concordant.

Figure 3-11 Breast Imaging Reporting and Data System (BI-RADS) 4 calcifications. Magnification view showing clustered pleomorphic calcifications ( circle ) that are suspicious with a 2% to 90% chance of malignancy. Biopsy revealed that the calcifications were present in benign duct profiles and reactive epithelium.

Figure 3-12 Breast Imaging Reporting and Data System (BI-RADS) 4 mass. Spot craniocaudal mammogram view ( A ) and ultrasound (US) image ( B ) demonstrate a nonspecific mass ( arrows ) with lobulated shape, ill-defined margins, and equal density on mammography and hypoechogenicity on US. This mass was sampled and found to represent fibrocystic changes.
BI-RADS 5 lesions are highly worrisome for malignancy and are associated with a greater than or equal to 90% 7 chance of malignancy ( Figs. 3-13 and 3-14 ). BI-RADS 5 lesions are typically removed surgically; however, a preceding needle biopsy can aid in surgical planning.

Figure 3-13 Breast Imaging Reporting and Data System (BI-RADS) 5 palpable invasive ductal carcinoma with associated calcifications. Spot compression ( A ) view and ultrasound (US) image ( B ) demonstrate the cause of the patient’s palpable lump ( underlies the triangle in A ). On mammography ( A ), the mass ( arrows ) is ill-defined, equal density, and associated with segmental fine pleomorphic calcifications ( arrowheads ). The calcifications are more conspicuous on the mammogram than the mass. On US ( B ), the mass has heterogeneous echogenicity with an echogenic rim ( arrowheads ). A positron emission tomograph–computed tomography ( C ) reveals increased activity at the mass ( circle ).

Figure 3-14 Breast Imaging Reporting and Data System (BI-RADS) 5 mass. Screening ( A ) detected a highly suspicious round, spiculated, high-density mass ( arrows ) on mammography. Ultrasound ( B ) revealed a round, ill-defined, hypoechoic mass ( arrows ) with an echogenic halo associated with dense posterior acoustic shadowing ( arrowheads ). The lesion was found to represent an invasive ductal carcinoma with ductal carcinoma in situ.
BI-RADS 6 lesions are previously sampled malignancies that have not yet been removed.

Imaging Characteristics
Shape, margin, and density are features of masses assessed mammographically with specific BI-RADS lexicon for each morphology. Each descriptor implies a level of concern allowing the mass to be placed into an overall BI-RADS assessment category. Shape descriptors include round, oval, lobular, and irregular. Margins are classified as either circumscribed, microlobulated, obscured (by surrounding tissue), indistinct, or spiculated. Density is compared with that of the surrounding tissue and classified as low, equal, or high density, or fat-containing. 7 Ultrasound shares most of the mammographic lexicon for mass shape and margin. Additionally, angular is a margin descriptor for ultrasound. With ultrasound, one gains the ability to assess the echogenicity (relative to fat), orientation (parallel to the chest wall or antiparallel), lesion boundary (either sharply demarcated or not), and through transmission of the sound waves (ability of the sound beam to go through the lesion being imaged and allow visualization of the tissue deep to it). 6, 7
MRI terminology for shape (round, oval, lobulated, or irregular) and margin (smooth, irregular, or spiculated) is similar to that for mammography. Additional information gained from MRI is the enhancement features of the mass. Enhancement can range from homogeneous throughout to more heterogeneous. The enhancement kinetics (change over time) is also part of the BI-RADS lexicon and helps determine if a mass is more likely benign or malignant. Masses that rapidly enhance and wash out quickly are most worrisome for malignancy. 7

Features of Typically Benign Mass Lesions
Masses with an oval or round shape, circumscribed margins, and equal or low density on mammography; homogeneous iso- or hypoechoic echogenicity with a parallel orientation, an abrupt interface with surrounding tissue, and no increased through transmission on ultrasound; and homogeneous slow and persistent enhancement on MRI are typically benign ( Fig. 3-15 ). Favored histology for this type of mass is a fibroadenoma, 18 – 20 complicated cyst, 21 or papilloma. 22

Figure 3-15 A typical appearance for a benign mass on mammography ( A, arrows ), ultrasound (US) ( B, arrows ), and magnetic resonance imaging (MRI) ( C, arrows ). This fibroadenoma has circumscribed margins on all modalities. It demonstrates homogeneous hypoechogenicity on US and homogeneous enhancement on MRI. The triangle in A indicates that the mass is palpable to the patient.

Features of Typically Malignant Mass Lesions
Masses with irregular shape, spiculated margins, and high density on mammography; angular margins, hypoechoic echogenicity, an antiparallel orientation to the chest wall, and decreased through transmission (or shadowing) on ultrasound; and heterogeneous rapid initial and washout kinetic enhancement on MRI are worrisome for malignancy. Favored histology for this type of mass is an invasive carcinoma, not otherwise specified ( Figs. 3-16 and 3-17 ). Another lesion to consider is a radial scar (nonmalignancy). 23, 24

Figure 3-16 A typical appearance for a malignant mass on mammography ( A, arrows ), ultrasound (US) ( B, arrows ), and MRI ( C, arrows ). This invasive ductal carcinoma has spiculated margins on mammography and MRI and angulated margins on US. It features heterogeneous enhancement on MRI.

Figure 3-17 Architectural distortion from an invasive ductal carcinoma on a full mediolateral oblique projection ( A, circle ) and a spot compression view over the abnormality ( B, circle ). The calcifications nearby are lucent-centered fat necrosis (benign and unrelated).

Calcification Morphology
Features of calcifications described through the BI-RADS lexicon include the morphology and the distribution on mammography. Calcification features can be classified as those that are typically benign, of intermediate concern/suspicious, or of a higher probability of malignancy.
Some calcification morphologies have such a characteristic appearance within the typically benign category that tissue sampling is not necessary. One such example is coarse popcorn-like calcifications, which represent degenerating fibroadenomas ( Fig. 3-18A ). 5 Another is lucent-centered calcifications resulting from fat necrosis (trauma) (see Fig. 3-18B ). 25 Unfortunately, not all calcifications can be specifically identified when they are new or changing.

Figure 3-18 Characteristically benign calcifications. Popcorn-like calcifications within fibroadenomas ( A ). Lucent-centered fat necrosis calcification ( B, arrow ).
Amorphous or indistinct ( Fig. 3-19A ) as well as coarse, heterogeneous (see Fig. 3-19B ) calcifications are of intermediate concern. These calcifications commonly referred for biopsy as ductal carcinoma in situ (DCIS) cannot be excluded based on the imaging features. 26

Figure 3-19 Intermediate concern/suspicious calcifications. Amorphous or indistinct calcifications from atypical ductal hyperplasia and fibrocystic change ( A, circle ) and coarse heterogeneous calcifications from stromal fibrosis ( B, circle ).
The higher probability of malignancy morphologies are fine pleomorphic, fine linear, or fine linear branching calcifications. 27 These are often given a BI-RADS 5 assessment and referred for biopsy because they usually represent DCIS, commonly intermediate-grade or high-grade ( Fig. 3-20 ). Early vascular or secretory calcifications can mimic fine linear branching calcifications and can require sampling to determine etiology.

Figure 3-20 Higher probability of malignancy calcifications. Linear/fine linear branching calcifications represent DCIS ( circle ).

Calcification Distribution
Distribution modifiers include diffuse/scattered and regional (which are more commonly benign), grouped or clustered (which are indeterminate; see Fig. 3-19 ), and linear (see Fig. 3-20 ) and segmental (which are the more worrisome descriptors; see Fig. 3-13 ). Diffuse/scattered and regional distributions are usually not biopsied. Linear and segmental distributions are the most worrisome because these imply a ductal process and are therefore suggestive of DCIS. 27
Grouped or clustered distribution is a nonspecific category and can represent benign or malignant processes. When calcifications are pleomorphic, the favored benign explanations are fibrocystic change, papilloma, and fibroadenoma. 5 Unfortunately, DCIS also can present this way. When calcifications are amorphous or indistinct, two benign possibilities are fibrocystic change (FCC) and sclerosing adenosis. 26 Again, DCIS can present this way, which is why these types of calcifications are sampled.

Non-masslike Enhancement on Magnetic Resonance Imaging
Non-masslike enhancement on MRI can be a sign of DCIS, much like calcifications on mammography. This finding is described by its patterns of distribution in the breast and internal enhancement; these two categories are in line with the distribution and morphology lexicon for calcifications. Possible distributions for non-masslike enhancement include focal, linear, ductal, segmental, regional, or diffuse. The internal enhancement is described as homogeneous/confluent, heterogeneous/nonuniform, stippled/punctate, clumped, or reticular/dendritic. 28 Many combinations of distribution and enhancement features are ultimately sampled, because nearly all can represent DCIS ( Figs. 3-21 and 3-22 ). The diffuse or regional distribution, especially if symmetric, is the least worrisome for malignancy.

Figure 3-21 Linear homogeneous enhancement on MRI found to represent DCIS on biopsy ( circle ).

Figure 3-22 Segmental clumped enhancement on MRI found to represent DCIS on biopsy ( arrows ). The patient had a known invasive ductal carcinoma ( circle ) at the time of the MRI examination.

Biopsy Techniques: Image-Guided Biopsy Methods
Modalities used for image-guided biopsies include mammography, ultrasound, and MRI. The method used is typically based on which modality shows the abnormality best and which is the safest for the patient. Stereotactic biopsy is the most common means of sampling a lesion. Mammogram images are used to guide biopsies of calcifications or lesions. Ultrasound is useful for most masses. MRI-guided biopsies are usually reserved for enhancing masses or non-masslike findings that are not visible on either mammography or ultrasound.

Needle Types
Three main needle types are used for performing breast biopsies. These include vacuum-assisted needles (10- to 12-gauge), throw or core needles (14- to 18-gauge), and fine needle aspiration needles (22- to 25-gauge). The vacuum-assisted needles harvest the most tissue 29 and are typically used in biopsying calcifications under stereotactic guidance or lesions seen on MRI. The throw or core needles are selected for biopsying masses with ultrasound guidance. Sampling of enlarged lymph nodes may use a small-gauge core needle (Temno) or fine needle aspiration, using a larger gauge needle. The selection is by the discretion of the physician performing the procedure. It is possible to obtain material for immunohistochemical assessment using either procedure.

Calcifications: A Special Case
Calcifications are usually biopsied with larger gauge vacuum-assisted devices because they harvest more tissue. 29 The differential diagnosis of calcifications includes DCIS and atypical ductal hyperplasia (ADH) as well as benign processes. Because the differentiation between DCIS and ADH is both qualitative and quantitative, providing adequate volume is helpful for the pathologist to assign the correct diagnosis. 30 Despite this, ADH may be upgraded to DCIS on excision in 10% to 27% of patients 30 ( Fig. 3-23 ). For this reason, patients with ADH on a core needle biopsy are referred to surgery for additional sampling of the tissue to ensure that cancer is not present. 31 – 34

Figure 3-23 Single magnification view demonstrating calcifications ( circle ), which were found to represent atypical ductal hyperplasia on core needle biopsy but were upgraded to ductal carcinoma in situ at final pathology.

Biopsy Site Markers
During a biopsy, a clip or metallic marker is often placed at the biopsy site. This enables the radiologist to return to the area during wire localization for surgery, if required. In some cases, the radiographic finding is removed or obliterated during the biopsy. 35 However, the postbiopsy radiographic appearance is not associated with a significant decrease in the risk of malignancy found on final pathology, nor does it imply that a cancer removed by core biopsy has been adequately treated. 35 If the patient undergoes mastectomy, the clip or marker can help the pathologist identify and evaluate the site of proven disease ( Fig. 3-24 ). Another benefit of clips or markers is for correlation of the biopsy site with the imaging finding. An immediate postbiopsy mammogram is usually obtained to determine whether the marker is in the expected site of disease. It is important to recognize if the lesion targeted was sampled appropriately ( Fig. 3-25 ). This is especially important in women with multiple sites of calcifications or in women for whom the ultrasound finding may not correlate with the mammographic lesion. In the first case, the wrong cluster of calcifications can be targeted, and in the second case, the ultrasound finding may be an incidental finding that does not explain the initial mammographic abnormality. It is important to recognize that if the wrong area was targeted, it is necessary to discuss this with the patient and plan for the next step.

Figure 3-24 Biopsy site marker ( arrowhead ) at the site of a recent breast biopsy ( circles ). Postbiopsy mammogram, craniocaudal and mediolateral projections ( A and B ), of the patient in Figure 3-1 .

Figure 3-25 Example of the biopsy marker post–ultrasound-guided breast biopsy, which does not correlate with the mammographic lesion of concern. The suspicious mass is readily apparent on the full mediolateral view of the left breast ( A, circle ). The ultrasound performed on the same day revealed an equally concerning palpable mass ( B, arrows ). The postbiopsy mammogram demonstrates the biopsy marker ( C, arrow ); under ultrasound guidance, it is cephalad to the mammographic finding ( circle ). A stereotactic-guided biopsy was then performed ( D ), with the postbiopsy mammogram revealing the new biopsy marker in the suspicious lesion ( E, circle ). This patient was found to have an invasive ductal carcinoma.

Accuracy of Core Needle Biopsies
Image-guided needle biopsies are accurate and safe procedures. 36, 37 The false-negative rate is approximately 1.2% to 4.0%. 38 This is comparable to a surgical diagnostic excision with wire localization. 39 The main risks include bleeding and infection.

Differential Diagnosis
Breast lesions fall into typical pathologic patterns. These include those that are stromal predominant (SP), stromal and epithelial (SE), infiltrative (IF), nodular (N), intraductal (ID), and intralobular (IL). The following paragraphs are organized by the commonly used terms for radiographic abnormalities that are routinely referred for biopsy. The descriptors are followed by identification of lesions that would appropriately explain the imaging appearance.

Masses

Round or Oval, Circumscribed
Round or oval masses with circumscribed masses are most often benign lesions ( Fig. 3-26 ). Examples of benign lesions with these imaging features include pseudoangiomatous stromal hyperplasia (PASH) (SP), 40 – 42 hamartomas (SP, N), 43 – 45 FCC (SP, SE), 21, 46 phyllodes tumor (SP, SE, N), 45, 47 fibroadenomas (SE, N), 20 granular cell tumor (IF), 42, 48 – 50 lymph nodes (N), tubular adenomas (N), 42, 51 papillomas (ID), apocrine metaplasia (ID), and lactational change (ID). 42, 52

Figure 3-26 Examples of benign lesions with round or oval shape and circumscribed margins. Pseudoangiomatous stromal hyperplasia (PASH) on ultrasound (US), shown as an oval, circumscribed, complex mass ( A, between arrows ). The patient’s mammogram did not demonstrate the mass. Phyllodes tumor on mammography ( B, under triangle ) and US ( C, between arrows ), shown as an oval, circumscribed, equal density, hypoechoic mass. A fibroadenoma on mammography ( D, arrows ) and US ( E, between arrowheads ), shown as an oval, circumscribed, equal density, hypoechoic mass. A papilloma on mammography ( F, arrows ) and US ( G, arrows ), shown as a round, circumscribed, equal density, hypoechoic mass associated with grouped calcifications. Granular cell tumor on mammography ( H, under bright circle) and US ( I, between cursors ) as a round, circumscribed, equal density, mixed echogenicity mass located in the subcutaneous fat in the low axilla.
If the circumscribed mass also contains fat, then the differential can be further limited to a hamartoma (SP, N), fat necrosis/oil cyst (SP, IF), 25, 53, 54 lymph node (N), lactational change/galactocele (ID), 52 or lipoma ( Fig. 3-27 ). However, if imaging confirms the presence of fat within the lesion, these masses are usually not sampled.

Figure 3-27 Examples of benign, circumscribed, fat-containing lesions. Hamartoma ( A, arrowheads ) and oil cysts ( B, arrowheads ).
Occasionally malignant lesions appear round and relatively circumscribed ( Fig. 3-28 ). Malignant masses that can mimic benign lesions on imaging include some of the variants of invasive ductal carcinoma such as mucinous, papillary, and medullary carcinoma. 5 Invasive ductal carcinoma, not otherwise specified, can also have a similar radiographic appearance, especially if high grade.

Figure 3-28 Examples of malignant lesions with round or oval shape and relatively circumscribed margins. Mucinous carcinoma on mammography ( A, arrows ) and ultrasound (US) ( B, arrows ) as a round, predominately circumscribed, equal density, hypoechoic mass. Papillary carcinoma on mammography ( C, arrows with biopsy marker ) and US ( D, between arrowheads ) as an oval, partially circumscribed, partially ill-defined, equal density, hypoechoic mass.

Complex
Ultrasound demonstrates the internal imaging features of masses extremely well. When masses are complex with cystic and solid components, the differential is focused to fibrocystic changes, PASH, phyllodes tumor, carcinomas, fibroadenomas, papillomas, ADH, and DCIS ( Fig. 3-29 ). 20, 21, 42, 46, 55, 56

Figure 3-29 Examples of complex masses (those with both solid and cystic components). Fibrocystic changes as an oval, circumscribed, mass ( A ) (incompletely shown to better demonstrate the internal characteristics, arrows ) that is predominately cystic. However, this mass has two echogenic nodules along the wall suspicious for solid components ( arrowheads ). The mass was excised because there was a concern for a papillary neoplasm. The first papilloma ( B, between arrowheads ) is an oval, ill-defined mass with subtle cystic components ( arrows ). The second papilloma ( C, arrowheads ) is a lobulated, circumscribed complex mass. DCIS may be an oval, circumscribed, complex palpable mass ( D, arrowheads ).

Irregular, Ill-Defined
Masses that are irregular and ill-defined can be benign or malignant, with a broad differential ( Fig. 3-30 ). Benign lesions included in this differential are PASH, postsurgical scar, diabetic mastopathy, fat necrosis, granular cell tumor, and FCC (SP, SE). 20, 25, 42, 48 – 50 ,57 FCC has many imaging features, including an asymmetry with irregular, ill-defined borders.

Figure 3-30 Examples of ill-defined and irregular masses. Invasive ductal carcinoma on mammography ( A, circle ) and ultrasound (US) ( B, arrowheads ). Stromal fibrosis on mammography ( C, circle ) and US ( D, between arrowheads ).

Spiculated
Spiculated masses are most commonly malignant; however, a few benign lesions have this imaging characteristic ( Fig. 3-31 ). The malignant masses include ductal carcinomas, lobular carcinomas, tubular carcinomas, and least commonly, DCIS (ID). 24, 58 The benign masses include sclerosing adenosis, postsurgical scars, fat necrosis, and radial scars. 23, 24, 53, 54

Figure 3-31 Examples of spiculated masses. Invasive ductal carcinoma (IDC) on mammography ( A, circle ) and ultrasound (US) ( B, arrowheads ), IDC on mammography ( C, circle ) and US ( D, arrowheads ).IDC on mammography ( E, circle ) and US ( F, arrowheads ), and a radial scar on mammography ( G, circle ) and US ( H, arrowheads ). The radial scar is more conspicuous on mammography.

Hyperintense on T2-Weighted Magnetic Resonance Imaging
Enhancing masses on MRI may have overlapping imaging features. One imaging sequence that can help narrow the differential diagnosis is the T2-weighted sequence. Masses that are bright, or hyperintense, on the T2-weighted sequence are PASH, phyllodes, metaplastic carcinoma, fibroadenomas, mucinous carcinomas (N), lymph nodes, and papillomas ( Fig. 3-32A ). 42, 55, 59 – 61 When invasive carcinoma has areas of necrosis, portions of the mass are hyperintense on the T2-weighted MRI sequences ( Fig. 3-32B ).

Figure 3-32 Examples of lesions that are hyperintense on T2-weighted fat-suppressed MRI. A, Papilloma with predominately bright signal on axial MRI image ( arrowheads ). B, Invasive ductal carcinoma with necrosis as evidenced by the areas of bright T2-signal intensity ( arrowheads ).

Ductal Enhancement on Magnetic Resonance Imaging
Ductal enhancement is a common indication for an MRI-guided breast biopsy ( Fig. 3-33 ). The differential diagnosis of ductal enhancement includes DCIS, ADH, and lobular carcinoma in situ (LCIS), as well as benign findings such as FCC, usual ductal hyperplasia, and fibrosis. 62

Figure 3-33 Examples of ductal enhancement on MRI. Linear ductal enhancement on this axial T1-weighted fat-saturation MR image ( A, circle ) representing DCIS. Segmental ductal enhancement on axial T1-weighted fat-saturation subtraction MR image ( B, circle ) and axial T1-weighted fat-saturation maximum intensity MRI scan ( C, circle ), which better shows the overall extent of low-grade DCIS. Linear ductal enhancement on this axial T1-weighted fat-saturation subtraction MRI ( D, circle ) representing fibrocystic change.

Filling Defect(s) on Galactography
The indication for a galactogram is a unilateral, single-duct, bloody or clear, spontaneous nipple discharge. This study allows visualization of the milk duct, which is not possible with routine mammography. The most likely explanation for this type of discharge and a ductal mass seen as a filling defect on the images is a papilloma ( Fig. 3-34A and B ). 63 Other lesions include DCIS ( Fig. 3-34C ), invasive carcinoma, or debris within a duct. 63

Figure 3-34 Examples of filling defects on galactography. A, Galactography demonstrates two filling defects ( circles ) in ductal branches that were found to represent papillomas. B, A single ultrasound image shows one of the masses as an oval, echogenic, circumscribed mass ( between arrows ) within a dilated fluid-filled duct ( arrowheads ). C, Galactogram demonstrating multiple filling defects ( two marked by arrowheads ) in multiple ducts and areas of ductal narrowing ( small arrow ) and dilatation ( large arrow ). This patient had widespread DCIS.

Architectural Distortion
Lesions that result in architectural distortion on imaging include a postsurgical scar, fat necrosis, recurrent cancer, radial scars, and invasive carcinomas (see Fig. 3-17 ). 23, 25, 58, 64

Calcifications

Grouped, Round, or Punctate
Grouped, round, or punctate calcifications require sampling if they are new or changing. However, these types of calcifications are typically benign ( Fig. 3-35 ). The differential diagnosis for this finding includes FCC, sclerosing adenosis, fibroadenoma, papilloma, DCIS, and lobular calcifications from atypical lobular hyperplasia (ALH) and LCIS. 5, 65, 66

Figure 3-35 Examples of punctate/round calcifications on magnification views. A, Grouped punctate calcifications secondary to fibrocystic changes ( circle ). B, Round calcifications secondary to fibrocystic changes with sclerosing adenosis ( circle ). C, Round calcifications secondary to focal ductal hyperplasia, lobular fibrosis, and fat necrosis ( circle ).

Grouped Amorphous
Because amorphous calcifications are of intermediate concern for malignancy, they are frequently sampled (see Fig. 3-19A ; Fig. 3-36 ). An important differential consideration is DCIS. 67 Other acceptable histologic correlates include FCC, sclerosing adenosis, ADH, columnar cell change, ALH, and LCIS. 5, 65, 66 – 68

Figure 3-36 Examples of grouped amorphous calcifications. Magnification views demonstrating grouped amorphous calcifications ( circles ) from low-grade DCIS ( A ) and atypical ductal hyperplasia ( B ).

Grouped Heterogeneous or Pleomorphic
Calcifications that are either heterogeneous or pleomorphic in morphology may form secondarily to benign or malignant etiologies (see Fig. 3-19B ; Fig. 3-37 ). When grouped, these types of calcifications are suspicious for malignancy, particularly if they are new or changing. Differential considerations include FCC, sclerosing adenosis, fat necrosis, fibroadenoma, columnar cell change, and DCIS. 5, 20, 25, 53, 68

Figure 3-37 Examples of heterogeneous pleomorphic calcifications. Magnification views of grouped clustered heterogeneous pleomorphic calcifications ( circles ) secondary to fibrocystic changes ( A ); calcifications in benign duct profiles ( B ); a degenerating fibroadenoma (the other calcifications seen are vascular) ( C ); and DCIS ( D ).

Linear
Linear calcifications or calcifications of various morphologies in a linear distribution are worrisome for malignant ductal processes. There are benign causes for linear calcifications (both morphology and distribution). However, because this morphology and distribution is associated with an 85.7% rate of malignancy, they are invariably sampled (see Figs. 3-20 and 3-23 ; Fig. 3-38 ). 27 The most common cause is DCIS (ID). Benign processes include calcification of vascular walls or secretory calcifications (linear morphology). FCC may present in a linear distribution but is more commonly round/punctate or pleomorphic in morphology.

Figure 3-38 Examples of linear and segmental calcifications on magnification views all secondary to DCIS. A, Segmental fine pleomorphic calcifications ( circle ). B, Linear/fine linear branching calcifications ( circle ). C, Linear pleomorphic heterogeneous calcifications ( circle ).

Segmental
When calcifications are present in a segmental distribution, regardless of morphology, DCIS is typically first in the differential (see Figs. 3-13 and 3-38 ). However, as with linear calcifications, FCC may result in a segmental distribution of calcifications.

Management after Biopsy
After a biopsy is performed for calcifications (and occasionally for masses), a radiograph of the tissue specimens is performed to confirm sampling of the targeted area ( Fig. 3-39 ). 36 The samples containing the calcifications (or density) can be separated from the rest of the cores into a collection chamber to aid the pathologist in evaluating the specimen. On review of the pathology report, the radiologist is looking for a specific discussion about what in the histology can explain the imaging finding. In the case of calcifications, a report that states “calcifications are in benign duct profiles” is very helpful at the time of radiographic-pathology correlation in determining concordance. Occasionally, a mass is sampled, and the report states that “there is no histologic finding to support the imaging finding of a mass.” In these cases, it is up to the imager to determine whether the pathology result could explain a mass on imaging and to determine if the biopsy was an adequate sample of the abnormality.

Figure 3-39 Specimen radiograph of samples obtained during a stereotactic biopsy for calcifications. The radiograph demonstrates calcifications in the samples ( circles ).
Correlation on MRI-guided biopsies can be more challenging. First, there has to be confidence on the part of the imager that the correct location was sampled. It is not possible to image the tissue ex vivo for proof of lesional tissue, but postbiopsy MRI can show hemorrhage and artifact from air intrusion or the marker identifying the biopsy site. In reviewing histology results for concordance, one must consider the morphology and distribution of the enhancing tissue.
Management of a patient following a biopsy is determined by the imaging findings, the level of suspicion, confidence that the targeted lesion was adequately sampled, and the histology result. Benign concordant lesions are commonly followed at 6 or 12 months. 36 Some benign lesions are referred for surgical excision because of their risk of future or concurrent malignancy (see later discussion). Malignant masses are excised. Occasionally, the histology result does not adequately explain the imaging appearance and is termed “benign discordant.” In these cases, surgical excision is recommended to allow confirmation of the histology findings ( Fig. 3-40 ).

Figure 3-40 Benign discordant result after core needle biopsy. The initial histology result revealed fibrocystic changes with calcifications in benign duct profiles. In this case, the imaging appearance, segmental heterogeneous pleomorphic and fine linear branching calcifications ( circles ), was more concerning than the histology. Surgical excision was recommended, and the final pathology was DCIS and atypical lobular hyperplasia.
High-risk lesions, such as radial scar (complex sclerosing lesion) and ADH, are referred for surgical excision. Several studies have shown a significant percentage of these cases are upgraded to a malignant diagnosis based on the findings in the surgical excision specimen: 4% to 28% for radial scar and 10% to 38% for ADH. 30 – 32 , 69 – 71 Other lesions such as papilloma, ALH, and LCIS are more controversial but have been reported in some studies to have a significant change in diagnosis when excised, leading some institutions to recommend surgical excision when these lesions are found on core biopsy. 22, 23, 30 – 32 , 34 , 72 – 79

Conclusions
Imaging findings of cancer are broad and overlap with benign lesions. For this reason, many breast abnormalities undergo image-guided biopsy. Using appropriate imaging modalities, BI-RADS lexicon, and radiology-pathology correlation allows for the correct management of patients following biopsies. Radiologists and pathologists need to work closely together to ensure the best outcome for the patient.

Suggested Readings

Andrino F, Calabrese M, Faedda C, et al. Tubular carcinoma of the breast: pathological, clinical, and ultrasonographic findings. A review of the literature. Radiol Med . 2006;111(6):773–782.
Balleyguier C, Ayadi S, Van Nguyen K, et al. BIRADS classification in mammography. Eur J Radiol . 2007;61(2):192–194.
Berg WA, Hruban RH, Kumar D, et al. Lessons from mammographic-histopathologic correlation of large-core needle breast biopsy. Radiographics . 1996;16(5):1111–1130.
Cohen MA. Cancer upgrades at excisional biopsy after diagnosis of atypical lobular hyperplasia or lobular carcinoma in situ at core-needle biopsy: some reasons why. Radiology . 2004;231(3):617–621.
Dershaw DD, Liberman L. Stereotactic breast biopsy: indications and results. Oncology (Williston Park) . 1998;12(6):907–916. discussion 916, 921–922
Jackman RJ, Marzoni FA, Jr., Rosenberg J. False-negative diagnoses at stereotactic vacuum-assisted needle breast biopsy: long-term follow-up of 1,280 lesions and review of the literature. AJR Am J Roentgenol . 2009;192(2):341–351.
Jara-Lazaro AR, Tse GM, Tan PH. Columnar cell lesions of the breast: an update and significance on core biopsy. Virchows Arch . 2008;452(6):589–598.
Liberman L. Clinical management issues in percutaneous core breast biopsy. Radiol Clin North Am . 2001;38(4):791–807.
Mendez A, Cabanillas F, Echenique M, et al. Mammographic features and correlation with biopsy findings using 11-gauge stereotactic vacuum-assisted breast biopsy (SVABB). Ann Oncol . 2004;15(3):450–454.
Schepps B, Scola FH, Frates RE. Benign circumscribed breast masses. Mammographic and sonographic appearance. Obstet Gynecol Clin North Am . 1994;21(3):519–537.
Sickles EA. Breast masses: mammographic evaluation. Radiology . 1989;173(2):297–303.
Telli ML, Horst KC, Guardino AE, et al. Phyllodes tumors of the breast: natural history, diagnosis, and treatment. J Natl Compr Canc Netw . 2007;5(3):324–330.
Tse GM, Tan PH, Pang AL, et al. Calcification in breast lesions: pathologists’ perspective. Breast Cancer Res Treat . 2008;110(1):1–7.
Ueng SH, Mezzetti T, Tavassoli FA. Papillary neoplasms of the breast: a review. Arch Pathol Lab Med . 2009;133(6):893–907.

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4 Surgical Approaches to Breast Lesions

David R. Brenin, MD, Anneke T. Schroen, MD, MPH

Fine Needle Aspiration Biopsy
Core Needle Biopsy
Fine Needle Aspiration or Core Needle Biopsy of Presumed Axillary Lymph Node
Excisional Biopsy
Lumpectomy
Surgery after Neoadjuvant Therapy
Mastectomy
Sentinel Lymph Node Biopsy
Axillary Dissection
Mesenchymal Lesions
This chapter discusses surgical techniques for the treatment of breast lesions from the perspective of breast surgeons. The authors attempt to address a few of the more common scenarios and potential pitfalls in which communication between the pathologist and surgeon is more important than usual (whether in requisition forms, pathology reports, or at tumor boards) in ensuring that the treatment of a breast cancer patient is optimized.

Fine Needle Aspiration Biopsy
The use of fine needle aspiration (FNA) biopsy as a technique of tumor diagnosis is generally attributed to Martin and Ellis, who first published their report describing FNA biopsy use in 1930. 1 FNA biopsy, defined as the sampling of a breast lesion with a 21-gauge needle or greater, has been widely used for the diagnosis of breast lesions in the United States since the 1970s.
In the hands of a skilled operator, FNA biopsy is safe, accurate, well tolerated by the patient, inexpensive, requires no special equipment, and can be easily carried out in almost any patient setting. When an adequate specimen is provided to an experienced cytopathologist, the diagnostic accuracy of FNA biopsy should be high, although it can vary widely. In an analysis of 31,340 FNA biopsies reported in various studies, Hermans found that sensitivity ranged from 65% to 98%, and specificity ranged from 34% to 100%. 1, 2 It is important for clinicians to ascertain the sensitivity of FNA biopsy at their own institutions. In skilled hands, FNA biopsy is the ideal method for answering the question “is this lesion most likely malignant or benign?” on the same day the biopsy is performed.
From a surgical perspective, FNA biopsy results can be broken down into five categories:

1. Negative for malignancy
2. Atypical
3. Suspicious for malignancy
4. Malignant
5. Unsatisfactory or scant
Accurate FNA biopsy requires that the operator is confident that the area biopsied corresponds to the area of concern. An FNA biopsy result of benign breast epithelium could lead to a delay in the diagnosis of malignancy if the lesion is simply missed or the wrong area of the breast is sampled. It is incumbent on the treating physician to confirm that the correct area of the breast is biopsied and that the results correlate with the physical examination and imaging findings. For these reasons, the authors recommend that the treating physician or breast imager perform the FNA biopsy or the pathologist do so in close coordination with the treating physician. A result interpreted as negative for malignancy that is believed to be concordant would likely lead to a recommendation of short-term follow-up or resumption of routine screening. All other results would likely lead to additional procedures, such as an excisional biopsy or a core biopsy, for additional pathologic detail or better operative planning.
It is important that the pathologist ensures that the treating physician understands that FNA biopsy cannot reliably distinguish between invasive ductal carcinoma and ductal carcinoma in situ (DCIS). It is best to obtain histologic confirmation of invasion prior to proceeding with axillary staging. In practice settings lacking the support of a cytopathologist, core needle biopsy is the minimally invasive biopsy technique of choice. Core needle biopsy also has the ability to distinguish invasive cancer from DCIS. However, compared with FNA, core biopsy requires expensive equipment and typically has a longer turnaround time for interpretation.

Core Needle Biopsy
Concerns regarding the possibility of an unrecognized “missed biopsy” in a patient undergoing a core biopsy are similar to those previously mentioned for a patient undergoing FNA biopsy. Therefore, it is again incumbent on the treating physician to confirm that the correct area of the breast is biopsied and that the results correlate with the physical examination and imaging findings. The authors recommend that the treating physician or breast imager perform the biopsy or do so in close coordination with the pathologist.
Core needle biopsy provides material for histologic evaluation and is the procedure of choice for suspected malignancies. From a surgical perspective, core needle biopsy results can be broken down into five categories.

1. Diagnoses that require surgical excision, which include invasive carcinoma and DCIS. Additional comments on the presence of microcalcifications and their association with malignancy or benign ducts can be very helpful in planning the extent of surgical excision. For example, if the DCIS is associated with calcifications, planning of wire placement for localized excision and utilization of specimen radiography can help ensure that the entire affected area has been removed.
2. Diagnoses that are histologically benign. As long as the histologic results correlate with the imaging features that prompted the biopsy, no surgical intervention is necessary. It is helpful to know all of the benign findings for good imaging correlation. If the lesion was classified as BI-RADS 5 (radiographically malignant), an excisional biopsy is performed regardless of the benign pathology due to concerns that this result is clinically discordant. Similarly, any benign discordant result as typically determined by the clinician performing the biopsy requires an excisional biopsy to verify the pathologic diagnosis.
3. Histologic findings that are associated with significant excisional biopsy “upgrades.” This includes atypical ductal hyperplasia, atypical lobular hyperplasia, and flat epithelial atypia (atypical columnar cell change). Rates of upgrade of 10% to 50%, primarily to DCIS, have been reported. 3 In newer series using larger bore core biopsy needles, this rate of upgrade may fall below 20%, but nonetheless an excisional biopsy for definitive pathology is still required. 3 Flat epithelial atypia (atypical columnar cell change) is treated like atypical ductal hyperplasia from a surgical perspective.
4. Lesions with conflicting evidence of significant “upgrades.” The necessity of excision is less clear for other lesions such as lobular carcinoma in situ (LCIS), intraductal papillomas, and radial scars. Often these lesions require radiographic correlation, and treatment varies among institutions. Whenever significant atypia is seen, however, excision ensues (e.g., pleomorphic LCIS, papilloma with atypia).
5. Pathologic interpretations that convey ambiguity, which include diagnoses such as “complex sclerosing lesion,” “atypical fibroepithelial lesion,” and “adenosis with focal cytologic atypia.” In these cases, the differential diagnosis is important to discuss so that the breast imager and surgeon recognize the need for more tissue.

Fine Needle Aspiration or Core Needle Biopsy of Presumed Axillary Lymph Node
Many breast centers routinely perform either a preoperative axillary ultrasound or a breast magnetic resonance imaging scan with axillary lymph node evaluation for patients with newly diagnosed breast cancer. 4, 5 If the axillary nodes appear abnormal, an ultrasound-guided core biopsy or FNA biopsy can be performed. Tissue from a biopsy of a presumed axillary lymph node may contain (individually or in combination) malignant cells, normal lymph nodes, fat, or normal breast tissue.
When evaluating malignant specimens from the upper/outer quadrant or axilla, it is important to note which of the following categories the specimen falls into:

• Tumor only with no residual normal tissue
• Tumor with residual lymph node
• Tumor with residual breast tissue
These distinctions are clinically significant because they allow the surgeon to ascertain if both the primary tumor location and nodal status are known.
Accurate communication between the pathologist and the treating physician is particularly important for specimens resulting from an axillary biopsy. A common scenario of an error in management resulting from miscommunication is that of a patient presenting with a lesion in the upper/outer quadrant of the breast that is mistaken by the treating physician as a lymph node when in fact it is a primary lesion in the breast. A pathology report from such a specimen labeled axillary biopsy or axillary node indicating “adenocarcinoma” for a biopsy containing malignant cells and normal breast tissue but no lymphatic tissue, could easily be misconstrued by the treating physicians as metastatic disease in an axillary lymph node. Such a patient might undergo a needless axillary dissection. Conversely, an axillary mass can be mistaken for the primary tumor, when in fact it is an axillary lymph node replaced with metastatic disease. In this scenario, the biopsy might contain malignant cells, lymphoid tissue, and no normal breast epithelium. A pathology report indicating “adenocarcinoma,” intended by the pathologist to indicate metastatic disease to a lymph node, might be misconstrued by the clinician as a positive biopsy of a primary tumor in the tail of the breast. In this case, a patient might undergo a “lumpectomy” and sentinel node biopsy only to leave behind the occult primary tumor that was never suspected to be present elsewhere in the breast.
Accurate communication of the findings, with a mutually agreed-on lexicon of terms, is vitally important. A diagnosis of “no tumor seen” or “no pathologic finding” would suffice for a negative biopsy but only if the pathologist can be assured that it is understood by the treating physician to indicate that normal lymph node was seen. In all other cases, it is essential to clearly state the findings in the report (e.g., malignant cells only, malignant cells with normal breast epithelium, fat only, or normal breast tissue only).

Excisional Biopsy
A core biopsy demonstrating cytologic atypia typically is followed by an excisional biopsy of the lesion sampled. The lesion is removed to rule out the presence of an adjacent malignancy. 3, 6 An excisional biopsy may also be performed for suspicious lesions identified on breast imaging that are not amenable to percutaneous needle biopsy.
When evaluating an excisional biopsy following a core biopsy, it is important to keep in mind that radiographic markers can migrate. The unrecognized migration of a radiographic marker can result in the wrong area of the breast being targeted for excision, leading to a “missed biopsy.” Therefore, identification of the prior biopsy site to confirm removal of the area previously sampled is critical. In the case of a migrated marker, a radiographic marker may be present in the excisional biopsy specimen, but no scar from the previous core biopsy is observed. A negative pathology report such as “biopsy clip with calcifications in benign ductal profiles” is the correct interpretation of the microscopic findings, but in the previously mentioned case, such a report could result in misdiagnosis. The pathology report from an excisional biopsy following a core biopsy should include a comment on concordance, indicating that the site of the previous core biopsy is identified in the specimen. The presence of a radiographic marker, but no microscopic evidence of a previous biopsy, should raise the question of a “missed biopsy.”

Lumpectomy
Breast-preserving surgery is the procedure of choice for most women with breast cancer. However, when compared with mastectomy, breast preservation carries with it an increased risk of local recurrence. In a modern meta-analysis, breast conservation therapy, defined as lumpectomy plus radiation therapy, entails a local recurrence risk of 7%. 7, 8 Tumor margin status has a significant impact on local recurrence risk, 9 and therefore the pathologist plays a pivotal role in the prevention of local failure.
Accurate margin measurements are dependent on good communication between surgeon and pathologist. Ideally, the lumpectomy specimen is oriented to allow individual margin assessments. Regardless of the specific method used, reporting the various margins separately facilitates directed reexcisions when needed. 10, 11 Directed reexcisions allow the removal of less tissue than reexcision of the entire lumpectomy bed.
Careful margin assessment with documentation of millimeter-measured distances to each of the six specimen margins is important. These distances are likely the most important factor considered in the determination of a patient’s definitive surgical therapy (reexcision, lumpectomy, or mastectomy). It is necessary to report margins for invasive disease and DCIS separately, because their acceptable margin width differs. When clinicians submit additional margins, separate comments are also important, as they are necessary to consider in the final margin measurements if a synoptic report is provided. Margin control for patients with extensive multifocal disease can be challenging. Therefore, it is important to note the presence of multifocality and its extent in the pathology report. A simple way to convey the extent of multifocality is to report the proportion of slides that contain tumor (e.g., 12 of 18 slides contain tumor) from the entirely submitted lumpectomy specimen.
Tumor size should be measured carefully, using the protocol presented in specimen processing, because tumor staging is often the major determinant of adjuvant therapy. For patients with invasive lobular breast cancer, tumor border type (pushing vs. infiltrative) can be important; tumors with infiltrative borders are more likely to have multifocally positive margins.
Multiple factors influence the appropriate treatment of patients with DCIS. An accurate pathology report, effectively conveying the volume, grade, and extent of disease, often plays a major role in the determination of an individual patient’s therapy. The pathologist should address the following findings when evaluating the lumpectomy specimen from a patient with DCIS:

• Size
• Grade
• Margins
• Calcifications present in malignant or benign ducts
• Unifocal or multifocal
• Extent of disease (proportion of slides containing disease)
• In the presence of invasive disease, distance of DCIS from the main area of invasive disease
LCIS is a common incidental finding identified in lumpectomy specimens obtained in the evaluation of palpable abnormalities or image-detected lesions. The presence and approximate volume of LCIS are important to note. In most cases, LCIS is not “premalignant,” and therefore no attempt is made to excise the lesion completely. Thus, comments on margins are unnecessary and can lead to confusion.

Surgery after Neoadjuvant Therapy
More than 85% of patients receiving neoadjuvant chemotherapy (that is, chemotherapy before surgery) can be expected to have a significant clinical response, defined as a reduction of tumor size by 50% or greater. 12 Complete clinical response, with disappearance of all clinically detectable disease, can occur, resulting in difficulty identifying the location of the tumor site in the specimen. This situation is best avoided by marking the original tumor site with a clip or tattoo at the time of initial diagnosis. When a clip is placed, the location of the original tumor site can be easily identified within the specimen (lumpectomy or mastectomy) using specimen mammography. An attempt should be made to quantify the volume of viable-appearing residual cancer in the mastectomy or lumpectomy specimen of a patient who received neoadjuvant therapy. In general, tumors responding to chemotherapy are reduced in size in one of two ways. Fifty percent of tumors diminish concentrically, leaving behind only normal breast tissue with or without significant fibrosis. The other 50% demonstrate fibrosis intermixed with viable tumor cells. 13
The pathologic findings at the time of lumpectomy often determine clinical management for patients who have received neoadjuvant therapy. Three results are possible:

1. Residual tumor with negative margins. After neoadjuvant chemotherapy, patients who desire breast-preserving surgery undergo a lumpectomy. The volume of tissue removed at the time of the procedure is typically not intended to encompass the entire pretreatment area of disease. Ideally, the patient’s tumor has diminished in size concentrically, resulting in wide negative margins and allowing for breast-preserving surgery.
2. Residual tumor with positive margins. Patients whose tumors have reduced in size but are characterized by viable malignant cells throughout the original tumor volume may have multifocally positive margins. Typically, they must return to the operating room to undergo mastectomy.
3. Complete pathologic response. In this case, it is important to confirm that a scar or treatment effect is present, again to confirm that the appropriate site was resected.

Mastectomy
The most common types of mastectomies performed today are the simple and modified radical mastectomies. A simple mastectomy entails resection of the entire breast only, whereas a modified radical mastectomy refers to a mastectomy with an en bloc level I and II axillary lymph node dissection.
Patients undergoing mastectomy may have multicentric cancer and in that case have undergone multiple preoperative breast biopsies. Accurate tumor staging and documentation of multicentric disease require the identification of all prior biopsy sites. Review of the preoperative mammography and pathology reports alerts the pathologist to the presence of multiple sites of interest and can often direct the initial processing of the specimen. It is prudent to consult with the surgeon and/or breast imager when multiple sites of disease are not apparent on initial inspection of a specimen from a patient expected to harbor multicentric disease. Specimen mammography can be of great value in locating difficult-to-identify biopsy sites or areas of nonpalpable disease. If the mastectomy specimen has already been processed, radiography can also be used on the blocks. In this way, biopsy clips or markers that remain deeper in the blocks can be easily identified.
Mastectomy specimens with close or positive margins can be of great concern. Treatment decisions regarding adjuvant radiation therapy and/or reoperative surgery are often affected by the presence of a close or positive margin. The identification of the exact location of a positive margin in a mastectomy specimen is often difficult. However, when possible, the determination of the general location of the positive margin helps guide attempts at reexcision.

Sentinel Lymph Node Biopsy
The recommended procedure for processing and interpretation of sentinel lymph node biopsy specimens is presented in Chapter 11 . Intraoperative analysis of sentinel lymph nodes may be requested routinely or selectively, depending on surgeon practice. Intraoperative analysis may yield one of four results:

1. Negative
2. Atypical (cannot exclude metastatic carcinoma)
3. Suspicious for metastatic carcinoma
4. Positive for metastatic carcinoma
Negative results should result in no further axillary surgery. Positive sentinel lymph nodes most commonly result in a completion axillary lymph node dissection. Atypical or suspicious sentinel lymph node analysis must be clearly communicated to the surgeon, for whom it may be prudent to defer final management decisions of the axilla until the permanent section results are available. Decisions based on such intraoperative results may also be influenced by the degree of clinical suspicion of nodal metastases and by preoperative discussions between surgeon and patient. Typically, an intraoperative decision to proceed with a completion axillary lymph node dissection is predicated on the existence of one positive sentinel lymph node, not the number of positive nodes. The surgeon should also be aware that intraoperative sentinel lymph node analysis may be particularly challenging with invasive lobular cancer.
Intraoperative analysis of sentinel lymph nodes can be accomplished through frozen section, touch prep, or a combination of the two techniques. All three have their advantages, disadvantages, and limitations. It is important that the pathologist ensures that the surgeons he or she works with understand that false-negative results are not uncommon with intraoperative sentinel node analysis. 14 Much less frequent, but more problematic, is the occasional false-positive intraoperative sentinel node assessment. The pathologist must be careful to accurately convey any concerns he or she might have regarding a specific case when communicating intraoperative sentinel lymph node biopsy results to the surgeon. A false-positive frozen section or touch prep will most likely result in a patient undergoing an unnecessary axillary dissection. If the intraoperative assessment is in doubt, it is best to alert the surgeon and defer a diagnosis until permanent sections are available.

Axillary Dissection
Currently, an axillary dissection is performed most commonly in the setting of known positive lymph nodes, diagnosed either by needle biopsy or sentinel lymph node biopsy. A standard axillary dissection includes nodal tissue from levels I and II of the axilla. It is important to report the number of positive lymph nodes, the total lymph nodes identified in the specimen, and the presence of extranodal extension. Traditionally, a minimum of 10 lymph nodes is considered necessary for a full axillary dissection. 15 Axillary dissection in the United States yields an average number of lymph nodes of approximately 14. Neoadjuvant chemotherapy commonly reduces this number. The total number of lymph nodes may serve as an indicator of the adequacy of the dissection of the pathologic examination of the tissue. Hence, a particularly low total number of nodes may result in a request to reexamine the specimen. The number of positive lymph nodes or the presence of extranodal extension influences adjuvant treatment recommendations, particularly the use of radiation therapy after mastectomy, the addition of specific radiation fields, and the use of adjuvant chemotherapy.

Mesenchymal Lesions
The approach to mesenchymal lesions has similar goals as for carcinoma: reducing recurrence and avoiding metastasis. However, although lumpectomies for carcinomas can be surgically adequate with margins of millimeters, mesenchymal malignancies often require margins of several centimeters to ensure adequate removal.
Malignant phyllodes tumors are treated in a fashion similar to sarcomas occurring elsewhere in the body. Wide local excision with histologically negative margins of greater than 1 cm is required. Mastectomy may be necessary to ensure wide negative margins for patients with larger tumors. Axillary staging is not required. When present, clinically suspicious lymph nodes should be individually biopsied because they are typically hyperplastic. Local recurrence rates up to 35% within 5 years for borderline and malignant phyllodes tumors have been reported. 16
Even benign (low-grade) phyllodes tumors are best treated with wide local excision; they have a 5-year local recurrence rate of up to a 13%. Local control is important, because low-grade phyllodes tumors can recur as higher grade lesions.
Given the differences in the amount of tissue that is taken, accurate assessment of fibroepithelial lesions is important on core biopsy. Distinguishing a cellular fibroadenoma from a low-grade (benign) phyllodes tumor can be diagnostically challenging. If the diagnosis of phyllodes is not clear, leaving some ambiguity is prudent (e.g., “fibroepithelial proliferation”). A surgeon can perform a local excision, and if the final diagnosis is phyllodes tumor, the patient can return for wider margins. If the final diagnosis is cellular fibroadenoma, then the surgeon has already performed the appropriate surgery with the best cosmetic outcome. 17
Angiosarcoma is one of the most frustrating mesenchymal lesions to manage from a surgical perspective. It often (but not necessarily) occurs 6 to 10 years after breast radiation. The tumor infiltrates the breast parenchyma in such a fashion that obtaining clear margins is challenging. Imaging often underestimates the tumor margins, and there are no gross features to reliably guide the extent of excision. Due to the nefarious infiltrative pattern of this malignancy, mastectomy and wide skin margins are often necessary ( Fig. 4-1 ). Paradoxically, the addition of adjuvant radiation therapy may decrease the risk of local recurrence and improve survival. 18

Figure 4-1 A 55-year-old woman with postradiation angiosarcoma. Angiosarcoma often presents with a bruiselike discoloration to the skin ( A ) and requires a large excision because obtaining clear margins can be problematic ( B and C ).

Suggested Readings

Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomized trials. on behalf of the Early Breast Cancer Trialists Collaborative Group. Lancet . 2005;366:2087–2106.
Mejinen P, Gilhuijs KG, Rutgers EJ. The effect of margins on the clinical management of ductal carcinoma in situ of the breast. J Surg Oncol . 2008;98(8):579–584.
Vanderveen KA, Ramsamooj R, Bold RJ. A prospective, blinded trial of touch prep analysis versus frozen section for intraoperative evaluation of sentinel lymph nodes in breast cancer. Ann Surg Oncol . 2008;15:2006–2011.

References

1 Martin HE, Ellis EB. Biopsy by needle procedure and aspiration. Ann Surg . 1930;92:169–181.
2 Hermans J. The value of aspiration cytologic examination of the breast. A statistical review of the medical literature. Cancer . 1992;69:2104.
3 Margenthaler J, Duke D, Monsees B, et al. Correlation between core biopsy and excisional biopsy in breast high-risk lesions. Am J Surg . 2006;192(4):534–537.
4 Hinson JL, McGrath P, Moore A, et al. The critical role of axillary ultrasound and aspiration biopsy in the management of breast cancer patients with clinically negative axilla. Ann Surg Oncol . 2008;15:250–255.
5 Holwitt DM, Swatske ME, Gillanders WE, et al. The combination of axillary ultrasound and ultrasound-guided biopsy is an accurate predictor of axillary stage in clinically node-negative breast cancer patients. Am J Surg . 2008;196:477–482.
6 Winchester DJ, Bernstein JR, Jeske JM, et al. Upstaging of atypical ductal hyperplasia after vacuum-assisted 11-gauge stereotactic core needle biopsy. Arch Surg . 2003;138:619–622.
7 Benson JR, Jatoi I, Keisch M, et al. Early breast cancer. Lancet . 2009;373(9673):1463–1479.
8 Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomized trials. on behalf of the Early Breast Cancer Trialists’ Collaborative Group. Lancet . 2005;366:2087–2106.

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