Table Of ContentOther books in this series:
Neuropathology
Gastrointestinal and Liver Pathology
Head and Neck Pathology
Endocrine Pathology
Other books coming soon in this series:
Dermatopathology
Bone and Soft Tissue Pathology
Genitourinary Pathology
Hematopathology
Gynecologic Pathology
Fine Needle Aspiration Cytology
Pulmonary Pathology
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© 2006, Elsevier Inc. All rights reserved.
ISBN-13: 978-0-443-06680-1
ISBN-10: 0-443-06680-9
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First published 2006
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“(T)he student begins with the patient,
continues with the patient, and ends his studies
with the patient, using books and lectures as tools,
as means to an end.”
Sir William Osler (1849–1919)
To my family, Siobhan and Paul
and to my friend and mentor, David L Page
Frances P O’Malley
To my parents, Arthur and Sheila Pinder;
thanks for everything.
To Ian Ellis and Chris Elston;
thanks for being friends and mentors.
To J, J, A, H, J & R and to Watford & LCFC;
thanks for the sense of perspective!
Sarah E Pinder
Contributors
Sunil Badve, MD Gavin Harris, BM BS, MRCPath
Pathologist Consultant Anatomical Pathologist
Department of Surgical Pathology Canterbury Health Laboratories
University Medical Center Christchurch,
Indianapolis, IN New Zealand
USA
Timothy W Jacobs, MD
Anita Bane, MB, MRCPath Pathologist
Pathology Fellow, PhD Student Department of Pathology
Department of Pathology and Laboratory Medicine Virginia Mason Medical Center
Mount Sinai Hospital Seattle, WA
Toronto, Ontario USA
Canada
Jonathan J James, FRCR
Beverly A Carter, MD Consultant Radiologist
Surgical Pathologist Nottingham Breast Unit
St Clare’s Mercy Hospital Nottingham City Hospital NHS Trust
St Johns, Newfoundland Nottingham
Canada United Kingdom
Ian O Ellis, BM BS, FRCPath Andrew HS Lee, MB BChir, MRCP, MRCPath
Professor of Cancer Pathology Consultant Histopathologist
Histopathology Department Histopathology Department
Nottingham City Hospital NHS Trust Nottingham City Hospital NHS Trust
Nottingham Nottingham
United Kingdom United Kingdom
Christopher WS Elston, MBBS, MD FRCPath Sunil R Lakhani, BSc, MBBS, MD, FRCPath, FRCPA
Professor of Tumour Pathology Professor of Pathology
Department of Histopathology Head, Molecular and Cellular Pathology
Nottingham City Hospital NHS Trust School of Medicine
Nottingham The University of Queensland Mayne Medical School
United Kingdom Herston, Queensland
Australia
Andrew J Evans, FRCF
R Douglas MacMillan, MD, FRCS
Consultant Radiologist
Nottingham Breast Unit Consultant Surgeon and Associate Clinical Director
Nottingham City Hospital NHS Trust Nottingham Breast Unit
Nottingham Nottingham City Hospital NHS Trust
United Kingdom Nottingham
United Kingdom
James J Going, MB, PhD, FRCPath
Syed K Moshin, MD
Senior Lecturer/Consultant Pathologist
Staff Pathologist
University Department of Pathology
Riverside Methodist Hospital
Glasgow Royal Infirmary
Columbus, OH
Glasgow
USA
United Kingdom
Anna Marie Mulligan, MB, MSc, MRCPath
Michael A Gonzalez, B Med Sci, BM BS, PhD,
Breast Pathology Fellow
MRCP(UK)
Department of Pathology and Laboratory Medicine
MRC Clinical Research Fellow
Mount Sinai Hospital Toronto, Ontario
MRC Cancer Cell Unit
Canada
Cambridge
United Kingdom
vii
viii CONTRIBUTORS
Frances P O’Malley, MB, FRCPC Nour Sneige, MD
Surgical Pathologist Professor of Pathology
Department of Pathology and Laboratory Medicine Chief, Sector of Cytopathology
Mount Sinai Hospital Department of Pathology
Associate Professor University of Texas MD Anderson Cancer Center
Department of Laboratory Medicine and Pathobiology Houston, TX
University of Toronto USA
Toronto, Ontario
Gregg Staerkel, MD
Canada
Professor of Pathology
David L Page, MD Director, Cytopathology Fellowship
Professor of Pathology Medical Director, Cytotechnology Program
Division of Anatomical Pathology Department of Pathology
Vanderbilt University School of Medicine University of Texas MD Anderson Cancer Center
Nashville, TN Houston, TX
USA USA
Sarah E Pinder, MBChB, FRCPath Donald L Weaver, MD
Consultant Breast Pathologist Professor of Pathology
Department of Histopathology Department of Pathology
Addenbrooke’s Hospital University of Vermont College of Medicine
Cambridge University Hospitals NHS Foundation Trust Burlington, VT
Cambridge USA
United Kingdom
Bruce J Youngson, MSc, MD, FRCP(C)
Jorge S Reis-Filho, MD
Staff Pathologist
Clinical Fellow Department of Pathology
Breakthrough Breast Cancer Research Centre Princess Margaret Hospital University Health Network
Institute of Cancer Research Toronto, Ontario
London Canada
United Kingdom
Jean F Simpson, MD
Professor of Pathology
Division of Anatomical Pathology
Vanderbilt University School of Medicine
Nashville, TN
USA
Foreword
The study and practice of anatomic pathology are both tion in the field of breast pathology. The content in each
exciting and overwhelming. Surgical pathology, with all chapter is extremely practical, well organized and con-
of the subspecialties it encompasses, and cytopathology cisely written, focusing on the thorough evaluation of
have become increasingly complex and sophisticated, all types of specimens including fine needle aspirates,
and it is not possible for any individual to master the core biopsies, wire localization biopsies and resection
skills and knowledge required to perform all of these specimens. There are overviews of the clinical and radi-
tasks at the highest level. Simply being able to make a ological aspects of breast diseases, which provide a
correct diagnosis is challenging enough, but the standard thoughtful background for the practicing pathologist,
of care has far surpassed merely providing a diagnosis. since these aspects go hand in hand.
Pathologists are now asked to provide large amounts of This edition of the series is organized into 27 chap-
ancillary information, both diagnostic and prognostic, ters covering all the major problems encountered in
often on small amounts of tissue, a task that can be breast pathology. There are separate chapters that
daunting even to the most experienced pathologist. describe the normal breast, inflammatory conditions,
Although large general surgical pathology textbooks the always-difficult sclerosing lesions of the breast,
are useful resources, they by necessity could not possi- papillary lesions, fibroadenomas and phyllodes tumors,
bly cover many of the aspects that pathologists need to stromal lesions, diseases of the nipple and fibrocystic
know and include in their reports. As such, the concept changes. Chapters 14 through 20 are entirely dedicated
behind Foundation in Diagnostic Pathology was born. to the ductal and lobular proliferations of the breast,
This series is designed to cover the major areas of sur- describing in great detail the subtle changes that occur
gical and cytopathology, and each edition is focused on in the spectrum from hyperplasia to atypical hyperpla-
one major topic. The goal of every book in this series is sia to in-situ and invasive carcinoma. Separate chapters
to provide the essential information that any patholo- are dedicated to describing the molecular genetics of
gist, whether general or subspecialized, in training or in ductal and lobular neoplasia, including pre-invasive
practice, would find useful in the evaluation of virtually lesions. A thoroughly updated discussion on sentinel
any type of specimen encountered. lymph node biopsies is also provided, as well as an
Drs Frances O’Malley and Sarah Pinder, superb overview of the use of immunohistochemistry in breast
breast pathologists from Mount Sinai Hospital in disease.
Toronto, Canada, and Addenbrooke NHS Trust in Cam- I wish to extend my sincerest gratitude to Drs O’Malley
bridge, UK, respectively, have edited what I believe to be and Pinder as well as all the authors who contributed
an outstanding, state-of-the-art book on the essentials of to this outstanding edition of Foundations in Diagnostic
breast pathology. The list of contributors is most impres- Pathology. I sincerely hope you enjoy this volume of the
sive and includes renowned pathologists from the series as much as I did.
United States, Canada and the United Kingdom, all of
whom have built a national and international reputa- JOHN R. GOLDBLUM, M.D.
ix
Preface
The practice of breast pathology is an exciting and focused on the most practical and clinically relevant
varied one with new developments in the understand- information.
ing of breast disease biology and genetics occurring The role of the surgical pathologist in the area of
seemingly daily. It is therefore difficult to keep up to date breast diseases has expanded from that of diagnostician
and the field can appear somewhat baffling to the to one of prognostication. We provide information on
trainee histopathologist. Similarly, the classification of the important histologic and biologic prognostic factors
breast lesions is undergoing regular changes, as exem- in breast cancer and we also cover in detail the complex
plified by columnar cell lesions, and this can be chal- and challenging issues associated with sentinel lymph
lenging to even the most experienced pathologist. For node biopsies.
these reasons we are pleased to act as joint editors for We are fortunate to have had many internationally
Foundations in Diagnostic Pathology – Breast Pathology. renowned experts in breast pathology contribute to
We believe that the standard, ordered format that is this book. We extend a sincere thanks to all for their
used, where appropriate, throughout the book, makes it time and effort. We hope that our readers will enjoy
particularly “user-friendly”. Following on from initial their words of wisdom, as we have done. We an-
chapters on diagnosis on cytology and core biopsy ticipate that the information in this book will provide a
samples and handling of breast specimens macroscopi- valuable resource for all those interested in breast
cally, we have aimed to cover the range of appearances pathology.
of normal breast as well as the broad spectrum of breast
lesions, both epithelial and stromal, benign and FRANCES P O’MALLEY, MB, FRCPC
malignant. In our discussion of these topics we have SARAH E PINDER, MB CHB, FRCPATH
xi
Acknowledgments
We acknowledge the support and patience of the staff and to Colette Devlin and Marie Maguire at Mount
at Elsevier, particularly Heather Krehling and Belinda Sinai Hospital, who provided excellent secretarial
Kuhn, who kept us on track. Special thanks goes to Dr assistance.
Anna-Marie Mulligan for her help with photography,
xiii
1 Diagnostic Methodologies: Fine Needle
Aspiration Cytology
Gregg Staerkel • Nour Sneige
Improvements in healthcare today typically come with Allied Diseases led to the use of the term thin-needle
the drawback of increased time and cost due to the aspiration and later fine needle aspiration.
greater complexity of the evolved procedure and/or the
need for highly trained personnel to maintain and run
high priced equipment. Consequently, it comes as a
pleasant surprise that fine needle aspiration is the
ROLE AND LIMITATION
antithesis to this trend and, because of its ease of opera-
tion, it is a do-anywhere procedure. An aspiration can
be performed during a routine doctor’s office or clinic
visit or at the patient’s bedside. It utilizes inexpensive For the evaluation of most lesions of the breast, fine
equipment and can typically be performed, interpreted needle aspiration represents a near perfect test. It is rel-
and reported in a matter of minutes thereby accelerat- atively easy to perform requiring no high-tech gadgetry;
ing a patient’s entry into treatment. An intra-operative/ costs are as low as core biopsy and substantially more
pre-operative aspiration can negate the need for a cost-effective than open biopsy. The procedure is safe,
frozen section/histologic examination of tissue, respec- yielding tissues that provide for a high diagnostic accu-
tively, the first step in a traditional ‘two step surgical racy in an extremely short timeframe. The main com-
procedure’ or eliminate the time, cost and morbidity petition to the fine needle aspiration in breast is the
associated with the additional surgical exploration and cutting needle biopsy. Both of these techniques can be
incision of secondarily disclosed nodules. performed as an outpatient procedure with little signifi-
It is largely accepted that the first individuals cant negative cosmetic effect, e.g., scarring, dimpling of
credited for laying the foundation for the development the breast due to loss of tissue.
of today’s needle aspiration were the surgeon Hayes Advantages of aspiration over cutting needle biopsy
Martin, Edward Ellis (pathologist James Ewing’s labo- are as follows:
ratory technologist), and the pathologist Fred Stewart at • Ability to immediately and accurately assess the ade-
The Memorial Center for Cancer and Allied Diseases in quacy of the specimen obtained (while some indi-
New York. In the late 1920s and 1930s, they demon- viduals endorse making touch preparations of cutting
strated the utility of needle aspiration in the diagnosis needle biopsies for an immediate assessment of ade-
of a large number of cases and detailed the procedure, quacy, these preparations taken prior to processing
which mirrors in large part the technique still used the tissue for histologic examination, do not consis-
today. Unfortunately, despite these early reports, the use tently reflect the final content of tissue seen).
of needle aspiration did not catch on. This setback was • Greater mobility allowing for an increased area of
thought to be due, in part, to a lack of communicating sampling (the core biopsy obtains tissue in one plane
its efficacy and not incorporating the merits of needle only);
aspiration into the training programs of surgical and • Processing times are significantly less when compared
pathology trainees. Also, contributing to the setback to both paraffin embedded and frozen section cutting
was the unsubstantiated belief, by some prominent indi- needle biopsies, thereby permitting a more timely
viduals, that the acquisition of a small amount of tissue immediate assessment and the processing of a larger
resulted in difficult/less than complete interpretations number of patients;
and that puncturing a tumor with needles carried a sig- • Greater sensitivity of the physical nature of the lesion
nificant danger of tumor tract seeding and induction of and therefore better needle localization;
metastatic disease. Needle aspirations would not make • Enhanced appreciation of the lesion’s texture which
a comeback until the clinicians and pathologists at The helps determine the need for additional needle passes
Karolinska Institute in Stockholm, Sweden, reported and diagnosis. e.g., a gritty, rubbery or no firm resist-
their findings for needle aspirations performed from ance feel suggests the possibilities of carcinoma,
approximately 1950 to 1980. These reports documented fibroadenoma and fat necrosis, respectively;
the overwhelming efficacy and accuracy of this tech- • Increased sensitivity; and
nique in the diagnosis of tumors at differing body sites. • Shorter time to final diagnosis.
The utilization of a much smaller gauge needle than the Disadvantages of aspiration when compared to cutting
individuals at The Memorial Center for Cancer and needle biopsy include:
1
2 BREAST PATHOLOGY
• Limited tissue available for ancillary studies and
research endeavors (paraffin embedded, cutting
TABLE 1-1
needle cores of tissue can yield hundreds of slides for
analysis whereas the average aspirate might have Equipment requirements for breast fine needle aspiration
between four and ten slides);
• Less familiarity/experience among pathologists; Disposable needles with transparent plastic hubs
• Low cellular yield due to the nature of the lesion, 23 to 25 gauge, 1 and 1.5” in length (longer and more
despite the performance of an appropriate aspiration, rigid needles, 20 to 22 gauge, may be needed for the rare
more deeply seated lesion)
e.g., desmoplastic stroma seen in a some types of
Disposable plastic syringes (10 or 20 cc)
carcinoma;
Syringe holder (optional)
• Difficulty in classifying proliferative lesions that have
Glass slides
a degree of atypia but lack unequivocal features of
Fixative (optional if pathologist desires only air dried tissue
malignancy, i.e., minimal nuclear atypia and/or for interpretation)
absence of single malignant cells; Rinse solution (optional)
• Inability to give an absolute assessment of the pres- Anesthetic agent for local anesthesia (optional)
ence of in-situ versus invasive disease, a significant Ethanol pads
drawback when pre-operative chemotherapy or sen- Gauze pads
tinel lymph node biopsy is considered;
• Slightly less specificity; and
• High rate of insufficiency when aspirating microcal-
cifications under imaging guidance due to the paucity
of epithelial tissues present. hand as better cutting or coring of the mass can be
These drawbacks have led to a decline in breast fine achieved. The needle, with syringe and holder attached,
needle aspirations, particularly for the evaluation of a is then inserted into the mass. The syringe plunger is
patient’s primary lesion. However, with the develop- pulled back, creating negative pressure, as the needle is
ment of new treatment protocols for the care of breast advanced forward and backward. It is not the suction
cancer patients, fine needle aspiration of lesions, other that directly results in obtaining a sample but rather the
than the index cancer, are increasingly used to rule cutting action of the needle. The suction helps to pull
in or out multicentric disease. In combination with tissue into the cutting path of the needle and to move
regional lymph node and distant site aspirations, the resulting fragments up into the needle’s shaft. Pumping
staging of a patient’s disease and planning of suitable the syringe plunger does not enhance sampling; in fact,
therapy can be more quickly and economically achieved. sampling can be reduced as a result of increased bleed-
Lastly, fine needle aspiration is now being used in ing. Moving the needle in different directions, other
obtaining tissues to assess proliferative breast changes than in an up and down manner, reduces cell yield due
and for the performance of marker studies to better to the increased bleeding that results from the laceration
assess patient risk for the development of breast cancer. of small capillaries. In general, needle movements that
The ability to perform either fine needle aspiration or are more frequent, longer in length and kept within the
cutting needle biopsy, based on a given set of tumor during the entire aspiration yield more tissue.
clinical/radiologic/pathologic findings, allows one to Movement and frequency will depend on the size of the
take advantage of the benefits that both procedures have lesion and the aspirator’s ability to maintain control.
to offer. Typically, 30 to 50 excursions with the needle are made
over a 10 to 20 second period. A blood-tinged specimen
will appear in the hub of the needle. Suction is then
released and the needle is withdrawn (Figure 1-1).
Although little bleeding occurs in a fine needle aspi-
FINE NEEDLE ASPIRATION PROCEDURE
ration, it is best to eliminate all bleeding, as cellular yield
decreases and lesion localization/demarcation is less
distinct with increased soft tissue hemorrhage. There-
Fine needle aspiration (FNA) of the breast requires fore, after withdrawing the needle, applying a gauze pad
simple and inexpensive equipment (Table 1-1). Most with one’s fingertips pressing directly over the puncture
lesions are painless when aspirated with the patient site for one to three minutes is recommended (a longer
feeling only the initial pinprick through the skin. Anes- time is applied for individuals with an easy bruising
thesia is not required for most breast aspirations, history or for those currently taking blood-thinning
however when used, it should be used sparingly as too agents).
much may infiltrate the connective tissue and, particu- After removing the needle from the patient, the
larly with a small nodule, can mask it to palpation. syringe is detached from the needle, filled with air and
Notable exceptions are gynecomastia and any nodule in reattached. The aspirator expresses a drop of the sample
close proximity to the nipple or areola. Preferably the acquired onto one or more slides. The drop is then
aspirator should access a subareolar mass through an smeared, fixed with 95% ethanol or air-dried, stained
extreme lateral approach avoiding the nipple and areola and interpreted. Acquisition of material to interpreta-
altogether. Key to performing an adequate aspiration is tion can take as little as 15 minutes. Non-palpable
the immobilization of the mass by the aspirator’s free masses require radiologic imaging (via sonography or
