Encyclopedia of Pathology

Series Editor: J. H. J. M. van Krieken

Anna Sapino
Janina Kulka Editors

Breast
Pathology
Encyclopedia of Pathology

Series Editor
J. H. J. M. van Krieken
The scope of this 15–20-volume set encompasses the entire field of pathology
ranging from general pathological terms to specific diseases to diagnostic
methods. Published as print edition and online version (eReference) in the
Springer Reference Program each topical volume sticks out by clearly and
homogenously structured entries. A team of international experts guarantee
that the essays and definitions are scientifically sound. The A-Z format of each
topical volume allows readers to quickly and easily find the information they
need. The major advantage of the encyclopedia is the way it makes relevant
information available not only to pathologists, but also to all clinicians and
researchers of the neighboring disciplines working together with pathologists
who occasionally might wish to look up terms online.

More information about this series at http://www.springer.com/series/14876

Anna Sapino • Janina Kulka
Editors

Breast Pathology

With 282 Figures and 29 Tables

Editors
Anna Sapino Janina Kulka
Unit of Pathology 2nd Department of Pathology
Candiolo Cancer Institute FPO-IRCCS Semmelweis University
Candiolo, Italy Budapest, Hungary
Department of Medical Sciences
University of Turin
Turin, Italy

ISBN 978-3-319-62538-6 ISBN 978-3-319-62539-3 (eBook)

ISBN 978-3-319-62540-9 (print and electronic bundle)
https://doi.org/10.1007/978-3-319-62539-3

© Springer Nature Switzerland AG 2020

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or
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illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way,
and transmission or information storage and retrieval, electronic adaptation, computer software, or
by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publication does not imply, even in the absence of a specific statement, that such names are exempt
from the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this
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regard to jurisdictional claims in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer Nature Switzerland AG
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To our Masters and Teachers,
Dr. Gianni Bussolati
Dr. Pietro Maria Gullino
Dr. Judit Mohácsy
Dr. John Douglas Davies
ThiS is a FM Blank Page
Series Preface

When Denis Diderot started the first encyclopedia in the eighteenth century, it
was a groundbreaking and timely event. It was the time of the Enlightenment,
and knowledge was seen as something which was to be spread to many and to
build upon by creating new knowledge. His ambition was to bring all available
knowledge together in one series of books so that every person who could read
has access to all there is to know. Nowadays, in a time of easily accessible
knowledge, the question is whether there is still need of an encyclopedia. It is
obvious that the amount of knowledge is such that it is not possible to bring it
all together in one encyclopedia. One may argue that the Internet is the
encyclopedia of today, but that misses an important point of Diderot, a point
that is probably even more valid today. He created a team that valued infor-
mation and selected what was worth to be presented in the encyclopedia. He
recognized that science is not a democratic process where the majority decides
what is true and valuable, but rather a growing body of knowledge in which
radical ideas from individuals may bring about huge changes, even though
most would reject these new ideas in the beginning. Indeed, the Internet lacks
such authority and it is not easy to select valuable information from nonsense,
especially when one is not an expert in a certain field.
It is therefore that an encyclopedia is only as good as the team that creates
it. It goes without saying the team that is responsible for the Encyclopedia of
Pathology consists of recognized experts in the field. Pathology is a growing
medical discipline in which the amount of information is probably already
more than that the whole encyclopedia of Diderot contained. For experts in
subspecialties within pathology, it is already almost impossible to keep an
overview on new developments and to select relevant from less relevant new
information. There are plenty of textbooks for every disease group, and
scientific literature is available for most pathologists through PubMed or
GoogleScholar. What is lacking is a systematic overview of what we know
in an alphabetical order, easily accessible to all. The encyclopedia of pathology
fills that gap. It is written by experts with the general pathologist in mind and
also specialist from other disciplines. It will consist of a series of volumes on
subspecialties, and when it is completed there will be an online version
combining these. Yearly updates from the online version is foreseen and
readers are welcome to provide suggestions for improvement. These will be
judged by the editorial team in order to keep the encyclopedia authoritative yet
using the expertise of many.

vii
viii Series Preface

Finally, it is my hope that the encyclopedia will grow into a reliable body of
knowledge in pathology, enabling communication through a common lan-
guage, and that it will grow and adapt to new developments.

Nijmegen, The Netherlands J. H. J. M. van Krieken

September 2019 Series Editor
Volume Preface

This new book on breast pathology as part of the Encyclopedia of Pathology

series intends to summarize the present state of knowledge about breast
diseases. Encyclopedia of Pathology, and its individual volumes, being living
documents, will be subject to updates, inclusion of new knowledge, and new
data in the online version of the series. The printed version is, therefore, a
snapshot of breast pathology from the years 2018 to 2019. Having said that,
we, editors of this volume, hope that our readers will find this book useful and
likeable even years from now. We ambitiously hope and wish this book
becomes one of those at your right-hand side by the microscope.
We are very grateful to all coauthors of the book who did their best to write
excellent chapters summarizing up-to-date knowledge about the respective
subjects included in the table of contents of this book. Going through the
individual contributions during the review process has been both great profes-
sional and personal experience for us. We thankfully acknowledge also the
continuous support of our editorial assistants at Springer, Mrs. Sunaina
Dadhwal and Mrs. Neha Thapa.
We wish our readers pleasant working hours assisted by this volume of
Encyclopedia of Pathology!

Candiolo, Italy Anna Sapino

Budapest, Hungary Janina Kulka
September 2019 Volume Editors

ix
Editors Biography

Dr. Anna Sapino obtained her M.D. degree at the University of Turin (Italy)
in 1982 and completed her residency in anatomic pathology at the University
of Milan in 1986. She started her career as a consultant pathologist at
the University Hospital in Turin in 1984 under the supervision of Prof.
Gianni Bussolati. In 1987 she accrued experience in experimental studies on
pre-neoplastic breast lesions through a sabbatical period spent in the USA at
the Michigan Cancer Foundation and at the Columbia University. Upon her
return to Italy, she set up her own cell biology lab working on effects of
hormones on breast cancer cells and mouse mammary gland organ cultures.
Her research activity has always been paralleled and inspired by breast cancer
diagnostic pathology and her career orientation reflects this approach. In 1998
Dr. Sapino was appointed Associate Professor and in 2005 full Professor of
Anatomic Pathology and Histopathology at the School of Medicine of the
University of Turin. From 2010 to 2015 she was recruited as Director of
Surgical Pathology at the University Hospital (Città della Salute e della
Scienza) in Turin and from 2013 to 2015 as Director of the Department of
Laboratory Medicine, then she moved to Candiolo Cancer Centre FPO-IRCCS
(Italy) as Director of the Pathology Unit. This unit is recognized as training
center for breast pathology by the European Society of Pathology (ESP). In
2017 she became Scientific Director of Candiolo Cancer Institute FPO-
IRCCS, a private nonprofit institution endorsed by the Italian Ministry of
Health for oncology research. In 2018 Dr. Sapino had also been appointed
Director of the Department of Medical Sciences of the School of Medicine at
the University of Turin (Italy). She has been member of the European Working
Group for Screening of Breast Pathology and coauthor of the European
Guideline for Breast Cancer Screening. From 2014 to 2018 she had been
chairing the European Working Group of Breast Pathology of the ESP. She
is member of the teaching staff for breast pathology of the European School of

xi
xii Editors Biography

Pathology (EScoP). She serves as member of editorial boards of many scien-

tific journals and as reviewer for international grant proposals. She has been
lecturing at several national and international meetings. Her scientific works
are published in international peer-reviewed journals (more than 300 papers,
H-index: 49). Over the years her scientific activity has focused on experimen-
tal and clinicopathological studies on breast cancer, with the key mission to
translate the achievements of basic science to the patient’s bedside.

Dr. Janina Kulka studied medicine at Semmelweis University, Budapest.

After receiving her degree in 1982, she successfully applied for a trainee
position in the 2nd Department of Pathology of Semmelweis University.
Four years later, after the specialization exam, she became Assistant Professor
in the same department. From 1992 to 1994 she was Research Fellow at the
South West Regional Breast Pathology Unit of the University of Bristol, UK,
under the supervision of Dr. J.D. Davies. She received her Ph.D. in 1999,
became full Professor of pathology in 2008, and received her D.Sc. degree in
2018. She has also served as a pathologist at the MaMMa Clinic, the first
multidisciplinary breast screening center in Hungary, founded in 1992.
Dr. Kulka was a member of the Mammographic Screening Subcommittee of
the “For a Healthy Nation” program, took an active part in the establishment of
mammographic screening centers in Hungary in 2002, and subsequently
participated in the regular external quality control procedures of the centers.
She introduced specimen mammography as part of routine workup of screen-
detected breast lesions and assembled the first national breast pathology
guidelines that included a description of workup of screen-detected breast
lesions. She is coauthor of the pathology chapter of the Hungarian multi-
disciplinary breast consensus document. She has been teaching medical stu-
dents for more than three decades and breast pathology for residents in
postgraduate courses for the last 15 years. In 2002 she joined and became a
member of the European Working Group for Breast Screening Pathology. She
contributed coauthored chapters to the European Guidelines for Quality Assur-
ance in Breast Cancer Screening and Diagnosis, to the second edition of the
Oxford Textbook of Oncology, and the fourth and fifth editions of the WHO
Classification of Tumours of the Breast volume. Recently, she was invited to
participate in the development of a dataset for the reporting of invasive breast
cancer by ICCR. She is author of several breast pathology chapters in Hun-
garian pathology, oncology, and surgery textbooks. She is author of more than
Editors Biography xiii

140 peer-reviewed scientific papers and contributed lectures to more than

150 national and international conferences. Dr. Kulka had been Secretary
and later President of the Hungarian Society of Pathologists, and a member
of the Executive Committee of the European Society of Pathology (ESP). She
has been a member of the Pathology Council of the Medical College, President
of the Hungarian Division of IAP, and a member of the Advisory Board and the
Educational Committee of ESP. Dr. Kulka has three grown-up children.
Series Editor Biography

J. H. J. M. van Krieken is a pathologist with special expertise in the fields of

hematopathology and the pathology of the gastrointestinal tract. He was
Professor for tumor pathology since 1999 and kept from 2005 to 2015 the
Chair of pathology at the Radboud University Nijmegen Medical Centre in
Nijmegen. He furthermore served as Chairman of the Board of the Oncology
Institute of the Radboud University, Nijmegen, from 2008 to 2016. Since
2016, he is the Rector Magnificus (Vice Chancellor) of the Radboud
University.
He was the Treasurer/Secretary of the European Association for
Hematopathology from 2000 to 2008, from 2003 to 2011 the Treasurer, from
2013 to 2015 the President of the European Society for Pathology (ESP), and
from 2015 to 2017 the past-President of the ESP. Furthermore, he coordinated
the ESP quality assessment program from 2008–2018 and was the chair of
IQN path from 2005–2008. He is (co) author of more than 600 papers in peer-
reviewed journals (H-index 86), has written chapters in books on pathology
and oncology, is editor of a Dutch textbook on oncology, and serves on the
editorial board of the American Journal of Surgical Pathology, was managing
editor of Virchows Archive from 2009–2015, and was the chief editor of the
Journal of Hematopathology from 2008–2018. Since 2011, he is member of
the German Academy of Sciences Leopoldina, and since 2014 of Academia
Europea and Honorary Fellow of the Royal Society of Pathology of Great
Britain and Ireland.

xv
Contributors

Francesca Ambrosi Department of Biomedical and Neuromotor Sciences

(DIBINEM)-Surgical Pathology Section, Alma Mater Studiorum – University
of Bologna, Bologna, Italy

Isabel Amendoeira Centro Hospitalar de São João (CHSJ), Porto, Portugal

IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade
do Porto, Porto, Portugal

Laura Annaratone Department of Medical Sciences, University of Turin,

Turin, Italy
Sofia Asioli Department of Biomedical and Neuromotor Sciences
(DIBINEM)-Surgical Pathology Section, Alma Mater Studiorum – University
of Bologna, Bologna, Italy
Chiara Baldovini Pathology Unit, Giannina Gaslini Institute, Genoa, Italy

Davide Balmativola Unit of Pathology, Candiolo Cancer Institute FPO-

IRCCS, Candiolo, Italy
Guillaume Bataillon Institut Curie, Paris, France

Jean-Pierre Bellocq Department of Pathology, Strasbourg University Hos-

pital, Strasbourg, France

Simonetta Bianchi Division of Pathological Anatomy, Department of Sur-

gery and Translational Medicine, University of Florence, School of Human
Health Sciences, Florence, Italy

Werner Boecker Gerhard Domagk-Institute of Pathology, University of

Münster, Münster, North-Rhine Westphalia, Germany

Horst Bürger Institute of Pathology Paderborn/Höxter, Paderborn, Germany

Grace Callagy Discipline of Pathology, NUI Galway, Galway, Ireland

NUI Galway Clinical Science Institute, Galway, Ireland

Eliano Cascardi Department of Emergency and Organ Transplantation,

Unit of Pathology, University of Bari, Bari, Italy
Unit of Pathology, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy

xvii
xviii Contributors

Isabella Castellano Department of Medical Sciences, University of Turin,

Turin, Italy

Suzanne Chartier Institut Curie, Paris, France

Catherine N. Chinyama Department of Pathology, Princess Elizabeth Hos-

pital, St Martins, Guernsey, Channel Islands, UK
Brighton and Sussex Medical School, Brighton, UK

Ewa Chmielik Tumor Pathology Department, Maria Sklodowska-Curie

Memorial Cancer Center and Institute of Oncology, Gliwice, Poland

Chiara Corti Division of Pathology, Fondazione IRCCS Ca’ Granda –

Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

Gábor Cserni Bács-Kiskun County Teaching Hospital, Kecskemét, Hungary

Department of Pathology, University of Szeged, Szeged, Hungary

Margaret C. Cummings Centre for Clinical Research, Faculty of Medicine,

The University of Queensland, Brisbane, QLD, Australia
Pathology Queensland: The Royal Brisbane and Women’s Hospital, Brisbane,
QLD, Australia

Clare D’Arcy Department of Histopathology, Irish National Breast Screen-

ing Programme and St. Vincent’s University Hospital, Dublin, Ireland

Dario de Biase Department of Pharmacy and Biotechnology, University of

Bologna, Bologna, Italy

Laurence de Leval Institute of Pathology, University Hospital Lausanne,

Lausanne, Switzerland

James S. DeGaetano Pathology Department, Mater Dei Hospital, Msida,

Malta

Luca Di Tommaso Pathology Unit, Humanitas Clinical and Research Cen-

ter, Department of Biomedical Sciences, Humanitas University, Milan,
Rozzano, Italy

Maria Giulia Disanto Unit of Pathology, Candiolo Cancer Institute

FPO-IRCCS, Candiolo, Italy

Ian Ellis Department of Histopathology, City Hospital Campus, Nottingham

University Hospitals, Nottingham City Hospital, Nottingham, UK

Vincenzo Eusebi Department of Pathology, University of Bologna, Bologna,

Italy

Margarida Sá Fernandes Centro Hospitalar de São João (CHSJ), Porto,

Portugal

Paulo Figueiredo Instituto Português de Oncologia de Coimbra, Coimbra,

Portugal
Contributors xix

Maria P. Foschini Department of Biomedical and Neuromotor Sciences

(DIBINEM), Unit of Anatomic Pathology at Bellaria Hospital, University of
Bologna, Bologna, Italy
Nicola Fusco Division of Pathology, Fondazione IRCCS Ca’ Granda –
Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
Zoran Gatalica Caris Life Sciences, Phoenix, AZ, USA
Emma Josephine Groen Department of Pathology, The Netherlands Cancer
Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Malcolm Hayes Pathology Department, BC Cancer Agency, University of
British Columbia, Vancouver, BC, Canada
Matthew P. Humphries Leeds Institute of Cancer and Pathology, University
of Leeds, Leeds, UK
Sergejs Isajevs Riga East University Hospital, Centre of Pathology/Faculty
of Medicine, University of Latvia, Riga, Latvia
Ivan Ivanov Department of Pathology, Medical University, Pleven, Bulgaria
Handan Kaya Pathology Department, Marmara University, Istanbul,
Turkey
Reena Khiroya University College London Hospital, London, UK
Anikó Kovács Department of Clinical Pathology, Sahlgrenska University
Hospital, Gothenburg, Sweden
Ute Krüger Department of Pathology, County Hospital, Kalmar, Sweden
Thomas Krausz Department of Pathology, University of Chicago, Chicago,
IL, USA
Janina Kulka 2nd Department of Pathology, Semmelweis University, Buda-
pest, Hungary
Manuela Lacerda Instituto de Patologia e Imunologia Molecular da
Universidadedo Porto (IPATIMUP), Porto, Portugal
Sunil R. Lakhani Centre for Clinical Research, Faculty of Medicine, The
University of Queensland, Brisbane, QLD, Australia
Pathology Queensland: The Royal Brisbane and Women’s Hospital, Brisbane,
QLD, Australia
Inta Liepniece-Karele Riga East University Hospital, Centre of Pathology/
Faculty of Medicine, University of Latvia, Riga, Latvia
Enrica Macorano Department of Emergency and Organ Transplantation,
Università degli Studi di Bari Aldo Moro – Policlinico, Bari, Italy
Lilla Madaras 2nd Department of Pathology, Semmelweis University,
Budapest, Hungary
xx Contributors

Gaetano Magro Department of Medical and Surgical Sciences and

Advanced Technologies, G.F. Ingrassia, Azienda Ospedaliero-Universitaria
“Policlinico-Vittorio Emanuele,” Anatomic Pathology Section, School of
Medicine, University of Catania, Catania, Italy
Eugenio Maiorano Department of Emergency and Organ Transplantation,
Unit of Pathology, University of Bari, Bari, Italy
Elena Maldi Unit of Pathology, Candiolo Cancer Institute FPO-IRCCS,
Candiolo, Italy
Caterina Marchiò Unit of Pathology, Candiolo Cancer Institute FPO-
IRCCS, Candiolo, Italy
Department of Medical Sciences, University of Turin, Turin, Italy
Institut Curie, Paris, France
Mauro Giuseppe Mastropasqua Department of Emergency and Organ
Transplantation, Università degli Studi di Bari Aldo Moro – Policlinico,
Bari, Italy
Jasna Metovic Department of Oncology, University of Turin, Turin, Italy
Dina Milowich Institute of Pathology, University Hospital Lausanne,
Lausanne, Switzerland
Luca Morandi Department of Biomedical and Neuromotor Sciences
(DIBINEM), Unit of Anatomic Pathology at Bellaria Hospital, University of
Bologna, Bologna, Italy
Linda Moskovszky Institute of Pathology and Molecular Pathology, Univer-
sity Hospital Zurich, Zurich, Switzerland
Mark O’Loughlin Discipline of Pathology, NUI Galway, Galway, Ireland
Gyula Pekar Division for Laboratory medicine, Department of Pathology,
Lund University, Lund, Sweden
Alberto Pisacane Unit of Pathology, Candiolo Cancer Institute FPO-IRCCS,
Candiolo, TO, Italy
Savelina Popovska University of Pleven, Pleven, Bulgaria
Department of Pathology, Medical University, Pleven, Bulgaria
Cecily Quinn Department of Histopathology , Irish National Breast Screen-
ing Programme and St. Vincent’s University Hospital, Dublin, Ireland
School of Medicine, University College Dublin, Dublin, Ireland
Moira Ragazzi Department of Oncology and Advanced Technologies, Oper-
ative Unit of Pathology, Azienda USL-IRCCS, Reggio Emilia, Italy
Emad Rakha Department of Histopathology, Division of Cancer and Stem
Cells, University of Nottingham, Nottingham City Hospital, Nottingham, UK
Peter Regitnig Diagnostic- and Research Institute of Pathology, Medical
University of Graz, Graz, Austria
Contributors xxi

Costantino Ricci Department of Biomedical and Neuromotor Sciences

(DIBINEM)-Surgical Pathology Section, Alma Mater Studiorum – University
of Bologna, Bologna, Italy
Lauren E. Rosen Department of Pathology, University of Chicago, Chicago,
IL, USA
Ales Ryska The Fingerland Department of Pathology, Charles University
Medical Faculty and University Hospital, Hradec Kralove, Czech Republic
Ian Said Huntingford Pathology Department, Mater Dei Hospital, Msida,
Malta
Lucia Salvatorelli Department of Medical and Surgical Sciences and
Advanced Technologies, G.F. Ingrassia, Azienda Ospedaliero-Universitaria
“Policlinico-Vittorio Emanuele,” Anatomic Pathology Section, School of
Medicine, University of Catania, Catania, Italy
Anna Sapino Unit of Pathology, Candiolo Cancer Institute FPO-IRCCS,
Candiolo, Italy
Department of Medical Sciences, University of Turin, Turin, Italy
Ivana Sarotto Unit of Pathology, Candiolo Cancer Institute FPO-IRCCS,
Candiolo, Italy
Abeer M. Shaaban Department of Cellular Pathology, Queen Elizabeth
Hospital Birmingham and University of Birmingham, Birmingham, UK
Angelo Sidoni Department of Experimental Medicine, Section of Pathologic
Anatomy and Histology, Medical School, University of Perugia, Perugia, Italy
Peter T. Simpson Centre for Clinical Research, Faculty of Medicine, The
University of Queensland, Brisbane, QLD, Australia
Alena Skalova Department of Pathology, Faculty of Medicine in Plzen,
Charles University, Plzen, Czech Republic
Biopticka laborator s.r.o, Pilsen, Czech Republic
Valerie Speirs Leeds Institute of Cancer and Pathology, University of Leeds,
Leeds, UK
Folakemi A. Torgersen The Fingerland Department of Pathology, Charles
University Medical Faculty and University Hospital, Hradec Kralove, Czech
Republic
Paul J. van Diest Department of Pathology, University Medical Center
Utrecht, Utrecht, The Netherlands
Zsuzsanna Varga Institute of Pathology and Molecular Pathology, Univer-
sity Hospital Zurich, Zurich, Switzerland
Vania Vezzosi Division of Pathological Anatomy, Department of Surgery
and Translational Medicine, University of Florence, School of Human Health
Sciences, Florence, Italy
xxii Contributors

Anne Vincent-Salomon Institut Curie, Paris, France

Elena Vissio Department of Medical Sciences, University of Turin, Turin,
Italy
Semir Vranic Department of Pathology, Clinical Centre and School of Med-
icine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
College of Medicine, Qatar University, Doha, Qatar
Celien Vreuls Department of Pathology, University Medical Center Utrecht,
Utrecht, The Netherlands
Noëlle Weingertner Department of Pathology, Strasbourg University Hos-
pital, Strasbourg, France
Clive Wells University College London Hospital, London, UK
Jelle Wesseling Department of Pathology, The Netherlands Cancer Institute-
Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
A
Abscess
Noëlle Weingertner and Jean-Pierre Bellocq
Department of Pathology, Strasbourg University
Hospital, Strasbourg, France
Synonyms
Pyogenic mastitis
Definition
A breast abscess is defined as a collection of
infected fluid or pus within the breast.
Breast abscesses are mainly classified as
“puerperal” (or “lactational”) – related to
childbirth – and “non-puerperal.” In a non-
puerperal context, the subareolar abscess is
the most frequently observed. Other rarer
situations include peripheral non-puerperal
abscesses, neonatal infections, skin-associated
infections, infections associated with breast
surgery, with medical or non-medical proce-
dures, and unusual infections. Abscesses repre-
sent 3–4% of all benign breast masses (Kasales
et al. 2014).
In this chapter, we will detail the most frequent
presentations of breast abscesses, namely, puer-
peral abscesses and non-puerperal periareolar or
subareolar abscesses.
© Springer Nature Switzerland AG 2020
A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
Puerperal Abscess
Puerperal abscess is the natural course of acute
puerperal mastitis. It occurs at the end of preg-
nancy but especially during lactation. Clinically,
it presents with the same symptoms as mastitis
but with a palpable mass (Mahoney and Ingram
2014). This mass is painful and inflammatory, with
a purulent flow at incision and possible general
signs (fever and malaise). Spontaneous evolution
may be fistulization. There is usually a context of
cracked nipple or skin abrasion, leading to retro-
grade infection. Staphylococcus aureus is the most
common organism responsible (50% of cases), but
Staphylococcus epidermidis and streptococci are
occasionally isolated. Breast abscesses associated
with methicillin-resistant Staphylococcus aureus
(MRSA) has been reported and is likely to be an
increasing problem. Typhoid is a well-recognized
cause of breast abscess in countries where this
disease is common (Kataria et al. 2013).
Clinical Features
• Incidence
Puerperal abscesses affect 1–9% of breast-
feeding mothers (Mahoney and Ingram 2014).
Infection is more frequent following a first
child and occurs most commonly within the
first 6 weeks of breastfeeding. Risk factors
include the first child at maternal age over
30, gestation of more than 41 weeks, and mas-
titis (Kataria et al. 2013). Breast abscesses may
2 Abscess

also occur at weaning, when the breasts

are more likely to be engorged (D’Alfonso
et al. 2015). An additional factor after about
6 months is that the baby’s teeth increase the
likelihood of nipple trauma.
• Site
Puerperal abscesses tend to be peripheral in
location.
• Treatment
Puerperal abscesses are readily managed with
appropriate antibiotics and aspiration or drainage
(Kataria et al. 2013). Ultrasound examination
must be performed to determinate whether an
abscess with visible pus is present. Aspiration
of pus may be guided with ultrasonography. Bac-
teriological examination of the aspirated material
must be performed, to help direct antibiotic ther-
apy. Incision and drainage may be performed if
aspiration is insufficient. Breast cancer should be
excluded in patients with an inflammatory lesion
that is solid on ultrasonography or on aspiration
or that does not settle entirely despite apparently
adequate antibiotic treatment.
• Outcome
Puerperal abscesses are readily recognized and
treated by clinicians. Recurrence is rare,
because they respond well to antibiotic therapy
and when indicated, percutaneous drainage Abscess, Fig. 1 Lactational abscess – clinical (A) and
(Kasales et al. 2014). ultrasound (B) features. (A) The breast is edematous and
indurated and there is a painful lump in the internal part of
the breast (star). (B) Ultrasound demonstrates a cystic
Macroscopy lesion (star) with a thick content, irregular contours and
Lactational abscesses are edematous pink-red perilesional edema (courtesy of Sébastien Molière, Depart-
masses with a central cavity filled with yellow ment of Radiology, Strasbourg University Hospital)
viscous fluid (pus) (Fig. 1). Enlarged axillary
lymph nodes may be encountered. Breast abscess presents as an acute inflam-
matory infiltrate with numerous neutrophils
Imaging associated with fibrin. In abscess resolution, neu-
Mammographic features of abscesses are non- trophilic inflammation is progressively replaced
specific and may include a mass, an architectural by granulation tissue with fibrosis and chronic
distortion or skin thickening. Ultrasound is useful inflammation. Epithelial changes linked to lacta-
to confirm the presence of an abscess, with a hypo- tion are observed around puerperal abscesses
echoic mass or a multiloculated fluid collection (Fig. 2).
with a thick, echogenic rim (D’Alfonso et al. 2015).
Differential Diagnosis
Microscopy Inflammatory carcinoma may be difficult to dif-
Core biopsy is sometimes indicated to rule out ferentiate from mastitis clinically and by imaging.
malignancy, or a specimen may be analyzed When a solid area is present on imaging studies
when surgery is indicated. or when treatment is not efficient, breast cancer
Abscess
Abscess, Fig. 2 Lactational abscess – microscopic fea-
tures (H&E x10). Acute inflammatory infiltrate (star);
mammary glands show lactational changes (arrow)
should be considered and tissue biopsy with his-
tologic analysis should be undertaken.
Non-puerperal Periareolar or Subareolar
Abscess
Non-puerperal periareolar or subareolar
abscesses are often subacute or chronic. Zuska’s
disease is sometimes used to describe patients
with subareolar abscess who present with nipple
retraction and a draining sinus (Mahoney and
Ingram 2014). Subareolar abscesses result from
obstruction of the lactiferous ducts by squamous
metaplasia of their epithelium, with production of
keratin and plugging. Subsequent inflammation
and infection then occur. Initial cases are usually
associated with staphylococcus but recurrent epi-
sodes often have mixed flora, including anaerobic
organisms (D’Alfonso et al. 2015).
Clinical Features
• Incidence
Subareolar non-puerperal abscesses are
strongly associated with cigarette smoking,
70–90% of patients reporting a history of
smoking. An association with vitamin defi-
ciency has also been suggested, as well as
increased prolactin level, phenothiazine
intake, and decreased estrogen level (Pereira
et al. 2012). Their incidence is approximately
3
1–2% of all symptomatic breast processes
(Kasales et al. 2014) and 5% the incidence
of breast cancer (Pereira et al. 2012). A
• Age
Non-puerperal subareolar abscesses affect
a wider age range (mid-teens through eighth
decade) with a peak incidence in the mid to late
fourth decade (Kasales et al. 2014).
• Sex
Non-puerperal subareolar abscesses may rarely
affect males (Kasales et al. 2014).
• Site
Most cases are unilateral but bilateral abscesses
are reported (Habif et al. 1970).
• Treatment
Treatment with antibiotics and aspiration or
drainage often fails in the management of non-
puerperal subareolar abscesses, with a high rate of
recurrence. These should be treated with a course
of appropriate antibiotics that include anaerobic
cover and most cases require surgical intervention
for definitive resolution, with excision of the
abscess, sinus track, and the involved terminal
portion of the subareolar duct (D’Alfonso et al.
2015). Cessation of smoking can be associated
with reversal of the process (Pereira et al. 2012).
• Outcome
Subareolar nonpuerperal abscesses are difficult
to treat. They recur frequently (>50% of cases)
and often require multiple drainage or surgical
procedures. Fistulas form in one third of
patients, most often after aspiration, incision,
or drainage (Kasales et al. 2014).
Macroscopy
Periareolar non-puerperal abscesses result in an
edematous pink-red and indurated nipple (Fig. 3),
which may have a cavitated central mass-like
lesion filled with pus. Lesions range in size from
1 to 5 cm (Kasales et al. 2014). Retraction of
the nipple may develop, as well as duct fistula.
An enlarged axillary lymph node may be
encountered.
Microscopy
Core biopsy is sometimes indicated to rule out
malignancy, or a specimen may be analyzed when
surgery is indicated.
4 Abscess
Subareolar abscesses present with acute,
subacute, or chronic inflammatory infiltrate with
fibrosis. Some subareolar abscesses may show
ducts with squamous metaplasia that contain
Abscess, Fig. 3 Non-puerperal subareolar abscess –
clinical aspect. Indurated, pink-red nodule on the nipple
(courtesy of Marie-Noëlle Roedlich, Department of Radi-
ology, Strasbourg University Hospital)
Abscess, Fig 4 Non-puerperal subareolar abscess –
microscopic features (A: H&E x4 and B: H&E x20).
Dense, subacute, inflammatory infiltrate beyond the
keratin plugs (Fig. 4). A foreign-body-like reaction
to keratin may also be seen (Kasales et al. 2014).
Differential Diagnosis
Subareolar abscesses have to be differentiated
from breast cancer, especially inflammatory
carcinoma.
Subareolar abscess are distinct from duct
ectasia (▶ Duct Ectasia and Periductal Mastitis).
Duct ectasia affects an older age group and is not
associated with smoking. The subareolar ducts are
dilated and the inflammation is less extensive and
less active.
Granulomatous lobular mastitis (▶ Granulo-
matous Mastitis) (GLM) may be associated with
abscess formation. This condition should be differ-
entiated from non-puerperal subareolar abscesses,
in which granulomatous inflammation may
develop in the late stages. In contrast to subareolar
abscess, GLM is generally peripheral and lobulo-
centric, is not associated with epithelial duct squa-
mous metaplasia and with smoking, but is associ-
ated with pregnancy (Pereira et al. 2012).
Others
Peripheral non-puerperal abscesses are rare and
are associated with chronic conditions such as
diabetes, rheumatoid arthritis, steroid treatment,
and trauma (Kasales et al. 2014).
epidermis of the nipple (arrow) and malpighian metaplasia
of the distal part of a galactophorous duct (star)
Acinic Cell Carcinoma
Neonatal breast infection and abscess
are uncommon but can occur in the first few
weeks of life when the breast bud is enlarged.
Staphylococcus aureus is the usual organism, but
occasionally it may be due to Escherichia coli
(Weidner 2012).
Primary infection of the skin of the breast,
which can present as cellulitis or an abscess, most
commonly affects the skin of the lower half of the
breast. These infections are often recurrent in
women who are overweight, have large breasts
or have poor personal hygiene, and in people
with skin conditions such as eczema. Epidermal
cysts are common in the skin of the breast and
may become infected. Hidradenitis suppurativa
may affect the breast. Pilonidal abscesses affect-
ing the nipple have been reported in hairdressers
or sheep shearers (Weidner 2012). Staphylococ-
cus aureus is the usual causative organisms in
skin-associated infections (Weidner 2012).
Breast infection and abscesses may occur
following needle biopsy, or surgery for breast
cancer, breast implants or mammoplasty.
Nipple rings can cause recurrent infection,
particularly in smokers.
Factitial diseases are created by the patient. Such
patients may undergo many investigations before
the nature of the disease is recognized. The diagnosis
is difficult to establish but should be considered
when the clinical situation appears suspicious.
Unusual Breast Infections
Breast abscesses are usually caused by staphylo-
coccus aureus, streptococcus, or anaerobic bacte-
ria. Tuberculosis may rarely be encountered
(▶ Granulomatous Mastitis). It may present with
an abscess resulting from infection of a tubercu-
lous cavity by an acute pyogenic organism such as
Staphylococcus aureus. Syphilis, actinomycosis,
mycotic, parasitic, and viral infections occasion-
ally affect the breast but are rare (Weidner 2012).
References and Further Reading
D’Alfonso, T. M., Ginter, P. S., & Shin, S. J. (2015).
A review of inflammatory processes of the breast with
a focus on diagnosis in core biopsy samples. Journal of
Pathology and Translational Medicine, 49(4), 279–287.
5
Habif, D. V., Perzin, K. H., Lipton, R., & Lattes, R. (1970).
Subareolar abscess associated with squamous metapla-
sia of the lactiferous ducts. American Journal of
Surgery, 119, 523–526. A
Kasales, C. J., Han, B., Stanley Smith, J., Jr.,
Chetlen, A. L., Kaneda, H. J., & Shereef, S. (2014).
Nonpuerperal mastitis and subareolar abscess of
the breast. American Journal of Roentgenology, 202,
W133–W139.
Kataria, K., Srivastava, A., & Dhar, A. (2013). Manage-
ment of lactational mastitis and breast abscesses:
review of current knowledge and practice. Indian
Journal of Surgery, 75(6), 430–435.
Mahoney, M. C., & Ingram, A. D. (2014). Breast
emergencies: types, imaging features, and manage-
ment. American Journal of Roentgenology, 202(4),
W390–W399.
Pereira, F. A., Mudgil, A. V., Macias, E. S., &
Karsif, K. (2012). Idiopathic granulomatous lobular
mastitis. International Journal of Dermatology, 51(2),
142–151.
Weidner, N. (2012). Infections of the breast. In D. J. Dabbs
(Ed.), Breast pathology (pp. 34–43). Philadelphia:
Elsevier Saunders.
Acinic Cell Carcinoma
Maria P. Foschini and Luca Morandi
Department of Biomedical and Neuromotor
Sciences (DIBINEM), Unit of Anatomic
Pathology at Bellaria Hospital, University of
Bologna, Bologna, Italy
Definition
Acinic cell carcinoma (ACC) is a special type
of breast carcinoma showing serous differenti-
ation, with zymogen-type cytoplasmic granules,
similar to acinic cell carcinoma arising in the
parotid gland (Eusebi et al. 2012; Foschini
et al. 2017).
Clinical Features
• Incidence
ACC is a rare tumor, but its real incidence is
difficult to assess, as most of our knowledge is
based on single case reports or small series. It
was first described by Roncaroli et al. (1996),
6 Acinic Cell Carcinoma

and then better delineated by Damiani et al. Macroscopy

(2000). Since then less than 50 cases have
been described in the English literature Macroscopic features are similar to those of
(Foschini et al. 2017). invasive carcinoma NST (▶ Invasive Carcinoma
• Age NST). Specifically ACC presents as a nodule,
ACC usually affects adults, aged from 20 to hard in consistency, with infiltrative margins,
80 years (mean 50). ranging in size from 11 mm to 50 mm. In one
• Sex instance, ACC arose within a fibroadenoma
ACC usually occurs in female patients. One (▶ Fibroadenoma) (Foschini et al. 2017).
case has been described in a male patient
(Shimao et al. 1998) and one case has been
reported in BRCA1 mutated patient
Microscopy
(Ripamonti et al. 2013).
ACC of the breast shows a wide variety of archi-
• Site
tectural patterns, and therefore diagnosis is mainly
Breast ACC affects the parenchyma with no
based on the recognition of the neoplastic cell
specific site; its presentation is similar to breast
features.
carcinoma of no special type (NST).
Breast ACC infiltrates parenchyma with small
• Treatment
glandular structures (Fig. 1 H&E) composed of
Breast ACC is a triple negative tumor, usually
large polygonal cells, with granular, clear, or
showing low aggressive potential. It is treated
amphophilic cytoplasm. The cytoplasm
with radical surgery, and, in most of the reported
contains granules that are seen on H&E stained
cases, radiation and/or chemotherapy are added.
sections, but they can be better evidenced
• Outcome
by PAS after diastase digestion or electron
Prognosis is difficult to assess due to the low
microscopy (Damiani et al. 2000). The
number of reported cases. From a recent
nucleus is centrally located, shows coarse
review (Foschini et al. 2017) most of the
chromatin and well-evident nucleolus (Figs. 2
patients are alive and free of recurrences or
and 3 H&E).
metastases at the time of last follow-up. Length
These cells can be arranged in solid as well as
of follow-up information ranges from 6 to
in microglandular structures devoid of basal
142 months (mean 42 months). Axillary
membrane (Fig. 4 Collagen IV immunostaining).
lymph-node metastases were present in 9/30
In most of the cases a wide range of architectural
cases. Distant metastases (liver, lungs, and
patterns is seen within the same tumor, while in
bone) were reported in three cases, two of
other cases one pattern is predominant. Usually
which died of disease.
the microglandular component is present at the

Acinic Cell Carcinoma,

Fig. 1 Low power view of
ACC with prevalent
microglandular architecture
(H&E)
Acinic Cell Carcinoma 7

Acinic Cell Carcinoma,

Fig. 2 At high power the
neoplastic cells show
granular cytoplasm and are A
arranged in small glandular
structures (H&E)

Acinic Cell Carcinoma,

Fig. 3 Neoplastic glands
are small, with irregular
outlines and lined by
multiple layers of neoplastic
cells (H&E)

2000). The microglandular component is char-

acterized by small glands, lined by one or multi-
ple layers of atypical cells, having the same
features of neoplastic cells located in the solid
component. In situ duct carcinoma, composed of
cells with acinic features, can be associated with
the invasive component.

Immunophenotype

Immunohistochemical profile is important to

Acinic Cell Carcinoma, Fig. 4 Basal membrane,
evidenced by Collagen IV immunostainig, shows small
capillary vessels, but it is not present around the neoplastic
glands
periphery of the tumor, giving an invasive pat-
tern of growth. Cases with pure microglandular
pattern of growth are on record (Damiani et al.
achieve a correct diagnosis, because it confirms
the acinic differentiation of cells. Specifically
ACC is positive for salivary type amylase
(Fig. 5), lysozyme, and alpha-1-antichimotrypsin.
Furthermore the majority of ACC cells are
strongly positive for S-100 protein (Fig. 6) and
epithelial membrane antigen (EMA) (Fig. 7) and
low molecular weight cytokeratins (CK) as CK7
and CK8.
8 Acinic Cell Carcinoma
Acinic Cell Carcinoma,
Fig. 5 Salivary type
amylase is strongly positive
in ACC cells
Acinic Cell Carcinoma, Fig. 6 S-100 antibody stains
most of the ACC neoplastic cells
Estrogen and progesterone receptors (ER, PR)
are usually negative, as well as androgen receptor
(AR). No HER2 amplification has been recorded.
Basal membrane is absent at the periphery of the
neoplastic glandular structures (Conlon et al. 2016).
On electron microscopy the neoplastic cells are
characterized by intracytoplasmic electron dense
granules (Damiani et al. 2000).
Molecular Features
Only few papers dealt with ACC molecular profile,
therefore knowledge on this subject is still incom-
plete. The following genes were found to be mutated
in ACC: TP53, PIK3CA, KMT2D, ERBB4, ERBB3,
NEB, BRCA1, MTOR, CTNNB1, INPP4B, FGFR2
(Guerini-Rocco et al. 2015; Piscuoglio et al. 2015).
In addition an MLL3 splicing mutation, a TSC2
missense mutation (A289V), and missense muta-
tions in MED12 (D1204E), MLL (K1225 N),
MLL2 (T2017S), TP63 (R594L) together with a
twofold increase in FOXA1 were described in one
case (Conlon et al. 2016).
The molecular profile detected in breast ACC is
quite different from that of salivary gland ACC,
while it is similar to that of breast poorly differenti-
ated carcinoma NST. These observations lead
Piscuoglio et al. (2015) to suggest that breast ACC
is a novel variant of breast triple negative carcinoma.
Differential Diagnosis
Several breast carcinomas should be differentiated
from ACC, and differential diagnosis is mainly
based on the immunohistochemical profile and on
the architectural pattern of growth.
ACC with solid growth pattern should be dif-
ferentiated from breast carcinoma NST (▶ Inva-
sive Carcinoma NST), oncocytic carcinoma
(▶ Invasive Oncocytic Carcinoma), and apocrine
carcinoma (▶ Apocrine Carcinoma). Breast carci-
noma NST does not express S-100 protein, which
is strongly positive in nuclei and cytoplasms of the
majority of ACC cells. Apocrine carcinoma
shows a strong and diffuse positivity for the apo-
crine marker GCDFP-15, while the same marker
is only focally positive in ACC. Oncocytic carci-
noma is excluded for its intense and diffuse pos-
itivity for the antimitochondrial marker and, when
electron microscopy is feasible, it shows numer-
ous intracytoplasmic mitochondria. Furthermore
Acinic Cell Carcinoma
Acinic Cell Carcinoma,
Fig. 7 EMA positivity in
ACC
and most importantly, none of these latter tumors
show serous acinar differentiation, demonstrated
with anti-lysozyme, anti-salivary type amylase,
and anti-alpha-1- antichimotrypsin.
Secretory carcinoma (▶ Invasive Secretory Car-
cinoma) of the breast can simulate ACC. Differen-
tial diagnosis is based on the cytological atypias
that in secretory carcinoma are quite bland, while
are more marked in ACC. In addition secretory
breast carcinoma is characterized by a typical
ETV6 rearrangement that is absent in ACC.
Differential diagnosis between ACC with
prominent microglandular pattern and micro-
glandular adenosis (MGA) (▶ Microglandular
Adenosis) is a more controversial issue, and
recent papers describe similar molecular fea-
tures. According to the original morphological
description (Clement and Azzopardi 1983),
MGA is characterized by small glandular struc-
tures lined by clear cells with empty cytoplasm,
surrounded by basal membrane. On the contrary,
ACC with microglandular pattern is composed
of cells with eosinophilic cytoplasm, with
intracytoplasmic granules (demonstrated both
with PAS after diastase digestion and electron
microscopy) and absence of basal membrane.
References and Further Reading
Clement, P. B., & Azzopardi, J. G. (1983). Microglandular
adenosis of the breast – A lesion simulating tubular
carcinoma. Histopathology, 7, 169–180.
Conlon, N., Sadri, N., Corben, A. D., & Tan, L. K. (2016).
Acinic cell carcinoma of breast: Morphologic and
immunohistochemical review of a rare breast cancer
subtype. Human Pathology, 51, 16–24.
9
A
Damiani, S., Pasquinelli, G., Lamovec, J., Peterse, J. L., &
Eusebi, V. (2000). Acinic cell carcinoma of the breast:
An immunohistochemical and ultrastructural study.
Virchows Archiv, 437, 74–81.
Eusebi, V., Ichihara, S., Vincent-Salomon, A., Sniege, A.,
& Sapino, A. (2012). Exceptionally rare types and
variants. In S. R. Lakhani, I. O. Ellis, S. J. Schnitt,
P. H. Tan, & M. van de Vijver (Eds.), WHO classifica-
tion of tumours of the breast (4th ed., p. 75). Lyon:
IARC Press.
Foschini, M. P., Morandi, L., Asioli, S., Giove, G.,
Corradini, A. G., & Eusebi, V. (2017). The morpholog-
ical spectrum of salivary gland type tumours of the
breast. Pathology, 49, 215–227.
Guerini-Rocco, E., Hodi, Z., Piscuoglio, S., Ng, C. K.,
Rakha, E. A., Schultheis, A. M., Marchiò, C., da
Cruz, P. A., De Filippo, M. R., Martelotto, L. G., De
Mattos-Arruda, L., Edelweiss, M., Jungbluth, A. A.,
Fusco, N., Norton, L., Weigelt, B., Ellis, I. O., & Reis-
Filho, J. S. (2015). The repertoire of somatic genetic
alterations of acinic cell carcinomas of the breast: An
exploratory, hypothesis-generating study. Journal of
Pathology, 237, 166–178.
Piscuoglio, S., Hodi, Z., Katabi, N., Guerini-Rocco, E.,
Macedo, G. S., Ng, C. K., Edelweiss, M., De Mattos-
Arruda, L., Wen, H. Y., Rakha, E. A., Ellis, I. O., Rubin,
B. P., Weigelt, B., & Reis-Filho, J. S. (2015). Are acinic
cell carcinomas of the breast and salivary glands dis-
tinct diseases? Histopathology, 67, 529–537.
Ripamonti, C. B., Colombo, M., Mondini, P., Siranoush,
M., Peissel, B., Bernard, L., Radice, P., & Carcangiu,
M. L. (2013). First description of an acinic cell carci-
noma of the breast in a BRCA1 mutation carrier: A case
report. BMC Cancer, 13, 46.
Roncaroli, F., Lamovec, J., Zidar, A., & Eusebi, V. (1996).
Acinic cell-like carcinoma of the breast. Virchows
Archiv, 429, 69–74.
Shimao, K., Haga, S., Shimizu, T., Imamura, H.,
Watanabe, O., Kinoshita, J., Nagumo, H., Utada, Y.,
Okabe, T., Kajiwara, T., Oshibe, N., & Aiba,
M. (1998). Acinic cell adenocarcinoma arising in the
breast of a young male: A clinicopathological, immu-
nohistochemical and ultrastructural study. Breast Can-
cer, 5, 77–81.
10
Adenoid Cystic Carcinoma
Maria P. Foschini and Luca Morandi
Department of Biomedical and Neuromotor
Sciences (DIBINEM), Unit of Anatomic
Pathology at Bellaria Hospital, University of
Bologna, Bologna, Italy
Definition
Adenoid cystic carcinoma (AdCC) of the breast is
a low-grade tumor, composed of epithelial,
myoepithelial, and basal cells, showing features
similar to the salivary gland counterpart.
Clinical Features
• Incidence
AdCC of the breast is a rare tumor, accounting
for less than 1% of all breast tumors.
• Age
It usually affects elderly female patients, even
if rare cases have been reported in children.
• Sex
AdCC usually affects female patients, rare
cases have been reported in males.
• Site
AdCC is more frequently located in the
retroareolar region, but it can affect all the
breast quadrants. It can present as a mass of
variable size or as screen detected nodule.
• Treatment
Radical surgery is the treatment of choice.
• Outcome
AdCC is a low malignant potential tumor
therefore prognosis is usually good. Recur-
rences and disease progression are rare. To
better predict prognosis, AdCC should be sub-
divided in three different categories: (i) AdCC
classical variant shows good prognosis, with
no recurrences or metastases, when local com-
plete surgical excision is achieved; (ii) AdCC
with solid-basaloid features (SB-AdCC) can
present recurrence and local metastases, but
in most of the cases, long-term follow-up did
not show tumor-related deaths; (iii) AdCC with
Adenoid Cystic Carcinoma
high-grade transformation is characterized by
the presence of high-grade malignant compo-
nent, in addition to the AdCC classical fea-
tures. These latter cases can lead to patient’s
death (D’Alfonso et al. 2014; Foschini et al.
2016, 2017; Shin and Rosen 2002).
Macroscopy
AdCC presents as a lobulated mass, hard in con-
sistency, whitish in color.
Microscopy
AdCC can present various morphological features
that reflect the three main categories (Foschini
et al. 2016, 2017).
AdCC classical variant: It is composed of a
mixture of epithelial, myoepithelial, and basal
cells, arranged in tubular, cribriform, and solid
structures. Tubular structures are usually present
at the periphery of the neoplastic nodule, thus
giving a peculiar infiltrative pattern of growth
(Fig. 1 H&E). Tubular AdCC is characterized by
round or elongated tubular structures, lined by
epithelial, basal, and myoepithelial cells (Fig. 2
H&E). The tubular structures contain basal mem-
brane or epithelial type of mucin. The tubular
structures usually infiltrate the fat tissue. The crib-
riform architecture is the most frequently
observed (Fig. 3a, b H&E). It shows two types
of glandular spaces. Epithelial cells surround
luminal spaces containing epithelial-type mucin,
which stains blue with Alcian blue pH 2.5.
Myoepithelial and basaloid cells surround
pseudoluminal spaces, containing basal mem-
brane evidenced by PAS staining after diastase
digestion. Cells show little pleomorphism, and
mitoses are rare. No necrosis or perineural or
lymphovascular invasion are seen. Sebaceous dif-
ferentiation can be focally encountered.
AdCC solid-basaloid variant (SB-AdCC): It
has been described by Shin and Rosen in 2002.
It usually presents as multiple neoplastic foci,
varying in size from a few millimeters to large
masses (Fig. 4a, b H&E). In addition to the fea-
tures present in the classical variant, it is com-
posed of large solid nests of cells with basaloid
Adenoid Cystic Carcinoma 11

Adenoid Cystic
Carcinoma, Fig. 1 AdCC
classical variant, showing
a central part with A
cribriform architecture and
a peripheral part (arrows)
with tubular architecture.
The AdCC with tubular
architecture shows
infiltrative pattern of
growth, invading the fatty
tissue (H&E)

Adenoid Cystic
Carcinoma, Fig. 2 AdCC
classical variant with
tubular architecture is
composed of elongated
glands, surrounded by two
or more cell layers. Focally
structures typical of AdCC
with two types of mucins
are visible (H&E)

features and nuclear atypia. Atypical mitotic fig-
ures are frequent; necrosis can be present as well
as perineural invasion (Figs. 5 and 6 H&E). When
perineural invasion is present a SB-AdCC variant
should always be suspected.
AdCC with high-grade transformation: In rare
cases, in addition to the classical AdCC features,
areas of high-grade tumor of different origin
(melanoma, spindle cell carcinoma, ▶ Invasive
Carcinoma NST, and ▶ Malignant Adenomyoe-
pithelioma (M-AME)) are present. The presence of
these high-grade tumor areas has prognostic impact,
as metastases and disease progression can occur.
Immunophenotype
cells are positive with high molecular weight CK,
as CK 14 and CK 5\6, p63 (Fig. 7 (a) p63
immunostaining in nuclei of myoepithelial cells in
cribriform and (b) and tubular components).
Myoepithelial cells are evidenced by myoepithelial
markers, as smooth muscle actin (SMA), calponin,
caldesmon. Basal cell markers, as collagen IV and
laminin, stain the basal membrane present in the
pseudoluminal spaces (Fig. 8 immunostaining with
Collagen IV). CD117 (cKit) is strongly present in
all the epithelial components. Proliferative markers,
as Ki67, stain a variable percentage of neoplastic
cells. High proliferative index is usually encoun-
tered in the SB-AdCC variant or in the areas of
high-grade transformation.

Immunohistochemical stainings are useful to high- Molecular Features

light the presence of the different cell types. Spe-
cifically the epithelial cells are positive with low- AdCC of the breast is most frequently a “triple
molecular weight cytokeratins (CKs) as CK7, CK8, negative tumor of low malignancy potential”
and epithelial membrane antigen (EMA). Basal (Foschini and Krausz 2010), as estrogen (ER) and
12 Adenoid Cystic Carcinoma

Adenoid Cystic
Carcinoma, Fig. 3 AdCC
classical variant with
cribriform architecture
(a and b) shows neoplastic
nests composed of cells
with mild atypia,
surrounding two types of
spaces. Glandular spaces
contain an epithelial type of
mucin that is weakly
basophilic on H&E stained
sections. Pseudoglandular
spaces contain eosinophilic
basal membrane (H&E)

progesterone receptors (PR) are usually negative
and HER2 protein is not overexpressed (Foschini
et al. 2017). A weak expression for androgen recep-
tor (AR) has been described (Vranic et al. 2010).
Nevertheless, papers, based on large cohorts of
AdCC, report focal ER positivity in a minority of
cases. In our experience ER positivity can be seen
in a minority of epithelial cells in AdCC classical
variant, while ER and PR are completely absent
in SB-AdCC and in AdCC with high-grade
transformation.
A novel isoform of ER, namely ER-alpha36,
has been detected in AdCC of the breast. This
novel isoform differs from the classical isoform
(ER-alpha66) as it does not show the transcrip-
tional activation domains; in addition, on
immunohistochemically stained sections, it is
mainly localized in the cytoplasm and on the cell
membrane. It mediates nonclassic (nongenomic)
estrogen signaling, therefore opening the possibil-
ity of novel therapies (Vranic et al. 2011).
Epidermal growth factor receptor 1 (EGFR)
protein can be overexpressed, even if this over-
expression is not accompanied by gene amplifica-
tion (Vranic et al. 2010).
MYB-NFIB fusion gene has been detected in
the majority of AdCC (Martelotto et al. 2015); in
addition it is maintained in SB-AdCC and in
AdCC with high-grade transformation (Fusco
et al. 2016; Righi et al. 2011).
The mutational profile of AdCC has been
described using whole exome sequencing
(Martelotto et al. 2015), which showed a sub-
stantial heterogeneity with lack of recurrent
mutations. The mutation rate was found to be
very low (0.27 nonsilent mutations/Mb), similar
to that reported for pediatric malignancies and
salivary gland AdCCs (0.31 nonsilent mutations/
Mb), and lower than that reported for triple neg-
ative breast cancers (TNBCs) (1.38 nonsilent
mutations/Mb). Unlike common TNBCs and
basal-like breast cancers, no somatic mutations
Adenoid Cystic Carcinoma 13

Adenoid Cystic Carcinoma, Fig. 4 SB-AdCC variant shows a multinodular type of growth, with neoplastic nodules
varying in size from a few millimeters (a) to larger neoplastic masses (b) (H&E)

Adenoid Cystic
Carcinoma, Fig. 5 SB-
AdCC at higher power
shows cellular atypia,
mitoses, and necrosis
(H&E)

targeting TP53, PIK3CA, RB1, BRCA1, or
BRCA2 were identified in breast AdCCs. The
most frequently mutated genes are: MYB,
BRAF, FBXW7, SMARCA5, SF3B1, FGFR2,
TLN2, PRKD1, RASA1, PTPN11, and MTOR.
On rare occasions mutations in RAS pathway
have been detected. Many of the mutations iden-
tified were likely clonal with a cancer cell frac-
tion >80%. Evaluating gene copy number
alterations, low level of genetic instability and
no amplifications or homozygous deletions were
identified.
14
When AdCC shows high-grade transformation,
progression to high-grade TNBC was found to
involve clonal shifts with enrichment of mutations
affecting EP300, NOTCH1, ERBB2, FGFR1,
KMT2C, STAG2, KDM6A, CDK12. These data con-
Adenoid Cystic Carcinoma, Fig. 6 SB-AdCC focal fea-
tures reminiscent of AdCC are present (H&E)
Adenoid Cystic
Carcinoma, Fig. 7 p63
immunostaining shows the
presence of basal and
myoepithelial cells both in
the cribriform (a) and in the
tubular (b) components
Adenoid Cystic Carcinoma
firm the morphological hypothesis, that high-grade
transformation is related to selected neoplastic
clones that acquire additional somatic mutations.
Differential Diagnosis
Several differential diagnoses should be carried
out, for the different variants.
AdCC classical variants. At the periphery of
the neoplastic nodules, AdCC usually shows
tubular architecture. Tubular AdCC should be dif-
ferentiated from several entities having a micro-
glandular pattern of growth. Microglandular
adenosis (▶ Microglandular Adenosis) should be
excluded, as this latter entity is composed of glan-
dular structures lined by a single type of cells; on
the contrary in AdCC, tubular structures are
surrounded by epithelial, myoepithelial, and
basal cells. In addition, in microglandular
adenosis, tubular structures are surrounded by a
Adenoid Cystic Carcinoma
Adenoid Cystic Carcinoma, Fig. 8 AdCC classical var-
iant with cribriform architecture: immunostaining with
collagen IV highlights the presence of basal membrane
inside the pseudoglandular spaces
layer of basal membrane, while AdCC tubular
structures contain basal membrane.
Sclerosing adenosis (▶ Sclerosing Adenosis) is
a very common disease, composed of small glan-
dular structures closely packed together, whereas
AdCC tubular structures are not packed together,
but they show a clear invasive pattern within
the fat tissue. The basal membrane distribution
(outside the glands in sclerosing adenosis and
inside the glands in tubular AdCC) is an addi-
tional helpful differential diagnostic criterion. Dif-
ferential diagnosis is more difficult when we
compare tubular AdCC with adenomyoepithelioma
(▶ Adenomyoepithelioma) with tubular architec-
ture. Both tumors share same morphological fea-
tures and the same cell composition (epithelial and
myoepithelial\basal cells), and in addition differen-
tial diagnosis is complicated by the description of
cases showing the two tumor types (AdCC and
adenomyoepithelioma) merging together. Usually
the typical areas of AdCC or adenomyoepithelioma
accompany the tubular type of growth, thus helping
to differentiate the two entities. Differential diagno-
sis can be more difficult in preoperative needle core
biopsies. In these latter cases differential diagnosis
could be tempted with the aid of CD117
immunostaining that is usually strong and diffuse
in AdCC, while it is weak and focal in adenomyoe-
pithelioma. Nevertheless, both entities are of low-
grade malignancy and need complete surgical
15
excision, therefore, the most important clue for
the patient’s correct treatment is to identify the
entity and more specific differential diagnosis can A
be referred to postoperative specimens.
AdCC cribriform should be differentiated by
several entities showing glandular spaces, as crib-
riform invasive carcinoma (▶ Invasive Cribriform
Carcinoma), collagenous spherulosis (▶ Collage-
nous Spherulosis), and infiltrating epitheliosis
(▶ Usual Ductal Hyperplasia (UDH)). Cribriform
invasive carcinoma is composed by one cell type
only; it is a pure epithelial cell tumor. The neo-
plastic cells surround glandular spaces, containing
epithelial type mucin only. Basal membrane is not
present inside the neoplastic lumina. All the neo-
plastic cells stain intensively with ER and with
epithelial markers, as low molecular weight
CK. Basal and myoepithelial markers are negative
in the neoplastic cells.
Collagenous spherulosis is a rare condition,
composed by basal\myoepithelial cells only, sur-
rounding pseudoglandular spaces filled with basal
membrane. On immunohistochemistry, basal
\myoepithelial cell markers, such as p63, CK14,
and CK5\6, are uniformly positive. Collagen IV
and Laminin stain the luminal content. Similarly,
infiltrating epitheliosis, being composed of basal
\myoepithelial cells only, shows a uniform posi-
tivity for basal and myoepithelial markers.
SB-AdCC variant should be differentiated by
basaloid carcinomas. The differential diagnosis is
mainly based on the detection of classical features
of AdCC. The differential diagnosis can be diffi-
cult when the solid-basaloid areas compose the
most of the tumor; in these latter cases, careful
search through the whole tumor is needed. Immu-
nohistochemistry for CD117 can be helpful, as the
strong and diffuse CD117 positivity is retained in
the SB-AdCC variant also. Differential diagnosis
is important, as, even if the SB-AdCC variant is
more aggressive than that of the classical variant,
its malignant potential is less than that of other
basaloid breast carcinomas.
AdCC with high-grade transformation. These
cases are characterized by AdCC classical associ-
ated with highly malignant areas. The detection of
the AdCC areas is necessary to achieve the correct
diagnosis.
16
References and Further Reading
Brill, L. B., Kanner, W. A., Fehr, A., Andrén, Y.,
Moskaluk, C. A., Löning, T., Stenman, G., & Frierson,
H. F., Jr. (2011). Analysis of MYB expression and
MYB-NFIB gene fusions in adenoid cystic carcinoma
and other salivary neoplasms. Modern Pathology, 24,
1169–1176.
D’Alfonso, T. M., Mosquera, J. M., MacDonald, T. Y.,
Padilla, J., Liu, Y. F., Rubin, M. A., & Shin, S. J. (2014).
MYB-NFIB gene fusion in adenoid cystic carcinoma of
the breast with special focus paid to the solid variant with
basaloid features. Human Pathology, 45, 2270–2280.
Foschini, M. P., & Krausz, T. (2010). Salivary gland-type
tumors of the breast: A spectrum of benign and malig-
nant tumors including “triple negative carcinomas” of
low malignant potential. Seminar in Diagnostic Pathol-
ogy, 27, 77–90.
Foschini, M. P., Rizzo, A., De Leo, A., Laurino, L., Sironi,
M., & Rucco, V. (2016). Solid variant of adenoid cystic
carcinoma of the breast: A case series with proposal of a
new grading system. International Journal of Surgical
Pathology, 24(2), 97–102.
Foschini, M. P., Morandi, L., Asioli, S., Giove, G.,
Corradini, A. G., & Eusebi, V. (2017). The morpholog-
ical spectrum of salivary gland type tumours of the
breast. Pathology, 49, 215–227.
Fusco, N., Geyer, F. C., De Filippo, M. R., Martelotto,
L. G., Ng, C. K., Piscuoglio, S., Guerini-Rocco, E.,
Schultheis, A. M., Fuhrmann, L., Wang, L., Jungbluth,
A. A., Burke, K. A., Lim, R. S., Vincent-Salomon, A.,
Bamba, M., Moritani, S., Badve, S. S., Ichihara, S.,
Ellis, I. O., Reis-Filho, J. S., & Weigelt, B. (2016).
Genetic events in the progression of adenoid cystic
carcinoma of the breast to high-grade triple-negative
breast cancer. Modern Pathology, 29, 1292–1305.
Martelotto, L. G., De Filippo, M. R., Ng, C. K., Natrajan, R.,
Fuhrmann, L., Cyrta, J., Piscuoglio, S., Wen, H. C., Lim,
R. S., Shen, R., Schultheis, A. M., Wen, Y. H., Edelweiss,
M., Mariani, O., Stenman, G., Chan, T. A., Colombo,
P. E., Norton, L., Vincent-Salomon, A., Reis-Filho, J. S.,
& Weigelt, B. (2015). Genomic landscape of adenoid
cystic carcinoma of the breast. Journal of Pathology,
237, 179–189.
Righi, A., Lenzi, M., Morandi, L., Flamminio, F., De
Biase, D., Farnedi, A., & Foschini, M. P. (2011).
Adenoid cystic carcinoma of the breast
associated with invasive duct carcinoma: A case
report. International Journal of Surgical Pathology,
19, 230–234.
Shin, S. J., & Rosen, P. P. (2002). Solid variant of mam-
mary adenoid cystic carcinoma with basaloid features:
A study of nine cases. American Journal of Surgical
Pathology, 26, 413–420.
Vranic, S., Frkovic-Grazio, S., Lamovec, J., Serdarevic,
F., Gurjeva, O., Palazzo, J., Bilalovic, N., Lee, L. M.,
& Gatalica, Z. (2010). Adenoid cystic carcinomas
of the breast have low Topo IIa expression but fre-
quently overexpress EGFR protein without
Adenomyoepithelioma
EGFR gene amplification. Human Pathology, 41,
1617–1623.
Vranic, S., Gatalica, Z., Deng, H., Frkovic-Grazio, S.,
Lee, L. M., Gurjeva, O., & Wang, Z. Y. (2011).
ER-a36, a novel isoform of ER-a66, is commonly
over-expressed in apocrine and adenoid cystic carci-
nomas of the breast. Journal of Clinical Pathology,
64, 54–57.
Wetterskog, D., Wilkerson, P. M., Rodrigues, D. N.,
Lambros, M. B., Fritchie, K., Andersson, M. K.,
Natrajan, R., Gauthier, A., Di Palma, S., Shousha, S.,
Gatalica, Z., Töpfer, C., Vukovic, V., A’Hern, R.,
Weigelt, B., Vincent-Salomon, A., Stenman, G., Rubin,
B. P., & Reis-Filho, J. S. (2013). Mutation profiling of
adenoid cystic carcinomas from multiple anatomical
sites identifies mutations in the RAS pathway, but no
KIT mutations. Histopathology, 62, 543–550.
Adenomyoepithelioma
Eugenio Maiorano1, Enrica Macorano2 and
Mauro Giuseppe Mastropasqua2
1
Department of Emergency and Organ
Transplantation, Unit of Pathology, University of
Bari, Bari, Italy
2
Department of Emergency and Organ
Transplantation, Universitá degli Studi di Bari
Aldo Moro – Policlinico, Bari, Italy
Definition
Adenomyoepithelioma (AME) is a benign tumor of
the breast, composed by a biphasic proliferation of
phenotypically distinct myoepithelial cells and
luminal epithelial cells.
Following the first description by Hamperl
(1970), Tavassoli (1991) identified three histo-
logic variants, in which myoepithelial and epithe-
lial cells are present in variable percentages,
namely, spindle, tubular, and lobulated AME
(Tavassoli 1991).
AME with malignant features (▶ Malignant
Adenomyoepithelioma (M-AME)) have seldom
been reported (Hayes 2011) and named AME
with carcinoma, when epithelial cells or myoepi-
thelial cells show malignant cytomorphological
features and malignant AME when these are pre-
sent in both components (Brogi 2014).
Adenomyoepithelioma
Clinical Features
• Incidence
AME is an extremely rare tumor, a few small
case series and single case reports having been
reported so far. (Decorsiere et al. 1988; McLaren
et al. 2005; Loose et al. 1992; Rosen 1987;
Tavassoli 1991). AME with carcinoma and
malignant AME are even more infrequent than
their benign counterpart (Ahmed et al., Ahmed
and Heller 2000).
• Age
It mostly occurs in postmenopausal women,
with sporadic cases occurring both in younger
(26 and 27 year old; Loose et al. 1992; Rosen
1987) and older patients (84 year old; Berna
et al. 1997).
• Sex
Women are far more commonly affected, with
sporadic cases described in males (Berna et al.
1997; Tamura et al. 1993).
• Site
AME usually is a solitary and unilateral mass,
which more commonly occurs in the peripheral
parts of the breast, and only occasionally may
be centrally located (Adejolu et al. 2011).
• Treatment
The standard treatment is surgical excision
with clear margins (Rosen 1987). Currently,
adjuvant treatments are considered only for
the management of those exceptional cases of
AME with carcinoma.
• Outcome
AME is considered a benign neoplasm; never-
theless, local recurrence has been reported in
sporadic cases, usually more than 2 years after
surgical excision (Loose et al. 1992) and pos-
sibly ascribed to incomplete tumor eradication.
AME with carcinoma may present either as
synchronous or metachronous lesions, follow-
ing recurrence of previously excised AMEs
(Tavassoli 1991).
Macroscopy
AME generally is a circumscribed, uniformly
solid, sometimes lobulated, firm and small
17
nodule. Its average size is 2.5 cm, ranging from
0.5 to 8.0 cm, without distinctive discoloration,
the cut surface appearing as tan, gray, white, yel- A
low, or pink (Rosen 1987). Occasionally, a small
multicystic component or multinodulation may
be detected (Laforga et al. 1998). Its clinical pre-
sentations include nipple discharge, pain, or
tenderness at palpation and, mammographically,
it appears as a rounded or lobulated, well-
circumscribed dense mass, sometimes showing
microcalcifications, while ultrasonography high-
lights a solid or cystic structure (Park et al. 2013;
Lee et al. 2010). Quite interestingly, strong
uptake of 18 F-Fluorodeoxyglucose by Positron
Emission Tomography has recently been reported
(Oba et al. 2017); this should be taken into
account as a potential pitfall of clinico-
instrumental investigations.
Microscopy
The cytomorphological features of AME have
been described in occasional cases or small case
series (Chang et al. 2002; Hock and Chan 1994;
Kurashina 2002; Mercado et al. 2007; Ng 2002;
Niemann et al. 1995; Saad et al. 2012; Valente and
Stuckey 1994; Zhang et al. 2004): clusters of
epithelial and myoepithelial cells represent the
major finding, the latter also displaying occasional
intracytoplasmic vacuolization. Mild to moderate
nuclear atypia was also noted, in the absence of
necrosis or mitotic activity. Nevertheless, the
diagnosis of AME was not achieved, and based
on fine needle aspiration cytology, most cases
were interpreted as benign neoplasms but suspi-
cion of malignancy was raised in some instances
(Brogi 2014). Proper identification of the
myoepithelial cell component, admixed with duc-
tal cells, seem the most reliable tool to rule out
malignancy.
In histologic preparations, AME usually is
sharply separated from adjacent tissues and may
show discrete fibrous encapsulation. Different
morphological patterns may distinctly or simulta-
neously be present, according to the variable per-
centage of myoepithelial and epithelial cells in
individual lesions (Hock and Chan 1994). The
18
spindle cell growth pattern consists in a predom-
inant proliferation of myoepithelial cells, some-
times showing clear and vacuolated (“soap
bubble”) cytoplasms, and sparse or hardly visible
epithelial-lined spaces (Fig. 1), resembling
myoepithelioma (Weidner et al., Weidner and
Levine 1988).
In the tubular pattern, glandular spaces are
far more evident (Fig. 2), oval or rounded in
shape, reminiscent of tubular adenoma. They
are composed by epithelial cells with darkly
stained cytoplasms and slightly hyperchromatic
nuclei. Myoepithelial cells may surround epithe-
lial cells in a basal position or form small
clusters. They appear as small cuboidal cells
with barely visible cytoplasm or as larger cells
with evident cytoplasmic clearing; occasionally,
the exuberant proliferation of myoepithelial cells
may lead to compression of the lumen in tubular
structures.
In the lobulated variant (Fig. 3), the growth
pattern is mostly solid and the tumor nests include
an admixture of clear, eosinophilic, and
plasmacytoid myoepithelial cells along with com-
pressed epithelial-lined spaces. A fibro-sclerotic
core is at times evident.
Papillary structures may seldom be present and
apocrine metaplasia may be detected in such areas
(Eusebi et al. 1987); squamous metaplasia may
Adenomyoepithelioma,Fig.1 Adenomyoepithelioma–
spindle cell variant: the tumor is composed by uniform
spindle cells, with scant cytoplasm and rounded or
angulated nuclei; duct-like structures represent a minority
of the tumor cell population and usually display a small
lumen (H&E
100)
Adenomyoepithelioma
infrequently occur, possibly as a consequence of
infarction, while cartilaginous metaplasia is
exceptionally uncommon.
The detection of infiltrative growth towards the
surrounding tissues, necrosis, prominent cyto-
logic atypia, and exuberant mitotic activity in
Adenomyoepithelioma,Fig.2 Adenomyoepithelioma–
tubular variant: duct-like structures are well evident, oval
or rounded in shape, and composed by epithelial cells, with
darkly stained cytoplasms and slightly hyperchromatic
nuclei and myoepithelial cells in a basal position. Occa-
sionally, the latter may be assembled in small clusters and
show either scant cytoplasm or prominent cytoplasmic
clearing. The exuberant proliferation of myoepithelial
cells may lead to compression of the lumen in tubular
structures (H&E
100)
Adenomyoepithelioma,Fig.3 Adenomyoepithelioma–
lobulated variant: clear, eosinophilic, and plasmacytoid
myoepithelial cells are widely represented, thus producing
a predominantly solid growth pattern with only occasional
epithelial-lined spaces, which look compressed
(H&E
100)
Adenomyoepithelioma 19

either the epithelial or the myoepithelial compo-

nent, are indicative of malignancy (Bult et al.
2000; Chen et al. 1994; Foschini et al. 1995; A
Hegy et al. 2009; Jones et al. 2003; Kihara et al.
2001; Michael et al. 1994; Oka et al. 2007;
Quereshi et al. 2009; Rasbridge and Millis 1998;
Simpson et al. 1998; Trojani et al. 1992); in such
instances, the designation AME with carcinoma
seems appropriate (Brogi 2014). Also, cases have
been described, in which both components show
malignant features, and named malignant AME
(Brogi 2014).
Occasional reports have highlighted the Adenomyoepithelioma, Fig. 4 Low-molecular-weight
simultaneous occurrence of AME in associa- (8–18) cytokeratins immunoreactivity is evident in the
tion with other breast lesions, such as ductal luminal epithelial component (200
)
adenoma (▶ Ductal Adenoma) (Guarino et al.
1993), collagenous spherulosis (▶ Collagenous
Spherulosis) (Reis-Filho et al. 2004), adenoid
cystic carcinoma (▶ Adenoid Cystic Carci-
noma) (Van Dorpe et al. 1998), DCIS or inva-
sive NST or lobular carcinoma (Han 2010;
Kuroda et al. 2008; Honda and Lyama 2009),
and phyllodes tumor (▶ Phyllodes Tumor)
(Buch et al. 2006).

Immunophenotype

Immunohistochemistry allows proper identifica-

tion of the distinct, epithelial and myoepithelial, Adenomyoepithelioma, Fig. 5 Smooth muscle actin-
cell components of AME and may be helpful, positivity depicts the basal component of myoepithelial
especially in those cases in which lumen forma- nature (100
)
tion is less evident. Luminal epithelial cells are
immunoreactive for low-molecular-weight (8–18)
cytokeratins (Fig. 4), epithelial membrane antigen
(EMA), carcinoembryonic antigen (CEA) (with a
luminal pattern) and, occasionally, for S-100 pro-
tein (McLaren et al. 2005).
Myoepithelial cells show consistent cytoplas-
mic staining for calponin, caldesmon, cytokeratin
14, smooth muscle actin (SMA) (Fig. 5), smooth
muscle myosin heavy chain (SMMHC), and p63
nuclear immunoreactivity (Dewar et al. 2011)
(Fig. 6). Also, cytokeratins 5/6 and CD10 may
be detected at lower rates, estrogen receptors
(ER) are often expressed in the epithelial compo-
Adenomyoepithelioma, Fig. 6 Myoepithelial cells in
nent, while progesterone receptors and HER2 are basal location also show p63 nuclear immunoreactivity
usually negative. (200
)
20
Molecular Features
No specific molecular alterations have been iden-
tified in AME, although cases have been reported
in the literature showing reciprocal translocations,
t (8;16) (p23; q21) (Gatalica et al. 2005), micro-
satellite instability, and allelic imbalance (Salto-
Tellez et al. 2005).
Differential Diagnosis
Tubular adenoma (▶ Tubular Adenoma of the
Breast) and AME, especially its tubular variant,
share several morphologic features, though the
former usually appears as a more sharply demar-
cated mass. Also, while myoepithelial cells may
be detected in tubular adenoma, these are usually
less conspicuous than in AME.
Myoepithelial cells also are present in ductal
adenomas (▶ Ductal Adenoma) (Guarino et al.
1993; Gusterson et al. 1987), being usually flat
or cuboidal and confined to the basal layer of duct-
like structures; cell clusters exclusively composed
of myoepithelial cells are not a feature of ductal
adenomas and surely help to rule out this entity in
the differential diagnosis.
Myoepithelioma is by definition a proliferation
of myoepithelial cells (Bigotti and Di Giorgio
1986), which may show spindle cell, epitheliod
or plasmacytoid morphology but invariably
expresses a myoepithelial immunophenotype
(i.e., calponin, cytokeratin 14, SMA and
SMMHC positivity). Although duct-like struc-
tures may occasionally be present, these are a
marginal component of myoepithelioma and
should not exceed 5% (as in salivary gland neo-
plasms) of the neoplastic cell component.
Pleomorphic adenoma (Iyengar et al. 2005;
Narita and Matsuda 1995; Nevado et al. 1991;
Reid-Nicholson et al. 2003) is composed by epi-
thelial and myoepithelial cells and is frequently
detected in subareolar location (Chen 1990).
Usually, chondromyxoid changes are quite
prominent and surely facilitate the correct diag-
nosis as these may only occasionally and focally
be detected in AME. Also, the duct-like struc-
tures in pleomorphic adenoma show a more
Adenomyoepithelioma
irregular profile and are unevenly distributed
throughout the lesion.
In some cases, AME may show a prominent
papillary pattern, thus prompting to consider
intraductal papillomas (▶ Intraductal Papilloma)
with adenosis in the differential diagnosis, in view
of the presence of obliterated glandular lumens
with spindle-shaped appearance. These features
suggested AME could be considered a variant of
ductal papilloma with prominent myoepithelial
hyperplasia.
References and Further Reading
Adejolu, M., Wu, Y., & Santiago, L. (2011). Adenomyoe-
pithelial tumors of the breast: Imaging findings with
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Ahmed, A. A., & Heller, D. S. (2000). Malignant
adenomyoepithelioma of the breast with malignant pro-
liferation of epithelial and myoepithelial elements:
A case report and review of the literature. Archives of
Pathology & Laboratory Medicine, 124, 632–636.
Berna, J. D., Arcas, J., & Ballester, A. (1997).
Adenomyoeepithelioma of the breast in a male. AJR.
American Journal of Roentgenology, 169, 917–918.
Bigotti, G., & Di Giorgio, C. G. (1986). Myoepithelioma
of the breast: Histologic, immunologic, and electro-
microscopic appearance. Journal of Surgical Oncol-
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Brogi, E. (2014). Myoepithelial neoplasms. In S. A. Hoda,
E. Brogi, F. C. Koerner, & P. P. Rosen (Eds.), Rosen’s
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Bult, P., Verwiel, J. M., & Wobbes, T. (2000). Malignant
adenomyoepithelioma of the breast with metastasis in
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tumor. Case report and review of the literature.
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Chang, A., Bassett, L., & Bose, S. (2002). Adenomyoe-
pithelioma of the breast: A cytologic dilemma. Report
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pathology, 26, 191–196.
Chen, K. T. (1990). Pleomorphic adenoma of the breast.
American Journal of Clinical Pathology, 93, 792–794.
Chen, P. C., Chen, C. K., & Nicastri, A. D. (1994).
Myoepithelial carcinoma of the breast with distant
metastasis and accompanied by adenomyoe-
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Decorsiere, J., Thibaut, I., & Bouissou, H. (1988). Les
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de Pathologie, 8, 311–316.
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21
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Adenosis, Other Types
Manuela Lacerda1 and Paulo Figueiredo2
1
Instituto de Patologia e Imunologia Molecular da
Universidadedo Porto (IPATIMUP), Porto,
Portugal
2
Instituto Português de Oncologia de Coimbra,
Coimbra, Portugal
Adenosis, Other Types
Synonyms
Adenomyoepithelial adenosis/apocrine adenosis/
secretory adenosis; Adenosis tumor/nodular
adenosis; Simple adenosis/adenosis; Tubular
adenosis
Definition
Adenomyoepithelial adenosis: A benign prolifer-
ative lesion characterized by the simultaneous
hyperplasia in both glandular and myoepithelial
cells of the units of the lobules.
Adenosis tumor: A clinically and/or macroscopi-
cally recognizable breast lesion that, histologi-
cally, primarily consists of sclerosing adenosis
(▶ Sclerosing Adenosis).
Tubular adenosis: A very rare benign lesion
composed of disorderly growing, noncrowded
narrow tubules that may mimic invasive
carcinoma.
Simple adenosis: An increase in size and number
of lobules.
Clinical Features
• Incidence
Adenomyoepithelial adenosis: In the literature,
few cases are reported.
Adenosis tumor: Rare.
Tubular adenosis: Very rare, only few cases
have been reported.
Simple adenosis: Incidental finding in surgical
specimens.
• Age
Adenomyoepithelial adenosis: The age range
is from 30 to 52 years (Hamperl 1970; Kiaer
et al. 1984).
Adenosis tumor: In the 27 cases studied by
Nielsen (1987), all patients were females,
aged 22 to 68 years.
Tubular adenosis: In the cases reported by Lee
(Lee et al. 1996), all patients were women aged
40 to 82 years.
Simple adenosis: Mainly in the reproductive or
perimenopausal age group.
Adenosis, Other Types
• Sex
These types of adenosis have been described in
female patients.
• Site
No special localization in the breast is known.
• Imaging, Clinical Presentation
Adenomyoepithelial adenosis: Except in those
cases where it is an incidental finding within a
specimen excised for another mammographic
or ultrasound alteration, the clinical presenta-
tion is a palpable mass. If the clinical presen-
tation is a mammographically detected mass, it
may show an irregularly shaped lesion with
spiculated margins with or without micro-
calcifications. The lesion is classified as
Bi-RADS 5 (Reston 1998).
Adenosis tumor: In almost all reported cases,
the clinical presentation was a palpable tumor.
Mammographic and ultrasound features are
often benign-appearing. Occasionally, its
appearance may be suggestive of malignancy
(DiPiro et al. 2000).
Tubular adenosis: In the case series published
by Lee et al. (1996), the clinical presentation
was a mass lesion but only in one case
(measuring 3 cm) was the mass produced by
tubular adenosis alone. In the remaining cases,
an in-situ ductal carcinoma (DCIS) was found
within the tubular adenosis or it was an inci-
dental finding in mastectomy specimens
performed for DCIS or invasive ductal carci-
noma (Lee et al. 1996).
Simple adenosis: No specific imaging charac-
teristics have been described.
• Treatment
The therapeutic approach and outcome should
be discussed in the preoperative multi-
disciplinary meeting (Rageth et al. 2016).
Adenomyoepithelial adenosis: The lesion
should be completely excised by surgery or
by vacuum-assisted systems (VANCB). Local
recurrences are reported (Kiaer et al. 1984).
Adenosis tumor: The treatment of a pure
adenosis tumor is excision (Heller and Fleming
1950).
Tubular adenosis: The treatment of pure tubu-
lar adenosis is excision. The pathology speci-
men should be carefully studied with the aim of
23
excluding any focus of in-situ or invasive
carcinoma.
Simple adenosis: No specific treatment is A
required.
• Outcome
Adenomyoepithelial adenosis: Local recur-
rences are reported (Kiaer et al. 1984). Tsuda
et al. (1994) reported a case of multiple foci of
obvious carcinoma in the adenomyoepithelial
adenosis and suggest that this lesion may have
progressed to the identified carcinoma. Whether
adenomyoepithelial adenosis is associated with
an increased risk or is a precursor lesion for
breast carcinoma is not yet known. It is prudent
to maintain follow-up of these patients.
Adenosis tumor: Adenosis tumors if
completely excised do not recur. None of 18
pure adenosis tumors described by Nielsen
treated by excision had recurred at follow-up
1–9 years later (mean 3.75 years). (Nielsen
1987).
Tubular adenosis: Tubular adenosis is a benign
lesion per se but whether it is a risk or a pre-
cursor lesion remains to be determined (Lee
et al. 1996).
Simple adenosis: Since this type of adenosis is
an incidental finding, no specific treatment is
required and it is not a risk factor.
Macroscopy
Adenomyoepithelial adenosis: When the presen-
tation is a mass the macroscopic aspect is a
firm, irregular area. In the case of incidental
findings, it may not have been identified
macroscopically.
Adenosis tumor: In the literature, this lesion is
described as an irregular, ill-defined or nodular
mass, with a gray or gray-white cut surface.
Tubular adenosis: Among the six cases reported
by Lee (Lee et al. 1996), one patient presented
with a 3 cm breast mass, and the others were found
in specimens resected for invasive carcinoma
NST (▶ Invasive Carcinoma NST) or DCIS
(▶ Ductal Carcinoma In Situ).
Simple adenosis: No specific macroscopic appear-
ance has been described.
24
Microscopy
Adenomyoepithelial adenosis: The lesion can be
well circumscribed or consist of sparse multiple
foci located in the terminal duct-lobular units
(Fig. 1). The ducts become incorporated in the
lesion and may have a distended or obliterated
shape. The stroma is sparse, occasionally with
adipose tissue. The glands vary slightly in shape
and size and may show apocrine features.
Myoepithelial cells proliferate around the glandular
cells in a centrifugal way or towards the lumen and
lead to its obstruction. The imbalance of the prolif-
eration of each component can produce different
patterns which must be recognized. Myoepithelial
cells may have a cuboidal or spindle shape. In H&E
sections (Fig. 2), the cytoplasm of myoepithelial
Adenosis, Other Types, Fig. 1 Adenomyoepithelial
adenosis (H&Ex50)
Adenosis, Other Types, Fig. 2 Adenomyoepithelial
adenosis (H&Ex400)
Adenosis, Other Types
cells is pale, vacuolated (cuboidal shaped) or eosin-
ophilic, fibroblastic like (spindle shaped) and may
have a palisading pattern. The glandular epithelium
is flattened, cuboidal or simple cuboidal. Atypia or
mitotic activity is infrequent.
Adenosis tumor: Organoid lobular configuration
may be seen on low power examination. The
glands, rounded or compressed, are organized in
different growth patterns. The luminal cells are
cylindrical, cuboidal, or flattened. Myoepithelial
cells are present, may have a spindle shape and are
clearly identified with smooth muscle-actin, p63,
and calponin immunohistochemistry. Microcysts,
apocrine metaplasia, or stromal elastosis can also
be found (Fig. 3 and Fig. 4).
Tubular adenosis: Proliferation of tubular units
in a haphazard pattern without a lobular
Adenosis, Other Types, Fig. 3 Adenosis tumor
(H&Ex25)
Adenosis, Other Types, Fig. 4 Adenosis tumor (p63 IHC
reaction x63)
Adenosis, Other Types
arrangement is observed. The tubular units may
show branching. Tubular structures have a
double-layered epithelium (luminal cells and
myoepithelial cells) surrounded by a basement
membrane. The tubules may contain a basophilic
or granular eosinophilic secretion. The stroma is
usually fibrous and acellular or edematous (Lee
et al. 1996).
Simple adenosis: Bonser et al. state that normal
lobules may contain from less than 10 to more
than 100 acini. (Bonser et al. 1961). Despite this
wide range, some lobules attain a sufficiently
large size to be regarded as pathological (Sloane
1985). Lee et al. characterize simple adenosis as
an increase in size and number of lobules (Lee
et al. 1996).
Immunophenotype
In all these four type of adenosis, immunohisto-
chemistry is useful to identify both luminal and
myoepithelial cell components. Luminal cells
express cytokeratins (CK): both low- and high-
molecular weight CKs can be detected (CK8/18,
CK5/6, CK14, MNF116) and myoepithelial cells
express smooth-muscle-actin, p63, and calponin
in addition to high-molecular weight CKs (Erel
et al. 2008).
Molecular Features
Adenomyoepithelial adenosis and Adenosis
tumor: There are no data to date describing the
molecular characteristics of these lesions.
Tubular adenosis: Da Silva L. et al. (2009)
described adenoid cystic carcinoma (ACC)
(▶ Adenoid Cystic Carcinoma) cases of the
breast associated with tubular adenosis that pre-
sented different molecular genetic alterations
from those found in the concomitant ACC.
Tubular adenosis was characterized by gains on
1q, 5p, 8q, 10q, 11p, and 11q and losses on 1p,
10q, 11q, 12q, 14q, 15q, and 16q.
Simple adenosis: There are no published data to
date about the molecular features of this type of
adenosis.
25
Differential Diagnosis
Adenomyoepithelial adenosis: In those cases where A
it is an incidental finding, a careful microscopic
examination is mandatory to exclude an invasive
NST or in-situ carcinoma within the lesion. In
the few published papers, adenomyoepithelial
adenosis is presented as an individual mass (Kiaer
et al. 1984; Tavassoli 1991). When a guided needle
core biopsy (NCB) is performed, the focus should
be on the cytological characteristic of both cell
components, namely, pleomorphism, overgrowth
or not of the myoepithelial component, and mitotic
activity. Immunostaining for epithelial and
myoepithelial components is mandatory in all
cases. If mitoses or pleomorphism is not identified
in the core biopsy, the case should be classified as
B3 (European guidelines for quality assurance in
breast cancer screening and diagnosis 2006). The
differential diagnosis is with the other dimorphic
lesions where both epithelial and myoepithelial
components are present (e.g., ▶ Adenomy-
oepithelioma and ▶ Malignant Adenomyoe-
pithelioma (M-AME)). Tsuda et al. reported a
case with multiple foci of an obvious carcinoma
in the adenomyoepithelial adenosis and suggested
that this lesion may have progressed to malignancy
(Tsuda et al. 1994).
Adenosis tumor: The most important differential
diagnosis is with tubular carcinoma (▶ Tubular
Carcinoma). Nielsen describes the macroscopic
and histologic features of adenosis tumors, tubular
carcinoma, and tubular adenoma (Nielsen 1987).
In needle core biopsies, the focus is on the
microscopic aspects of the growth pattern and
shape of the glands (multiple and round or
compressed in adenosis tumors, uniform and
angulated in tubular carcinoma) and the presence
of myoepithelial cells in adenosis tumors and its
absence in tubular carcinoma. Immunohistochem-
istry is often needed to identify the presence of
myoepithelial cells. Nuclear atypia or epithelial
hyperplasia are infrequent but when present
should be reported. In core biopsies adenosis
tumors are classified in the B3 category.
Tubular adenosis: Tubular adenosis shows an
infiltrative growth similar to microglandular
adenosis (▶ Microglandular Adenosis) and
26
adenomyoepithelial adenosis but differs from
them by the interdigitating tubular configuration;
it also differs from microglandular adenosis
due to the presence of myoepithelial cells. The
most important differential diagnosis is with
tubular carcinoma (▶ Tubular Carcinoma). The
absence of angular shaped tubules with occa-
sional transverse bars, a lack of prominent lumi-
nal snouts, a generally acellular collagenous
stroma rather than a desmoplastic one and the
presence of the myoepithelial cells highlighted
by immunostaining, support the diagnosis of
tubular adenosis (Lee et al. 1996). In core biopsy
this lesion is classified in the B3 category.
References and Further Reading
Bonser, G. M., Dossett, J. A., & Jull, J. W. (1961). Human
and experimental breast cancer. London: Pitman
Medical Publications Co. Ltd.
Da Silva, L., Buck, L., Simpson, P. T., Reid, L.,
McCallum, N., Madigan, B. J., & Lakhani,
S. R. (2009). Molecular and morphological analysis of
adenoid cystic carcinoma of the breast with synchronous
tubular adenosis. Virchows Archive, 454, 107–114.
DiPiro, P., Gulizia, J. A., Lester, S. C., & Meyer, J. E. (2000).
American Journal of Radiology, 175, 31–34.
Erel, S., Tuncbilek, I., Kismet, K., Kilicoglu, B., Ozer, E.,
& Mehmet, A. A. (2008). Adenomyoepithelial
adenosis of the breast: Clinical, radiological and path-
ological findings for differential diagnosis. Breast
Cancer, 3, 427–430.
European guidelines for quality assurance in breast
cancer screening and diagnosis. (2006). European
Commission, 4th edn 6a (pp. 221–256).
Hamperl, H. (1970) The myoepithelia (myoepithelial cells)
normal state; regressive changes; hyperplasia; tumors.
In H-W. Altmann, et al., (Eds.), Current topics in
pathology (Vol. 53, pp. 161–213). Berlin/Heidelberg:
Springer.
Heller, E. L., & Fleming, J. C. (1950). Fibrosing
adenomatosis of the breast. American Journal of
Clinical Pathology, 20, 141–146.
Kiaer, H., Nielsen, B., Paulsen, S., Sørensen, I. M.,
Dyrebog, U., & Blichert-Tft, M. (1984). Adenomyoe-
pithelial adenosis and low-grade malignant
adenomyoepithelioma of the breast. Virchows Archive
(A), 405, 55–67.
Lee, K. C., Chan, J. K., & Gwi, E. (1996). Tubular adenosis
of the breast: A distinctive lesion mimicking invasive
carcinoma. American Journal of Surgical Pathology,
20, 46–54.
Nielsen, B. B. (1987). Adenosis tumor of the breast – a
clinic – pathological investigation of 27cases.
Histopathology, 11, 1259–1275.
Angiosarcoma of the Breast
Oberman, H. A. (1984). Benign breast lesions confused
with carcinoma. In R. W. McDivtt, H. A. Oberman,
L. Ozzello, N. Kaufman (Eds.), The breast. Baltimore:
Williams and Wilkins. United States-Canadian
Academy of Pathology Monographs in Pathology,
25, 1–33.
Rageth, C. J., O’Flynn, E. A. M., Comstock, C., Kurtz, C.,
Kubik, R., Madjar, H., Lepori, D., Kampmann, G.,
Mundinger, A., Baege, A., Decker, T., Hosch, S.,
Tausch, C., Delaloye, J. F., Morris, E., & Varga, Z.
(2016). First International Consensus Conference on
lesions of uncertain malignant potential in the breast
(B3 lesions). Breast Cancer Research and Treatment,
159, 203–213.
Reston, V. A., & American College of Radiology. (1998).
Illustrated breast imaging report and system
(BI-RADS), 3rd edn. American College of Radiology
5B 6.
Sloane, J. P. (1985). Non-neoplastic epithelial changes. In
J. P. Sloane (Ed.), Biopsy pathology of the breast,
Biopsy pathology series (pp. 69–92). London:
Chapman and Hall Medical.
Tavassoli, F. A. (1991). Myoepithelial lesions of the breast.
Myoepitheliosis, adenomyoepithelioma and
myoepithelial carcinoma. American Journal of
Surgical Pathology, 15, 554–568.
Tsuda, H., Mukai, K., Fukutomi, T., & Hirohashi, S.
(1994). Malignant progression of adenomyoepithelial
adenosis of the breast. Pathology International,
44, 475–479.
Angiosarcoma of the Breast
Alberto Pisacane
Unit of Pathology, Candiolo Cancer Institute
FPO-IRCCS, Candiolo, TO, Italy
Definition
A tumor composed of malignant cells with endo-
thelial differentiation.
Clinical Features
• Incidence
Angiosarcoma (AS) of the breast is a rare dis-
ease accounting for about 1% of all soft tissue
breast tumors.
It may present as primary AS, without pre-
vious history of mammary carcinoma or any
Angiosarcoma of the Breast 27

associated factor, or as secondary AS, most Low-grade tumors confer better outcomes
commonly associated with previous breast in terms of disease-free survival interval.
irradiation. Conversely, no statistically significant corre- A
Primary AS represents <0.05% of all pri- lation between tumor size and likelihood of
mary breast cancers. local recurrence has been identified in pri-
Secondary AS presents a median of mary AS, as far as no correlation seems to
10.5 years after radiotherapy for breast cancer. exist between tumor grade and the rate of
In those patients undergoing breast conserving local recurrence, distant metastases and
surgery with adjuvant radiotherapy, the esti- death owing to disease.
mated incidence of radiation-induced AS is
0.05–0.3%.
Macroscopy
AS rarely occurs after mastectomy with
axillary dissection without irradiation and dur-
In secondary AS single or multiple erythematous-
ing pregnancy.
violaceous nodules and/or papules may be present
• Age
on the breast skin. On gross examination AS
Primary AS more frequently affects young and
appear as poorly circumscribed, brown and hem-
middle-aged women (median age 30–55 ys).
orrhagic masses, friable, spongy or firm in breast
Secondary AS presents in older women
parenchyma.
(median age 67–71 ys) after radiotherapy for
breast cancer.
• Sex
Microscopy
Rare cases of AS have been described in male
breast.
Microscopic spectrum ranges from tumors dem-
• Site
onstrating well-formed vessels with mild cyto-
Primary AS arises within the breast paren-
logic atypia, to morphologically atypical and
chyma and usually presents with fullness or
undifferentiated pleomorphic sarcoma
swelling, which can rapidly grow forming pal-
(Nascimento et al. 2008).
pable mass or masses, without skin changes.
Tumors are histologically graded using
Secondary AS arises in the cutaneous tissue
Rosen’s three-tier system into low (I), intermedi-
and might secondarily invade breast
ate (II), or high (III) grade.
parenchyma.
Low-grade AS (Fig. 1 H&E) are composed of
• Treatment
complex anastomosing vascular channels. The
Because of rarity of AS, few data are available
endothelium is flat with minimal nuclear atypia
to support treatment decisions. Surgical resec-
tion is key, with mastectomy preferred over
breast-conserving therapy. Lymph node dis-
section is not routinely recommended.
The role of adjuvant radiotherapy and che-
motherapy is poorly defined, with many agents
showing activity and varying clinical benefit. It
is generally agreed that multimodality therapy
is the best for this aggressive tumor.
• Outcome
The 5-year survival rate of secondary AS
patients is in the range of 27%–48%. The
5-year disease-free survival rate is 35%.
Tumor size, grade, and number of foci are Angiosarcoma of the Breast, Fig. 1 Low-grade AS:
important prognostic factors. neoplastic vessels dissect mammary parenchyma (H&E)
28
and no cellular stratification. Tumor dissects the
stroma, causing distortion with little destruction
of the preexisting lobules and ducts. The mitotic
rate is low (median 2/10 HPF). Necrosis is gener-
ally absent.
Intermediate-grade AS (Fig. 2 H&E) are more
cellular and are characterized by intermingled
areas of low and moderate nuclear atypia. The
endothelial cells lining neoplastic vessels are gen-
erally plump, multilayered, frequently arranged in
papillary structures. Solid areas are not present.
Mitotic rate is low (median 3/10 HPF). Necrosis
may be present.
High-grade AS (Fig. 3) show a generally solid
growth pattern with very poorly defined vascular
Angiosarcoma of the Breast, Fig. 2 Intermediate-grade
AS: cellular area of moderate nuclear atypia; an entrapped
duct is in the center (H&E)
Angiosarcoma of the Breast, Fig. 3 High-grade AS:
cellular area of solid growth with very poorly defined
vascular channels (H&E)
Angiosarcoma of the Breast
channels, often with prominent areas of hemor-
rhage (so called “blood lakes”). Tumor cells are
mostly spindled or epithelioid and show diffuse
and prominent nuclear atypia. Mitotic figures are
easily observed. Necrosis is frequent, and the
tumor growth is infiltrating with dissection of
adjacent breast parenchyma. High-grade AS may
contain low- or intermediate-grade elements,
especially at the periphery of the lesion.
Immunophenotype
Fli-1, FactorVIII, CD31, CD34, and ERG used in
combination have the greatest sensitivity (94%)
and specificity (up to 100%).
Molecular Features
MYC gene amplification and protein over-
expression has been demonstrated in secondary
AS, and more rarely in primary AS.
Differential Diagnosis
The most challenging differential diagnoses of
breast AS are represented by low-grade pseudo-
angiomatous and angiomatous proliferations.
Above all, hemangiomas, pseudoangiomatous
stromal hyperplasia (PASH), and atypical vascu-
lar lesions (AVLs) must be kept in mind (Bowman
et al. 2012; Rosen et al. 1988).
Hemangiomas and other benign vascular
tumors are generally well-circumscribed lesions
composed of well-formed vascular channels and
lack a dissecting growth pattern within breast
parenchyma (▶ Hemangioma of the Breast).
PASH is a benign proliferation of stromal
myofibroblasts, which express CD34 and focally
smooth muscle actin or desmin, but not other
more specific endothelial markers (CD31, Factor
VIII, or ERG) (▶ Pseudoangiomatous Stromal
Hyperplasia).
AVLs, typically develop 2–5 years after
radiotherapy and is histologically characterized
by a focal proliferation of dilated, sometimes
anastomosing, vascular channels lined by a sin-
gle layer of endothelial cells in the papillary and
reticular dermis. Although AVLs lack cytologic
Apocrine Carcinoma
atypia, their exact nature is not fully elucidated
(▶ Atypical Vascular Lesions).
Immunohistochemical staining combined with
fluorescence in situ hybridization for MYC are help-
ful in distinguishing post-radiation atypical vascular
lesions from low-grade secondary AS. Amplifica-
tion of MYC have been described in secondary AS
and are absent in AVLs (Mentzel et al. 2012).
References and Further Reading
Bowman, E., Oprea, G., Okoli, J., Gundry, K., et al. (2012).
Pseudoangiomatous stromal hyperplasia (PASH) of the
breast: A series of 24 patients. Breast Journal, 18(3),
242–247.
Lucas, D. R. (2009). Angiosarcoma, radiation-associated
angiosarcoma, and atypical vascular lesion. Archives of
Pathology & Laboratory Medicine, 133, 1804–1809.
Mentzel, T., Schildhaus, H. U., Palmedo, G., Buttner, R., &
Kutzner, H. (2012). Postradiation cutaneous
angiosarcoma after treatment of breast carcinoma is
characterized by MYC amplification in contrast to
atypical vascular lesions after radiotherapy andcontrol
cases: Clinicopathological, immunohistochemical and
molecular analysis of 66 cases. Modern Pathology,
25, 75–85.
Nascimento, A. F., Raut, C. P., & Fletcher, C. (2008).
Primary angiosarcoma of the breast, clinicopathologic
analysis of 49 cases, suggesting that grade is not
prognostic. The American Journal of Surgical
Pathology, 32, 1896–1904.
Rosen, P. P., Kimmel, M., & Ernsberger, D. (1988). Mam-
mary angiosarcoma, the prognostic significance of
tumor differentiation. Cancer, 62, 2145–2151.
Apocrine Carcinoma
Semir Vranic1,2 and Zoran Gatalica3
1
Department of Pathology, Clinical Centre and
School of Medicine, University of Sarajevo,
Sarajevo, Bosnia and Herzegovina
2
College of Medicine, Qatar University,
Doha, Qatar
3
Caris Life Sciences, Phoenix, AZ, USA
Synonyms
Carcinoma with apocrine differentiation; Invasive
apocrine carcinoma
29
Definition
Carcinoma with apocrine differentiation A
(invasive apocrine carcinoma) is defined by
“WHO Classification of Tumours of the Breast”
as “any invasive carcinoma in which cells show
the cytological features of apocrine cells”
(O’Malley and Lakhani 2012). More strictly, it
is a breast cancer characterized by apocrine mor-
phology (abundant eosinophilic and granular
cytoplasm, centrally/eccentrically located nuclei
with prominent nucleoli and distinct cell bor-
ders) and a distinct steroid receptor profile:
Estrogen receptor (ER)-negative and androgen
receptor (AR)-positive cells (Vranic et al. 2013)
(Fig. 1a–c).
On the basis of gene expression profiling stud-
ies, several investigators defined “molecular apo-
crine groups” including “molecular apocrine
breast cancer” [MABC] and “Luminal Androgen
Receptor” [LAR] breast cancer, all of which are
characterized by increased AR signaling, lack of
ER, and absence of basal differentiation. It should
be noted here that “molecular apocrine groups”
(as defined by microarray studies) are not fully
equivalent to apocrine carcinoma differentiation
defined by morphology and steroid receptor
profile.
Clinical Features
• Incidence
Invasive apocrine carcinoma is a rare special
type of breast cancer constituting 0.3–4% of all
breast cancers (depending on the criteria used
for its definition). When strictly defined as
above, it constitutes ~1% of all breast cancers.
• Age
Typically affects postmenopausal women.
A recent comprehensive analysis based on the
SEER [The Surveillance, Epidemiology, and
End Results] data confirmed the prevalence of
apocrine carcinomas among the elderly women
(Zhang et al. 2017).
• Sex
Invasive apocrine carcinoma predominantly
affects women although rare cases of apocrine
30
carcinoma (both in situ and invasive) among
males have also been described (Vranic
et al. 2013).
• Site
The tumor location of invasive apocrine carci-
noma does not differ from that of invasive
carcinoma of no special type (NST) (▶ Inva-
sive Carcinoma NST).
• Treatment
Current therapeutic approach to the patients
with invasive apocrine carcinoma is similar to
that of breast carcinoma NST. A subset of
invasive apocrine carcinomas (30–50%) are
HER-2/neu positive (amplified) and are ame-
nable for anti-HER2 treatment modalities.
Consistent AR expression and activation of
AR signaling pathways may represent a new
avenue for the anti-AR treatment modalities of
patients with advanced and/or metastatic apo-
crine carcinomas.
• Outcome
Clinical studies reporting outcome (overall
survival and disease-free survival) of the
patients with invasive apocrine carcinoma
are contradictory due to the lack of consistent
criteria for its definition (O’Malley and
Lakhani 2012; Vranic et al. 2013). A recent
SEER analysis, based on 840 patients with
invasive apocrine carcinoma, revealed that
apocrine carcinomas tend to behave more
aggressively in comparison with NST carci-
nomas. However, the worse outcome was
significantly diminished after matching for
demographic and clinicopathologic character-
istics (Zhang et al. 2017).
Macroscopy
Gross and radiologic characteristics of invasive
apocrine carcinomas are not specific and are sim-
ilar to those of breast carcinomas NST (O’Malley
and Lakhani 2012). Apocrine carcinomas usually
present as a firm, whitish mass with infiltrative
borders. Mammography may reveal micro-
calcifications, particularly if apocrine in situ
component is present. Exceptionally, apocrine
carcinomas may present with nipple discharge
Apocrine Carcinoma
due to encysted (encapsulated) lesions with pap-
illary architecture and apocrine morphology
(Vranic et al. 2013).
Microscopy
Apocrine cells have abundant eosinophilic/granu-
lar cytoplasm (called “type A” cells), with cen-
trally/eccentrically located nuclei and prominent
nucleoli (positive for Periodic Acid Schiff
staining, PAS). The tumor cells usually show dis-
tinct cell borders (Fig. 1a). Another, less common
type of apocrine cells (called “type B” cells)
exhibits foamy and vacuolated cytoplasm resem-
bling histiocytes (O’Malley and Lakhani 2012;
Vranic et al. 2013). The tumor cells show marked
nuclear pleomorphism and atypia while the num-
ber of mitotic figures (easily appreciated by light
microscopy) may vary. Invasive apocrine carcino-
mas are typically grade 2 or 3 carcinomas (graded
by the Elston-Ellis modification of the Bloom and
Richardson grading system). Apocrine ductal car-
cinoma in situ (DCIS) is commonly seen in asso-
ciation with its invasive counterpart. Apocrine
DCIS is usually high-grade DCIS with
comedonecrosis and calcifications. Similar to
its ductal counterpart, a subset of apocrine
carcinomas may develop through a multistep pro-
gression process (“linear progression model”):
Apocrine hyperplasia (metaplasia)!apocrine
atypia!apocrine DCIS!invasive apocrine
carcinoma) (Fig. 2) (Costa et al. 2013; Gromov
et al. 2015). This model has also been confirmed
by a molecular study that revealed common
mutations in both preinvasive (e.g., apocrine
DCIS) and invasive apocrine carcinomas (Costa
et al. 2013).
Immunophenotype
Breast apocrine cells including invasive apocrine
carcinomas show a characteristic steroid receptor
profile: no expression of estrogen receptor-alpha-
66 (ER-alpha66) and progesterone (PR) receptors
and strong expression of androgen receptor
(AR) (Fig. 1b, c). Apocrine cells express
Apocrine Carcinoma 31

Apocrine Carcinoma, Fig. 1 Hematoxylin and Eosin positively for androgen receptor (AR). Her-2/neu protein
(H&E) staining of a case of invasive carcinoma of the was overexpressed exhibiting a complete, intense mem-
breast with a characteristic apocrine morphology; the brane positivity in the majority of neoplastic apocrine cells
tumor cells are negative for ER-a66 (ER), but stain (HER2).

Apocrine Carcinoma, Fig. 2 A concept of apocrine carcinoma progression and development: Apocrine hyperplasia
(metaplasia)!apocrine atypia!apocrine DCIS!invasive apocrine carcinoma.

ER-alpha36 variant that locates to the cytoplasm
and cytoplasmic membrane (Vranic et al. 2011).
Apocrine cells are also positive for gross cystic
disease fluid protein-15 (GCDFP-15) and
negative for Bcl-2 (Gatalica 1997). Celis et al.
defined a specific “apocrine protein signature”
that includes positive biomarkers AR, CD24,
15-PDGH [prostaglandin dehydrogenase], ACMS1
[acyl-CoA synthetase medium-chain family mem-
ber 1]), and negative biomarkers (ER, PR, Bcl-2,
GATA-3) (Gromov et al. 2015). Recently, additional
novel biomarkers of apocrine differentiation have
been identified (HMGCS2 and FABP7) (Gromov
et al. 2015).
HER-2 protein is overexpressed (with under-
lying HER-2/neu gene amplification) in 30–50%
32
of invasive apocrine carcinomas (Fig. 1d) (Vranic
et al. 2013).
Invasive apocrine carcinomas typically stain for
luminal cytokeratins including CK7, CK8/18, and
CK9/19. CK20 expression has also been described
in one study (Shao et al. 2012). Basal markers
(basal cytokeratins [CK5/6, CK14, CK17], p63,
P-cadherin, S-100, CD10, vimentin) are usually
absent or positive in only small subset of invasive
apocrine carcinomas, while EGFR protein is pre-
sent in ~50–60% of cases (with uncommon EGFR
gene alterations) (Vranic et al. 2013).
Molecular Features
“Molecular apocrine breast cancers” exhibit a
poor prognostic gene signature with a high-risk
recurrence score and overall poor outcome. If
strictly defined by morphology and ER-/AR+ ste-
roid receptor profile, invasive apocrine carcino-
mas are either triple-negative (50–70%) or HER2-
positive breast carcinomas (30–50%).
Several comprehensive molecular studies
revealed common mutations of TP53 and
PIK3CA/PTEN/AKT genes. Interestingly, patients
with germline PTEN mutations (Cowden syn-
drome, OMIM #158350) are prone to develop
breast carcinomas with apocrine differentiation.
Mutations within the mitogen-activated protein
kinase [MAPK] pathway (KRAS, NRAS, BRAF)
may also be occasionally seen in a subset of
invasive apocrine carcinomas. Other targetable
mutations are much less common (Vranic et al.
2013, 2017).
HER-2/neu gene is amplified in 30–50% of
invasive apocrine carcinomas, while HER-2/neu
gene mutations are rare. EGFR protein expression
is common while underlying EGFR gene alter-
ations are uncommon: EGFR gene amplification
is present <10% of the cases and EGFR gene
mutations have not been described so far. Simi-
larly, cMET overexpression is present in ~25% of
the cases without cMET gene alterations (Vranic
et al. 2017). Growth hormone-releasing hormone
(GHRH) and its receptors (GHRH-R) are also
overexpressed in vast majority of invasive apo-
crine carcinomas. In contrast, insulin-like growth
Apocrine Carcinoma
factor receptor 1 (IGF-1R) expression appears to
be downregulated in apocrine carcinomas.
Differential Diagnosis
Apocrine differentiation may be seen in invasive
carcinomas NST (▶ Invasive Carcinoma NST) as
well as some special types such as pleomorphic
lobular carcinoma (▶ Pleomorphic Lobular Carci-
noma) with which apocrine carcinoma shares some
morphologic and molecular characteristics; anti-
body to E-cadherin can aid diagnosis in such
cases as apocrine carcinomas predominantly
(>80%) retain E-cadherin expression in contrast
to pleomorphic lobular carcinomas. Primary breast
oncocytic carcinoma (▶ Invasive Oncocytic Carci-
noma) and a subset of lipid-rich and secretory car-
cinomas (▶ Invasive Secretory Carcinoma) may
also pose diagnostic dilemmas as well as metaplas-
tic carcinomas (▶ Invasive Metaplastic Carci-
noma), which latter also may have morphologic
characteristics similar to apocrine carcinomas
(e.g., eosinophilic cytoplasm in squamous cells).
Apocrine carcinomas may be occasionally con-
fused with a granular cell tumor (▶ Granular Cell
Tumor) (S-100 and pancytokeratins may help),
while apocrine carcinomas composed of “type B”
cells may resemble a benign histiocytic
(inflammatory) lesion (CD68, CD163, and
pancytokeratins are helpful).
In addition, metastatic neoplasms to the breast
exhibiting eosinophilic cytoplasm may mimic apo-
crine carcinoma. These include metastatic malig-
nant melanoma and oncocytic carcinomas. In such
cases, a comprehensive immunohistochemical
workup along with the clinical history may help
render the correct diagnosis.
References
Costa, L. J., Justino, A., Gomes, M., Alvarenga, C. A.,
Gerhard, R., Vranic, S., Gatalica, Z., Machado, J. C., &
Schmitt, F. (2013). Comprehensive genetic characteri-
zation of apocrine lesions of the breast. Cancer
Research, 73, 2013.
Gatalica, Z. (1997). Immunohistochemical analysis of apo-
crine breast lesions. Consistent over-expression of
androgen receptor accompanied by the loss of estrogen
Atypical Ductal Hyperplasia
and progesterone receptors in apocrine metaplasia and
apocrine carcinoma in situ. Pathology Research and
Practice, 193, 753–758.
Gromov, P., Espinoza, J. A., & Gromova, I. (2015).
Molecular and diagnostic features of apocrine breast
lesions. Expert Review of Molecular Diagnostics, 15,
1011–1022.
O’Malley, F., & Lakhani, S. R. (2012). Carcinoma with
apocrine differentiation. In S. R. Lakhani, I. O. Ellis,
S. J. Schnitt, P. H. Tan, & M. J. van de Vijver (Eds.),
World Health Organization classification of tumours of
the breast (4th ed., pp. 53–54). Lyon: International
Agency of Research and Cancer (IARC).
Shao, M. M., Chan, S., Yu, A., Lam, C., Tsang, J., Lui, P.,
Law, B., Tan, P. H., & Tse, G. (2012). Keratin expres-
sion in breast cancers. Virchows Archiv, 461, 313–322.
Vranic, S., Gatalica, Z., Frkovic-Grazio, S., Deng, H.,
Lee, L. M. J., Gurjeva, O., & Wang, Z. Y. (2011).
ER-a36 a novel isoform of ER-a66 is commonly over-
expressed in apocrine and adenoid cystic carcinoma of
the breast. Journal of Clinical Pathology, 64, 54–57.
Vranic, S., Schmitt, F., Sapino, A., Costa, J. L., Castro, M.,
Reddy, S., & Gatalica, Z. (2013). Apocrine carcinoma
of the breast: A comprehensive review. Histology and
Histopathology, 28, 1393–1409.
Vranic, S., Feldman, R., & Gatalica, Z. (2017). Apocrine
carcinoma of the breast: A brief update on the molec-
ular features and targetable biomarkers. Bosnian
Journal of Basic Medical Sciences, 17, 9–11.
Zhang, N., Zhang, H., Chen, T., & Yang, Q. (2017). Dose
invasive apocrine adenocarcinoma has worse prognosis
than invasive ductal carcinoma of breast: Evidence
from SEER database. Oncotarget, 8, 24579–24592.
Atypical Ductal Hyperplasia
Werner Boecker
Gerhard Domagk-Institute of Pathology,
University of Münster, Münster,
North-Rhine Westphalia, Germany
Synonyms
Atypical intraductal hyperplasia; Ductal
intraepithelial neoplasia 1B (DIN 1B)
Definition
Atypical ductal hyperplasia (ADH) is defined as a
local proliferation of evenly spaced monotonous
cells with an atypical architecture, characterized
by smooth geometrical growth patterns as
33
micropapillae, arcades, Roman bridges, bars
crossing the glandular space, and finally full-
blown lesions with solid or cribriform growth A
(Fig. 1). As discussed below, the definition of
ADH has undergone remarkable changes. It is
the great achievement of Azzopardi who shifted
our view from usual ductal hyperplasia to ductal
in situ microcancer as the decisive step in early
breast cancer development.
In rare cases, atypical ductal proliferation
(ADH/DCIS) may evolve from primarily benign
proliferative breast lesions, or they may show
apocrine features (see below).
Clinical Features
• Incidence
The frequency of ADH diagnosis has multi-
plied with the advent of mammographic
screening with figures of 12–17% of cases
performed due to the presence of micro-
calcifications. In biopsies from mass lesions
identified in screening programs, ADH is
only found in 2–4% of specimens.
• Age
Late 40s, screening programs.
• Sex
Female
• Site
Either breast, any quadrant, probably prefer-
ence of upper outer quadrant.
• Clinic, Treatment, and Core Biopsy
ADH, generally, is asymptomatic. Clustered
microcalcifications (Fig. 2) are thought to be
the most common findings on a screening
mammogram that usually require minimal
invasive biopsy (MIB) techniques such as
vacuum-assisted core biopsy. However, due
to the limited amount of tissue in core biopsies,
ADH cannot be reliably diagnosed with
these techniques because the atypical epithelial
foci in these biopsies may form part of an
established in situ neoplastic lesion, with or
without associated invasion. For this reason,
the European Working Group for Breast Screen-
ing Pathology (EWGBSP) recommended to
abandon the term ADH in core biopsies in
34
favor of “atypical epithelial proliferation, ductal
type” (AEPDT) (Wells et al. 2006). In the
five category reporting system of core needle
biopsies, which was initially proposed by the
UK National Coordinating Group for Breast
Screening Pathology and later adopted and
recommended by the EWGBSP, “atypical epi-
thelial proliferation, ductal type,” is listed as B3
which includes lesions with uncertain malignant
potential. This explains why in the literature
“upstaging” of excisions after stereotactic breast
core biopsies of patients with nonpalpable sus-
picious microcalcifications and/or lesions of
AEPDT to DCIS or invasive carcinoma are
found in 12–52%; likewise, using vacuum-
assisted biopsy devices, which reveal more con-
tiguous tissue than core biopsy needles, the
reported rate of “upstaging” of AEPDT to
breast cancers ranges from 0% to 28%.
Recently Weigel et al. (2011) analyzed the
rate and the histological spectrum for malig-
nancy of minimally invasive biopsies with
“uncertain malignant potential (B3)” in digital
mammography screening. One hundred forty-
eight of 979 MIBs (15.1%) were categorized as
B3. Among these B3 lesions, calcifications
(61.5%) were the most important screening
abnormalities. In agreement with several ana-
log studies, the authors found AEPDT to be the
most frequent entity (35%), followed by radial
scars (28%) and papillary lesions (20%).
Furthermore, with 40.4% AEPDT was the sub-
type with the highest rate of finally detected
malignancy (DCIS n = 16, invasive cancer
n = 3) in surgical excision biopsies (19/47).
The lesion-specific positive predictive value
(PPV) was highest for AEPDT compared to
other B3-lesions with a PPV of 0.40, similar
to the respective PPVs of 0.32 to 0.59 reported
from analog screening settings (see also Menes
et al. 2017).
The NHSBSP guidelines (2001) suggest
that if a low- or intermediate-grade atypical
epithelial proliferation is found in a vacuum-
assisted biopsy that is lacking in extent or
degree of ductal/lobular involvement to be
classified as DCIS, the lesion should be
Atypical Ductal Hyperplasia
categorized as B3, and an indication for a
diagnostic biopsy to exclude a DCIS should
be made. Nevertheless, the number of foci of
atypical ductal proliferation and the number
of cores involved may help in making a clin-
ical decision about a surgical diagnostic exci-
sion. In the study of Sneige et al. (2003) on
61 cases of vacuum-assisted biopsy atypical
ductal proliferations, the lesions were con-
fined to an average of 1.5 large ducts or lob-
ular units and were associated with
microcalcifications in all cases. Surgical spec-
imens showed ADH in 15 cases, no residual
lesion in 24 cases, and ductal carcinoma in
situ only in 3 cases. It was found that micro-
calcifications that contain atypical ductal pro-
liferations in less than three lobules or ducts
and/or that are removed completely do not
reveal higher-risk lesions on excision; thus,
it was concluded removal in such cases to be
unnecessary. Similar results were published
by Wagoner et al. (2009). In practice, we
therefore modify the NHSBSP and EWGBSP
guidelines for cases in which sufficient mate-
rial is available and in which the mammogram
shows only minor changes that have been
removed by the procedure and finally where
the atypical epithelial proliferation is con-
fined to single terminal duct-lobular units
(TDLUs) and spares the ducts. Follow-up of
these patients with annual control mammog-
raphy seems a reasonable management
option. The same holds true for ADH in diag-
nostic biopsies. In contrast, if ducts or several
TDLU areas are involved by atypical prolif-
erations in core biopsies or in cases in which
the mammogram shows more extended
changes, which usually indicates grade
1 DCIS, we prefer further diagnostic and, if
necessary, therapeutic procedures.
• Outcome
Dupont and Page (1989) proposed the term
ADH for lesions in which “some but not all
the features of DCIS” are present and demon-
strated that the subsequent general risk of inva-
sive breast carcinoma for these lesions is about
four to five times that of the general population.
Atypical Ductal Hyperplasia
Macroscopy
ADH is not associated with any specific macro-
scopic features.
Microscopy
The presence of a focal proliferation (usually less
than 3 mm) of atypical uniform ductal-type cells
with rounded or oval slightly hyperchromatic
nuclei and with an atypical architecture with
even spacing of cells is now universally recog-
nized as indicating ADH. In most cases,
this atypical proliferation is confined to a
TDLU. At low magnification, the lobular
architecture with its moderately “unfolded”
Atypical Ductal Hyperplasia, Fig. 1 (H&E) Atypical
ductal hyperplasia. (a) Scanning view showing unfolded
TDLU with atypical ductal hyperplasia (center) with two
foci of columnar cell change (arrows) and lobular hyper-
plasia (asterisks); (b–d) higher magnification of the lesions
35
ductules or acini and the relationship to ducts is
easily appreciated (Fig. 1). The atypical archi-
tecture includes micropapillae, rigid bars, A
Roman bridges, and cribriform patterns. The
key features of ADH are shown in Fig. 3 and
Table 1.
Demarcation of ADH at the Lower and Upper
Limits
At the lower limit, “flat epithelial atypia” (FEA)
(▶ Columnar Cell Lesions) and ADH are cur-
rently recognized as members of the low-grade
carcinogenesis pathway. Any form of atypical
architectural growth pattern (micropapillae, bars,
Roman bridges, etc.) is regarded as the essential
criterion for ADH and for the distinction between
FEA and ADH.
in a. (b) ADH with monotonous atypical cells with atypical
architecture characterized by cribriform growth. (c)
Columnar cell change with psammomatous type micro-
calcification. (d) Atypical lobular hyperplasia
36
Atypical Ductal Hyperplasia, Fig. 2 Mammographic
microcalcification (a) and corresponding picture in histo-
logic section (b) (H&E)
At the upper limit, we are concerned with
distinguishing ADH from low-grade DCIS
(▶ Ductal Carcinoma In Situ). Although some
pathologists incorporate an assessment of the
size of a lesion in their analysis of ductal pro-
liferations (two glandular spaces or aggregate
diameter of 2 mm), the reliance on quantitative
findings does not have a strong foundation.
Rather, it should be emphasized that such size
considerations do provide guidelines rather
than precise biological definitions. We propose
a pragmatically founded definition of ADH as a
focal atypical ductal-type proliferation (usually of
about 2–5 mm in diameter) involving TDLU
structures, but with no, or only minor ductal
involvement, in contrast with DCIS which is char-
acterized by its spread into the ductal system in a
segmental manner (Fig. 4).
Atypical Ductal Hyperplasia
It must be acknowledged that the extension of
an otherwise classic low-grade DCIS into lob-
ules (lobular cancerization) should be regarded
as part of the DCIS and thus should be included
into any size considerations of a DCIS. This
suggestion is based on observations of several
studies who found that DCIS with “ADH” at the
periphery of the excision was associated with
recurrences at the same location. In this context,
the additional diagnosis of “ADH” may be mis-
leading to the clinician and hence may be dan-
gerous for the patient.
Rare Types of Atypical Ductal Proliferations
In rare cases, atypical ductal proliferation
(ADH/DCIS) may evolve from primarily benign
proliferative breast lesions, such as col-
umnar cell change (▶ Columnar Cell Lesions),
papilloma (▶ Intraductal Papilloma) mucocele-
like lesions (▶ Mucocele-like Lesion), radial
scar (▶ Radial Scar), sclerosing adenosis
(▶ Sclerosing Adenosis), and fibroadenoma
(▶ Fibroadenoma). In such instances, identify-
ing the underlying benign lesion is important for
an appropriate diagnosis. It should be empha-
sized that the same cytological and architectural
criteria used for the identification of the benign
background lesion are also applied in this con-
text as discussed in the corresponding chapters.
There are two main problems in this setting.
These are related (1) to the extent of the atypical
proliferation and (2) to the clinical impact of
such findings. At the time of writing, there was
no generally accepted solution to these problems.
The author defines ADH in benign lesions as par-
tial involvement of atypical ductal proliferation,
having features of low-grade DCIS, in an otherwise
typically benign lesion, most important, without
DCIS outside the benign lesion.
Another rare morphological variation of
this theme includes cases with apocrine type
morphology (▶ Benign and Atypical Apocrine
Lesions). O’Malley and colleagues (2004) use
cytological criteria (usual apocrine, borderline
features, and “as in DCIS”) and extension
criteria (<4 mm, 4–8 mm, >8 mm) to distinguish
between benign, borderline, and malignant
categories. According to Raju et al. (1993), the
Atypical Ductal Hyperplasia
Atypical Ductal Hyperplasia, Fig. 3 Cellular algorithm
of ductal-type lesions of the breast. Usual ductal hyperpla-
sia (UDH) contains phenotypically the whole set of lumi-
nal cells contrasting with the robust CK8/18+ phenotype of
Atypical Ductal Hyperplasia, Table 1 Key features of
atypical ductal hyperplasia
ADH Monomorphic epithelial proliferation with
regular placement of cells and atypical
architecture with smooth geometrical growth
patterns such as micropapillae, arcades, Roman
bridges, bars crossing the glandular space, and
in full-blown lesions with cribriform growth
The cells contain eosinophilic to pale cytoplasm
and round to oval monotonous nuclei
Confined to individual TDLU(s), lacking the
ductal segmental spread of low-grade DCIS
Often associated with lamellar
microcalcifications
criteria of atypical apocrine hyperplasia are met
whenever a lesion shows features of low-grade
apocrine DCIS and is of small size. There is
good reason to believe that the same fundamen-
tal extension criteria used to define classical
atypical ductal proliferations (distinguishing
such lesions from low-grade DCIS) also
apply to lesions with low-grade atypical apo-
crine proliferations. Among the cytological hall-
marks of low-grade apocrine lesions are a
smaller cell size, cytoplasmic eosinophilia or
pallor with less coarse granularity than in classic
37
low-grade intraepithelial neoplasias (LG-IEN), including
flat epithelial atypia, atypical ductal hyperplasia, low-grade
DCIS, and lobular neoplasia. (From Boecker et al. 2017)
benign apocrine cells, and moderately stained
regular nuclei with usually small nucleoli and a
higher nucleus-to-cytoplasm ratio. In contrast,
high-grade apocrine lesions are defined by pleo-
morphic, hyperchromatic nuclei, coarse chroma-
tin, and prominent nucleoli.
Immunophenotype
Several groups demonstrated that the epithelial
cells in the putative low-grade ductal pathway
precursors, including classical ADH, were posi-
tive for glandular keratins CK7, CK19, and CK8/
CK18 but negative for basal keratins CK5
(Fig. 5) and CK14 and myoepithelial markers.
Strong E-cadherin membranous staining has
been used to define ductal-type carcinomas,
both in situ and invasive. Overexpression of
HER2 is rare with only weak basal expression
in ADH, in contrast to high expression and
amplification rates in high-grade DCIS (▶ Duc-
tal Carcinoma In Situ). The cellular constituents
of ADH demonstrate increased expression rates
with Ki-67 (usually <5%), ERa, the anti-
apoptotic proto-oncogene bcl-2, and the cell
38
Atypical Ductal Hyperplasia, Fig. 4 (H&E) Growth
patterns of ADH. High-power views. (a) Ductule
highlighting the proliferation of the same cell type both
in the periphery and within a single micropapilla. The
tumor cells in the micropapilla, however, tend to be smaller
with more darkly staining nuclei with slight variation in
size and spacing. (b) Ductule with multiple micropapillae
in a background of FEA. Same case as a. (c) Ductule with
proliferation of a single cell type forming a rigid bar
cycle regulator cyclin D1, compared with adja-
cent normal breast lobular units. The
myoepithelial cells stain strongly for p63, CK5/
14, and myoepithelial markers such as smooth-
muscle actin, calponin etc.
Atypical Ductal Hyperplasia
crossing the lumen in the background of FEA. The nuclei
are round and hyperchromatic. (d) Ductule showing pro-
liferation of cells forming irregular bars and an abortive
cribriform pattern and micropapillae with psammomatous
microcalcifications. (e) In this ductule, many rigid bars
cross the lumen forming a cribriform growth pattern.
Same case as c. (f–g) Proliferation of a single cell type
forming many arcades resembling the pillars supporting
Roman bridges
Molecular Features and Tumorigenesis
The traditional tumorigenesis model of linear
progression implies a cascade from benign duc-
tal proliferations to invasive breast carcinoma.
Atypical Ductal Hyperplasia
Atypical Ductal Hyperplasia, Fig. 5 (H&E) ADH and
low-grade DCIS. (a) ADH. Enlarged TDLU with
distended ductules which contain a monomorphous cell
population with a cribriform growth pattern with a normal
duct on the left side. (b) Low-grade DCIS with cribriform
growth pattern in ducts and distended lobules
This concept resolves around usual ductal hyper-
plasia (▶ Usual Ductal Hyperplasia (UDH)) as
the central and initial event in the tumorigenesis
process and has at the same time its reflection in
the notion of the ADH definition of Jensen and
Page that “The lower boundary of ADH is
defined by examples of florid hyperplasia and
focal areas of cellular uniformity and even place-
ment.” However, this concept is in contrast to the
concept of J. Azzopardi, relating to the relation-
ship between ductal microcancer and usual duc-
tal hyperplasia, that “one of the more striking
findings was the absence of any evidence of
transition from areas of epitheliosis (usual ductal
hyperplasia, the author) to cancer except perhaps
in a single case.” As early as in 1987, Azzopardi,
therefore, suggested a de novo evolution of
breast cancer from glandular cells of the normal
lobular breast epithelium. This view was
39
supported by immunohistochemical studies of
several groups demonstrating CK5/CK14 mosai-
cism in UDH lesions in contrast to robust nega- A
tivity for basal keratins CK5 and CK14 and
positivity for glandular keratins (CK7+
CK8/CK18+ CK19+) of ductal proliferations of
the low-grade pathway. Recently, precision
immunofluorescence studies showed that usual
ductal hyperplasia represents a heterogeneous epi-
thelial lesion of the luminal lineage, including
CK5+/CK14+ progenitor cells. In contrast, low-
grade intraepithelial neoplasia of the breast, based
on their key characteristic of a robust CK18-
positive phenotype, is thought to originate from
the CK18+ cell population of normal breast epi-
thelium. These findings support the view that
usual ductal hyperplasia and low-grade
intraepithelial neoplasia are different entities
rather than a spectrum of the same disease
(Table 2). As discussed above, the findings of
“clinging carcinoma” of Azzopardi have intro-
duced profound changes in the conception of
early tumorigenesis of ductal breast carcinoma.
Later on, several studies have demonstrated that
FEA commonly coexists on the same microscopic
slides as ADH, lobular neoplasia (LN), or low-
grade DCIS and losses at 16q and 17p were the
most frequent changes in ADH, similar to the
other early lesions of the low-grade pathway
(FEA and low-grade DCIS) and tubular and
grade 1 invasive (no special type) breast carci-
noma. In line with these observations, Aulmann
et al. (2009) and colleagues examined the relation-
ships between tubular carcinoma (▶ Tubular Car-
cinoma), low-grade DCIS (▶ Ductal Carcinoma
In Situ), and FEA (▶ Columnar Cell Lesions)
concerning the mitochondrial DNA mutation pat-
terns and found that most cases of low-grade
DCIS and FEA were directly related to tubular
cancer with a possible precursor role. The current
prevailing view is that FEA and ADH may repre-
sent an initial morphologic nonobligate precursor
of the low-grade ER-dependent pathway to carci-
noma. Concerning high-grade neoplasias, given
the high number of individual genetic alterations
including high-level amplifications in high-grade
DCIS and their invasive counterparts, it seems
unlikely that a relevant fraction of high-grade
DCIS derive from these low-grade ductal lesions.
40 Atypical Ductal Hyperplasia

Atypical Ductal Hyperplasia, Table 2 Comparison of histological features of UDH, ADH, and low-grade DCISa
Histological Low-nuclear-grade
features UDH ADH DCIS
Size Variable size but rarely extensive Small More extensive,
ductal-lobular
involvement
Cellular Mixed epithelial cells with Monotonous cell population with Identical to ADH
composition variations in size and shape regular spacing
Myoepithelial cells usually around Myoepithelial cells around the ductal
the ductal periphery periphery
Architecture Fenestrating growth pattern with Atypical with well-delineated Identical to ADH
irregular lumina: Streaming pattern geometric structures
common with long axes of nuclei (micropapillae, bars, Roman bridges,
arranged parallel to the direction of arcades, and cribriform pattern) or
cellular bridges, which often have a solid growth
“tapering” appearance
Lumina Irregular lumina, often ill-defined Usually well-formed rounded Identical to ADH
peripheral slit-like spaces are spaces
common and useful distinguishing
features
IH Mosaicism of CK5- (CK14-) CK8-/CK18-positive cells, lacking Identical to ADH
positive cells. Myoepithelial cells CK5 and CK14. Residual normal
around the periphery CK5- and/or CK14-positive cells
usually attenuated or in a luminal
position
Focal ER positivity Uniformly and strongly ER+ cells
Nuclear Uneven Even, occasionally uneven Identical to ADH
spacing
Nucleoli Indistinct Single, small Identical to ADH
Mitoses Infrequent with no abnormal forms Infrequent, abnormal forms rare Identical to ADH
Necrosis Rare Rare If present, confined
to small particulate
debris in luminal
spaces
Major diagnostic features are shown in bold type
a
Modified version of the table in “European Guidelines for Quality Assurance in Mammography Screening – Fourth
Edition,” Office for Official Publications of the European Communities

Differential Diagnosis UDH (▶ Usual Ductal Hyperplasia (UDH)) is

Concerning the decision-making of epithelial pro-
liferations of ductal type is fraught with two main
problems: (1) the lesion cannot be easily classified
as either neoplastic or hyperplastic in nature, or
(2) the distinction between FEA on the one hand
and low-grade DCIS on the other hand may be a
problem. Whenever a definitive diagnosis cannot
be reached, this should be indicated, rather than
prematurely diagnosing the lesion as ADH.
Pathologists should refrain from using ADH as a
blanket term for indecisive findings and should
instead seek external consultation.
one of the differential diagnoses (Fig. 6). The
key here is to recognize the heterogeneous cell
proliferation of UDH contrasting with the
monotonous single-type neoplastic cell prolifer-
ation in ADH. UDH shows a robust CK5/CK14
mosaicism, whereas ADH is strongly positive
for CK8/CK18 and ER and negative for
CK5/CK14. Importantly, Jain et al. (2011)
found an 8% decrease in the number of lesions
classified as atypical ductal hyperplasia in favor
of usual hyperplasia using in an interobserver
study a ADH-5 cocktail (cytokeratins (CK) 5,
14, 7, 18, and p63) by immunohistochemistry;
Atypical Ductal Hyperplasia
Atypical Ductal Hyperplasia, Fig. 6 Atypical ductal
hyperplasia versus usual ductal hyperplasia. H&E stain of
ADH showing monomorphous cell proliferation with crib-
riform growth pattern in (a) and CK5/CK14 immunostain
with CK5/CK14-negative neoplastic cells contrasting with
in clinical practice, this could lead to a decrease
in the number of surgeries carried out for
intraductal proliferative lesions. One important
problem remains: as intermediate-grade neoplas-
tic intraepithelial proliferations, ductal type, may
exhibit more variability in cytological and archi-
tectural characteristic than classical prolifera-
tions of the low-grade ductal pathway, the
differentiation of these lesions from conven-
tional ductal hyperplasia is one of the greatest
41
CK5/CK14-positive myoepithelial cells in the periphery in
(b). Usual ductal hyperplasia showing the fenestrating
growth pattern in H&E routine section in (c) and strong
immunostaining for CK5/CK14 in proliferating cells with
the typical CK5/CK14þ mosaicism (d)
challenges. In the authors’ experience, the typi-
cal CK5/CK14 staining pattern usually helps to
solve the problem as intermediate malignant
ductal-type proliferations usually fail to stain
for keratins CK5 and CK14. Finally, micro-
papillary ductal growth patterns of epithelial
proliferations may occasionally also pose prob-
lems in the differential diagnosis in which, again,
CK5/CK14 immunohistochemistry may help to
solve the problem.
42
Occasionally cells with more advanced cellular
atypia may grow in just one or two layers.
Currently, most experts in the field agree that flat
epithelial lesions with high-nuclear-grade mor-
phology should be termed high-grade DCIS
irrespective of their size.
The most important distinguishing feature of
ADH to lobular neoplasia (▶ Lobular In Situ Neo-
plasia) is its cohesive growth; the latter, by its
discohesive growth and typical change of cell
shape from polygonal to round tumor cells, is
usually easily recognizable on H&E sections.
Molecularly the presence or loss of the adhesion
molecule E-cadherin may be helpful in
distinguishing between growth patterns of ductal
and lobular type.
References and Further Reading
Aulmann, S., Elsawaf, Z., Penzel, R., Schirmacher, P., &
Sinn, H. P. (2009). Invasive tubular carcinoma of the
breast frequently is clonally related to flat epithelial
atypia and low-grade ductal carcinoma in situ.
The American Journal of Surgical Pathology, 33,
1646–1653.
Azzopardi, J. (1979). Problems in breast pathology.
London: W.B. Saunders.
Boecker, W., Stenman, G., Schroeder, T., Schumacher, U.,
Loening, T., Stahnke, L., Löhnert, C., Siering, R. M.,
Kuper, A., Samoilova, V., Tiemann, M., Korsching, E.,
& Buchwalow, I. (2017). Multicolor immunofluores-
cence reveals that p63- and/or K5-positive progenitor
cells contribute to normal breast epithelium and usual
ductal hyperplasia but not to low grade intraepithelial
neoplasia of the breast: New concepts on the cellular
hierarchy using in-situ multicolour experiments.
Virchows Archiv, 470, 493–504.
Dupont, W. D., & Page, D. L. (1989). Relative risk of
breast cancer varies with time since diagnosis of atyp-
ical hyperplasia. Human Pathology, 20, 723–725.
Jain, R. K., Mehta, R., Dimitrov, R., Larsson, L. G.,
Musto, P. M., Hodges, K. B., Ulbright, T. M.,
Hattab, E. M., Agaram, N., Idrees, M. T., & Badve, S.
(2011). Atypical ductal hyperplasia: Interobserver and
intraobserver variability. Modern Pathology, 24(7),
917–923.
Lakhani, S. R., Ellis, I. O., Schnitt, S. J., Tan, P. H., &
van de Vijver, M. J. (2012). WHO-classification of
tumours of the breast. Lyon: IARC.
Menes, T. S., Kerlikowske, K., Lange, J., Jaffer, S.,
Rosenberg, R., & Miglioretti, D. L. (2017). Subsequent
breast cancer risk following diagnosis of atypical
ductal hyperplasia on needle biopsy. JAMA Oncology,
3, 36–41.
Atypical Vascular Lesions
Moinfar, F., Man, Y. G., Bratthauer, G. L., Ratschek, M., &
Tavassoli, F. A. (2000). Genetic abnormalities in mam-
mary ductal intraepithelial neoplasia-flat type (“cling-
ing ductal carcinoma in situ”): A simulator of normal
mammary epithelium. Cancer, 88, 2072–2081.
O’Malley, F. P., & Bane, A. L. (2004). The spectrum of
apocrine lesions of the breast. Advances in Anatomic
Pathology, 11, 1–9.
Page, D. L., & Rogers, L. W. (1992). Combined histologic
and cytologic criteria for the diagnosis of mammary
atypical ductal hyperplasia. Human Pathology, 23,
1095–1097.
Raju, U., Zarbo, R. J., Kubus, J., & Schultz, D. S. (1993).
The histologic Spectrum of apocrine breast prolifera-
tions: A comparative study of morphology and DNA
content by image analysis. Human Pathology, 24,
1973–1981.
Sneige, N., Lim, S. C., Whitman, G., Krishnamurthy, S.,
Sahin, A. A., Smith, T. L., & Stelling, C. B. (2003).
Atypical ductal hyperplasia diagnosis by directional
vacuum-assisted stereotactic biopsy of breast micro-
calcifications. Considerations for surgical excision.
American Journal of Clinical Pathology, 119, 218–243.
Wagoner, M. J., Laronga, C., & Acs, G. (2009). Extent and
histologic pattern of atypical ductal hyperplasia present
on core needle biopsy specimens of the breast can
predict ductal carcinoma in situ in subsequent excision.
American Journal of Clinical Pathology, 131, 112–121.
Weigel, S., Decker, T., Korsching, E., Biesheuvel, C.,
Wöstmann, A., Böcker, W., Hungermann, D.,
Roterberg, K., Tio, J., & Heindel, W. (2011). Minimal
invasive biopsy results of “uncertain malignant poten-
tial” in digital mammography screening: High preva-
lence but also high predictive value for malignancy.
Fortschritte auf dem Gebiet der Röntgenstrahlen und
der bildgebenden Verfahren, 183, 743–748.
Wells, C. A., Amendoeira, I., Apostolikas, N., et al. (2006).
Quality assurance guidelines for pathology.
In N. M. Perry, M. Broeders, & C. de Wolf (Eds.),
European guidelines for quality assurance in breast
cancer screening and diagnosis (p. 219). Luxembourg:
Office for Official Publication of the European
Communities.
Atypical Vascular Lesions
Lauren E. Rosen and Thomas Krausz
Department of Pathology, University of Chicago,
Chicago, IL, USA
Synonyms
Cutaneous atypical vascular lesions (AVLs) of
the breast have been described using a variety
Atypical Vascular Lesions
of terms including post-mastectomy lymph-
angiomatosis, benign lymphangiomatous pap-
ules, benign lymphangioendothelioma, acquired
lymphangiectasis, and lymphangioma circum-
scriptum (Baker and Schnitt 2017; Weaver and
Billings 2009).
Definition
AVLs are benign vascular proliferations of the
skin that occur following radiation therapy for
breast cancer within the field of radiation. The
term AVL was proposed by Fineberg and
Rosen in 1994 to reflect the fact that these
lesions were occasionally mistaken for
angiosarcoma, and because their relationship
to post-irradiation angiosarcomas (PIAS) is
not fully understood (Fineberg and Rosen
1994).
Clinical Features
• Incidence
AVLs occur in the field of radiation after radi-
ation therapy for breast cancer, with a latency
period of 1 month to 20 years, occurring most
frequently between 3 and 6 years post-
treatment (Ginter et al. 2017).
• Age
AVLs are seen in a population ranging in age
from 29 to 95 years, most occurring in the fifth
and sixth decades (Ginter et al. 2017).
• Sex
All reported cases of AVLs of the breast have
occurred in females, likely reflecting the higher
incidence of breast cancer in this population
(Weaver and Billings 2009).
• Site
AVLs occur most commonly in mammary or
axillary skin, and can rarely involve the breast
parenchyma. AVLs also occur in sites other
than the breast following radiation therapy for
various malignancies, such as gynecologic
tumors and multiple myeloma (Brenn and
Fletcher 2005).
43
• Treatment
AVLs are treated by excision with free margins
and close clinical follow-up to monitor for devel- A
opment of new lesions (Baker and Schnitt 2017).
• Outcome
In approximately 10–20% of cases, AVLs can
recur or new lesions can arise within the radi-
ation field following complete excision (Baker
and Schnitt 2017). Rare cases of progression to
angiosarcoma (▶ Angiosarcoma of the Breast)
have been reported, but it is unclear if these
represent cases of angiosarcoma with AVL-like
areas which were misdiagnosed on biopsy, or
an angiosarcoma developing in the same area
as an AVL (Brenn and Fletcher 2005). It has
been suggested that vascular type AVLs have a
higher risk of progression to angiosarcoma
than the lymphatic type; however, this claim
has not been well supported (Patton et al.
2008). While few reports raise the possibility
that AVLs have the potential to progress to
angiosarcoma in rare circumstances, overall
the current evidence suggests that AVLs follow
a benign course (Ginter et al. 2017).
Macroscopy
AVLs typically present as discrete flesh-toned to
reddish or bluish papules arising in the field of
radiation, and less frequently as vesicles, cystic
lesions, or erythematous plaques (Brenn and
Fletcher 2005; Koerner 2014). The lesions are
generally less than 5 mm in size (range
1–20 mm), and can be single or multiple, with
up to half of patients developing multiple lesions
either at the time of initial diagnosis or subse-
quently (Baker and Schnitt 2017; Ginter et al.
2017; Flucke et al. 2013).
Microscopy
On low power, AVLs are frequently circum-
scribed lesions located within the superficial der-
mis. AVLs can be wedge-shaped with their base
oriented toward the dermal-epidermal junction
(Baker and Schnitt 2017). The lesions are
44
generally flat, but may appear as exophytic pap-
ules that project from the skin surface. The over-
lying epidermis is usually normal or mildly
acanthotic (Koerner 2014). When AVLs involve
the breast parenchyma, they are usually encased
within fibrous tissue without involvement of the
mammary glandular tissue (Brenn and Fletcher
2005). AVLs are composed of ectatic, angulated,
and variably anastomosing thin-walled vascular
channels lined by a single layer of monomorphous
endothelial cells (Baker and Schnitt 2017; Weaver
and Billings 2009) (Fig. 1a: H&E). While in
most cases the lesions are limited to the superficial
dermis, in some cases the vessels extend into
the deep dermis where they are often smaller,
compressed, and infiltrative with focal dissection
of collagen and infiltration of adnexal structures
(Brenn and Fletcher 2005). More rarely, the
lesions can extend into the subcutis. Two distinct
morphologic subtypes of AVL have been
described, lymphatic type and vascular type.
Both patterns are often seen within the same
lesion (Patton et al. 2008; Ginter et al. 2017).
The lymphatic type is the most common sub-
type of AVL, and is comprised of variably-sized
anastomosing vascular channels lined by a mono-
layer of attenuated to hobnail endothelial cells
reminiscent of lymphangioma (Gengler et al.
2007; Koerner 2014). Endothelial-lined stromal
projections can be seen within the vascular
lumens, which are characteristically devoid of
erythrocytes (Flucke et al. 2013; Patton et al.
2008). The vessels are typically tightly clustered
within the superficial dermis; however, in a minor-
ity of cases, they extend into the deep dermis
where they have a more infiltrative appearance.
The lining endothelium is commonly hyper-
chromatic, but lacks significant nuclear atypia,
prominent nucleoli, and mitoses (Patton et al.
2008; Requena et al. 2002).
Vascular type AVLs are composed of round to
elongated capillary sized vessels that grow irreg-
ularly within the superficial or deep dermis, rem-
iniscent of a capillary hemangioma (Patton et al.
2008). In contrast to lymphatic type AVLs, these
lesions show intraluminal red cells and the vessels
are surrounded by a layer of pericytes. Vascular
type AVLs can show mild random nuclear atypia
Atypical Vascular Lesions
and rare mitotic figures; however, endothelial
multilayering and necrosis are absent. The adja-
cent stroma may contain sparse to dense chronic
inflammatory infiltrate composed of lymphocytic
aggregates with occasional germinal centers, or
there may be adjacent hemorrhage or hemosiderin
(Ginter et al. 2017; Patton et al. 2008).
Immunophenotype
Lymphatic type AVLs are positive for CD31,
D2-40, ERG, and positive or negative for CD34
(Fig. 1b: CD34 immunostaining; 1C: D2-40
immunostaining; 1D: CD31 immunostaining). Vas-
cular type AVLs are positive for CD31, CD34, and
ERG, but negative for D2-40 (Baker and Schnitt
2017). The pericytes surrounding the vessels in
vascular type AVLs are positive for smooth muscle
actin (Brenn and Fletcher 2005).
Molecular Features
Amplification of MYC has been implicated in
the development of PIAS (Fernandez et al.
2012; Fraga-Guedes et al. 2015; Mentzel et al.
2012). The MYC oncogene is a transcription fac-
tor that has a role in cell proliferation, cellular
differentiation, apoptosis, and angiogenesis.
Dysregulated MYC expression due to gene ampli-
fication promotes cell proliferation through inap-
propriate progression to S-phase from G1 phase
of the cell cycle. Amplification of MYC occurs
in other sarcomas, such as high-grade chon-
drosarcomas, proximal type epithelioid sarcomas,
and myxoid liposarcomas (Fraga-Guedes et al.
2015). Many studies have found high-level ampli-
fications of MYC by fluorescence in situ hybridi-
zation (FISH) in the majority of post-radiation and
lymphedema associated angiosarcomas, but not
in primary cutaneous angiosarcomas or AVLs
(Fernandez et al. 2012; Fraga-Guedes et al.
2015; Mentzel et al. 2012). Interestingly in one
study, two patients had AVLs lacking MYC ampli-
fication adjacent to MYC amplified PIAS (Fraga-
Guedes et al. 2015). Amplification of MYC by
FISH has a strong correlation with MYC
Atypical Vascular Lesions
Atypical Vascular Lesions, Fig. 1 (a) AVL composed of
irregular thin-walled dilated vascular spaces dissecting
through collagen. The nuclei are widely spaced and lack
expression by immunohistochemistry (IHC).
FLT4 is a gene that encodes for VEGFR3 and
plays a role in lymphatic differentiation. FLT4
gene amplification is detected by FISH in 25%
of PIAS, and is absent in AVLs, but the gene is
co-amplified with MYC limiting its utility in this
setting (Cornejo et al. 2015; Guo et al. 2011). One
study demonstrated TP53 mutations in the major-
ity of AVLs studied, and hypothesized that TP53
mutations may occur early in neoplastic develop-
ment of AVL (Santi et al. 2011).
Differential Diagnosis
The main differential diagnosis for AVL is
angiosarcoma (▶ Angiosarcoma of the Breast),
particularly those that arise following radiation,
termed PIAS. Both AVL and PIAS arise in the
skin of the breast or chest wall following radia-
tion, occur in middle aged to elderly women, and
are characterized by anastomosing vascular chan-
nels. PIAS have a latency period of 5–6 years,
which overlaps with the 3–6 year interval of AVLs
45
cytologic atypia [H&E, 40X], (b) AVL with variable pos-
itivity for CD34 [20x], (c and d) AVL with strong diffuse
positivity for D2-40 (c) and CD31 (d) [20x]
(Weaver and Billings 2009). The majority of PIAS
are high grade, but low and intermediate grade
tumors have been described in which there is
morphologic overlap with AVLs. AVLs may be
multiple but are usually small pink papules (<
1 cm) while PIAS are often larger (>2 cm) and
present as violaceous or erythematous plaques
with ulceration (Weaver and Billings 2009;
Brenn and Fletcher 2005). AVLs are relatively
circumscribed and limited to the superficial der-
mis, however can invade into the deep reticular
dermis and rarely into the subcutis; while PIAS
often invade through the dermis and into the sub-
cutis (Weaver and Billings 2009; Brenn and
Fletcher 2005). The nuclei of AVLs are hyper-
chromatic and can show mild random atypia
(Fig. 2a: H&E), while the nuclei in PIAS are
uniformly enlarged with prominent nucleoli
(Weaver and Billings 2009; Brenn and Fletcher
2005). Features that favor a diagnosis of AVL
include circumscription, vessels lined by a single
layer of endothelial cells, bloodless spaces, deli-
cate projections of endothelial lined stroma into
the vascular spaces, and associated chronic
46
Atypical Vascular Lesions, Fig. 2 (a) AVL with irregu-
larly shaped, dilated vascular channels and random cyto-
logic atypia with variably enlarged and hyperchromatic
nuclei [H&E, 40x]. (b and c) AVL with low Ki-67 prolif-
eration index (b) and negativity for c-myc (c) [40x]. (d)
Post-radiation angiosarcoma is composed of invasive
inflammation. Proliferation activity evaluated by
Ki67 is low and cMYC is negative (Udager et al.
2016; Requena et al. 2002) (Fig. 2b and c: Ki67
immunostaining and cMYC immunostaining,
respectively); (Table 1). Findings that favor
PIAS include infiltration of the subcutis, promi-
nent dissection of dermal collagen, hemorrhage
and extravasated red blood cells, marked cyto-
logic atypia, mitotic figures, necrosis, and multi-
layering of the endothelial cells (Fig. 2d: H&E).
Proliferation activity evaluated by Ki67 is
high and cMYC is overexpressed in nuclei
(Udager et al. 2016; Requena et al. 2002)
Atypical Vascular Lesions
(dissecting collagen), irregular vascular channels lined by
focally multilayered neoplastic endothelium with marked
diffuse nuclear atypia and extravasated red blood cells
[H&E, 40x]. (e and f) Post-radiation angiosarcoma
with high Ki-67 proliferation index (e) and c-myc positiv-
ity (f) [40x]
(Fig. 2e and f: Ki67 immunostaining and cMYC
immunostaining, respectively). AVLs can very
rarely show more worrisome features such as
scattered variably enlarged nuclei with prominent
nucleoli, an occasional mitosis, focal, limited
multilayering (usually not more than a double
layer of endothelium), poor circumscription, and
extension into subcutis (Weaver and Billings
2009). In addition, AVLs and PIAS can coexist,
and PIAS may exhibit AVL-like areas, which can
be indistinguishable from a true AVL in a limited
biopsy. For this reason, it is recommended that a
diagnosis of AVL should not be made on a small
Atypical Vascular Lesions 47

Atypical Vascular AVL AS

Lesions,
Histology
Table 1 Histologic,
immunohistochemical, and Relative circumscription +++  A
molecular features of AVL Anastomosing vessels ++ +++
versus post-radiation Dissection of dermal collagen + +++
angiosarcoma. (Adapted Infiltration into subcutis /+ +++
from Fineberg and Rosen
Stromal projections into lumen +++ +
(1994) and Flucke et al.
(2013)) Multilayered endothelium /+ +++
Hyperchromatic endothelial nuclei +++ ++
Significant cytologic atypia  +++
Enlarged nuclei /+ +++
Prominent nucleoli /+ +++
Mitotic figures /+ +++
Extravasated red blood cells or blood lakes  ++
Chronic inflammation +++ +
Immunohistochemistry
CD34 ++ +
CD31 +++ +++
ERG +++ +++
D2-40 ++ +
Molecular
MYC amplification/expression  +++
FLT-4 amplification/expression  +
AVL, atypical vascular lesion; AS, post radiation angiosarcoma; , absent; /+ rare focal
finding; +, occasionally present; ++, present in most cases; +++, present in all cases

biopsy, with preferred classification as an atypical acquired progressive lymphangioma, reactive

vascular proliferation with the definitive diagnosis
deferred to excision (Baker and Schnitt 2017).
Immunohistochemistry can be useful in
distinguishing AVL from PIAS. The endothelial
markers CD31, CD34, and ERG are generally
positive in both AVLs and angiosarcoma. While
positive in most AVLs, D2-40 is less frequently
positive in angiosarcomas (Flucke et al. 2013).
Ki-67 may be useful in distinguishing between
the two, as it is high (>20%) in PIAS, and low
or absent in most AVLs (Requena et al. 2002).
Prospero homeobox 1 (Prox-1) is a lymphatic
endothelial marker that is strongly expressed in
angiosarcomas but only focally positive in AVLs
(Flucke et al. 2013). The majority of PIAS show
MYC protein expression by IHC or amplification
by FISH, while AVLs do not. However, AVLs can
very rarely show rare MYC positive endothelial
cells by IHC (Udager et al. 2016).
Benign lesions that can mimic AVLs include
hemangioma (▶ Hemangioma of the Breast),
angioendotheliomatosis, and diffuse dermal
angiomatosis. Clinicopathologic correlation is
mandatory to distinguish these entities from
AVLs, and history of radiotherapy to the region
is very important in solving the differential diag-
nostic dilemma. Hemangiomas are small and
often incidental superficial lesions composed of
dilated vascular channels lined by bland endothe-
lial cells (Ginter et al. 2017). Microvenular hem-
angiomas typically occur on the trunk, but can
involve the breast and are characterized by a
well-circumscribed proliferation of thin-walled
vessels with attenuated endothelial cells, which
dissect through the dermal collagen, mimicking
vascular type AVLs (Baker and Schnitt 2017).
Hobnail hemangiomas preferentially involve the
trunk and thighs, and are characterized by dilated
vessels lined by hobnail endothelial cells within
the superficial dermis with stromal papillary pro-
jections and thin narrow vascular channels in the
deep dermis, mimicking lymphatic type AVLs.
48
However, hobnail hemangiomas contain extrava-
sated red blood cells, hemorrhage, and hemosid-
erin deposition, which distinguish the lesion from
lymphatic type AVLs (Flucke et al. 2013). In
addition, atypical hemangiomas can show
increased vascular anastomoses, infiltration, and
nuclear hyperchromasia, similar to AVLs (Ginter
et al. 2017).
Acquired progressive lymphangioma, also
known as benign lymphangioendothelioma pre-
sents as slowly enlarging erythematous papules
with a mean size of 1.5 cm that predominately
involve the limbs and rarely also the breast. It is
comprised of dilated, irregular, and anastomosing
vascular spaces containing red blood cells involv-
ing the superficial dermis. The dermis is often
hyalinized with a band of acellular collagen sep-
arating the lesion from the overlying epidermis.
Similar to AVLs, benign lymphangioen-
dotheliomas show endothelial lined papillary stro-
mal projections, hobnailing of bland endothelial
cells, and lack intraluminal red blood cells. With
extension into the deep dermis, lymphangioen-
dotheliomas have a pseudomalignant appearance
with prominent dissection of collagen and wrap-
ping of vascular channels around collagen bun-
dles and dermal adnexae (Flucke et al. 2013).
Reactive angioendotheliomatosis is a rare
vascular disorder that occurs in the setting of
co-existent systemic disease, such as renal and
cardiac disease. It presents as multifocal erythem-
atous macules, papules, plaques, or ecchymoses
typically involving the limbs; however, rare
cases with breast involvement have been reported.
Reactive angioendotheliomatosis is characterized
histologically by a proliferation of closely packed
capillaries predominately involving the dermis
with occasional extension into the subcutis. The
capillaries lack endothelial atypia and multi-
layering, and are often accompanied by stromal
hemosiderin, a mild chronic inflammatory infil-
trate, microthrombi, and extravasated red blood
cells (Weaver and Billings 2009).
Diffuse dermal angiomatosis is a rare vas-
cular lesion of the breast which presents as non-
healing painful plaques or ulcers on the breast skin
surrounded by prominent vessels and occurs most
frequently in obese women with macromastia.
Atypical Vascular Lesions
Histologically, diffuse dermal angiomatosis is
characterized by an extravascular endothelial cell
proliferation involving the dermal stroma. In a
small biopsy, diffuse dermal angiomatosis may
be difficult to distinguish from an atypical vascu-
lar lesion, or even a low-grade angiosarcoma
(Requena et al. 2002; Baker and Schnitt 2017).
References
Baker, G. M., & Schnitt, S. J. (2017). Vascular lesions
of the breast. Seminars in Diagnostic Pathology, 34,
410–419.
Brenn, T., & Fletcher, C. D. M. (2005). Radiation-
associated cutaneous atypical vascular lesions
and angiosarcoma. Clinicopathologic analysis of
42 cases. American Journal of Surgical Pathology,
29, 983–996.
Cornejo, K. M., Deng, A., Wu, H., et al. (2015). The
utility of MYC and FLT4 in the diagnosis and treat-
ment of postradiation atypical vascular lesion and
angiosarcoma of the breast. Human Pathology, 46,
868–875.
Fernandez, A. P., Sun, Y., Tubbs, R. R., et al. (2012). FISH
for MYC amplification and anti-MYC immunohisto-
chemistry: Useful diagnostic tools in the assessment of
secondary angiosarcoma and atypical vascular prolifera-
tions. Journal of Cutaneous Pathology, 39, 234–242.
Fineberg, S., & Rosen, P. P. (1994). Cutaneous angiosarcoma
and atypical vascular lesions of the skin and breast after
radiation therapy for breast carcinoma. American Journal
of Clinical Pathology, 102, 757–763.
Flucke, U., Requena, L., & Mentzel, T. (2013). Radiation-
induced vascular lesions of the skin: An overview.
Advance in Anatomic Pathology, 20, 407–415.
Fraga-Guedes, C., Andre, S., Mastropasqua, M. G., et al.
(2015). Angiosarcoma and atypical vascular lesions of
the breast: Diagnostic and prognostic role of MYC
gene amplification and protein expression. Breast Can-
cer Research Treatment, 151, 131–140.
Gengler, C., Coindre, J. M., Leroux, A., et al. (2007).
Vascular proliferation of the skin after radiation therapy
for breast cancer: Clinicopathologic analysis of a series
in favor of a benign process: A study from the French
sarcoma group. Cancer, 109, 1584–1598.
Ginter, P. S., McIntire, P. J., & Shin, S. J. (2017). Vascular
tumours of the breast: A comprehensive review with
focus on diagnostic challenges encountered in the core
biopsy setting. Pathology, 49, 197–214.
Guo, T., Zhang, L., Change, N. E., et al. (2011). Consistent
MYC and FLT4 gene amplification in radiation-
induced angiosarcoma but not in other radiation-
associated atypical vascular lesions. Genes, Chromo-
somes & Cancer, 50, 25–33.
Koerner, F. C. (2014). Sarcoma. In S. A. Hoda, E. Brogi,
F. C. Koerner, & P. P. Rosen (Eds.), Rosen’s breast
Atypical Vascular Lesions
pathology (pp. 1143–1148). Philadelphia: Lippincott
Williams & Wilkins.
Mentzel, T., Schildhaus, H. U., Palmedo, G., et al. (2012).
Postradiation cutaneous angiosarcoma after treatment
of breast carcinoma is characterized by MYC amplifi-
cation in contrast to atypical vascular lesions after
radiotherapy and control cases: Clinicopathological,
immunohistochemical and molecular analysis of
66 cases. Modern Pathology, 25, 75–85.
Patton, K. T., Deyrup, A. T., & Weiss, S. W. (2008).
Atypical vascular lesions after surgery and radiation
of the breast. A clinicopathologic study of 32 cases
analyzing histologic heterogeneity and association
with angiosarcoma. American Journal of Surgical
Pathology, 32, 943–950.
49
Requena, L., Kutzner, H., Mentzel, T., et al. (2002). Benign
vascular proliferations in irradiated skin. American
Journal of Surgical Pathology, 26, 328–337.
Santi, R., Cetica, V., Franchi, A., et al. (2011). Tumour A
suppressor gene TP53 mutations in atypical vascular
lesions of breast following radiotherapy. Histopathol-
ogy, 58, 455–466.
Udager, A. M., Ishikawa, M. K., Lucas, D. R., et al. (2016).
MYC immunohistochemistry in angiosarcoma and
atypical vascular lesions: Practical considerations
based on a single institutional experience. Pathology,
47, 697–704.
Weaver, J., & Billings, S. D. (2009). Postradiation cutane-
ous vascular tumors of the breast: A review. Seminars
in Diagnostic Pathology, 26, 141–149.
B
Benign and Atypical Apocrine
Lesions
Reena Khiroya and Clive Wells
University College London Hospital, London, UK
Synonyms
Apocrine adenosis; Apocrine atypia; Apocrine
change; Apocrine metaplasia; Atypical apocrine
adenosis
Definition
Apocrine metaplasia: This is a change of native
breast ductal epithelial cells into cells showing
eosinophilic granular cytoplasm, a large open
nucleus with a single nucleolus, and decapitation
secretion. Apocrine metaplasia can be subtyped
into simple, papillary, and complex depending on
architectural complexity. Apocrine metaplasia can
coexist with columnar cell change (▶ Columnar
Cell Lesions), sometimes even involving the same
duct spaces.
Apocrine adenosis: This is apocrine change
in sclerosing adenosis (▶ Sclerosing Adenosis).
Some authors use a different definition, as
a haphazard proliferation of bland glands
with apocrine differentiation and use this
term as synonymous with adenomyoepithelial
adenosis.
© Springer Nature Switzerland AG 2020
A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
Atypical apocrine change within sclerosing
adenosis (atypical apocrine adenosis): Generally
seen in postmenopausal women, these cases are
defined as having a 3 variation in nuclear size.
They have no necrosis and few mitoses.
Atypical apocrine hyperplasia: This is a rare
lesion within ducts which shows complex bridg-
ing and a 3 variation in nuclear size but which
does not have the periductal inflammation, peri-
ductal fibrosis, and mitotic activity associated
with apocrine ductal carcinoma in situ. There is
not a universal agreement on the upper size cutoff
to differentiate this lesion from apocrine DCIS.
Clinical Features
• Incidence
Microscopic apocrine change is frequent in the
female breast after the age of 30, is uncommonly
observed in women younger than 19, and
increases with age, persisting postmenopausally.
Atypical apocrine lesions are uncommon, and
the precise incidence is unknown.
• Age
19–90
• Sex
Female
• Site
Breast parenchyma, no specific localizations
• Treatment
Benign apocrine changes and apocrine cell meta-
plasia: Apocrine metaplasia is quite common
52 Benign and Atypical Apocrine Lesions

within the breast, is not premalignant and hence but when found in the ducts and lobules within the
does not require surgical intervention. breast, these appear to be a consequence of meta-
Atypical apocrine change within sclerosing plasia, possibly related to columnar cell change
adenosis (atypical apocrine adenosis): Insufficient (▶ Columnar Cell Lesions) and hormonal stress.
cases have been studied to determine if surgical Apocrine cells have eosinophilic granular cyto-
excision is warranted or not (in view of the clin- plasm due to secretory vacuoles, a large open
ical concern of concurrent apocrine DCIS or nucleus with a single nucleolus, and decapitation
invasive apocrine carcinoma (▶ Apocrine Carci- secretion. Apocrine cells carry androgen receptor,
noma). Atypical apocrine change in a papilloma: as do some examples of columnar cell change and
Complete surgical excision recommended. therefore this may be a response to androgenic
Atypical apocrine hyperplasia: Complete stimulation. Although some authors believe that
surgical excision recommended. apocrine cells are a normal constituent of the
• Outcome breast, they can sometimes be seen as partial
Benign apocrine lesions pose no long-term risk metaplasia within a duct, the rest of the lining of
to the patient. which is columnar cell change (Fig. 1 (H&E)).
Regarding atypical apocrine lesions, Apocrine cells often form the lining of type
Fuehrer et al. (2012) showed that the rate of 1 cysts. Type 1 cysts have a high concentration of
breast cancer diagnosis in follow-up of patients potassium relative to sodium and chloride
diagnosed with atypical apocrine change
within sclerosing adenosis (8.1%) was not
appreciably different from that of the cohort
overall (7.8%). Calhoun and Booth (2014)
showed that out of seven patients diagnosed
with atypical apocrine change within scleros-
ing adenosis, none of these diagnoses were
upgraded to ductal carcinoma in situ (▶ Ductal
Carcinoma In Situ) or invasive carcinoma fol-
lowing surgical excision; hence it remains
unclear whether a diagnosis of atypical apo-
crine change within sclerosing adenosis in iso-
lation requires surgical excision or not.

Macroscopy

Apocrine lesions of the breast can present as

cystic or solid breast lesions, which may be
associated with microcalcification (calcium phos-
phate or calcium oxalate/Weddellite micro-
calcifications). They can form macroscopically
visible cystic spaces. Juvenile papillomatosis
shows a “Swiss cheese”-like appearance due to
the formation of multiple cysts.

Microscopy
Benign and Atypical Apocrine Lesions,
Fig. 1 Columnar cell change and apocrine metaplasia
Apocrine cells are a normal constituent of the occurring within same duct spaces, with associated micro-
sweat glands around the nipple and in the axilla, calcifications (H&E)
Benign and Atypical Apocrine Lesions 53

concentration (K/Na ratio greater than 1.5). They

also contain high concentrations of androgens,
estrogen conjugates, and epidermal growth fac-
tor. Conversely, type 2 cysts have high concen-
trations of sodium and chloride relative to B
potassium concentration (K/Na ratio less than
1.5). Type 2 cysts also have lower concentrations
of sex hormones and epidermal growth factor
receptor.
As type 1 cysts have been shown to contain
androgens and, given their nuclear androgen
receptors (AR), they may be subject to
continuous stimulation leading to proliferation.
This may lead to papillary proliferation unless
the cyst becomes extremely tense when the
lining becomes attenuated. Apocrine metaplasia
is a major component of fibrocystic change
(▶ Fibrocystic Breast Changes) and is a diagnos-
tic feature of this condition.
Metaplastic change within many organs is
related to the development of cancer, for example,
in the lung and cervix, but is not a sine qua non.
Apocrine metaplasia is quite common within the Benign and Atypical Apocrine Lesions,
Fig. 2 Apocrine metaplasia and apocrine cysts (H&E)
breast and usually is not premalignant. There are,
however, some examples where apocrine change
may well form the precursor of certain types of
carcinoma. The common benign apocrine lesions Apocrine Cells in Other Lesions
will be described below. Apocrine cells can also be seen associated
with sclerosing adenosis (▶ Sclerosing Adenosis)
Apocrine Cysts and also in other lesions such as complex
Grossly palpable cysts lined by apocrine fibroadenomas (▶ Fibroadenoma), hamartomas
epithelium usually contain cyst fluid with a (▶ Hamartoma), and papillomas (▶ Intraductal
high K+/Na+ ratio, which is characteristic of Papilloma) and are the major constituent of other
the type 1 cyst. Apocrine cells form the lesions such as apocrine adenoma. They are not a
lining of type 1 cysts (Fig. 2 (H&E)) and may constituent of phyllodes tumors as these appear to
be seen as a flattened lining if the cyst is be monoclonal lesions unless in extremely rare
extremely tense precluding the development of examples; the phyllodes tumor (▶ Phyllodes
papillary apocrine metaplasia. It is often, how- Tumor) may have developed within a complex
ever, seen as papillary apocrine metaplasia, fibroadenoma.
which has been classified by Page (Page et al.
1996) into simple (Fig. 3 (H&E)), complex Fibroadenoma and Hamartoma with Apocrine
(Figs. 4 and 5 (H&E)), and highly complex. In Change
his study of premalignant conditions, the simple Dupont and Page (1994) identified a group of
and complex forms were not related to subse- fibroadenomas (▶ Fibroadenoma) with features
quent malignancy. There were too few of the leading to a slightly increased risk of subsequent
highly complex variety as defined in the study carcinoma of 2.17. These lesions had either
to comment on the possible premalignant con- apocrine metaplasia (Fig. 6 (H&E)), sclerosing
notation of these. adenosis (▶ Sclerosing Adenosis), or epithelial
54
Benign and Atypical Apocrine Lesions, Fig. 3 Simple
apocrine metaplasia (H&E)
hyperplasia. It is unclear which of these compo-
nents would be responsible for greater risk, and
also nowadays some of these so-called complex
fibroadenomas may better be classified as
hamartomas (▶ Hamartoma), especially those for-
merly called pericanalicular where there is little
lobular stromal proliferation. Much of this distinc-
tion is semantic as fibroadenomas in general
appear to be a special type of hamartoma rather
than a clonal lesion.
Of note, some benign fibroepithelial lesions may
occasionally show apocrine cysts and apocrine
metaplasia with attenuated or absent myoepithelial
cells (Cserni 2008). In these rare cases, further
immunohistochemistry as well as careful assess-
ment for other accompanying features of malig-
nancy (significant cytological atypia, desmoplastic
stromal response, mitotic activity, loss of the normal
lobular architecture) is essential in order to avoid
misclassification of a benign lesion.
Benign and Atypical Apocrine Lesions
Benign and Atypical Apocrine Lesions,
Fig. 4 Papillary apocrine metaplasia (H&E)
Papilloma with Apocrine Change
Most large duct papillomas (▶ Intraductal Papil-
loma) have a simple columnar lining around a
papillary core, which may be associated with reg-
ular hyperplasia. Some, however, may develop
apocrine change (Fig. 7 (H&E)), and this may
appear rather solid in some cases. Atypical apo-
crine change (Fig. 8 (H&E)) can be seen in papil-
lomas and is discussed below. Encapsulated
papillary carcinomas (▶ Encapsulated Papillary
Carcinoma) do not have apocrine elements within
them. Apocrine change within papillary lesions is
generally regarded as a sign of benignity, but
atypical apocrine proliferation within a papilloma
may cause difficulty in distinguishing these atyp-
ical papillomas from apocrine ductal carcinoma in
situ developing in the papilloma.
Apocrine Change within Sclerosing Adenosis
This is a relatively uncommon lesion where apo-
crine cells form the majority of the epithelial
Benign and Atypical Apocrine Lesions
Benign and Atypical Apocrine Lesions,
Fig. 5 Complex apocrine metaplasia (H&E)
component in a background of sclerosing
adenosis (▶ Sclerosing Adenosis) (Fig. 9
(H&E)). It has also been called apocrine
adenosis, but this term has also been used for
an unusual change in adenomyoepitheliomas
(▶ Adenomyoepithelioma). Unless there is clear
atypia within this, the consequences are unclear.
However, there are some worrying features of
cases of apocrine atypia within sclerosing
adenosis which demand further investigation
(see below).
Apocrine Adenoma
This is an unusual apocrine proliferation, which
resembles a tubular adenoma (▶ Tubular Ade-
noma of the Breast) but composed entirely of
apocrine cells. These lesions are extremely rare
and are not thought to have an increased risk of
55
Benign and Atypical Apocrine Lesions,
Fig. 6 Apocrine metaplasia within a fibroadenoma (H&E)
subsequent carcinoma; however too few are
reported to quantify the absolute risk.
Atypical Apocrine Lesions
Atypia in apocrine cells is difficult to quantify as
apocrine cells have large nuclei, and in standard
3–5 mm sections the nuclear size can appear quite
variable due to the plane of the section of each
nucleus. However, benign apocrine cells can
often appear quite pleomorphic even in cytolog-
ical preparations where the actual nuclear size
can be more readily appreciated. Currently the
accepted definition of atypia in apocrine prolif-
erations is a variation in nuclear size of greater
than three times. Atypical apocrine lesions are
rare but fall mainly into two types: atypical apo-
crine change within sclerosing adenosis
(atypical apocrine adenosis) and atypical apo-
crine hyperplasia.
56
Benign and Atypical Apocrine Lesions,
Fig. 7 Apocrine change within a benign papilloma (H&E)
Atypical Apocrine Change Within Sclerosing
Adenosis (Atypical Apocrine Adenosis)
This was investigated by Seidman et al. (1996)
who discovered a 5.5 increased relative risk of
subsequent breast cancer in postmenopausal
women. These cases are defined as having a
3 variation in nuclear size. They have no necro-
sis and few mitoses. If necrosis is present or
mitotic activity is prominent, the possibility of
cancerization of lobules by high-grade apocrine
ductal carcinoma in situ (▶ Ductal Carcinoma In
Situ) should be considered. Some of these lesions
appear to arise in the context of a complex scle-
rosing lesion (▶ Complex Sclerosing Lesion), and
occasional cases have an association with
established apocrine ductal carcinoma in situ.
Atypical Apocrine Hyperplasia
This is a rare lesion within ducts, which shows
complex bridging and a 3 variation in nuclear
size but which does not have the periductal
Benign and Atypical Apocrine Lesions
Benign and Atypical Apocrine Lesions,
Fig. 8 Atypical apocrine change within a papilloma
(H&E)
inflammation, periductal fibrosis, and mitotic
activity associated with apocrine ductal carci-
noma in situ. Necrosis, if present, indicates that
the lesion is apocrine ductal carcinoma in situ.
Size cutoffs for defining a lesion as apocrine duc-
tal carcinoma in situ rather than atypical apocrine
hyperplasia have been suggested at 2 mm or
4 mm, but there is not a universal agreement
on this.
Apocrine Change in Core Biopsies
Apocrine metaplasia may be responsible for
microcalcification on mammography as it may
contain Weddellite calcification. This is a reflec-
tion of fibrocystic change. If no other lesion
is present and there is no atypia, the patient
can be reassured and discharged from the
clinic. Similarly patients with apocrine change
within fibroadenomas or hamartomas can also be
reassured. Papillomas (▶ Intraductal Papilloma)
with apocrine change are currently recommended
to require excision, which may be performed by
Benign and Atypical Apocrine Lesions
Benign and Atypical Apocrine Lesions,
Fig. 9 Apocrine change within sclerosing adenosis
(H&E)
vacuum excision biopsy unless clear atypia is
identified on the core biopsy. Apocrine change
within sclerosing adenosis is controversial. If
there is no apocrine atypia within this, some
pathologists would regard this as a benign
(B2) lesion. As the relative risk of these lesions
is still controversial, some pathologists would still
call these atypical (B3) even without cytological
atypia of the apocrine cells. Clearly atypical apo-
crine change should be subject to further interven-
tion and given a B3 designation. Many of these
cases will, however, be associated with sclerosing
lesions which will qualify for a B3 designation in
their own right. Atypical apocrine hyperplasia
(Fig. 10 (H&E)) should always raise the possibil-
ity of associated apocrine ductal carcinoma in situ
and excision undertaken.
Juvenile Papillomatosis
Juvenile papillomatosis is a term given to a local-
ized area of fibrocystic change which generally
occurs in young women but which can also be
57
Benign and Atypical Apocrine Lesions,
Fig. 10 Atypical apocrine hyperplasia in a core biopsy
(H&E)
seen in patients up to 60 years old. The lesion
usually presents as a single discrete mass although
multifocal and bilateral lesions have been
described. The lesion is composed of multiple
cysts, hence its alternative name of “Swiss
cheese disease.” The lining of the cysts is usually
apocrine metaplasia with a marked papillary com-
ponent. The original description (Rosen et al.
1985) also cited regular hyperplasia, sclerosing
adenosis, and abundant foamy macrophages as
associated features (Fig. 11 (H&E)). The risk of
subsequent carcinoma is not dissimilar to that of
the general population at approximately one in ten
women although cases with bilateral disease or a
positive family history are stated to be at increased
risk. In essence, therefore, this lesion can be
thought of as a localized area of fibrocystic change
(▶ Fibrocystic Breast Changes) and it should not
be confused with true papillary proliferations such
as papillary hyperplasia of young adults (Rosen
58
Benign and Atypical Apocrine Lesions,
Fig. 11 Juvenile papillomatosis showing multiple cyst
formation (H&E)
1985) or multiple papilloma syndrome (Papotti
et al. 1984), the latter having an increased propen-
sity for the development of in situ carcinoma. The
proliferation is not papillary in the sense of the
two above conditions and is not exclusively in
juveniles. This terminology appears to have led
to confusion between the three conditions, and the
authors would prefer that this lesion is referred to
as localized fibrocystic change (“Swiss cheese
disease”) rather than given the designation of a
“papillary” lesion. It is therefore included in this
chapter instead of being linked with true papillary
lesions.
Immunophenotype
Benign apocrine metaplasia: Apocrine cells con-
tain AR and a number of proteins designated as
gross cystic disease fluid proteins (GCDFP) such
as GCDFP 15, GCDFP 24, and GCDFP 44. They
are positive for cytokeratin (CK) 8/18 and nega-
tive for CK 5 and hence represent fully differen-
tiated epithelial cells. Although normal apocrine
cells are AR positive and estrogen (ER) and
Benign and Atypical Apocrine Lesions
progesterone receptor (PR) negative, because in
the breast they are metaplastic, some cells may be
seen which are intermediate between columnar
cells and fully differentiated apocrine cells. In
this case they may have both ER and PR. HER2
staining can be a little controversial in that occa-
sionally some otherwise normal apocrine cells
lining cysts may show membrane staining on the
basal and lateral aspects of the cell but not on the
luminal surface. The significance and function of
this are unknown.
Atypical apocrine lesions: Apocrine carcino-
mas (▶ Apocrine Carcinoma) are interesting in
that they carry AR but may also be positive for
ER and PR and are often HER2 positive. Some,
however, may be triple negative. Atypical apo-
crine lesions also have this variability in that
they may lose functional markers of apocrine dif-
ferentiation such as GCDFP 15, 24, and 44. The
use of p53 and Ki-67 immunohistochemistry has
been suggested to help differentiate between
benign and malignant apocrine lesions (Collins
et al. 2011).
A proportion of atypical apocrine lesions show
intermediate overexpression of HER2 (2+)
(Fig. 12 (IHC)) but no amplification of the gene.
Immunostaining for HER2 can help in the assess-
ment of atypical apocrine lesions as, if there is
strong positivity for HER2 and amplification, it is
likely that one is dealing with cancerization of
lobules by apocrine ductal carcinoma in situ, and
further sections should be taken to try to identify
more typical in situ carcinoma.
Molecular Features
Gromov et al. (2015) and Celis et al. (2007)
propose that carcinomas with apocrine features
arise from atypical and benign precursors. It has
been demonstrated that malignant lesions acquire
mutations as they become more aggressive. Celis
et al. studied cases of sclerosing adenosis with
apocrine metaplasia and identified non-obligate
putative apocrine precancerous lesions as defined
by the expression of p53 and/or MPR14 (S100A9)
which is a marker highly overexpressed in pure
invasive apocrine carcinomas.
Benign and Atypical Apocrine Lesions
Benign and Atypical Apocrine Lesions,
Fig. 12 Atypical apocrine change within a papilloma
showing intermediate expression of HER2 protein
Selim et al. (2002) showed that cases of apo-
crine cell metaplasia showed loss of heterozygos-
ity (LOH)/allelic instability (AI), most frequently
involving 11q (INT2), 1p (MYCL1), and 13q
(D13S267). In their study, one case of apocrine
metaplasia was associated with DCIS. In this
case, one area of DCIS showed allelic alterations
at 11q (INT2) and 17p (TP53), as did the area of
apocrine metaplasia in the same case. This area
also showed LOH at 17q (D17S250). The other
focus of DCIS, however, also showed allelic loss
at 16q.
A proportion of atypical apocrine lesions
show intermediate overexpression of HER2
(2+) but no amplification of the gene. A possible
scenario is that continued stimulation by andro-
gen may lead to the development of established
neoplasia in these cases, and continued stimula-
tion of the overexpressed receptor may lead to
amplification of the gene and hence uncontrolled
proliferation.
59
Differential Diagnosis
Atypical apocrine change within sclerosing
adenosis (▶ Sclerosing Adenosis) (atypical apo-
crine adenosis) can be misdiagnosed as B
invasive apocrine carcinoma (▶ Apocrine Carci-
noma). Atypical apocrine hyperplasia could also
potentially be diagnosed as DCIS (▶ Ductal Car-
cinoma In Situ) if the size or extent of the lesion is
overestimated.
References and Further Reading
Calhoun, B. C., & Booth, C. N. (2014). Atypical apocrine
adenosis diagnosed on breast core biopsy: Implications
for management. Human Pathology, 45, 2130–2135.
Celis, J. E., Moreira, J. M. A., Gromova, I., Cabezón, T.,
Gromov, P., Shen, T., Timmermans, V., & Rank, F.
(2007). Characterization of breast precancerous lesions
and myoepithelial hyperplasia in sclerosing adenosis with
apocrine metaplasia. Molecular Oncology, 1, 97–119.
Collins, L. C., Cole, K. S., Marotti, J. D., Hu, R.,
Schnitt, S. J., & Tamimi, R. M. (2011). Androgen
receptor expression in breast cancer in relation to
molecular phenotype: Results from the Nurses’ Health
Study. Modern Pathology, 14, 924–931.
Cserni, G. (2008). Lack of myoepithelium in apocrine
glands of the breast does not necessarily imply malig-
nancy. Histopathology, 52, 253–255.
Fuehrer, N., Hartmann, L., Degnim, A., Allers, T.,
Vierkant, R., Frost, M., & Visscher, D. (2012). Atypical
apocrine adenosis of the breast: Long-term follow-up
in 37 patients. Archives of Pathology and Laboratory
Medicine, 136, 179–182.
Gromov, P., Espinoza, J. A., & Gromova, I. (2015).
Molecular and diagnostic features of apocrine breast
lesions. Expert Review of Molecular Diagnostics, 15,
1011–1022.
Page, D. L., Dupont, W. D., & Jensen, R. A. (1996).
Papillary apocrine change of the breast: Associations
with atypical hyperplasia and risk of breast cancer.
Cancer Epidemiology, Biomarkers and Prevention, 5,
29–32.
Papotti, M., Gugliotta, P., Ghiringhello, B., & Bussolati, G.
(1984). Association of breast carcinoma and multiple
intraductal papillomas: An histological and immu-
nohistochemical investigation. Histopathology, 8,
963–975.
Rosen, P. P. (1985). Papillary duct hyperplasia of the breast
in children and young adults. Cancer, 56, 1611–1617.
Rosen, P. P., Holmes, G., Lesser, M. L., Kinne, D. W., &
Beattie, E. J. (1985). Juvenile papillomatosis and breast
carcinoma. Cancer, 55, 1345–1352.
Seidman, J. D., Ashton, M., & Lefkowitz, M. (1996).
Atypical apocrine adenosis of the breast:
60
A clinicopathologic study of 37 patients with 8.7-year
follow-up. Cancer, 77, 2529–2537.
Selim, A. G. A., Ryan, A., El-Ayat, G., & Wells, C. A.
(2002). Loss of heterozygosity and allelic imbalance in
apocrine metaplasia of the breast: Microdissection
microsatellite analysis. The Journal of Pathology,
196, 287–291.
Breast Fat Necrosis
Inta Liepniece-Karele and Sergejs Isajevs
Riga East University Hospital,
Centre of Pathology/Faculty of Medicine,
University of Latvia, Riga, Latvia
Synonyms
Adipose tissue necrosis
Definition
Breast fat necrosis is a benign nonsuppurative
inflammatory process of adipose tissue usually
complicating breast trauma, breast surgery, or
radiation treatment. It was initially described in
1920 by Lee, BE & Munzer, JT.
Clinical Features
The etiological factors include trauma or micro-
trauma, radiotherapy, biopsy, anticoagulation
(warfarin), surgery, duct ectasia (▶ Duct Ectasia
and Periductal Mastitis), and breast infections
(Tan et al. 2006; Kaplan et al. 2005). The breast
can be injured in a motor vehicle accident, which
occurs in 16% of cases of seat belt-restrained
victims. Fat necrosis was observed secondary
to the direct injection of silicone or paraffin into
the breast. Transplantation of a large amount of
autologous fat can result in fat necrosis, because
fat cells are not nourished adequately until neo-
vascularization occurs. Other rare causes
include polyarteriitis nodosa, Weber-Christian
disease, and granulomatous angiopanniculitis.
Breast Fat Necrosis
Sometimes, the cause of fat necrosis is unknown
(Tan et al. 2006; Kaplan et al. 2005).
Fat necrosis of the breast may be a challenging
diagnosis on mammography, ultrasound, CT,
PET-CT, and MRI. The extent of associated fibro-
sis, liquefied fat, and calcifications determine the
imaging findings of fat necrosis. The diagnosis of
fat necrosis using fine needle aspiration cytology
(FNAC) is limited by inadequate samples. Core
biopsy is more sensitive.
Clinical presentation of fat necrosis is variable
(Chala et al. 2004) ranging from an incidental
benign finding (indolent single or multiple round
oil cysts or nodules on imaging) to a lump highly
suggestive of cancer (palpable and radiologically
visible irregular masses with overlying skin
retraction). It can be associated with pain, skin or
nipple retraction, erythema and lymphadenopa-
thy. The lesion characteristically is situated near
the skin or areola, since these are the sites within
the breast that are most vulnerable to trauma. The
average period for patients to present with a breast
lump from time of trauma is 68.5 weeks (Tan et al.
2006; Kaplan et al. 2005).
• Incidence
The incidence of the disease is estimated to be
up to 0.6% in the breast, representing 2.75% of
all benign lesions. Fat necrosis is found in
0.8% in surgical specimens of breast tumors
and in 1% of breast reduction surgery cases
(Tan et al. 2006; Kaplan et al. 2005).
• Age
Variable, the average age of clinical presenta-
tion is 50 years.
• Sex
Mainly described in female breast.
• Site
Variable.
• Treatment
In patients with a new palpable finding, the
history of a traumatic event can be helpful in
making the diagnosis of fat necrosis. Manage-
ment includes short-term follow-up with imag-
ing and physical examination, including
mammographic follow-up. Fat necrosis often
resolves on its own. If the lump does not dis-
appear over time, or increase in size, operation
Breast Fat Necrosis 61

may be recommended to remove the affected

area. Excisional biopsy is required when the
clinical and radiological features resemble
carcinoma.
• Outcome B
Edema is characteristic in the hyperacute
inflammatory phase. Fat cell necrosis releases
cytoplasmic triglycerides into the interstitial
space leading to a fat-containing cavity called
“oil cyst”. The fatty acids can react with cal-
cium ions, which accumulate around the cavity
forming “calcified oil cyst.” Non-encapsulated
fatty acids or granulation tissue can be attacked
by the immune system and reabsorbed leaving Breast Fat Necrosis, Fig. 1 Magnification  200, H&E
staining
a fibrous scar (Tan et al. 2006; Kaplan et al.
2005; Taboada et al. 2009).

Macroscopy

Initially fat necrosis appears as an area of hemor-

rhage in fat. After several weeks, the affected area
becomes bright yellow (saponification), chalky
white (calcification) or yellow-gray (fibrosis).
Cystic degeneration may occur.

Microscopy

Microscopic appearance of the fat necrosis

depends on the age of the lesion. Initial changes Breast Fat Necrosis, Fig. 2 Magnification  40, H&E
staining
are disruption of fat cells accompanied by hemor-
rhage and lipid laden histiocytes (Figs. 1, 2, and 3
H&E). Progression of the lesion is marked by the
formation of multinucleated histiocytes, hemosid-
erin deposits, and calcification. Variable amount
of lymphocytes, plasma cells, sometimes with
eosinophils is present at this stage. Fibrosis
develops peripherally as the demarcation. In
some cases, the area of necrotic fat and cellular
debris may become cystic. Dystrophic calcifica-
tion may occur in older lesions.

Immunophenotype

In rare cases, immunohistochemical stains for Breast Fat Necrosis, Fig. 3 Magnification  100, H&E
cytokeratin may be necessary to exclude an staining
62
underlying carcinoma. Foamy histiocytes may be
confirmed by positive CD68 and negative
pancytokeratin immunostains (Tan et al. 2006;
Kaplan et al. 2005).
Differential Diagnosis
Breast Tuberculosis
Breast tuberculosis (▶ Granulomatous Mastitis)
(tuberculous mastitis) is more frequent in pre-
menopausal women. In younger patients, the
lesion is more likely to have signs and symptoms
of an abscess, whereas in older women tuberculo-
sis tends to cause a mass that simulates carcinoma.
The patients usually have ipsilateral axillary gran-
ulomatous lymphadenitis. The most common
form of tuberculous mastitis is nodular mastitis
with slowly growing solitary mass. Macroscopi-
cally, the lesion consists of nodular, indurated
gray or tan tissue with yellow-to-white foci of
caseous necrosis, which may simulate non-
infective fat necrosis. Microscopically granulo-
matous lesions are present with Langhans giant
cells and caseous necrosis containing typical bac-
teria detected by Ziehl Neelsen stain. The granu-
lomas tend to be associated with ducts (Tan et al.
2006; Kaplan et al. 2005), while fat necrosis is not
specifically associated to glandular structures.
Similarly to fat necrosis, the chronic evolution is
fibrosis.
Abscess
Breast abscess (▶ Abscess) commonly seen in
lactating women, frequently caused by Staphylo-
coccus aureus that penetrates through a nipple
fissure (Tan et al. 2006; Kaplan et al. 2005). Lac-
tational mastitis and abscess formation develop as
a result of obstruction to the flow in one or more
major lactiferous ducts. The histologic appear-
ance varies from acute inflammation that may be
accompanied by focal necrosis, to organized
chronic abscesses.
Subareolar abscesses usually occur in non-
lactating premenopausal women. The process
is characterized by repeated episodes of
abscess formation in subareolar region as the
result of duct obstruction caused by squamous
Breast Fat Necrosis
metaplasia in terminal portion of lactiferous
ducts.
Breast Infarction
Breast infarction (▶ Infarct of Breast Tissue)
(Kaplan et al. 2005) most frequently occurs dur-
ing pregnancy or postpartum (Tan et al. 2006).
The lesion presents clinically as a discrete mass
that usually is asymptomatic, but sometimes pain
and tenderness are reported. The breast infarction
usually occurs in women less than 35 years. The
gross appearance of the infarcted tissue is vari-
able: hemorrhage in acute onset and pallor or
yellow discoloration in older infarcts similar to
fat necrosis. Microscopic findings depend on the
duration of the infarct. Early lesions are charac-
terized by hemorrhage. Ischemic changes involve
glandular tissues, a feature not seen in fat necrosis.
Infarction is demarcated by a zone of granulation
tissue with variable inflammatory reaction, hemo-
siderin deposits, and fibrosis.
Lupus Mastitis
Lupus mastitis can occur in 2% of patients with
systemic lupus erythematosus. Lupus mastitis is a
form of lupus panniculitis characterized by nodu-
lar lesions clinically and by fat necrosis in various
stages of evolution histologically. It can present as
palpable nodules accompanied by calcifications
on mammography reflecting the evolution from
local panniculitis to fat necrosis (Tan et al. 2006;
Kaplan et al. 2005).
Breast Lipoma
Breast lipoma with central necrosis is uncommon;
just few cases have been reported. Lipoma appears as
a round or oval radiolucent mass with a thin capsule.
Mammography shows eggshell calcifications.
Mondor’s Disease or Superficial
Thrombophlebitis
The cause of this lesion is trauma, physical exer-
tion, operations performed on the breast or chest
wall (Tan et al. 2006; Kaplan et al. 2005). At
difference with fat necrosis, physical examination
shows a subcutaneous cord. Microscopically, the
characteristic feature is thrombophlebitis (Tan
et al. 2006; Kaplan et al. 2005).
Breast Implant-Associated Malignant Lymphoma
References and Further Reading
Bowman, E., Oprea, G., Okolo, J., Rizzo, M., Garram-
Mendola, S., Manne, U., Smith, G., Pambuccian, S.,
& Bumpers, H. L. (2012). Pseudoangiomatous stromal
hyperplasia (PASH) of the breast: A series of
24 patients. Breast, 18, 242–247.
Chala, L. F., de Barros, N., de Camargo Moraes, P.,
Endo, E., Kim, S. J., Pincerato, K. M.,
Carvalho, F. M., & Cerri, G. G. (2004). Fat necrosis
of the breast: Mammographic, sonographic, computed
tomography, and magnetic resonance imaging findings.
Current Problems in Diagnostic Radiology, 33,
106–126.
Kaplan, V., Kelley, C. J., & Babu, E. D. (2005). Fat necro-
sis of the breast – A review. The Breast, 15, 313–318.
Lee, B. E., & Munzer, J. T. (1920). Fat necrosis of the
female breast and its differentiation from carcinoma.
Annals of Surgery, 37, 188–195.
Taboada, J. L., Stephens, T. W., Krishnamurthy, S.,
Brandt, K. R., & Whitman, G. J. (2009). The many
faces of fat necrosis in the breast. American Journal of
Roentgenology, 192, 815–825.
Tan, P. H., Lai, L. M., Carrington, E. V., Opaluwa, A. S.,
Ravikumar, K. H., Chetty, N., Kaplan, V., Kelley, C. J.,
& Babu, E. D. (2006). Fat necrosis of the breast –
A review. The Breast, 15, 313–318.
Breast Implant-Associated
Malignant Lymphoma
Laurence de Leval and Dina Milowich
Institute of Pathology, University Hospital
Lausanne, Lausanne, Switzerland
Synonyms
Breast implant-associated anaplastic large cell
lymphoma (BI-ALCL)
Definition
Breast implant-associated anaplastic large cell
lymphoma (BI-ALCL) is a very rare form of
T-cell lymphoma that arises in association with
various kinds of breast implants. In the recently
revised WHO classification of hematological
malignancies, BI-ALCL is introduced as a new
provisional disease entity, distinct from the other
63
types of ALCLs already recognized (Oishi
2018). While the morphological and
immunophenotypical features of BI-ALCL are
indistinguishable from those of systemic ALK-
negative ALCL, the specificity of the newly B
described entity is its clinical presentation in
association with and the vicinity of a breast
implant.
Clinical Features
• Incidence
A nationwide study based on the pathology
registry in the Netherlands established that BI
are associated with a markedly increased risk
(400 times) of developing ALCL, but the abso-
lute risk remains very small, estimated to one
case for every 50,000 women with BI by the
age of 50 years, one per 12,000 by the age of
70, and one per 7,000 by the age of 75. The
mean interval between implant insertion and
lymphoma diagnosis is 10–13 years in differ-
ent studies, but wide variations (1–32 years)
are observed. There is no clear-cut association
with the type of implant (silicone, saline, tex-
tured or not).
• Age
The mean age of patients is 50 years.
• Sex
All reported cases have occurred in women.
• Site
BI-ALCL is by definition a neoplasm arising in
the vicinity of a mammary prosthesis.
• Treatment
Surgical management with complete surgical
resection (total capsulectomy and implant
removal) is essential to achieve optimal
event-free survival in patients with BI-ALCL.
In cases restricted to the seroma cavity, the
addition of chemotherapy does not appear to
affect outcome.
• Outcome
While most patients have excellent outcome,
several studies have highlighted an association
between the clinical pattern and disease
aggressiveness, i.e., most cases presenting as
a seroma appear to be cured with surgery alone
64 Breast Implant-Associated Malignant Lymphoma

and infrequently experience recurrences,

while the presence of a solid tumor mass is
an adverse prognostic factor. Clemens MW
et al. conducted a clinical follow-up study of
87 patients (median follow-up time
45 months): the overall survival rate was
93% at 3 years and 89% at 5 years, respec-
tively. Patients with lymphoma confined to
the fibrous periprosthetic capsule had a better
outcome than those with lymphoma spread
beyond the capsule, and patients who
underwent complete surgical excision (total
capsulectomy and breast implant removal)
had a better overall survival than those who
received partial excision, chemotherapy, or
radiation therapy only. A detailed longitudinal
analysis of patients who died of BI-ALCL
showed locoregional dissemination of the dis-
ease to the breast, locoregional lymph nodes,
chest wall, and mediastinum but no systemic
dissemination typical of other lymphomas. It
was therefore suggested to use a staging sys-
tem for BI-ALCL similar in its principles to Breast Implant-Associated Malignant Lymphoma,
those applied to solid tumors (Clemens Fig. 1 (H&E) Caspulectomy specimen in a case of BI-
ALCL presenting as a seroma, showing a lymphoid prolif-
et al. 2016). eration embedded in fibrinous material at the surface of the
periprosthetic capsule (A) with mild infiltration into the
capsule (B, arrow)
Macroscopy

Most cases present as a periprosthetic effusion
(seroma or “in situ” lymphoma) as illustrated in
Fig. 1. Figure 1a shows a lymphoid proliferation
embedded in fibrinous material at the surface of
the periprosthetic capsule; panel 1b shows an
area of mild infiltration into the capsule
(arrow). Only a minority of cases present as a
tumor mass infiltrating into the adjacent breast
parenchyma (Fig. 3a), with or without an
associated effusion (Clemens et al. 2016).
A significant proportion of the patients
(around 30%) may present with axillary lymph-
adenopathy, which is not proven involved
by lymphoma in all instances. Lympho-
matous involvement of axillary lymph nodes
is usually characterized by a low-tumor
burden and can feature a sinusoidal, perifollicular,
diffuse, or Hodgkin-like pattern, often associated
to fibrosis. Lymph node involvement at initial
presentation was found to correlate with an infe-
rior overall survival (Ferrufino-Schmidt et al.
2018). Rare cases present with disseminated
disease.
Microscopy
In cases with seroma-associated presentation,
tumor cells may be identified in cytological
samples from pericapsular effusions or on
capsulectomy specimens. The tumor cells are
large and pleomorphic, with large nuclei and
abundant cytoplasm (Fig. 2). Cells with
horseshoe-shaped nuclei and a paranuclear
cytoplasmic inclusion (“hallmark cells”)
typically encountered in all forms of ALCL are
also found in BI-ALCL (Fig. 2, arrows). The
neoplastic cells may resemble Hodgkin-like
Breast Implant-Associated Malignant Lymphoma
Breast Implant-Associated Malignant Lymphoma,
Fig. 2 (H&E) Cytological features of BI-ALCL composed
of large pleomorphic cells, including several “hallmark cells“,
with eccentric horseshoe-shaped nuclei and a prominent para-
nuclear Golgi region (arrows) (A and B)
Reed-Sternberg cells. In capsulectomy speci-
mens, the tumor cells are embedded within a
proteinaceous and fibrinous meshwork at the
surface of the capsule and may show varying
degrees of capsular infiltration (Figs. 1b and 2).
In the minority of cases characterized by a mass-
forming lesion (Fig. 3), the tumor cells
infiltrate into the adjacent breast tissue and may
be accompanied by a pronounced inflammatory
component including prominent eosinophilia;
necrosis is frequent and sclerosis is sometimes
observed.
Immunophenotype
Images A–D on Fig. 4 are from a tumoral BI-ALCL
and images E–F from a seroma-associated case.
The tumor cells have an immunophenotype similar
to that of systemic ALK-negative ALCL: they
65
Breast Implant-Associated Malignant Lymphoma,
Fig. 3 (H&E) Breast tumorectomy specimen in a case of
BI-ALCL presenting as a tumor mass diffusely infiltrating
the breast tissue, with focal necrosis (A). Higher power
examination shows diffuse cohesive sheets of large pleo-
morphic lymphoid cells (B)
show strong expression of CD30 with a membrane
and paranuclear dot-like pattern of staining
(Fig. 4a), incomplete expression of T-cell antigens,
and no ALK expression (Fig. 4b). BI-ALCL fre-
quently expresses EMA (Fig. 4c) but is negative for
cytokeratins, and features activated cytotoxic
immunophenotype (expression of TIA-1,
granzyme B (Fig. 4d), and/or perforin (Fig. 4f)).
CD45 is expressed in most cases. CD15 is weakly
positive in a significant proportion of cases.
Regarding T-cell antigens, CD43 is almost con-
stantly expressed, CD4 expression is frequent,
and positivity for CD2 and CD3 is more common
than for CD5. CD8 expression is unusual, but rare
cases may coexpress CD4 and CD8. MUM1 is
consistently positive and EBV is consistently neg-
ative. Ki67 stains a very high proportion of the
nuclei indicating a high proliferation fraction
(Fig. 4e).
66
Breast Implant-Associated Malignant Lymphoma,
Fig. 4 Immunohistochemical findings in BI-ALCL: the
tumor cells are strongly positive for CD30 with a mem-
brane and paranuclear dot-like pattern (A), negative for
ALK (B), positive for EMA (C), and positive for granzyme
B indicating an activated cytotoxic profile (D); Ki67 stains
Molecular Features
T-cell receptor genes are rearranged in most cases.
Limited information is available on the genetic
lesions underlying the development and progression
Breast Implant-Associated Malignant Lymphoma
a very high proportion of the nuclei indicating a high
proliferation fraction (E) and perforin, another marker of
activated cytotoxic phenotype, produces fine granular pos-
itivity in a subset of the tumor cells (F). Images A-D are
from the tumoral BI-ALCL and images E-F from the
seroma-associated case
of BI-ALCL and its molecular pathogenesis.
Conventional cytogenetics and/or sequencing ana-
lyses have been reported in a small number of cell
lines established from BI-ALCL or from primary
lymphoma specimens.
Breast Implant-Associated Malignant Lymphoma
Three IL2-dependent TLBR (T-cell breast
lymphoma) cell lines established from seroma-
associated BI-ALCL had clonally abnormal
complex karyotypes with a modal number
of 47 chromosomes in one cell line (TLBR-1)
and a hypertriploid pattern in TLBR-2 and
TLBR-3. Functional studies on these three cell
lines showed evidence of STAT3 activation,
while pharmacological inhibition of STAT3 inhi-
bition induced in vitro cell death.
Seven cases of BI-ALCL were successfully
analyzed by whole exome or targeted next-
generation sequencing using a large panel of
465 cancer-associated genes, and of these only
four showed somatic variants (reviewed in
Letourneau et al. 2018). The STAT3 S614R variant
was detected by whole exome sequencing or
targeted sequencing in two cases (including the
primary tumor from which TLBR-1 cell line was
derived), as the sole abnormality in the latter and in
combination with pathogenic mutations in TP53
and SOCS1 in the other case. One somatic variant
was detected in the other two cases, affecting JAK1
(G1097 V) or DNMT3A (W176X). In one case of
BI-ALCL which presented as a solid tumor mass
and recurred as an in situ capsular lesion, dual gain-
of-function mutations in JAK1 and STAT3 were
identified in both specimens, suggesting pathoge-
netic mechanisms overlapping with those of sys-
temic ALK-negative ALCLs (Letourneau et al.
2018) However, rearrangements of the IRF4/
DUSP22 locus at 6p25 and of TP63 (frequently
observed in systemic or primary cutaneous ALCL)
have not been found in any of the cases tested so far
(Oishi et al. 2018).
Differential Diagnosis
– Primary breast implant-associated ALCL is cyto-
logically and by immunophenotype indistin-
guishable from systemic ALK-negative ALCL.
Although rarely, systemic ALCL in patients with
breast implants may manifest in the breast with a
presentation mimicking BI-ALCL. Likewise,
primary cutaneous ALCL involving the breast
in women harboring breast implants may grow
near the breast implant, and in that situation the
67
origin of the neoplasm may be questioned. Stag-
ing and clinical history are therefore critical to
establish the correct diagnosis.
– Other types of lymphomas have been reported to
occur in association with breast implants: mycosis B
fungoides/Sézary syndrome, extranodal NK/T-
cell lymphoma, nasal type, and different types
of B-cell lymphomas (diffuse large B-cell lym-
phoma, follicular lymphoma, lymphoplasmacytic
lymphoma, primary effusion lymphoma, mar-
ginal zone B-cell lymphoma). These lymphomas
differ from BI-ALCL both by their morphology
and immunophenotype.
– Hodgkin lymphoma is an entity with
significant overlapping morphological and
immunophenotypical features with BI-ALCL.
The Hodgkin/Reed-Sternberg cells of Hodgkin
lymphoma are typically scarce in a prominent
inflammatory background, coexpress CD30
and CD15, and have a B-cell genotype with
expression of a markedly attenuated B-cell
immunophenotype. They are usually negative
for T-cell antigens. Although Hodgkin lym-
phoma very rarely occurs in extranodal locali-
zations, an exceptional case of Hodgkin
lymphoma arising adjacent to a breast implant
has been reported in a woman who had a his-
tory of follicular lymphoma, and the Hodgkin
lymphoma was shown to represent transforma-
tion from the preexisting follicular lymphoma.
– Chronic inflammatory lesions associated to a
breast implant may contain occasional CD30+
activated lymphoid cells and must be distin-
guished from BI-ALCL.
References and Further Reading
Clemens, M. W., Medeiros, L. J., Butler, C. E., Hunt, K. K.,
Fanale, M. A., Horwitz, S., Weisenburger, D. D.,
Liu, J., Morgan, E. A., Kanagal-Shamanna, R.,
Parkash, V., Ning, J., Sohani, A. R., Ferry, J. A.,
Mehta-Shah, N., Dogan, A., Liu, H., Thormann, N.,
Di Napoli, A., Lade, S., Piccolini, J., Reyes, R.,
Williams, T., McCarthy, C. M., Hanson, S. E.,
Nastoupil, L. J., Gaur, R., Oki, Y., Young, K. H., &
Miranda, R. N. (2016). Complete surgical excision is
essential for the management of patients with breast
implant-associated anaplastic large-cell lymphoma.
Journal of Clinical Oncology, 34(2), 160–168.
68
Ferrufino-Schmidt, M. C., Medeiros, L. J., Liu, H., Clemens,
M. W., Hunt, K. K., Laurent, C., Lofts, J., Amin, M. B.,
Ming Chai, S., Morine, A., Di Napoli, A., Dogan, A.,
Parkash, V., Bhagat, G., Tritz, D., Quesada, A. E., Pina-
Oviedo, S., Hu, Q., Garcia-Gomez, F. J., Jose Borrero, J.,
Horna, P., Thakral, B., Narbaitz, M., Hughes, R. C., 3rd,
Yang, L. J., Fromm, J. R., Wu, D., Zhang, D., Sohani,
A. R., Hunt, J., Vadlamani, I. U., Morgan, E. A., Ferry,
J. A., Szigeti, R., C Tardio, J., Granados, R., Dertinger, S.,
Offner, F. A., Pircher, A., Hosry, J., Young, K. H., &
Miranda, R. N. (2018). Clinicopathologic features and
prognostic impact of lymph node involvement in patients
with breast implant-associated anaplastic large cell lym-
phoma. The American Journal of Surgical Pathology,
42(3), 203–305.
Breast Implant-Associated Malignant Lymphoma
Letourneau, A., Maerevoet, M., Milowich, D., Dewind, R.,
Bisig, B., Missiaglia, E., & de Leval, L. (2018, 2018).
Dual JAK1 and STAT3 mutations in a breast implant-
associated anaplastic large cell lymphoma. Virchow
Archiv. https://doi.org/10.1007/s00428-018-2352-y.
Oishi, N., Brody, G. S., Ketterling, R. P., Viswanatha, D. S.,
He, R., Dasari, S., Mai, M., Benson, H. K., Sattler, C. A.,
Boddicker, R. L., McPhail, E. D., Bennani, N. N.,
Harless, C. A., Singh, K., Clemens, M. W., Medeiros,
L. J., Miranda, R. N., & Feldman, A. L. (2018). Genetic
subtyping of breast implant-associated anaplastic large
cell lymphoma. Blood, 132(5), 544–547.
Rupani, A., et al. (2015). Lymphomas associated with
breast implants: A review of the literature. Aesthetic
Surgery Journal, 35(5), 533–544.
C
Collagenous Spherulosis
Alena Skalova
Department of Pathology, Faculty of Medicine
in Plzen, Charles University, Plzen, Czech
Republic
Biopticka laborator s.r.o, Pilsen, Czech Republic
Synonyms
Adenoid cystic hyperplasia; Mucinous
spherulosis; Spherulosis
Definition
Collagenous spherulosis (CS) of the breast is a
benign lesion most frequently associated with
other benign proliferative processes, including
papilloma (▶ Intraductal Papilloma), papillary
duct hyperplasia, radial sclerosing lesions
(▶ Radial Scar and ▶ Complex Sclerosing
Lesion), sclerosing adenosis (▶ Sclerosing
Adenosis), and atypical ductal hyperplasia
(▶ Atypical Ductal Hyperplasia). Originally
reported by Clement et al. in 1987, the lesion
was first described as an incidental microscopic
finding of intraluminal clusters of collagen-rich,
eosinophilic, or star-shaped fibrillar spherules
(Clement et al. 1987).
© Springer Nature Switzerland AG 2020
A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
Clinical Features
• Incidence
Collagenous spherulosis (CS) is very rare, with
an estimated incidence of less than 1% in exci-
sional specimens (Resetkova et al. 2006) and
about 0.2% in cytology material (Sola Perez
et al. 1993). CS may go unrecognized in about
48% of cases or may be misdiagnosed as atyp-
ical hyperplasia in 17% of cases or as in situ
and/or invasive carcinoma in 11% of cases
(Mooney et al. 1999).
• Age and sex
The patients were all women ranging in age
from 36 to 90 years (mean age, 52 years;
median age, 50 years) in the largest published
study (Resetkova et al. 2006).
• Treatment and outcome
Although rare, CS is a distinct, morphologi-
cally well-defined entity most often reported in
association with benign proliferative changes.
Processes most frequently associated with col-
lagenous spherulosis lesions include columnar
cell hyperplasia (▶ Columnar Cell Lesions),
radial scar (▶ Radial Scar), sclerosing adenosis
(▶ Sclerosing Adenosis), papillomas (▶ Intra-
ductal Papilloma), ductal hyperplasia without
atypia (▶ Usual Ductal Hyperplasia (UDH)),
and adenomyoepithelioma (▶ Adenomyoe-
pithelioma) (Reis-Filho et al. 2004). Less fre-
quently, CS has been observed in specimens
70 Collagenous Spherulosis

with a concurrent malignant process, most

commonly lobular carcinoma in situ (LCIS)
(▶ Lobular In Situ Neoplasia) (Resetkova
et al. 2006; Mooney et al. 1999). Association
of CS with LCIS and other benign and malig-
nant breast lesions is interpreted as most
likely coincidental. CS could present as a
mammographically suspicious mass or den-
sity and could be associated with micro-
calcifications. Treatment of the patient and
clinical outcome of CS is dependent on
accompanying breast lesion.
Collagenous Spherulosis, Fig. 2 The eosinophilic
spherules of CS have a concentric fibrillary pattern with
Macroscopy darker peripheral staining (H&E)

CS is an incidental finding in breast samples

variable thickness and staining intensity (Fig. 2
removed for other reasons, and it is not visible at
H&E). The hyaline material present within the
macroscopy.
intraluminal space is rich in collagen type IV of
the basement membrane origin.
Microscopy
Immunophenotype
CS is characterized by presence of eosinophilic
intraluminal collagen-rich spherules measuring
The myoepithelial cells surrounding the basement
20–100 mm in diameter, surrounded by flattened
membrane deposits in CS express myoepithelial
myoepithelial cells (Fig. 1 H&E). Most frequently,
markers, such as smooth muscle actin, smooth
it shows a central floccular aggregate with radiating
muscle myosin heavy chain, calponin, p63
spikes that merge with the scalloped projections at
(Fig. 3a P63 immunostaining), and cytokeratin
the periphery. The material may also be finely
14 (CK14) (Fig. 3b CK14 immunostaining).
granular and more evenly distributed in concentric
onion skin-like pattern. The periphery of the sphere
may be marked by an eosinophilic cuticle of Differential Diagnosis

Cribriform architecture characterizes, in addition

Collagenous Spherulosis, Fig. 1 Collagenous
spherulosis (CS) associated with benign columnar cell
hyperplasia (H&E)
to CS, a broad spectrum of benign and malignant
proliferations in the breast, chiefly invasive crib-
riform carcinoma (▶ Invasive Cribriform Carci-
noma), ductal carcinoma in situ (▶ Ductal
Carcinoma In Situ), and adenoid cystic carcinoma
(AdCC) (▶ Adenoid Cystic Carcinoma). The dif-
ferential diagnosis can be especially challenging
in needle core biopsies (Rabban et al. 2006).
AdCC of the breast is a rare, special type
of invasive breast carcinoma, accounting for
0.05–0.10% of all primary carcinomas of the
breast. The myoepithelial immunophenotypic
overlap between cribriform pattern AdCC of
the breast and CS could lead to diagnostic
Columnar Cell Lesions
Collagenous Spherulosis, Fig. 3 Immunostainings with p63 (a) and CK 14 (b) highlight myoepithelial cells, which
form incomplete lining of the spherules
pitfalls in evaluating cribriform lesions of the
breast, especially in core needle biopsies. While
smooth muscle actin and p63 are expressed by
both entities, other myoepithelial markers,
calponin and smooth muscle myosin heavy
chain, are expressed only by CS and thus can
be used to distinguish it from AdCC (Reis-Filho
et al. 2004). In contrast, the staining for c-kit and
EMA may facilitate identification of the ductules
characteristic for AdCC.
References and Further Reading
Clement, P. B., Young, R. H., & Azzopardi, J. G. (1987).
Collagenous spherulosis of the breast. American
Journal of Surgical Pathology, 11, 411–417.
Mooney, E. E., Kayani, N., & Tavassoli, F. A. (1999).
Spherulosis of the breast. A spectrum of mucinous
and collagenous lesions. Archives of Pathology &
Laboratory Medicine, 123, 626–630.
Rabban, J. T., Swain, R. S., Zaloudek, C. J., Chase, D. R., &
Chen, Y. Y. (2006). Immunophenotypic overlap between
adenoid cystic carcinoma and collagenous spherulosis of
the breast: Potential diagnostic pitfalls using myoepithelial
markers. Modern Pathology, 19, 1351–1357.
Reis-Filho, J. S., Fulford, L. G., Crebassa, B., et al. (2004).
Collagenous spherulosis in an adenomyoepithelioma of
the breast. Journal of Clinical Pathology, 57, 83–86.
Resetkova, E., Albarracin, C., & Sneige, N. (2006).
Collagenous spherulosis of breast: Morphologic study
of 59 cases and review of the literature. American
Journal of Surgical Pathology, 30, 20–27.
Sola Perez, J., Perez-Guillermo, M., Bas Bernal, A., et al.
(1993). Diagnosis of collagenous spherulosis of the
breast by fine needle aspiration cytology: A report of
two cases. Acta Cytologica, 37, 725–728.
71
Columnar Cell Lesions
Margaret C. Cummings1,2, Peter T. Simpson1 and
Sunil R. Lakhani1,2
1
Centre for Clinical Research, Faculty of
Medicine, The University of Queensland,
Brisbane, QLD, Australia
2
Pathology Queensland: The Royal Brisbane and
Women’s Hospital, Brisbane, QLD, Australia
Synonyms
For columnar cell lesions: Columnar cell change,
Columnar cell hyperplasia, Columnar alteration
with prominent apical snouts and secretions
(CAPSS), Atypical cystic ducts, Atypical cystic
lobules, Blunt duct adenosis, Columnar alteration
of lobules, Columnar cell metaplasia, Enlarged
lobular units with columnar alteration, Hyperplas-
tic enlarged lobular units, Hyperplastic unfolded
lobules
For flat epithelial atypia (FEA): Columnar cell
change with atypia, Columnar cell hyperplasia
with atypia, Columnar cell lesion with atypia,
Columnar alteration with prominent apical snouts
and secretions with atypia, Atypical columnar cell
lesions, Atypical cystic duct, Atypical cystic
lobules, Atypical cystic lobules type A, Clinging
carcinoma (monomorphic type), Ductal
intraepithelial neoplasia of the flat monomorphic
72
type (Flat DIN 1), Hypersecretory hyperplasia
with atypia, Pretubular hyperplasia, Small ectatic
ducts lined by atypical cells with apocrine snouts
Definition
Columnar cell lesions refers to a group of prolif-
erative lesions in the breast which have a charac-
teristic cystic dilatation of acini of terminal duct
lobular units such that they appear enlarged and
unfolded, and which are lined by cells showing a
columnar morphology. Columnar cell lesions that
display cytological atypia are referred to as flat
epithelial atypia (FEA).
Clinical Features
• Incidence
As a typical feature of columnar cell lesions is
the presence of calcification, they have been
increasingly identified through the use of
screening mammography and have been
described as occurring in up to 50% of core
needle biopsies that are performed for micro-
calcification. A frequency of 1.9% has been
reported for FEA in reduction mammoplasty
specimens (Desouki et al. 2013) and between
2.4% and 4.5% in core needle biopsies derived
from breast screening programs (Said et al.
2015; Yu et al. 2015). For FEA, excluding
those cases which coexist with higher grade
lesions, such as atypical hyperplasia, in situ
or invasive carcinoma, an incidence of up to
12.2% has been reported (Berry et al. 2016).
• Age
Reflecting the general age distribution of
women undergoing screening mammography,
an age range in the 40s–60s has been described
for women with columnar cell lesions
including FEA.
• Sex
Columnar cell lesions, including FEA, have
only been reported in females, no doubt
because of the lack of lobular units in male
breast tissue.
• Site
These lesions occur only in breast tissue.
Columnar Cell Lesions
• Clinical Presentation
Columnar cell lesions are most commonly
identified on core needle biopsy taken
because of microcalcification which has
been identified on screening mammography.
The microcalcification has been variably
described as indistinct, amorphous, fine,
irregular, and pleomorphic. Calcification
such as this can also be seen in more signifi-
cant breast diseases, hence the need for core
needle biopsy. There are no mammographic
features that can be used to distinguish colum-
nar cell lesions showing atypia from those
without atypia. Columnar cell lesions may
also be identified histologically when a core
needle biopsy has been taken for another rea-
son, such as a nonspecific density and they
may also be found incidentally in surgical
excision specimens.
• Treatment
For columnar cell change and columnar cell
hyperplasia diagnosed on core needle biopsy,
no further treatment is required.
The situation with regards to the manage-
ment of patients in whom FEA is diagnosed on
core needle biopsy is not so straightforward.
A contributing factor to this uncertainty is the
not insignificant frequency of FEA in the
screening population. A related factor is the
difficulty of making the diagnosis of FEA his-
tologically. Pathologists concerned about the
possibility of underdiagnosis and the implica-
tions of missing an atypical lesion tend to over-
diagnose the condition, which of course makes
the most appropriate management difficult to
determine. And for the instances where FEA is
accurately diagnosed, another confounding
factor is the possible pathology upgrade on
surgical excision, and this is of the most imme-
diate concern, considerations of long-term risk
reduction being less relevant. The most com-
monly described treatment for FEA identified
on core needle biopsy is surgical excision. If no
higher grade lesion, such as in situ or invasive
carcinoma is identified initially in the excision
specimen, all the material should be blocked
thoroughly and levels performed as required.
However, the presence of FEA at the margin of
Columnar Cell Lesions
a surgical excision specimen is not an indica-
tion for further surgery.
If FEA is found to coexist with atypical
ductal hyperplasia, in situ or invasive carci-
noma, then naturally the treatment recommen-
dation is dictated by the higher grade lesion.
Other treatment recommendations for
FEA found on core needle biopsy include radi-
ology and pathology correlation with multi-
disciplinary team discussion. Some may
recommend using vacuum-assisted biopsy to
excise any residual tissue showing micro-
calcification or other areas of radiological con-
cern, instead of advocating surgical excision.
If no further microcalcification is identified
radiologically, if the extent of involvement of
the terminal duct lobular units by FEA is small
and the patient does not have a personal history
of breast cancer, ongoing radiological surveil-
lance instead of surgical excision has been
suggested as the preferred management
(Berry et al. 2016; Acott and Mancino 2016).
However, long-term follow-up studies of
women with FEA diagnosed on core needle
biopsy for whom the management has been
prolonged surveillance are not yet available,
and some use this lack of definitive informa-
tion to support the use of surgical excision as
the primary treatment recommendation.
• Outcome
The clinical outcomes of the various colum-
nar cell lesions have not been precisely
defined, and while some generalizations
can be made, there is still a lack of clarity
with respect to the long-term significance of
these lesions. A lower level of risk has been
attributed to columnar cell change and
columnar cell hyperplasia compared with
that for FEA.
The biological importance of columnar cell
lesions is underscored by their association with
other breast lesions such as atypical ductal
hyperplasia (▶ Atypical Ductal Hyperplasia)
and lobular neoplasia, including atypical lobu-
lar hyperplasia and lobular carcinoma in situ
(▶ Lobular In Situ Neoplasia), which have
been noted to coexist with them, sometimes
in the same terminal duct lobular unit (Schnitt
73
and Collins 2009). An association with tubular
carcinoma (▶ Tubular Carcinoma), which
together with columnar cell lesions and lobular
neoplasia forms the eponymously named
Rosen’s triad, was first described in 1999
(Rosen 1999). Whether or not columnar cell
lesions constitute a direct precursor lesion or C
are an indicator of a more general increased
risk of subsequent breast cancer has not been
established. The time course of possible pro-
gression to in situ or invasive carcinoma and
actual upgrade rates are also contentious areas.
There is probably sufficient evidence to sup-
port columnar cell lesions being at least one
early feature of the low-grade breast neoplasia
pathway, but the data are difficult to compare
and analyze because of the range of methodol-
ogies the various studies have used. In some
follow-up studies it is not clear if the subse-
quent carcinoma has been in the same area as
the initial columnar cell lesion. When colum-
nar cell lesions are removed at core biopsy it is
generally not known how much, if any, lesional
tissue remains. It is difficult to then interpret
the significance of subsequent cancers as it
would not be known from precisely what tissue
they may have arisen.
An association between columnar cell
lesions and carcinoma has also been investi-
gated by assessing whether columnar cell
lesions are present in breast tissue adjacent to
in situ and invasive carcinomas. Another way
to explore this association is to retrospectively
study biopsies taken previously from women
with invasive carcinomas to see if columnar
cell lesions, including FEA, might have been
present earlier. Follow-up studies have investi-
gated whether cancers arising subsequent to
columnar cell lesions have occurred in the
same area or somewhere else in the ipsilateral
breast or indeed in the contralateral breast, the
latter, of course, not being used to support any
direct precursor role (Boulos et al. 2008).
Another confounding factor is that many of
the studies have not been able to provide infor-
mation as to the size or possible multifocality
of the columnar cell lesions although
pathology-radiology correlation as to the
74 Columnar Cell Lesions

extent of residual calcification has been very had atypical ductal hyperplasia (Verschuur-
helpful in this regard. Maes et al. 2012b).
Overall, the long-term relative risk of carci-
noma for those women with nonatypical
Macroscopy
columnar cell lesions diagnosed in isolation
appears to be very low, similar to that seen for
Columnar cell lesions, including FEA are diag-
nonatypical proliferative breast disease in gen-
nosed microscopically, and except for occasional
eral, around the order of a 1.5-fold increase
floridly cystic examples, are not able to be identi-
(Verschuur-Maes et al. 2012b).
fied macroscopically.
A closely related issue with columnar cell
lesion is that of the potential upgrade to more
significant lesions, particularly in situ and
Microscopy
invasive carcinoma, which occurs when there
is an immediate surgical excision taken on
A distinctive feature of columnar cell lesions on
the basis of a columnar cell lesion identified
low power examination is the cystic dilatation of
on core biopsy. A very wide range of upgrade
enlarged terminal duct lobular units, and for
rates (between 0% and 67%) has been
columnar cell change and columnar cell hyperpla-
described in the literature, and this consider-
sia, these gland spaces often have an irregular
able variation partly reflects the very different
contour (Fig. 1). The lesions may also be conspic-
ways in which the upgrade rate has been cal-
uous on low power examination because of a
culated. The numerator is generally those who
basophilic appearance, partly due to the regular
have had a malignancy in the subsequent exci-
arrangement of the cells, which are generally uni-
sion specimen, while the denominator can
form, columnar to cuboidal in shape, and mostly
include all women who have had a columnar
orientated perpendicular to the basement mem-
cell lesion on core biopsy, or only those who
brane. Quite frequently, small apical cytoplasmic
have gone on to surgical excision. This of
blebs or snouts are seen, projecting into the lumen
course would give a higher upgrade rate. In
of some glandular spaces, but these are not usually
this latter group too, other clinical and radio-
prominent. Thin, pale proteinaceous secretions
logical features may have also contributed to
which may be pink or blue are commonly seen
the decision to recommend surgical excision,
in the gland lumina (Fig. 2). Luminal micro-
thus confounding the analysis of columnar cell
calcification, often the reason for these lesions
lesions. Some studies have reviewed columnar
cell lesions when there is also atypical ductal or
lobular hyperplasia present, while others have
specifically excluded cases with concomitant
atypical lesions. Many more studies have
addressed upgrade rates from FEA than from
pure columnar cell change or columnar cell
hyperplasia. The problem of correctly diagnos-
ing these lesions histologically only adds to
the difficulty of obtaining meaningful outcome
data. Verschuur-Maes in a comprehensive
meta-analysis of 24 papers concerning the
risk of carcinoma in women with columnar
cell lesions derived pooled underestimation
risks of 1.5% for columnar cell lesions without
atypia, 9% for columnar cell lesions with Columnar Cell Lesions, Fig. 1 Columnar cell lesion.
atypia compared with 20% for those who also Cystic dilatation of terminal duct lobular unit. (H & E)
Columnar Cell Lesions
Columnar Cell Lesions, Fig. 2 Columnar cell
lesion. dilated gland lumina containing watery secretions.
(H & E)
Columnar Cell Lesions, Fig. 3 Columnar cell lesion and
columnar cell hyperplasia. Luminal microcalcification.
(H & E)
being detected radiologically, may be seen and
these range from being fine to granular or coarse
and even sometimes psammomatous (Fig. 3). The
nuclei of columnar cell change or hyperplasia are
generally oval or elongated, with smooth nuclear
membranes and fine chromatin. Nucleoli usually
are not seen and mitoses are rarely identified.
Occasionally the underlying myoepithelial cells
become cuboidal and even relatively prominent.
For columnar cell change, 1–2 layers of cells are
seen above the basement membrane, with greater
numbers seen for columnar cell hyperplasia
(Fig. 4), where stratification of cells can occur
within dilated acini, often giving an impression
of hyperchromasia. Luminal tufting of cells, blunt
75
Columnar Cell Lesions, Fig. 4 Columnar cell hyperpla-
sia. irregularly dilated gland spaces with some overlapping
of cells. (H & E)
Columnar Cell Lesions, Fig. 5 Columnar cell hyperpla-
sia. Luminal tufting of cells and small micropapillae. (H & E)
micropapillae, and luminal secretions can occur
(Fig. 5).
Enlarged or dilated acini of terminal duct lob-
ular units, often appearing rounded or distended
(Fig. 6) rather than the more convoluted contours
of columnar cell change, characterize lesions of
FEA and these are lined by 3–5 layers of cells.
With a loss of polarity, the cells have a more
haphazard overlapping arrangement. “Flat” refers
to the absence of complex architectural features
such as Roman bridges or well-developed rigid
micropapillae. Apical cytoplasmic projections,
characteristic of columnar cell change, may on
occasion be more pronounced. The lining epithe-
lial cells are usually rounded, with a low-grade
76
Columnar Cell Lesions, Fig. 6 Flat epithelial atypia.
Rounded dilated acini of terminal duct lobular unit. (H & E)
Columnar Cell Lesions, Fig. 7 Flat epithelial atypia.
Overlapping cells with monomorphic atypia and occa-
sional nucleoli visible. (H & E)
monomorphic appearance (Fig. 7) unlike that seen
in columnar cell change or hyperplasia. The nuclei
are enlarged, with an increased nuclear to cyto-
plasmic ratio and hyperchromasia, making the
lesions appear distinctive on low-power examina-
tion. The cellular crowding, loss of polarity, and
increased nuclear to cytoplasmic ratio all contrib-
ute to a basophilic appearance. Nuclear mem-
branes may be irregular, the chromatin relatively
dense, and nucleoli can generally be seen. Stromal
changes, such as a chronic inflammatory infiltrate
and a fibrinous or myxoid change can be found in
the intralobular stroma, surrounding glandular
spaces involved by FEA. Microcalcification, as
occurs in columnar cell change and hyperplasia,
Columnar Cell Lesions
can also be seen in gland lumina and this may be
granular or irregular (Schnitt and Collins 2009).
Immunophenotype
Columnar cell lesions, including columnar cell
change, columnar cell hyperplasia, and FEA,
show an immunoprofile similar to that seen in
atypical ductal hyperplasia (▶ Atypical Ductal
Hyperplasia) and low-grade ductal carcinoma in
situ (▶ Ductal Carcinoma In Situ), reflecting the
clonality of these entities. Diffuse expression of
the low molecular weight cytokeratins CK7,
CK8/18, and CK19 can be seen in the luminal
cells, with complete absence of expression of
high molecular weight cytokeratins such as
CK14, CK5/6, and 34bE12. Unlike the cells of
the normal terminal duct lobular units which show
a heterogeneous pattern of staining, columnar cell
lesions show diffuse, intense staining with anti-
bodies to both estrogen and progesterone receptor
proteins. This is also in contrast with the cells of
apocrine metaplasia which are usually uniformly
negative for hormone receptor proteins and some-
times can be confused with those of columnar cell
lesions. The proliferation rate of columnar cell
lesions as indicated by Ki67 staining is generally
low, with less than 10% of cells staining, and
while it may be increased compared with that of
the adjacent noninvolved breast tissue, it is not a
reliable discriminating feature and nor can it be
used to distinguish between FEA and nonatypical
columnar cell lesions. The immunoprofile of
columnar cell lesions also includes Bcl2 positiv-
ity, with strong diffuse cytoplasmic staining, pos-
itive E-cadherin, and absence of staining with
HER2 immunohistochemistry.
Molecular Features
Prompted by morphological similarities with
more advanced lesions, potential molecular
changes in columnar cell lesions have been inves-
tigated to try to determine the clinical significance
of these entities as possible (even nonobligate)
precursors of atypical ductal hyperplasia or
Columnar Cell Lesions
in situ and invasive carcinoma, as part of the low-
grade breast neoplasia pathway. A variety of
methods of analysis have been used, and while
the findings so far are suggestive of a causal rela-
tionship, rather than just co-occurrence, the evi-
dence currently available is relatively scanty.
A loss of heterozygosity study of clinging ductal
carcinoma in situ, also called ductal intraepithelial
neoplasia (DIN) flat type, one of the earlier names
for what is now referred to as FEA, demonstrated
changes at chromosomes 11q21-23.2, 16q23.1-
24.2, and 3p14.2 in 50%, 45%, and 41% of infor-
mative cases, respectively, with corresponding
changes identified in the in situ and invasive carci-
noma also present in these cases (Moinfar 2009).
These findings were later supported by the work of
Aulman in a study of FEA, tubular carcinoma, and
low-grade ductal carcinoma in situ where loss of
heterozygosity was noted for 16q in up to 80% of
cases, 8p21 (26% of cases) 3p14 (20% of cases),
1p35 (20% of cases), and 11q14 (24% of cases),
with many comparable losses seen in the adjacent
low-grade ductal carcinoma in situ and tubular
carcinoma (Aulmann et al. 2009).
Using comparative genomic hybridization
Simpson was able to demonstrate chromosomal
losses (6q, 11q, 12q, 16q, 17p, 19q, and 22) and
gains (3p, 3q, 7, 8q, 12p, 15q, 16p, 19, and 20) in
columnar cell lesions, with increasing chromo-
somal changes seemingly occurring in parallel
with increasing cytological and architectural
atypia, particularly the recurrent loss of 16q
(Simpson et al. 2005).
Gains and losses of 17 breast cancer-related
genes were documented for columnar cell lesions
with accompanying ductal carcinoma in situ and
invasive carcinoma. Copy number gains were
identified for C11orf30, MYC, CPD, MTDH,
CCND1, CCNE1, ESR1, and TOP2A, while losses
were seen for CDH1 and TOP2A in a small num-
ber of cases, the copy number changes increasing
from columnar cell lesions through to invasive
carcinomas. The relative infrequency of the
changes in the columnar cell lesions compared
with those for the in situ and invasive carcinomas
suggested that they may represent relatively late
events in the presumed low-grade pathway
(Verschuur-Maes et al. 2014).
77
Twenty-five percent of invasive breast carcino-
mas have been demonstrated to contain an acti-
vating mutation in the catalytic subunit of
phosphatidylinositol-3-kinase (PIK3CA), and the
presence of these mutations have been investi-
gated in columnar cell lesions, with one study
showing them to be present in 13/24 (54%) cases C
(Troxell et al. 2012) and in 31/62 (50%) of colum-
nar cell/usual ductal hyperplasia lesions in another
(Ang et al. 2014). However, the same point muta-
tions were not consistently identified in the
corresponding carcinoma, sometimes with differ-
ent mutations identified, or wild-type PIK3CA in
the carcinoma with mutations in the columnar cell
lesions, or vice versa, wild-type in the columnar
cell lesions and point mutations identified in the
carcinomas making the association less certain.
Promoter methylation of the tumor suppressor
genes ID4, CCND2, and CDH13 has been dem-
onstrated in columnar cell lesions with increasing
levels shown to occur in parallel with progression
to invasive carcinoma (Verschuur-Maes et al.
2012a) supporting a precursor role for these
lesions, although atypia was not associated with
increased levels. Other changes identified as
linked to the early phase of the low-grade pathway
include, in columnar cell hyperplasia, down-
regulation of the let-7c microRNA in the epithelial
compartment and upregulation of miR-132 in the
stroma surrounding columnar cell hyperplasia
(Bjorner et al. 2014) possibly reducing some con-
trols on anti-proliferative activity.
Differential Diagnosis
The diagnosis of columnar cell change, columnar
cell hyperplasia, and FEA can be difficult to be
certain about, particularly on a core needle biopsy
where there may be only limited material for
evaluation; however, distinguishing FEA is par-
ticularly important as it is associated with a dif-
ferent management outcome for the patient.
Similar to columnar cell lesions, apocrine
metaplasia (▶ Benign and Atypical Apocrine
Lesions) can also be seen in cystically dilated
acini and the lining cells may also show apical
snouts. The cytoplasm of apocrine cells is more
78
eosinophilic and granular than that of columnar
cell lesions, the apical snouts are usually quite
inconspicuous, and the nuclei of apocrine cells
tend to be more round and to have a central prom-
inent nucleolus. Subtle, refractile calcium oxalate
crystals can be associated with apocrine metapla-
sia rather than the darker blue calcium phosphate
seen with columnar cell lesions. Immunostaining
for both hormone receptors and Bcl-2 is usually
negative in apocrine lesions.
Cystic columnar cell lesions may contain lumi-
nal mucin, and this may calcify and may be fine,
granular, or more coarse. Rupture of such cysts
with mucin extravasation into the stroma creates a
differential diagnosis with mucocele-like lesions
(▶ Mucocele-like Lesion). The distinction may be
difficult to make on a core biopsy.
Usual ductal hyperplasia (▶ Usual Ductal
Hyperplasia (UDH)) may be a consideration
when a columnar cell lesion becomes more pro-
liferative, but this is not commonly a difficulty
because of the characteristic columnar shape of
the cells on the one hand and the more heteroge-
neous architectural features associated with usual
ductal hyperplasia on the other. As they are both
benign lesions, differentiating the two does not
have practical consequences.
Distinguishing columnar cell change and
columnar cell hyperplasia from FEA is the key
consideration. Columnar cell hyperplasia shows a
relatively orderly multilayered stratification of
cells; the lining cells in FEA tend to have fewer
layers and show a loss of polarization, including a
loss of the perpendicular orientation that charac-
terizes both columnar cell change and columnar
cell hyperplasia. The affected gland spaces of
FEA appear more rounded and rigidly distended,
and with a more basophilic appearance overall.
Monomorphic cytological atypia, with rounder
nuclei and perceptible nucleoli, is seen. Architec-
tural atypia, however, in the form of cellular brid-
ges, arcades, punched out cribriform spaces, or
more structured micropapillae, together with
polarization of cells around these various forma-
tions, indicates either atypical ductal hyperplasia
or low-grade ductal carcinoma in situ. Though, of
course, both atypical ductal hyperplasia and FEA
may coexist.
Columnar Cell Lesions
References
Acott, A. A., & Mancino, A. T. (2016). Flat epithelial
atypia on core needle biopsy, must we surgically
excise? American Journal of Surgery, 212, 1211–1213.
Ang, D. C., Warrick, A. L., Shilling, A., Beadling, C.,
Corless, C. L., & Troxell, M. L. (2014). Frequent
phosphatidylinositol-3-kinase mutations in prolifera-
tive breast lesions. Modern Pathology, 27, 740–750.
Aulmann, S., Elsawaf, Z., Penzel, R., Schirmacher, P., &
Sinn, H. P. (2009). Invasive tubular carcinoma of the
breast frequently is clonally related to flat epithelial
atypia and low-grade ductal carcinoma in situ. The
American Journal of Surgical Pathology, 33,
1646–1653.
Berry, J. S., Trappey, A. F., Vreeland, T. J., Pattyn, A. R.,
Clifton, G. T., Berry, E. A., et al. (2016). Analysis of
clinical and pathologic factors of pure, flat epithelial
atypia on core needle biopsy to aid in the decision of
excision or observation. Journal of Cancer, 7, 1–6.
Bjorner, S., Fitzpatrick, P. A., Li, Y., Allred, C., Howell, A.,
Ringberg, A., et al. (2014). Epithelial and stromal
microRNA signatures of columnar cell hyperplasia
linking Let-7c to precancerous and cancerous breast
cancer cell proliferation. PLoS One, 9, e105099.
Boulos, F. I., Dupont, W. D., Simpson, J. F.,
Schuyler, P. A., Sanders, M. E., Freudenthal, M. E.,
et al. (2008). Histologic associations and long-term
cancer risk in columnar cell lesions of the breast:
A retrospective cohort and a nested case-control
study. Cancer, 113, 2415–2421.
Desouki, M. M., Li, Z., Hameed, O., Fadare, O., &
Zhao, C. (2013). Incidental atypical proliferative
lesions in reduction mammoplasty specimens: Analysis
of 2498 cases from 2 tertiary women’s health centers.
Human Pathology, 44, 1877–1881.
Moinfar, F. (2009). Flat ductal intraepithelial neoplasia of
the breast: A review of diagnostic criteria, differential
diagnoses, molecular-genetic findings, and clinical
relevance – it is time to appreciate the Azzopardi con-
cept! Archives of Pathology & Laboratory Medicine,
133, 879–892.
Rosen, P. P. (1999). Columnar cell hyperplasia is associ-
ated with lobular carcinoma in situ and tubular carci-
noma. American Journal of Surgical Pathology, 23,
1561.
Said, S. M., Visscher, D. W., Nassar, A., Frank, R. D.,
Vierkant R. A., Frost, M. H. et al (2015). Flat epithelial
atypia and risk of breast cancer: A Mayo cohort study.
Cancer, 121, 1548–1555.
Schnitt, S., & Collins, L. (2009). Biopsy interpretation of
the breast (1st ed., pp. 96–122). Philadelphia:
Lippincott Williams and Wilkins.
Simpson, P. T., Gale, T., Reis-Filho, J. S., Jones, C.,
Parry, S., Sloane, J. P., et al. (2005). Columnar cell
lesions of the breast: The missing link in breast cancer
progression? A morphological and molecular analysis.
The American Journal of Surgical Pathology, 29,
734–746.
Complex Sclerosing Lesion
Troxell, M. L., Brunner, A. L., Neff, T., Warrick, A.,
Beadling, C., Montgomery, K., et al. (2012).
Phosphatidylinositol-3-kinase pathway mutations are
common in breast columnar cell lesions. Modern
Pathology, 25, 930–937.
Verschuur-Maes, A. H., de Bruin, P. C., & van Diest, P. J.
(2012a). Epigenetic progression of columnar cell
lesions of the breast to invasive breast cancer. Breast
Cancer Research and Treatment, 136, 705–715.
Verschuur-Maes, A. H., van Deurzen, C. H.,
Monninkhof, E. M., & van Diest, P. J. (2012b). Colum-
nar cell lesions on breast needle biopsies: Is surgical
excision necessary? A systematic review. Annals of
Surgery, 255, 259–265.
Verschuur-Maes, A. H., Moelans, C. B., de Bruin, P. C., &
van Diest, P. J. (2014). Analysis of gene copy number
alterations by multiplex ligation-dependent probe
amplification in columnar cell lesions of the breast.
Cellular Oncology (Dordrecht), 37, 147–154.
Yu, C. C., Ueng, S. H., Cheung, Y. C., Shen, S. C.,
Kuo, W. L., Tsai, H. P., et al. (2015). Predictors of
underestimation of malignancy after image-guided
core needle biopsy diagnosis of flat epithelial atypia
or atypical ductal hyperplasia. The Breast Journal, 21,
224–232.
Complex Sclerosing Lesion
Anna Sapino1,2 and Davide Balmativola1
1
Unit of Pathology, Candiolo Cancer Institute
FPO-IRCCS, Candiolo, Italy
2
Department of Medical Sciences,
University of Turin, Turin, Italy
Synonyms
Complex papillary sclerosing lesion; Non-
encapsulated sclerosing lesion; Radial sclerosing
lesion; Scleroelastotic scar
Definition
Complex Sclerosing Lesion (CSL) is a benign
proliferation of the breast. While the term “radial
scar” (RS) (▶ Radial Scar) is typically reserved
for small lesions (<1 cm), the term “complex
sclerosing lesion” refers to a larger scar lesion
(1 cm) characterized by fibroelastosis, sclerosis,
and sclero-hyalinosis with entrapped ducts and a
79
variety of epithelial structures with a complex
pattern of growth, which can include intraductal
papillomas (▶ Intraductal Papilloma), sclerosing
adenosis (▶ Sclerosing Adenosis), and usual-type
ductal hyperplasia (▶ Usual Ductal Hyperplasia
(UDH)) (Racz et al. 2017; Ellis and Simpson
2012; Eusebi and Millis 2010; Kennedy C
et al. 2003).
Clinical Features
Occasionally, CSLs may be palpable firm irregu-
lar masses (Hicks and Lester 2017) or a radiolog-
ical finding of a mass with spiculated margins,
but more commonly CSLs cause architectural dis-
tortion on imaging, frequently containing micro-
calcifications. These radiological patterns may be
indistinguishable from invasive carcinoma. On
ultrasound, CSL is seen as hypoechoic area or
mass and at Magnetic Resonance Imaging (MRI)
as an irregular enhancing lesion, usually with
lower enhancement than invasive carcinoma
(Hicks and Lester 2017).
• Incidence
Some authors suggest CSLs are not uncommon,
being present in 14–28% of autopsy studies.
However, the literature reports that only
0.03–0.09% of all diagnosis performed on core
needle biopsies are CSLs. The majority of
patients have multiple lesions and almost 50%
have bilateral CSLs (Hicks and Lester 2017).
• Age
In analogy to radial scar, CSLs are lesions
mainly detected during screening (mean age
50 years).
• Sex
CSLs are found in female breasts, but very
occasionally CSL occurs in male breasts.
• Site
No specific site had been described as concerns
laterality or quadrant of the breast.
• Treatment
The management of radiologically detected
CSL is still controversial because the reported
incidence of malignancy on excisional speci-
mens following a diagnosis of CSL/RS on core
80
needle biopsy (CNB) varies widely, between
0% and 23% (Nakhlis et al. 2018). However,
the majority of cancers associated with CSL
are small, well-differentiated invasive carci-
noma and low grade DCIS. On the other
hand, some authors suggest that CSLs are asso-
ciated with considerable risk of finding breast
carcinoma in adjacent tissue, prompting rec-
ommendation for excision (Kennedy et al.
2003). In conclusion, if epithelial atypia is
present on CNB, excision is recommended
due to the risk of having malignancy associated
to the CSL. It is possible to proceed with
observation when radiological and pathologi-
cal features agree on CSL diagnosed on
vacuum-assisted CNBs in the absence of
other associated high risk lesions (Racz et al.
2017). CSLs diagnosed on excisional surgery
specimens do not require additional treatment
(Patterson et al. 2004).
• Outcome
As above reported CSL itself is considered
a proliferative benign lesion which exhibits
various secondary alterations in the epithelium
and carries an approximately twofold
increased risk of breast cancer (Racz et al.
2017). For this reason, CSLs are diagnosed as
“lesion of undetermined risk” on core biopsies.
Macroscopy
At difference with radial scar, CSLs are generally
of sufficient size to produce an irregular firm
mass, of yellow-white color, indurated, some-
times with central retraction. The central core is
usually firmer than the area of radiating arms;
most lesions are <2 cm. The gross appearance
may be indistinguishable from that of an invasive
carcinoma (Ellis and Simpson 2012); neverthe-
less, CSLs are usually firm but not as hard as
invasive carcinomas.
Microscopy
CSLs are heterogeneous lesions, characterized
by lobulocentric proliferations and varying
degrees of proliferative epithelial changes: cysts,
Complex Sclerosing Lesion
epitheliosis/usual type hyperplasia, apocrine
metaplasia, and sclerosing adenosis (Racz et al.
2017; Ellis and Simpson 2012). All these lesions
may be associated with cytological atypia.
At low magnification, two different regions
can be identified, although not pathognomonic
of CSL:
• Central nidus: It is formed by hyalinized col-
lagen stroma with elastosis entrapping and
distorting tubules (two cell layers are retained)
(Fig. 1, H&E).
• Corona: Sclero-hyalinized bands of connec-
tive tissue radiating from central nidus and
containing distorted tubular structures, fre-
quently pointed and of different size. These
bands dissect normal parenchyma and/or cystic
lobules and/or lobular structures with various
degrees of proliferation and atypia (Fig. 2,
H&E).
CSL frequently involves papillomas leading
to the diagnosis of “complex papillary
sclerosing lesions” (CPSL). The sclero-
hyalinazed tissue is predominant in such cases
and areas of infiltrating epitheliosis (▶ Usual
Ductal Hyperplasia (UDH)) may be frequently
seen. In some cases of CSL, multiple foci of
“adenosquamous proliferation” (ASP), often
regarded as representing benign squamous meta-
plasia, are situated within the nidus and
permeated between ducts beyond the corona
Complex Sclerosing Lesion, Fig. 1 Small tubules
are entrapped in sclero-elastotic stroma in the central
nidus of a complex sclerosing lesion (H&E)
Complex Sclerosing Lesion
Complex Sclerosing Lesion, Fig. 2 At the periphery of
the nidus are radial structures formed by sclero-hyalinized
stroma entrapping distorted tubular structures (H&E)
Complex Sclerosing Lesion, Fig. 3 Immunostaining
for p63 stains nuclei of myoepithelial cells. In some tubules
only rare nuclei are evident
of the CSL, with reactive hypercellular stroma.
ASP may be related to infarction in the instance
of papilloma or following previous fine needle-
or CNBs (Wilsher et al. 2017). These ASPs
have been considered as precursors of
metaplastic carcinoma (▶ Invasive Metaplastic
Carcinoma) (Denley et al. 2000), in particular
81
Complex Sclerosing Lesion, Fig. 4 Immunostaining for
Cytokeratins 5/6 shows positivity of luminal epithelial
cells in a focus of adenosquamous proliferation in a com-
plex sclerosing lesion
low grade adenosquamous carcinoma (▶ Low-
Grade Adenosquamous Carcinoma), which are
not a rare event in CSL (Tan et al. 2015).
Immunophenotype
Immunostains for myoepithelial markers (e.g.,
p63 or p40, calponin, smooth muscle myosin
heavy chain, cytokeratin 5/6) may be helpful
to distinguish entrapped benign tubules from
a tubular carcinoma (▶ Tubular Carcinoma);
however, in areas of sclero-hyalinosis, the
myoepithelium may be very attenuated or even
undetectable (Fig. 3, Immunostaining for p63). In
analogy, basal cytokeratins (CK5/6, CK14) may
not be just expressed at the periphery by basal/
myoepithelial cells but also by luminal epithelial
cells, particularly in cases associated with ASP
(Fig. 4, Immunostaining for Cytokeratins 5/6).
Molecular Features
No specific molecular genetics of CSL have been
described (Ellis and Simpson 2012).
PIK3CA mutations are present in 50–75% of
sclerosing lesions (Wilsher et al. 2017). The muta-
tion is a hallmark of ASP in CSL (Wilsher et al.
2017). Evidence suggests that radial scar/complex
sclerosing lesions, sclerosing papilloma or similar
lesions, are phenotypically similar to low-grade
82
adenosquamous carcinoma (▶ Low-Grade
Adenosquamous Carcinoma); their distinction is
often subjective and is poorly defined in
the literature.
Differential Diagnosis
On core biopsy, it may be difficult to distinguish
the distorted glandular structures of CSL from
invasive carcinoma. Therefore, biopsies should
be reported with caution, using phrasing as “con-
sistent with radial scar/complex sclerosing
lesion,” also considering the frequency of addi-
tional pathology on excision. The differential
diagnosis with tubular carcinoma (▶ Tubular
Carcinoma) has already been considered in the
chapter “radial scar” (▶ Radial Scar) demonstra-
tion of myoepithelial cells by immunohistochem-
istry is useful.
Gobbi et al. (2003) showed that distinction
from metaplastic carcinomas (▶ Invasive Meta-
plastic Carcinoma) arising in radial sclerosing
lesions (RS, CSL, CPSL) and “pseudoinfiltrative
glands” is often difficult and stressed that “to
avoid overdiagnosis of malignancy in the reac-
tive process, the lesion should present increased
cellularity and clumps of cytokeratin
positive plump spindle cells, besides the ‘reac-
tive’ spindle cells and squamous elements”. It
has also been stated that ductules of radial scars
do not display a syringoid appearance
(Ho et al. 2006).
References and Further Reading
Denley, H., Pinder, S. E., Tan, P. H., Sim, C. S., Brown, R.,
Barker, T., Gearty, J., Elston, C. W., & Ellis, I. O.
Complex Sclerosing Lesion
(2000). Metaplastic carcinoma of the breast arising
within complex sclerosing lesion: A report of fivecases.
Histopathology, 36, 203–209.
Ellis, I. O., & Simpson, J. F. (2012). Radial scar and
complex sclerosing lesion. In S. R. Lakhani (Ed.),
WHO classification of tumors of the breast
(pp. 114–115). Lyon: IARC Press.
Eusebi, V., & Millis, R. R. (2010). Epitheliosis, infiltrating
epitheliosis, and radial scar. Seminar in Diagnostic
Pathology, 27, 5–12.
Gobbi, H., Simpson, J. F., Jensen, R. A., Olson, S. J., & Page,
D. L. (2003). Metaplastic spindle cell breast tumors aris-
ing within papillomas, complex sclerosing lesions, and
nipple adenomas. Modern Pathology, 16, 893–901.
Hicks, D. G., & Lester, S. C. (2017). Diagnostic pathology:
Breast (2nd ed.). Philadelphia: Elsevier.
Ho, B. C., Tan, H. W., Lee, V. K., & Tan, P. H. (2006).
Preoperative and intraoperative diagnosis of low-grade
adenosquamous carcinoma of the breast: Potential
diagnostic pitfalls. Histopathology, 49, 603–611.
Kennedy, M., Masterson, A. V., Kerin, M., & Flanagan, F.
(2003). Pathology and clinical relevance of radial scars:
A review. Journal of Clinical Pathology, 56, 721–724.
Nakhlis, F., Lester, S., Denison, C., Wong, S. M.,
Mongiu, A., & Golshan, M. (2018). Complex scleros-
ing lesions and radial sclerosing lesions on core needle
biopsy: Low risk of carcinoma on excision in cases
with clinical and imaging concordance. Breast Journal,
24, 133–138.
Patterson, J. A., Scott, M., Anderson, N., & Kirk, S. J.
(2004). Radial scar, complex sclerosing lesion and risk
of breast cancer. Analysis of 175 cases in Northern
Ireland. European Journal of Surgical Oncology, 30,
1065–1068.
Racz, J. M., Carter, J. M., & Degnim, A. C. (2017).
Challenging atypical breast lesions including flat epi-
thelial atypia, radial scar, and Intraductal papilloma.
Annals of Surgical Oncology, 24, 2842–2847.
Tan, Q. T., Chuwa, E. W., Chew, S. H., Lim-Tan, S. K., &
Lim, S. H. (2015). Low-grade adenosquamous carci-
noma of the breast: A diagnostic and clinical challenge.
International Journal of Surgery, 19, 22–26.
Wilsher, M. J., Owens, T. W., & Allcock, R. J. (2017).
Next generation sequencing of the nidus of early
(adenosquamous proliferation rich) radial sclerosing
lesions of the breast reveals evidence for a neoplastic
precursor lesion. Journal of Pathology: Clinical
Research, 3, 115–122.
D
Diabetic Mastopathy
Savelina Popovska1,2, Ivan Ivanov2 and
Vincenzo Eusebi3
1
University of Pleven, Pleven, Bulgaria
2
Department of Pathology, Medical University,
Pleven, Bulgaria
3
Department of Pathology, University of
Bologna, Bologna, Italy
Synonyms
Diabetic mastopathy; Lymphocytic mastitis; Scle-
rosing lymphocytic lobulitis
Definition
Diabetic Mastopathy (DMP), also known as lym-
phocytic mastitis or sclerosing lymphocytic
lobulitis, is a relatively rare, fibro-inflammatory
complication of diabetes mellitus (DM) (insulin-
dependent diabetes of early onset and long dura-
tion), Hashimoto thyroiditis, Sjogren’s disease,
and other autoimmune disorders (Weidner and
Dabbs 2012). Soler and Khardori were the first
to describe the entity in 1984. They reported
12 cases of DMP in a group of female patients,
aged 25–40 years, with type I DM of 8–30 years
from onset. The complications registered included
limited mobility of the small joints of the hand,
and neuro-, retino-, and nephropathy. The authors
© Springer Nature Switzerland AG 2020
A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
reported tumor-like lumps in the breast, which
clinically mimicked carcinoma, but on histology,
the lesion proved benign (Soler and Khardori
1984).
The term “diabetic mastopathy” was intro-
duced by Byrd et al., who described the presence
of stromal fibrosis and perivascular lymphocytic
infiltrates (Byrd et al. 1987). The histology of the
lesion was illustrated in 1990 (Foschini et al.
1990) and the presence of a lymphocytic lobulitis
was emphasized.
The changes are nonspecific, and mammary
lesions with similar features had been reported in
nondiabetic patients. A large number of patients,
who present with DMP, however, suffer from
autoimmune diseases. Thus, this same lesion
was also designated as sclerosing lymphocytic
lobulitis (Weidner and Dabbs 2012).
The pathogenesis of DMP is not fully under-
stood. According to one of the most widely
accepted theories, DMP is an autoimmune pro-
cess, comparable to those seen in other organs.
Other theories suggest that DMP is consequent
to insulin supplementation. Still others claim
that it may occur as a result of the alteration
of collagen metabolism and change in its
structural and antigenic properties in the context
of hyperglycemia (Soler and Khardori 1984;
Tomaszewski et al. 1992). The most widely
accepted pathogenesis is related to autoimmu-
nity because DMP is often combined with auto-
immune disorders of the thyroid gland (Weidner
and Dabbs 2012).
84
It is assumed that key factors for the develop-
ment of DMP are the nonenzymatic glycation of
proteins, caused by long persisting hyperglyce-
mia (nonenzymatically glycosylated proteins)
and the formation of advanced glycosylation
end products in cases of long-term diabetes.
The glycated proteins form intermolecular
cross-linking products that are not easily degrad-
able and are deposited in the breast stroma.
Changes in the end products and the deposits
of modified matrix in the breast stroma are
immunogenic and are identified as neoantigens.
These cause a secondary humoral response by
activation of antibody-producing B lympho-
cytes. This local immune response, including
the activation of macrophages, leads to lympho-
kine secretion and subsequent impairment of
the lobular and ductal epithelium. Lymphokines,
in turn, act as a growth factor in activation of
fibroblasts and increased collagen production
(Camuto et al. 2000).
Clinical Features
• Incidence
DMP accounts for approximately 1% of
benign lesions of the breast (Foschini et al.
1990). It is usually associated with type
I DM but it can also be seen, though rarely,
in type II DM patients (Weidner and Dabbs
2012).
• Age
The average age of female patients with DM,
suffering from DMP varies between 34 and
47 years. In most of the DM-associated cases,
the interval between DM onset and its clinical
presentation of DMP is approximately 20 years
(Rosen 2009). Long-term insulin-dependent
DM and premenopause are considered to be
among the main predisposing factors for the
development of DMP in females (Weidner and
Dabbs 2012).
• Sex
The changes manifest mostly in female
patients. Single cases have been reported in
male patients with insulin-dependent DM
(Lee et al. 1996; Rosen 2009).
Diabetic Mastopathy
• Site
No specific sites are described.
• Treatment
DMP is a lesion, which may cause diagnostic
difficulties in clinical practice, because of its
clinical presentation and imaging, which
sometimes resemble malignant conditions
(Foschini et al. 1990; Weidner and
Dabbs 2012). After the histological diagnosis
of DMP, regular ultrasound and mammogra-
phy follow-up examination is the wisest
approach.
• Outcome
DMP is usually associated with a favorable
prognosis, and spontaneous regression of the
lesion is possible. Recurrences after surgical
treatment may occur in some of the cases
(Weidner and Dabbs 2012).
Due to the high incidence of relapses, sur-
gery is not considered effective in the treatment
of DMP. In clinically and morphologically ver-
ified cases of DMP, any conservative treatment
is advisable.
Macroscopy
Diagnosis of DMP is a challenge for both
clinicians and radiographers. On mammography,
the lesion is not well-delineated, with heter-
ogeneous density and no calcifications. It may
be a focally asymmetric mass or a well-
circumscribed nodule resembling a
fibroadenoma. Some cases can be interpreted as
a carcinoma. All these characteristics make the
findings rather unspecific (Rosen 2009; Weidner
and Dabbs 2012).
Ultrasound examination may be a helpful diag-
nostic method in DMP cases. It is also useful in
core-needle biopsy diagnosis and follow-up of
patients (Rosen 2009).
The hyperdensity seen in DMP can also cause
difficulties in distinguishing DPM from breast
carcinoma. In such cases, MRI is a reliable tech-
nique for diagnosing malignant neoplastic lesions
(Rosen 2009).
At macroscopy, DMP usually presents as pal-
pable, mobile lump, firm on palpation, with gray-
Diabetic Mastopathy 85

white surface. Lumps are irregular in shape, with stroma (Fig. 4a, b). These same cells were
no distinct borders between the lesion and the interpreted as epithelioid fibroblasts and first
surrounding healthy tissue. Occasionally, DMP reported by Tomaszewski et al. (1992) and are
may present as a tumor-like lesion (Foschini seen in about 75% of the cases.
et al. 1990; Weidner and Dabbs 2012). Though rare, there are cases of DMP showing
necrosis and granuloma formation (Weidner and
Dabbs 2012). The histological findings in DMP
Microscopy in male patients share many similarities with the
findings seen in women. Morphologically, DMP D
Histologically, DMP is characterized by presence in the male breast is characterized by lympho-
of spindle to epithelioid myofibroblasts within a cytic periductitis, perivasculitis, dense fibrotic
collagenized frequently dense stroma. In addition, stroma, and epithelioid myofibroblasts (Lee
the main features of the lesion include circumfer- et al. 1996).
ential intralobular, periductal, and perivascular
B type lymphocyte infiltration. The intralobular
lymphocytic reaction is frequently very intense
and shows neat borders, as seen at low power, a
feature often very indicative of the disease. Duct-
ules are consistently atrophic and show thick basal
lamina. (Foschini et al. 1990; Tomaszewski et al.
1992) (Figs. 1, 2, and 3). The stroma varies from
loose to dense. It lacks inflammatory cells. Never-
theless, in the stroma, cells with round to elon-
gated nuclei, evident nucleoli, and abundant
amphophilic cytoplasm are present. These cells
are sparse or can be clumped in nests within the

Diabetic Mastopathy, Fig. 2 Dense lymphoid infiltrate

is located within the lobular stroma. Some ductules are
atrophic (H&E)

Diabetic Mastopathy, Fig. 1 A lobule is typically filled

by a dense lymphoid infiltrate. Ductules are mostly atro- Diabetic Mastopathy, Fig. 3 The cells present in the
phic and difficult to see at low magnification. The inflam- lobular stroma are constituted by lymphocytes and plasma
matory reaction shows neat peripheral borders (H&E) cells. Ductules show thick basal lamina (H&E)
86
Diabetic Mastopathy, Fig. 4 (H&E) (a) Sclerohyaline
acellular fibrous tissue centered by a clump of epithelioid
fibroblasts showing ovoid nuclei and well visible nucleoli.
Diabetic Mastopathy, Table 1 Histopathological char-
acteristics of DMP
Inflammation
Lymphocytic infiltrates are composed of mature
lymphocytes, do not form follicles, and do not infiltrate
the epithelium
Lobulo-centric inflammation together with periductitis
and perilobulitis
Lymphocytic vasculitis
Fibrosis
Involutional changes in lobules with thick basal lamina
(sclerotic lobulitis)
Loose to dense, collagenized stroma
Epitheloid fibroblasts
Proliferation of epithelioid fibroblasts with irregular
often pleomorphic nuclei
Immunophenotype
IHC staining is recommended in all cases of DMP.
Usually, the epithelioid fibroblasts express CD
34, actin (and occasionally CD68) and are negative
for all keratins, S100, desmin, factor VIII, CD45,
and CD20 (Weidner and Dabbs 2012). Immunophe-
notyping of the inflammatory infiltrates demon-
strates that these are predominantly composed of
polyclonal B lymphocytes. The inflammatory infil-
trates consist of small B lymphocytes with no signs
of atypia, expressing light chain immunoglobulins
(Weidner and Dabbs 2012). Immunophenotyping
based on immunohistochemistry (IHC) and flow
Diabetic Mastopathy
(b) Hyaline fibrous tissue with sparse fibroblasts showing
abundant cytoplasm. The nuclei are irregular and may
simulate neoplastic cells
Diabetic Mastopathy, Table 2 Immunohistochemical
findings in DMP
The inflammatory infiltrate is constituted predominantly
by mature B lymphocytes (CD20 – positive), that are
polyclonal and express light chain immunoglobulin
HLA-DR antigen is expressed in the lobular epithelium
Epithelioid fibroblasts are positive for CD 34 and actin
and are negative for keratins
cytometry have demonstrated that the proliferation
of mature B lymphocytes is not clonal and is not
related to increased risk for the development of lym-
phoma. The expression of HLA-DR3, 4, or 5 in the
epithelial cells of the affected lobular units may also
be observed. The presence of HLA-DR phenotype,
related to increased risk of autoimmune diseases and
the findings of circulating autoantibodies in DMP
patients is probative for the autoimmune pathogene-
sis of the condition (Lammie et al. 1991).
Molecular Features
So far, specific molecular studies are not available.
Differential Diagnosis
DMP requires exclusion of several pathological
conditions, affecting the breast. Among these are
Duct Ectasia and Periductal Mastitis
granulomatous mastitis (▶ Granulomatous Mas-
titis), sclerotic lipogranuloma, vasculitis, lupus
panniculitis, rheumatoid nodules, and infarction
(▶ Infarct of Breast Tissue). The abundance of
inflammatory cell infiltrates and epithelioid
(myo)fibroblasts with pleomorphic nuclei often
requires the lesion to be differentiated from an
invasive carcinoma (Weidner and Dabbs 2012).
Because of the wide spectrum of differential
diagnoses and different etiology of DMP, a thor-
ough examination of every single case is
required in terms of its morphological and
immunohistochemical characteristics and their
correspondence to the established diagnostic
criteria.
The histopathological and IHC character-
istics of DMP are presented on Tables 1 and 2.
References and Further Reading
Byrd, B. F., Hartman, W. H., Graham, L. S., & Hogle, H. H.
(1987). Mastopathy in insulin-dependent diabetics.
Annals of Surgery, 205, 529–532.
Camuto, P. M., Zetrenne, E., & Ponn, T. (2000). Diabetic
mastopathy. A report of 5 cases and a review of the
literature. Archives of Surgery, 135, 1190–1193.
Foschini, M. P., Cavazza, A., Macedo Pinto, I. M., &
Eusebi, V. (1990). Diabetic fibrous mastopathy. Report
of two cases. Virchows Archiv. A, Pathological
Anatomy and Histopathology, 417(6), 529–532.
Lammie, G. A., Bobrow, L. G., Staunton, M. D.,
Levison, D. A., Page, G., & Millis, R. R. (1991).
Sclerosing lymphocytic lobulitis of the breast –
Evidence for an autoimmune pathogenesis.
Histopathology, 19(1), 13–20.
Lee, A. H. S., Zafrani, B., Kafiri, G., Rozan, S., & Millis, R. R.
(1996). Sclerosing lymphocytic lobulitis in the male
breast. Journal of Clinical Pathology, 49, 609–611.
Rosen, P. P. (2009). Inflammatory and reactive tumors. In
P. P. Rosen (Ed.), Rosen’s breast pathology (3rd ed.,
pp. 33–70). Philadelphia: Lippincott Williams &
Wilkins.
Soler, N. G., & Khardori, R. (1984). Fibrous disease of the
breast, thyroiditis, and cheiroarthropathy in type
I diabetes mellitus. Lancet, 1(8370), 193–195.
Tomaszewski, J. E., Brooks, J. S., Hicks, D., &
Livolsi, V. A. (1992). Diabetic mastopathy:
A distinctive clinicopathologic entity. Human
Pathology, 23, 780–786.
Weidner, N., & Dabbs, D. J. (2012). Reactive and
inflammatory conditions of the breast. In D. J.
Dabbs (Ed.), Breast pathology (pp. 22–33). Philadel-
phia: Saunders.
87
Duct Ectasia and Periductal
Mastitis
Isabel Amendoeira1,2 and Margarida Sá Fernandes1
1
Centro Hospitalar de São João (CHSJ), Porto,
Portugal
2
IPATIMUP - Instituto de Patologia e Imunologia
Molecular da Universidade do Porto, Porto, D
Portugal
Synonyms
Mastitis obliterans; Periductal mastitis (PDM);
Plasmacell mastitis
Definition
Periductal mastitis (PDM)/Duct ectasia (DE) is a
common benign breast condition mostly seen in
women. It is still debatable whether they are two
clinical and pathological entities, which affect
different age groups and have different etiologies
or if PDM and DE are part of the same disease
process, PDM preceding DE.
PDM/DE affects larger ducts and is character-
ized by duct dilatation, periductal inflammation,
and fibrosis.
Clinical Features
• Incidence
DE represents an incidental finding in about
8% of patients undergoing breast surgery.
• Age
PDM/DE occurs most frequently in women
between the age 30 and 70 years. In infancy
(average age is 38 months) and childhood, bleed-
ing is the most common presenting symptom and
the male:female ratio is 10:4, in contrast to adult
population, probably representing a developmen-
tal abnormality (McHoney et al. 2011).
• Sex
More frequent in women. It is very rare in men
as well as in infancy and childhood (O’Malley
and Pinder 2011).
88 Duct Ectasia and Periductal Mastitis

• Site
Major ducts. May be bilateral.
• Treatment
PDM/DE is a benign lesion with no increased
risk of malignancy. Excision biopsy should be
curative, although not always recommended.
Recurrence is not common (Dabbs 2016).
• Outcome
Although it may be asymptomatic, spontane-
ous and intermittent nipple discharge (clear,
yellow, green, or brown), pain, mass, and Duct Ectasia and Periductal Mastitis, Fig. 1 Gross.
edematous skin changes are described as the
first symptoms and are seen in younger
patients. In a later stage, duct dilatation, nipple 2017). The ductal epithelium is often thin and
retraction, and periductal fibrosis are seen more may be disrupted by inflammatory cells and mac-
preferentially in older patients (Dixon et al. rophages (Fig. 2) (O’Malley and Pinder 2011).
1983, 1996). Periductal inflammatory infiltrate, predominantly
Ulceration of the skin, abscess, and fistulas lymphocytes, and fibrosis are also
may occur and are often described at a later characteristic. Granulomatous inflammation with
stage and can mimic a carcinoma (Moinfar giant cells can occur (O’Malley and Pinder 2011).
2007). Although the inflammatory process is centered in
Mammography abnormalities include large major ducts, it can extend to the peripheral lob-
rod-like branching calcifications, usually ules. Lymphocytic infiltrate in lobules without
>1 mm, with lucent centers. Calcifications granulomas can be seen (Rosen et al. 2014). Stasis
are usually widespread, bilateral, and radially material can be discharged in stroma by disruption
oriented to the nipple-areolar complex of the ducts and cause inflammation and abscess
(Kamal et al. 2009). Lobulated smooth nod- formation (Rosen et al. 2014).
ules or spiculated masses suggesting carci- Duct content is often varied: granular amor-
noma have been described as well (Rosen phous, proteinaceous material admixed with
et al. 2014). foam-cells and desquamated duct epithelial cells.
Histiocytic reaction around cholesterol crystals
can be identified (Rosen et al. 2014).
Macroscopy
The thick layer of hyaline and elastic tissue in a
later stage can encase ducts and in some cases the
The most characteristic alteration in the mammary
lumen becomes totally obliterated by granulation
specimen is the presence of dilated subareolar
tissue – the so called “mastitis obliterans.” Within
ducts; depending on duct contents, cream-
the sclerotic duct, the persisting epithelium may
colored, soft or brown, different kinds of secretion
proliferate forming secondary glands, a pattern
can be observed (Fig. 1 gross appearance:
that resembles a recanalized thrombus in a blood
enlarged ducts are converging toward nipple).
vessel (Rosen et al. 2014).

Microscopy Immunophenotype

The hallmark of PDM/DE is the presence of three No specific variation of immunophenotypes

or more dilated ducts with luminal material and is described. The origin of foamy cells is contro-
foamy macrophages, periductal inflammation, versial and three types have been described:
fibrosis, and hyperelastosis (Ramalingam et al. epithelial derived (expressing cytokeratins and
Duct Ectasia and Periductal Mastitis
Duct Ectasia and Periductal Mastitis, Fig. 2 (H&E) Histiocytes and lymphocytes disrupt the duct epithelium
(Left (400x)); The lumen of the dilated duct is filled with granular, amorphous, eosinophilic material (right (100x))
epithelial membrane antigen); histiocytic-like
(expressing CD68 and MAC387); cells with inter-
mediate features with immunoreactivity for CD68
and GCDFP-15 (Damiani et al. 1998).
Molecular Features
No important studies are available.
Differential Diagnosis
Although clinical features and mammography can
raise problems of differential diagnosis with car-
cinoma, pathologic diagnosis is usually
straightforward.
Differential diagnosis should include cysts,
fibrocystic changes (▶ Fibrocystic Breast
Changes), and diabetic sclerosing lymphocytic
lobulitis (▶ Diabetic Mastopathy). Lobular cysts
are round with no inflammation, no fibrosis, and
no elastic tissue around the wall (O’Malley and
Pinder 2011); fibrocystic changes are character-
ized by cysts frequently with apocrine metapla-
sia and apocrine hyperplasia, usual epithelial
hyperplasia and stromal fibrosis; diabetic scle-
rosing lymphocytic lobulitis is thought to be an
autoimmune disease, perilobular and peri-
vascular lymphocytic infiltrate, lobular atrophy,
and fibrosis being the main features (Dabbs
2016).
89
References and Further Reading
Dabbs, D. (2016). Breast pathology (2nd ed.). Philadel-
phia, PA: Elsevier [2017].
Damiani, S., Cattani, M., Buonamici, L., & Eusebi, V. (1998).
Mammary foam cells. Virchows Archiv, 432, 433–440.
Dixon, J., Anderson, T., Lumsden, A., Elton, R., Roberts,
M., & Forrest, A. (1983). Mammary duct ectasia. Brit-
ish Journal of Surgery, 70, 601–603.
Dixon, J., Ravisekar, O., Chetty, U., & Anderson,
T. (1996). Periductal mastitis and duct ectasia: Differ-
ent conditions with different aetiologies. British Jour-
nal of Surgery, 83, 820–822.
Kamal, R., Hamed, S., & Salem, D. (2009). Classification
of inflammatory breast disorders and step by step diag-
nosis. The Breast Journal, 15, 367–380.
Liu, L., Zhou, F., Wang, P., Yu, L., Ma, Z., Li, Y., Gao, D.,
Zhang, Q., Li, L., & Yu, Z. (2017). Periductal mastitis:
An inflammatory disease related to bacterial infection
and consequent immune responses? Mediators of
Inflammation, 2017, 5309081.
McHoney, M., Munro, F., & MacKinlay, G. (2011). Mammary
duct ectasia in children: Report of a short series and review
of the literature. Early Human Development, 87, 527–530.
Moinfar, F. (2007). Essentials of diagnostic breast pathol-
ogy. Berlin: Springer.
O’Malley, F., & Pinder, S. (2011). Breast pathology
(2nd ed.). Edinburgh: Churchill Livingstone/Elsevier.
Ramalingam, K., Vuthaluru, S., Srivastava, A., Dinda, A.,
& Dhar, A. (2017). Ultra structural changes occurring
in duct ectasia and periductal mastitis and their signif-
icance in etiopathogenesis. PLoS One, 12, e0173216.
Rosen, P., Hoda, S., Brogi, E., & Koerner, F. (2014).
Rosen’s breast pathology (4th ed.). Philadelphia:
Wolters Kluwer Health/Lippincott Williams & Wilkins.
Sweeney, D., & Wylie, E. (1995). Mammographic appear-
ances of mammary duct ectasia that mimic carcinoma
in a screening programme. Australasian Radiology, 39,
18–23.
90 Ductal Adenoma

• Site
Ductal Adenoma Mostly unilateral, in the form of single or mul-
tiple nodules. Bilaterality has been reported in
Handan Kaya patients with Carney Syndrome (Carney and
Pathology Department, Marmara University, Stratakis 1996; Carney and Toorkey 1991)
Istanbul, Turkey • Symptoms and Treatment
Ductal adenoma may present as a palpable
mass or sometimes with nipple discharge.
Synonyms On mammography, it is a well-delineated
nodule, with smooth margins with or
Sclerosing Papilloma is used as a synonym in without coarse calcifications; ultrasonography
WHO 2012 (Foschini et al. 2012). may exhibit hypoechoic structure, sometimes
located within a cyst and MR imaging shows
smooth and clear margins (Matsubayashi et al.
Definition 2016). Excision is curative.
• Outcome
Solid benign tumor of the breast ducts, involving Benign lesion with no reported tendency to
small or medium size ducts described by recurrence.
Azzopardi and Salm (Azzopardi and Salm
1984). These lesions may rarely arise from large-
Macroscopy
sized ducts (Lammie and Millis 1989).
The typical gross appearance is well-
circumscribed, round nodule(s). Macroscopically,
Clinical Features
the lesions’ size varies from 0.5 cm to 4.0 cm. The
cut surface is greyish-white and may be gritty.
• Incidence
It is an uncommon disease.
• Age Microscopy
It is most frequently seen in women over
50 years. Microscopically these lesions are typically
• Sex located in the lumen of a duct demonstrating
Female single or multiple adenomatous nodules

Ductal Adenoma,
Fig. 1 Dilated duct
showing in intraductal
adenomatous growth with
areas of poorly cellular
connective tissue (H&E)
Ductal Carcinoma In Situ
composed of ductal epithelial and myoepithelial
cells surrounding a central scar (Fig. 1). Charac-
teristically, they are circumscribed by a thick layer
of hyalinized fibrosis which often contains
elastic fibers derived from the original ducts.
Hyalinized fibrosis with entrapped tubules,
epithelial atypia, and pseudoinvasion pattern
may mimic malignancy. Demonstration of base-
ment membrane, dual cell population with epithe-
lial and myoepithelial cells forming the tubules
can be helpful in differential diagnosis. Myxoid
change, calcifications, and infarction can be
encountered. More than half of the reported
cases showed apocrine differentiation; squamous
metaplasia has also been described.
Immunophenotype
Epithelial, myoepithelial, and basal membrane
markers are expressed as in normal structures.
Molecular Features
Molecular basis of these tumors is unknown. Next
generation sequencing of 50 cancer-related genes
and Sanger sequencing analysis of nine ductal
adenomas showed 56% (5/9) harboring mutated
genes and from those 30% demonstrated mutant
AKT1 and 22% (3/9) an additional GNAS muta-
tion, 11% (1/9) had mutant PIK3CA. AKT
1 E17 K mutations demonstrated in breast papil-
lomas without atypia supports the relation
between sclerosing intraductal papillomas and
ductal adenomas (Troxell et al. 2010).
Differential Diagnosis
Duct ectasia, cyst, and epithelial hyperplasia
can be seen and dominant myoepithelial cell
proliferation may lead to misdiagnosis of
adenomyoepithelioma (▶ Adenomyoepitheli-
oma) (Azzopardi and Salm 1984; Carney and
Toorkey 1991). Ductal adenomas presenting stro-
mal proliferation and fibrosis associated with the
distortion of tubular structures show an overlap
with sclerosing adenosis (▶ Sclerosing Adenosis)
91
and complex sclerosing lesions (▶ Complex Scle-
rosing Lesion). Although sometimes it is not pos-
sible to make a differential diagnosis,
demonstrating only small foci of papillary growth
pattern by examining multiple section levels
favors ductal adenoma diagnosis.
References and Further Reading D
Azzopardi, J. G., & Salm, R. (1984). Ductal adenoma of
the breast: A lesion which can mimic carcinoma.
Journal of Pathology, 144, 15–23. https://doi.org/
10.1002/path.1711440103.
Carney, J. A., & Stratakis, C. A. (1996). Ductal adenoma
of the breast and the Carney complex. American Jour-
nal of Surgical Pathology, 20, 1154–1155.
Carney, J. A., & Toorkey, B. C. (1991). Ductal adenoma
of the breast with tubular features. A probable compo-
nent of the complex of myxomas, spotty pigmentation,
endocrine overactivity, and schwannomas. American
Journal of Surgical Pathology, 15, 722–731.
Foschini, M., Simpson, J., & O’Malley, F. (2012). Ductal
adenoma. In S. Lakhani, I. Ellis, S. Schnitt, P. Tan, &
M. Van de Vijyer (Eds.), WHO classification of tumors
of the breast (pp. 117–118). Lyon: IARC.
Lammie, G. A., & Millis, R. R. (1989). Ductal adenoma
of the breast – A review of fifteen cases. Human Pathol-
ogy, 20, 903–908.
Matsubayashi, R. N., Momosaki, S., & Muranaka, T.
(2016). Ductal adenoma of breast: imaging characteris-
tics and radiologic-pathologic correlation of unique find-
ings which reflect “pseudoinvasion”. Breast Cancer, 23,
597–606. https://doi.org/10.1007/s12282-015-0608-9.
Troxell, M. L., Levine, J., Beadling, C., Warrick, A., Dunlap,
J., Presnell, A., Patterson, J., Shukla, A., Olson, N. R.,
Heinrich, M. C., & Corless, C. L. (2010). High preva-
lence of PIK3CA/AKT pathway mutations in papillary
neoplasms of the breast. Modern Pathology, 23, 27.
Ductal Carcinoma In Situ
Isabella Castellano1 and Jasna Metovic2
1
Department of Medical Sciences, University of
Turin, Turin, Italy
2
Department of Oncology, University of Turin,
Turin, Italy
Synonyms
Ductal intraepithelial neoplasia; Intraductal carci-
noma; Noninvasive ductal breast cancer; Pre-
invasive breast cancer
92
Definition
Ductal carcinoma in situ (DCIS) is a neoplastic
proliferation confined to the mammary ductal-
lobular system, which is surrounded by a
myoepithelial layer and a basal membrane. DCIS
covers a heterogeneous group of diseases charac-
terized by subtle to marked cytological atypia,
without any invasion of the stromal tissue
(Lakhani et al. 2012).
Clinical Features
• Incidence
DCIS incidence gradually and constantly
increased over the past decades (from 5.8
per 100,000 women in 1975 to 34.4 per
100,000 women in 2014), according to data
of the National Cancer Institute’s Surveil-
lance, Epidemiology, and End Results Pro-
gram (SEER 2014). DCIS consequently
constitutes around 20% of all breast cancer
diagnoses.
The widespread use of mammography, as
well as implementation of national breast
screening programs (Ernster and Barclay
1997), contributed to the diagnosis of breast
cancer in early stage. According to different
studies, approximately 1 in every 1300 screen-
ing mammography leads to a diagnosis of
DCIS (Ernster et al. 2002).
• Age
DCIS rarely occurs in women younger than
40 years, and its incidence rises between
40 and 70 years, with a plateau after the age
of 70.
• Sex
DCIS is common in women. However,
according to SEER database, DCIS represents
9.4% of all male breast carcinomas (Anderson
and Devesa 2005) with an average age of
62 years. Although all DCIS subtypes could
be present in both genders, in general, papillary
in situ (▶ Intraductal Papillary Carcinoma)
lesions are more common in men (Staerkle
et al. 2006).
Ductal Carcinoma In Situ
• Site
The anatomic location of DCIS is similar to
invasive carcinoma location. The majority
of tumors are found in the upper outer quad-
rant (43.9%), followed by the upper inner
quadrant (9.0%), the central quadrant
(8.5%), the lower outer quadrant (8.1%), and
finally the lower inner quadrant (6.9%)
(Ernster et al. 2000).
In a study by Verkooijen et al. (2002), 35%
of DCIS were present in two different quad-
rants. Multi-quadrant presentation is often
observed, especially in micropapillary DCIS
(Bellamy et al. 1993).
• Treatment
Surgery: over the past 20 years, the surgical
approach of DCIS changed from radical mastec-
tomy with sentinel node (▶ Sentinel Node) to
conservative surgery, without any intervention
on axilla, as recommended by ASCO (Lyman
et al. 2014) and NCCN guidelines (2015)).
Some studies suggest that low-grade lesions can
be treated only with surgical excision excluding
radiotherapy (EORTC Breast Cancer Coopera-
tive Group et al. 2006), while others reported
that being often multicentric, low-grade DCIS
may recur and it may remain radiologically
silent, even if extensive (Tot and Gere 2008).
Mastectomy with immediate breast recon-
struction is used for large/diffuse DCIS, in case
of contralateral prophylactic mastectomy
(Rutter et al. 2015), especially in younger
women, as well as in patients with BRCA
mutations or with positive family history for
ovarian cancer (Elsayegh et al. 2014). The
main feature that guides surgical approach is
the lesion size, measured with mammography
and magnetic resonance (MR). In case of con-
servative approach, the margins should be free
of disease with a minimum recommended dis-
tance of 2 mm (Pilewskie and Morrow 2018).
Very recently three multi-institutional, random-
ized phase III trials are addressed to avoid sur-
gery in case of low-grade DCIS, in favor of an
active surveillance strategy (Elshof et al. 2015;
COMET trial- https://clinicaltrials.gov/ct2/show/
NCT02926911; Francis et al. 2015).
Ductal Carcinoma In Situ
Radiotherapy: conservative surgery is gen-
erally associated with postsurgical radiother-
apy, regardless of DCIS histology.
Randomized trials have proven that RT reduces
local recurrence rates by 50% (McCormick
et al. 2015; EORTC Breast Cancer Cooperative
Group et al. 2006); however, many studies are
now addressed to avoid radiation in low-risk
DCIS. Several trials have been performed
using the multigene assay, Oncotype DX ®
(Genentech, Houston, TX), able to quantify
the 10-year risk of local recurrences, both for
in situ and invasive breast cancer. The results
are reported as a numerical score called “DCIS
Score,” which classifies patients into low-,
intermediate-, and high-risk group. It has
been proposed to avoid radiotherapy in low-
risk categories (Solin et al. 2013).
Hormonal treatment: 75–80% of DCIS
express estrogen receptor (ER). Hormonal treat-
ment (HT) is debated; nevertheless, HT for
patients with ER-positive DCIS has been dem-
onstrated to reduce recurrent events of about
37% in patients with conservative surgery
(Wapnir et al. 2011). The NSABP B-35 trial
demonstrated similar rates of disease-free sur-
vival comparing tamoxifen and aromatase
inhibitors in postmenopausal patients with
DCIS (Margolese et al. 2016).
Anti-HER2 therapy: Although trastuzumab
treatment (Kuerer et al. 2011) or lapatinib
(Decensi et al. 2011) in HER2-positive DCIS
is proposed, so far, the clinical effect of anti-
HER2 blockade is unclear. A prospective, ran-
domized phase III multi-institutional clinical
trial – National Surgical Adjuvant Breast Pro-
ject (NSABP) – treating HER2-positive DCIS
patients with trastuzumab associated with
radiotherapy (Siziopikou et al. 2013) is cur-
rently in progress.
• Outcome
The age at diagnosis has been identified as the
strongest predictor of invasive and in situ local
recurrences. For women under 45 years of age
at diagnosis, the 10-year local recurrence-free
survival and invasive local recurrence-free sur-
vival after breast-conserving surgery and
93
radiation were 73% and 78%, respectively
(Kong et al. 2014). The presence of comedo-
necrosis is closely related to the risk of ipsilat-
eral recurrences following lumpectomy, and a
meta-analysis demonstrated that this risk
ranges from 1.3 to 5.0 (Wapnir et al. 2011;
Wai et al. 2011).
Observational studies reported that about
14–50% of DCIS may progress to invasive D
carcinomas (King et al. 2017; Erbas et al.
2006; Pluchinotta 2018). Many evidences
suggested that the majority of invasive carci-
noma may derive from DCIS disease. Actually,
invasive cancers are generally accompanied by
DCIS, which share similar molecular features.
However, a high number of DCIS was found in
autopsy studies, to emphasize that not all DCIS
will progress to invasive cancer (Pluchinotta
2018).
Macroscopic Features
The majority of DCIS are detected by mammog-
raphy due to microcalcifications; thus, the macro-
scopic appearance may be completely negative.
Sometimes these lesions may form a nodular
thickening or spot gray-yellow lesions with strand
of dense material that may exude from the cut
surface, especially in case of comedo-necrosis.
To better define extension of the lesion, margin
status, and the correlation with radiological fea-
tures (calcifications on mammography and on
intraoperative radiogram), the use of large histo-
logical sections in routine clinical practice is
encouraged. However, not every case of DCIS
calcifies, or calcifications may be partially pre-
sent, and, when measured by mammography, the
real size of the lesion may be underestimated. In
10% of cases, DCIS grows in form of nodular
mass or architectural distortion (Giuseppetti
et al. 2018). At ultrasound, DCIS calcifications
manifest as echogenic foci within the breast tis-
sue, unlike non-calcified DCIS, which may appear
as hypoechoic mass with microlobulated margins.
MR is the most sensitive examination to evaluate
94
the correct size of DCIS, mainly in high-grade
lesions (Greenwood et al. 2013). The most
common morphologic feature of DCIS at MR is
“nonmass” enhancement (60–81% of cases)
(Greenwood et al. 2013). Although many
studies have demonstrated overestimations of the
disease extent by MR (Rominger et al. 2016), this
method principally guides the surgical treatment
approach.
Microscopy
Nuclear Grade
Classification of DCIS should be based primarily
on nuclear grade, as it represents the most
significant predictor of local recurrence at both
univariate and multivariate analyses (Wapnir
et al. 2011).
Depending on the degree of nuclear atypia,
DCIS is generally classified in low-, intermedi-
ate-, and high-grade DCIS. In particular, low
grade is characterized by small, monomorphic,
well-polarized cells, with uniform size and
regular chromatin pattern and rare mitotic
figures (Fig. 1a. H&E). Microcalcifications
are often of psammomatous/granular/powdery
type. DCIS of intermediate nuclear grade
consists of cells similar to those of low grade
but with variability in size, shape and placement,
occasional nucleoli, mitotic figures, and
coarse chromatin (Fig. 1b. H&E). Finally, high-
nuclear-grade DCIS is composed of highly
atypical cells, large in size, with pleomorphic
and poorly polarized irregular nuclei, prominent
nucleoli, numerous mitotic figures, and presence
of necrosis (Fig. 1c. H&E) (Tavassoli and
Devilee 2003).
Histological Growth Patterns
The histological variants are solid, cribriform,
micropapillary, papillary, comedo (Fig. 2. H&E),
apocrine, and mixed (Bellamy et al. 1993). Solid
DCIS is characterized by an orderly proliferation
of crowded neoplastic cells that expand the ducts
(Fig. 2a. H&E). Cribriform DCIS is formed by
well-defined roundish lumens regularly spaced,
lined by uniform polarized cells (Fig. 2b. H&E).
Ductal Carcinoma In Situ
The lumens may contain amorphous material with
apoptotic cells, calcifications (generally with
powdered/granular pattern), and necrosis. Micro-
papillary DCIS is composed of numerous epithe-
lial projections lacking fibrovascular cores
(Fig. 2c. H&E); these cell clusters may detach in
the lumen and flow to the nipple (Castellano et al.
2010). Papillary DCIS (▶ Intraductal Papillary
Carcinoma) is characterized by fibrovascular pap-
illary fronds. In some cases, the papillary over-
growth fills the lumen completely, simulating
solid DCIS, but fibrovascular cores are still iden-
tifiable. WHO classification system categorized
papillary lesions as a separate group, composed
of intraductal (▶ Intraductal Papillary Carci-
noma), encapsulated (▶ Encapsulated Papillary
Carcinoma), and solid papillary carcinoma
(▶ Solid Papillary Carcinoma) (Lakhani et al.
2012). While the intraductal papillary carcinoma
is characterized by the presence of myoepithelial
layer, the other two entities may lack it at the
periphery of the lesion. For this reason, there is
no universal agreement on how to stage papillary
carcinomas; however, it is suggested that both
encapsulated and solid type should be managed
as DCIS form. Comedo DCIS is characterized by
a strongly atypical cell proliferation distending
and enlarging ducts with central necrotic debris
and amorphous calcifications (Fig. 2d. H&E).
These generally appear as crushed-stone-like/
casting-type calcifications, distributed with a lin-
ear or segmental pattern at mammography exam-
ination. The periductal stroma may be dense and
thick and frequently shows a mild inflammatory
reaction. Comedo DCIS usually belongs to high
or intermediate histopathology nuclear grade.
The “DIN” Classification
In 2003 Tavassoli et al. proposed a novel classi-
fication system (Tavassoli and Devilee 2003),
suggesting to replace the term DCIS in favor of
“ductal intraepithelial neoplasia” (DIN), reserv-
ing the term “carcinoma” only for invasive
tumors.
The subgroup of lesions classified as “DIN 1”
encompasses a series of low-grade intraductal
proliferations, such as flat epithelial atypia
(▶ Columnar Cell Lesions) (DIN1a), atypical
Ductal Carcinoma In Situ
Ductal Carcinoma In Situ, Fig. 1 (a) Low-grade DCIS
is characterized by small, monomorphic, well-polarized
cells, with uniform size. (b) Intermediate-grade DCIS con-
sists of cells variable in size, shape, and placement and
ductal hyperplasia (▶ Atypical Ductal Hyperpla-
sia) (ADH) (DIN 1b), and low-grade DCIS
(DIN1c). Molecular studies demonstrated that
these lesions share similar genetic alterations, typ-
ical of low-grade neoplasia (Reis-Filho
et al. 2005).
DIN 2 represents intermediate-nuclear-grade
DCIS, with intermediate level of differentiation
between low- and high-grade lesions. This
latter called DIN 3 is characterized by atypical
95
presents occasional mitotic figures and coarse chromatin.
(c) High-grade DCIS is composed of highly atypical cells,
large in size, with pleomorphic and poorly polarized irreg-
ular nuclei and presence of necrosis (H&E, 20x)
and pleomorphic cells and shows genetic alter-
ations of high-grade neoplasia (Reis-Filho
et al. 2005).
DIN terminology did not reach widespread
consensus. Thus, the WHO in 2012 (Lakhani
et al. 2012) abandoned the term DIN in favor of
DCIS classifications based on the nuclear grade.
Some authors still support the use of “DIN”
nomenclature, in order to reduce negative psycho-
logical impact on patients and confusion in
96
Ductal Carcinoma In Situ, Fig. 2 Different histologic
subtypes of DCIS. (a) Solid DCIS is characterized by a
proliferation of crowded neoplastic cells, which fills the
lumen. (b) Cribriform DCIS is represented by neoplastic
lumens regularly spaced. The lumens contain amorphous
material with calcifications. (c) Micropapillary DCIS is
medical management of in situ lesions
(Galimberti et al. 2013).
Immunophenotype
Myoepithelial cells around DCIS may be
highlighted by antibodies which stain either
their cytoplasm (smooth muscle actin, calponin,
Ductal Carcinoma In Situ
composed of numerous epithelial projections into the
lumen. Clusters of neoplastic cells without fibrovascular
cores are floating in the lumen. (d) Comedo DCIS is
characterized by enlarged ducts containing necrotic debris.
The periductal stroma shows mild inflammatory reaction
(H&E, 10x)
CD10, cytokeratin 5/6) or their nucleus (p63 and
p40) (Fig. 3. p63 immunostaining). In routine
practice, the use of both nuclear and cytoplasmic
antibodies is recommended. ERs and progester-
one receptors (PR) are included as part of the
workup of DCIS by the National Comprehensive
Cancer Network guidelines. ER is found positive
in 75–80% of DCIS lesions. Its expression is
generally related to low-intermediate-nuclear-
Ductal Carcinoma In Situ 97

grade DCIS cases (Fig. 4. ER immunostaining in Molecular Features

low-grade DCIS). Routine testing of PR is still
debated (Lakhani et al. 2012). HER2 is over- Several studies have demonstrated that nuclear
expressed in 50 to 60% of DCIS with high grade is related not only to prognosis but also to
nuclear grade, comedo-necrosis, and presence distinct genetic alterations and different evolu-
of stromal microinvasion (Fig. 5. HER2 tionary pathways (Bombonati and Sgroi 2011).
immunostaining). HER2 may play a pivotal Low-grade DCIS is generally ER/PR positive
role in the progression to invasive carcinoma and HER2 negative, and it is commonly associ-
(Curigliano et al. 2015), and its expression is ated with concomitant chromosomal alterations, D
frequently related to recurrence after surgical such as deletion of 16q and gains of 1q and 16p.
excision, mainly in patients without radiation On the other hand, high-grade DCIS, frequently
therapy (Holmes et al. 2011). ER/PR negative and HER2 positive, is
Similar to invasive breast cancer, the expres-
sion of ER, PR, HER2, and Ki67 may classify
DCIS in “surrogate molecular subtypes,” Luminal
A and B, HER2, and triple negative. Nevertheless,
the prognostic impact of this classification is to
be clarified.
Additional markers such as TP53, Bcl2, and
androgen receptor (AR) have been studied as
promising prognostic markers. Specifically, it
has been demonstrated that TP53 commonly
occurs in high-grade, HER 2-positive DCIS rather
than in ER-/PR-positive low-grade lesions
(Vincent-Salomon et al. 2008). On the other
hand, Bcl2 is highly expressed in low-grade
DCIS (Mustonen et al. 1997).
Limited information is available on AR role
Ductal Carcinoma In Situ, Fig. 4 ER uniform immuno-
in DCIS. Some studies proposed its use in associ- reactivity in 100% of neoplastic cell nuclei in low-grade
ation with ER (AR/ER ratio) as significant prog- micropapillary DCIS (10x)
nostic marker of recurrent disease (Ravaioli
et al. 2017).

Ductal Carcinoma In Situ, Fig. 3 A discontinuous

myoepithelial layer is shown by p63 nuclear Ductal Carcinoma In Situ, Fig. 5 HER2 overexpression
immunostaining around DCIS (20x) in high-grade comedo-DCIS (20x)
98
characterized by complex karyotypes (Reis-
Filho et al. 2005; Lopez-Garcia et al. 2010),
including gain in 1q+, 5p+, 8q+, and 17q+; loss
in 8p , 11q , 13 , and 14q ; and focal ampli-
fications on 6q22, 8q22, 11q13, 17q12,
17q22–24, and 20q13 (Reis-Filho and Lakhani
2003; Shackney and Silverman 2003). As a result
of such molecular profile, it is hypothesized that
DCIS may progress along two distinct pathways
of low or high grade. The low-grade arm is char-
acterized by pathways related to ER activation
and well-differentiated invasive carcinoma (such
as tubular carcinoma (▶ Tubular Carcinoma)).
The majority of high-grade DCIS lesions show
identical genomic profile of invasive cancers
(Abba et al. 2015). It has been shown that TP53
(Kim et al. 2015), PTEN (Yates et al. 2015)
mutations, as well as amplifications of chromo-
some 20, 11, and 17 (Aubele et al. 2000) may
occur in the transition from normal epithelium to
in situ carcinoma cells (Casasent et al. 2017).
Concomitant factors such as stromal environ-
ment, cell-mediated immune mechanisms, vas-
cular spaces, and myoepithelial cells contribute
to progression of DCIS to invasive breast cancer
(Mardekian et al. 2016; Adriance et al. 2005). In
particular, tumor suppressor functions of
myoepithelial layer are well established, with
the maintenance of integrity of basal membrane
and epithelial cell polarity (Polyak and Hu 2005).
A study conducted by Allinen et al. (2004), com-
paring the microenvironment of normal and can-
cerous breast tissue, discovered that the DCIS
myoepithelial layer displayed the most abundant
gene expression changes of all the microenviron-
mental cell types. Actually, myoepithelium sur-
rounding DCIS shows some morphological
differences compared to normal breast tissue,
losing the power to polarize luminal epithelial
cells and showing a discontinuity in the expres-
sion of myoepithelial markers (Rakha et al.
2017). Moreover, it has been shown that genes
that are specific for normal myoepithelial cells,
such as CTK14, CTK17, and EGFR, are absent
or downregulated in DCIS myoepithelial cells
(Polyak and Hu 2005).
Besides myoepithelium, basal membrane rep-
resents a constitutive barrier to invasion,
Ductal Carcinoma In Situ
composed of collagen type IV, laminin 1, and
some proteoglycans. The overexpression of
some markers, such as matrix metalloproteinase
2 (MMP2), involved in extracellular matrix
remodeling, may provoke basal membrane degra-
dation (Abba et al. 2004), allowing cancer stromal
invasion.
Recently, a number of studies have focused
on analysis of microRNA (miRNA), a class of
small RNA molecules that control mRNA expres-
sion and regulate stem cell division, cell
growth, apoptosis, and carcinogenesis. In com-
parison to normal breast tissue, in DCIS,
some miRNAs are under- or overexpressed
(Hannafon et al. 2011). miRNA deregulations
seem to occur during the transition from
normal to DCIS epithelium, such as the loss of
miR-125b and miR-132 and the gain of miR-182
and miR-183 (Hannafon et al. 2011). A specific
miRNA signature was described as differently
expressed in invasive and DCIS lesions (Volinia
et al. 2012).
Finally, DNA methylation seems to play a piv-
otal role in early breast carcinogenesis with an
increase of methylated genes from normal breast
to DCIS (Mardekian et al. 2016).
Differential Diagnosis
The differential diagnosis of DCIS may include
(i) epitheliosis/usual ductal hyperplasia (UDH),
(ii) atypical ductal hyperplasia (ADH), (iii) lobu-
lar carcinoma in situ (LCIS), and (iv) minimally
invasive carcinoma:
1. The solid growth pattern of DCIS can be
misinterpreted as florid epitheliosis/UDH
lesions (▶ Usual Ductal Hyperplasia (UDH)).
Cell proliferation of epitheliosis is heteroge-
neous; cells show different shapes, sizes, and
streaming arrangements and irregular periph-
eral fenestrations. Cells forming the bridges in
low grade DCIS are more clonal and arranged
haphazardly or transversely to the long axis
and do not manifest streaming pattern. More-
over, an immunohistochemical mosaicism of
CK5/14+ and CK5/14- cells is characteristic
Ductal Carcinoma In Situ
Ductal Carcinoma In Situ, Fig. 6 Microinvasive carci-
noma. Cytokeratin AE1-AE3 immunoreaction highlights
single cells or clusters infiltrating the mildly inflamed
stroma around high-grade DCIS (20x)
for epitheliosis/UDH, while low grade DCIS is
composed of clonal cells, uniformly negative
for basal CK5/14 and positive for ER (Böcker
2006).
2. The differential diagnosis between ADH
(▶ Atypical Ductal Hyperplasia) and DCIS
can be difficult, especially with well-
differentiated, non-comedo DCIS. Intraductal
proliferation of monomorphic epithelial
cells with histologic and cytologic features of
ADH is identical to those seen in low-grade
DCIS (Page and Rogers 1992). Actually, ADH
and low-grade DCIS belong to the same
morphologic range and beside that correlate
as well on molecular level (Bombonati and
Sgroi 2011). To diagnose ADH, cell prolifera-
tion should be confined to one or a few separate
lobules, occupying less than two duct spaces
or < 2 mm in maximum extent. For this rea-
son, core biopsy samples containing ADH
should be diagnosed as “intraductal atypical
proliferation,” reserving the original term
only for surgical specimens. This extent/size
criterion does not apply to intermediate- and
high-grade DCIS lesions (Böcker 2006).
3. Differential diagnosis of LCIS (▶ Lobular In
Situ Neoplasia) from solid DCIS with mono-
morphic round and hyperchromatic nuclei is
important and difficult. Mixed lesions showing
overlap of lobular/ductal proliferation may be
99
observed. Poor cellular cohesion and the pres-
ence of intracytoplasmic lumina favor LCIS,
whereas cohesive growth, lack of cytoplasmic
lumina, polarization of cells at the periphery of
the involved spaces, and microacinar forma-
tions favor diagnosis of low-grade DCIS
(Böcker 2006). E-cadherin is typically absent
in ALH/LCIS and expressed in DCIS. In addi-
tion, the expression of high-molecular-weight D
cytokeratin (CK34bE12) is usually seen in
LCIS but not in DCIS (Bratthauer et al. 2002).
4. Microinvasive carcinoma (▶ Microinvasive
Carcinoma of the Breast). Foci of invasive
carcinomas 1 mm or less can be present around
DCIS, mainly in inflamed periductal stroma.
Cytokeratins may stain single neoplastic cells
or small cell clusters invading the periductal
stroma (Fig. 6. Microinvasive carcinoma.
AE1-AE3 immunostaining). Additionally, a
careful study of myoepithelial layer is useful
in the diagnosis of microinvasion. An
uncommon invasive cribriform carcinoma
(▶ Invasive Cribriform Carcinoma) can be
mistaken for cribriform DCIS (Lakhani
et al. 2012).
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E

Encapsulated Papillary Clinical Features

Carcinoma
• Incidence
Eliano Cascardi1,2 and Anna Sapino2,3 EPC is an extremely uncommon type of carci-
1
Department of Emergency and Organ noma and it accounts for less than 2% of all
Transplantation, Unit of Pathology, University of breast cancers (Li et al. 2018).
Bari, Bari, Italy • Age
2
Unit of Pathology, Candiolo Cancer Institute It generally affects postmenopausal women;
FPO-IRCCS, Candiolo, Italy the mean age at diagnosis is around
3
Department of Medical Sciences, University of 65–70 years (Mogal et al. 2016).
Turin, Turin, Italy • Sex
This malignancy is frequently diagnosed in
female patients, but EPCs have also been
Synonyms described in men.
• Site
Encysted papillary carcinoma; Intracystic EPC is usually unifocal. It may arise in the
papillary carcinoma larger and more centrally placed ducts, often
located in the subareolar area and rarely in
external quadrants of the breast (Solorzano
Definition et al. 2002).
• Clinical Presentation
Encapsulated papillary carcinoma (EPC) was It can be asymptomatic or manifests as a pal-
described for the first time in 1969 as a papillary pable and mobile breast mass or with a bloody
entity arising from the ductal–lobular system, nipple discharge. Radiologic manifestations of
developing in a cyst, and surrounded by a fibrous EPC are not specific, being suggestive of either
capsule. benign tumors (▶ Fibroadenoma) or medullary
The WHO Working Group, in the fourth edi- carcinoma (▶ Invasive Carcinoma with Med-
tion, considered EPC as a malignant non-invasive ullary Features) or ▶ Invasive Mucinous Car-
neoplastic ductal proliferation with a papillary cinoma (Costa et al. 1998). Ultrasound is more
architecture circumscribed by a fibrous capsule specific, depicting the presence of the
(Lakhani et al. 2012). However, cases of EPC intracystic growth with a heterogeneous
may show invasion. echostructure.

© Springer Nature Switzerland AG 2020

A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
104 Encapsulated Papillary Carcinoma

• Treatment
Because of its low incidence, no clearly
defined guidelines have been established for
EPC treatment. Breast conserving surgery is
the standard treatment for patients with the
pure form. In addition to surgical excision,
several studies report on the use of adjuvant
radiation, chemotherapy, or endocrine therapy
in the management of EPC; however, their role
remains undefined (Solorzano et al. 2002;
Fayanju et al. 2007).
Due to the low incidence of axillary lymph
node metastases, sentinel node (▶ Sentinel Encapsulated Papillary Carcinoma, Fig. 1 Low power
Node) evaluation is suggested only in EPC magnification of encapsulated papillary carcinoma shows a
associated to invasive component (Solorzano well-defined lesion surrounded by a fibrous capsule. The
proliferating epithelium has a papillary and cribriform pat-
et al. 2002). tern (H&E 4)
• Outcome
EPC presents a favorable prognosis, even
when associated with invasion (Rakha et al.
2011), showing low local recurrence, rare dis-
tant metastases, and an excellent survival (91%
disease-free survival rate at 10-year follow-up)
(Lefkowitz et al. 1994).

Macroscopy

On gross examination, EPC appears as a nodular

and friable lesion, usually well-delimited or
within a large cystic cavity containing bloody
material. The size may be variable, with a reported
Encapsulated Papillary Carcinoma, Fig. 2 Encapsu-
median tumor size of 2.25 cm (Zhang et al. 2018). lated papillary carcinoma with invasion. Foci of invading
cancer cells are beyond the fibrous capsule (H&E  4)

Microscopy eosinophilic cytoplasm, sometimes with apocrine

Histopathological examination of EPC shows a
well-defined lesion surrounded by a fibrous cap-
sule (Fig. 1). EPC presents papillary, cribriform,
or solid pattern, with fibrovascular core covered
by a single or multiple layers of cancer cells (Hill
and Yeh 2005). Myoepithelial cells are not pre-
sent, neither at the periphery of the lesion nor
within the fibrovascular cores.
Cancer cells are often monomorphic and
monotonous and show minimal atypia (slight
nuclear pleomorphism and low mitotic index).
Commonly, the malignant cells are cuboidal with
differentiation (Kővári et al. 2018) and usually
show hyperchromatic nuclei with low or interme-
diate nuclear grade (Costa et al. 1998). Rare cases
of high nuclear grade EPC have been described.
EPC presenting high nuclear grade, spindle cells
with malignant features and necrosis or associated
with invasive growth seems to be more aggressive
(Costa et al. 1998). True invasion in EPC is a rare
event and corresponds to the presence of infiltrat-
ing cancer nests outside the fibrous capsule
(Fig. 2). EPC may be accompanied by peripheral
foci of ductal carcinoma in situ (DCIS) (▶ Ductal
Carcinoma In Situ), usually with similar nuclear
Encapsulated Papillary Carcinoma
Encapsulated Papillary Carcinoma, Fig. 3 Immuno-
histochemical staining for basal keratins (CK14) shows
absence of myoepithelial cells both at the periphery and
within the intracystic papillary structures (IHC  4)
grade and histological features (papillary or solid
DCIS).
Immunophenotype
Due to the absence of the myoepithelial layer
within the papillae and around the tumor,
calponin, p63, basal keratins (CK5 and CK14),
and CD10 immunostaining are negative (Fig. 3).
However, a moderate or intense immunohisto-
chemical staining for type IV collagen is reported
(Esposito et al. 2009). The majority of EPC cases
are classified as Luminal A and B types, being
positive for estrogen and progesterone receptors
and negative for HER2. Isolated triple-negative
EPC cases have been reported (Zhang et al. 2018).
EPC is a low-proliferating tumor: the Ki67 prolif-
eration index is generally below 20%. GCDFP-15
may be expressed in EPC showing apocrine dif-
ferentiation (Kővári et al. 2018).
Molecular Features
The genomic profile of EPC shows low number of
genomic aberrations, loss of 16q, and PIK3CA
mutations. These genetic alterations have been
correlated with good clinical outcome of EPC in
analogy to other ER-positive breast tumors
(Duprez et al. 2012). In a recent study of special
105
type breast carcinomas, it has been shown that all
EPCs had low recurrence score using the
Oncotype DX test (Turahvili et al. 2017).
Differential Diagnosis
To differentiate EPC from other papillary
breast lesions is difficult on preoperative core needle
biopsies and surgical excision is necessary for accu-
E
rate pathological diagnosis (Valdes et al. 2006).
Intraductal and sclerosing papillomas
(▶ Intraductal Papilloma) at difference from
EPC show a layer of myoepithelial cells along
the fibrovascular cores of the papillae. In general,
papillary DCIS (▶ Intraductal Papillary Carci-
noma) affects multiple ducts and myoepithelial
cells surround their periphery, while EPC presents
negative staining for myoepithelial markers
(Collins et al. 2006).
True invasion has to be differentiated from
displaced fragments of tumor tissue outside the
fibrous capsule that may follow preoperative fine
needle aspiration or core biopsy sampling. Reac-
tive changes in and around the fibrous capsule
together with hemosiderin laden macrophages
favor pseudoinvasion.
References and Further Reading
Collins, L. C., Carlo, V. P., Hwang, H., Barry, T. S., Gown,
A. M., & Schnitt, S. J. (2006). Intracystic papillary
carcinomas of the breast: A reevaluation using a panel
of myoepithelial cell markers. The American Journal of
Surgical Pathology, 30, 1002–1007.
Costa, I., Fonseca, D., Lopes, P., Bento, M. J., & Lopes,
C. (1998). Intracystic (encysted) papillary carcinoma of
the breast: A clinical, pathological, and immunohisto-
chemical study. Human Pathology, 29, 1097–1104.
Duprez, R., Wilkerson, P. M., Lacroix-Triki, M., Lambros,
M. B., MacKay, A., Hern, R. A., Gauthier, A., Pawar,
V., Colombo, P. E., Daley, F., Natrajan, R., Ward, E.,
MacGrogan, G., Arbion, F., Michenet, P., Weigelt, B.,
Vincent-Salomon, A., & Reis-Filho, J. S. (2012).
Immunophenotypic and genomic characterization of
papillary carcinomas of the breast. The Journal of
Pathology, 226, 427–441.
Esposito, N. N., Dabbs, D. J., & Bhargava, R. (2009). Are
encapsulated papillary carcinomas of the breast in situ or
invasive? A basement membrane study of 27 cases.
American Journal of Clinical Pathology, 131, 228–242.
106
Fayanju, O. M., Ritter, J., Gillanders, W. E., Eberlein, T. J.,
Dietz, J. R., Aft, R., & Margenthaler, J. A. (2007).
Therapeutic management of intracystic papillary carci-
noma of the breast: The roles of radiation and endocrine
therapy. The American Journal of Surgery, 194,
497–500.
Hill, C. B., & Yeh, I. T. (2005). Myoepithelial cell staining
patterns of papillary breast lesions: From intraductal
papillomas to invasive papillary carcinomas. American
Journal of Clinical Pathology, 123, 36–44.
Kővári, B., Ormándi, K., Simonka, Z., Vörös, A., &
Cserni, G. (2018). Apocrine encapsulated papillary
carcinoma of the breast: The first reported case with
an infiltrative component. Journal of Breast Cancer,
21, 227–230.
Lakhani, S.R., Ellis, I.O., Schnitt, S.J., Tan, P.H., & van de
Vijver, M.J.. (2012). WHO classification of tumors of
the breast (pp. 106–107). World Health Organization.
ISBN-10: 9283224337. Lyon, IARC press.
Lefkowitz, M., Lefkowitz, W., & Wargotz, E. S. (1994).
Intraductal (intracystic) papillary carcinoma of the
breast and its variants: A clinicopathological study of
77 cases. Human Pathology, 25, 802–809.
Li, X., Xu, Y., Ye, H., Qin, S., Hou, F., & Liu, W. (2018).
Encapsulated papillary carcinoma of the breast:
A clinicopathological study of 49 cases. Current Prob-
lems in Cancer, 42, 291–301.
Mogal, H., Brown, D. R., Isom, S., Griffith, K., & Howard-
McNatt, M. (2016). Intracystic papillary carcinoma of
Encapsulated Papillary Carcinoma
the breast: A SEER database analysis of implications
for therapy. The Breast, 27, 87–92.
Rakha, E. A., Gandhi, N., Climent, F., van Deurzen, C. H.,
Haider, S. A., Dunk, L., Lee, A. H., Macmillan, D., &
Ellis, I. O. (2011). Encapsulated papillary carcinoma of
the breast: An invasive tumor with excellent prognosis.
The American Journal of Surgical Pathology, 35,
1093–1103.
Solorzano, C. C., Middleton, L. P., Hunt, K. K., Mirza, N.,
Meric, F., Kuerer, H. M., Ross, M. I., Ames, F. C., Feig,
B. W., Pollock, R. E., Singletary, S. E., & Babiera,
G. (2002). Treatment and outcome of patients with
intracystic papillary carcinoma of the breast. The Amer-
ican Journal of Surgery, 184, 364–368.
Turahvili, G., Brogi, E., Morrow, M., Hudis, C., Dickler,
M., Norton, L., & Wen, H. Y. (2017). The 21-gene
recurrence score in special histologic subtypes of breast
cancer with favorable prognosis. Breast Cancer
Research and Treatement, 165(1), 65–76.
Valdes, E. K., Tartter, P. I., Genelus-Dominique, E.,
Guilbaud, D. A., Rosenbaum-Smith, S., & Estabrook,
A. (2006). Significance of papillary lesions at percuta-
neous breast biopsy. Annals of Surgical Oncology, 13,
480–482.
Zhang, J., Zhang, T., Wu, N., Zhao, X., Wang, Q., Jiang, Y.,
Gao, M., & Gu, L. (2018). Intracystic papillary carci-
noma of the breast: Experience of a major Chinese
cancer center. Pathology-Research and Practice, 214,
579–585.
F

Fibroadenoma
Elena Maldi1 and Anna Sapino1,2
1
Unit of Pathology, Candiolo Cancer Institute
FPO-IRCCS, Candiolo, Italy
2
Department of Medical Sciences, University of
Turin, Turin, Italy
Synonyms
Benign fibroepithelial lesion
Definition
Fibroadenoma (FA) is a common benign neo-
plasm of the breast. It is classically defined as a
biphasic lesion, meaning a proliferation of both
the epithelial and stromal component.
Clinical Features
• Age & Sex
FA has been described at any age, but it
occurs mainly in young women of
reproductive age. Juvenile FA occurs at ages
between 10 and 18 years (Wechselberger
et al. 2002).
• Site
It may be multiple and bilateral, with no site
preference.
© Springer Nature Switzerland AG 2020
A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
• Imaging
Mammography can detect FA if a calcific com-
ponent is present, otherwise it cannot distin-
guish FAs and cysts. FA is a round or ovoid
hypoechoic lesion at ultrasound evaluation.
• Treatment & Outcome
FAs are painless lesions with slow growth thus
they do not require any treatment, but imaging
follow up. About 10% to 40% of FAs resolve
spontaneously or if completely excised they do
not recur (Song et al. 2014). Cases of juvenile FA
(see below) can grow rapidly and occupy most of
the breast resulting in esthetic problems due to
breast asymmetry or hypertrophy. Complete
lumpectomy is recommended because they may
recur in 33% at 5 years (Song et al. 2014).
Complex FAs (see below) are associated
with increased risk (1.89 times) of breast can-
cer compared to simple FAs if associated with
proliferative diseases and when there is a rele-
vant family history of breast cancer (Dupont
et al. 1994). In general, FA-carcinoma associ-
ation varies between 0.1% and 0.3% in the
screened population (Dupont et al. 1994).
Macroscopy
FA is a firm, fibro-elastic, round–oval nodule with
smooth or rarely nodular margins. The cut surface
shows a relatively homogenous whitish tissue,
with a delicate lobulated pattern, and in many
cases, slits are also present.
108
Microscopy
FA is a biphasic hyperplastic lesion that arises in
the terminal duct lobular unit (TDLU) where spe-
cialized intralobular mammary stroma proliferates
causing distortion of the glandular component
(Kuijper et al. 2001).
Two different growth patterns (with no clinical
significance) are reported:
– Pericanalicular: circumferential proliferation
of stromal cells around ducts. Intralobular
stroma may be part of the stromal growth
(Fig. 1 H&E).
– Intracanalicular: proliferation of stromal cells
causing compression of the ducts (Fig. 2
H&E).
Mitotic figures in either component are unusual
but may be present in young or pregnant women.
Stromal cellularity of FA may be prominent and
homogeneous. In elderly woman, FA may become
sclerotic and dystrophic calcifications may occur.
The epithelial component of FA may show hyper-
plastic features of varying degrees.
Variants:
– Myxoid FA shows prominent myxoid
changes in the stromal component and may
be associated to Carney syndrome. On frozen
sections or on FNA myxoid FA may be
Fibroadenoma, Fig. 1 Pericanalicular fibroadenoma:
the stroma is sclerotic and the epithelial structures are
partly compressed. (H&E)
Fibroadenoma
misinterpreted as mucinous carcinoma
(▶ Invasive Mucinous Carcinoma).
– Cellular FA displays prominent cellularity of
stromal component. Differential diagnosis of
intracanalicular cellular FA with benign
phyllodes tumor (▶ Phyllodes Tumor) is chal-
lenging (Fig. 3 H&E).
– Complex FA shows at least one of the
following features: cystic component
>3 mm, epithelial calcifications, sclerosing
adenosis (▶ Sclerosing Adenosis), and
(papillary) apocrine hyperplasia (Page and
Anderson 1987; Dupont et al. 1994).
– Juvenile FA or giant type FA is a rare variant
characterized by rapid growth; they occur
Fibroadenoma, Fig. 2 Intracanalicular fibroadenoma:
myxoid stroma compresses and distorts the epithelial com-
ponent. (H&E)
Fibroadenoma, Fig. 3 In this case of intracanalicular
fibroadenoma the stroma is cellular, and occasional leaf-
like protrusions are present, simulating a benign phyllodes
tumor. (H&E)
Fibroadenoma
typically in adolescence. They show high
stromal cellularity and pericanalicular
growth pattern with usual hyperplasia (Song
et al. 2014; Calcaterra et al. 2009). Apical
snouts and gynecomastia-like micropapillary
projections and rare mitoses are features
of the luminal epithelial layer (Fig. 4 H&E).
Atypia or malignant proliferations, either duc-
tal or lobular, are found as incidental finding after
FA excision. Atypia present only in the context of
the FA, sparing the surrounding normal tissue, is
not considered at high risk of developing breast
cancer, if FA is removed. Invasive or in situ can-
cers are very rare in FA. Invasive carcinoma may
arise within the FA or more frequently invasion is
the result of an extrinsic infiltration (Hoda
et al. 2014).
Immunohistochemical Features
Estrogen and progesterone receptors positivity is
confined to the epithelium. CD34 may be variably
positive in the stroma.
Molecular Features
No specific molecular feature has been described
in FA. Cytogenetic aberrations, in particular in the
12q13–15 region have been reported, but no spe-
cific mutations have been found to drive FA
Fibroadenoma, Fig. 4 Juvenile fibroadenoma: an epi-
thelial structure within a juvenile FA shows signs of hyper-
plasia and apical snouts. (H&E)
109
development (Loke et al. 2018). A recent study
has shown that MED12 mutations are common
particularly among intracanalicular FAs
(Volckmar et al. 2017).
Differential Diagnosis
The main differential diagnosis is between
intracanalicular FA and phyllodes tumor
(PT) (▶ Phyllodes Tumor). PT may be suspected
when rapid growth or skin ulceration are reported, F
otherwise FA and PT are clinically indistinguish-
able. At ultrasound examination, large PT may be
more heterogeneous because of secretion within
the lumen of ducts. The stroma in FA is typically
uniform and less cellular than in PT, with no atypia
or overgrowth. The presence of areas, at 10x fields,
composed only of stroma favor the diagnosis of PT
and accumulation of histiocytes within the lumen
of distorted epithelial structures is a feature mainly
observed in PT. Mitotic count may help distinguish
between FA and PT, being virtually absent in
FA. Differential diagnosis between FA and PT is
particularly difficult in core biopsies (Hoda et al.
2014; Yasir et al. 2014), in this case the lesion
should be better classified as “fibroepithelial
lesion” and surgery is suggested.
References and Further Reading
Calcaterra, V., Coscia, D. R., Sgarell, A., Burroni, B.,
Podetta, M., Andorno, A., Ferrari, A., & Larizza, D.
(2009). Recurrence of giant juvenile breast
fibroadenoma in a girl with Turner’s syndrome.
Journal of Pediatric Endocrinology and Metabolism,
22, 281–283.
Dupont, W. D., Page, D. L., Parl, F. F., Vnencak-
Jones, C. L., Plummer, W. D., Jr., Rados, M. S., &
Schuyler, P. A. (1994). Long term risk of bresat cancer
in woman with fibroadenoma. New England Journal of
Medicine, 331, 10–15.
Hoda, S. A., Brogi, E., Koerner, F. C., & Rosen, P. P.
(2014). Rosen’s breast pathology (pp. 213–232).
Philadelphia: Lippincott Williams & Wilkins.
Kuijper, A., Mommers, E. C. M., van der Wall, E., &
van Diest, P. J. (2001). Histopathology of fibroadenoma
of the breast. American Journal of Clinical Pathology,
115, 736–742.
Loke, B. N., Nasir, N. D., Thike, A. A., Lee, J. Y. H.,
Lee, C. S., Teh, B. T., & Tan, P. H. (2018).
110
Genetics and genomics of breast fibroadenomas.
Journal of Clinical Pathology, 71, 381–387.
Page, D. L., & Anderson, T. J. (1987). Diagnostic
histopathology of the breast (p. 362). Edinburgh:
Churchill Livingstone.
Song, B. S., Kim, E. K., Seol, H., et al. (2014). Giant
juvenile fibroadenoma of the breast: A case report and
brief literature review. Annals of Pediatric
Endocrinology & Metabolism, 19, 45–48.
Volckmar, A. L., Leichsenring, J., Flechtenmacher, C., et al.
(2017). Tubular, lactating, and ductal adenomas are
devoid of MED12 Exon2 mutations, and ductal adenomas
show recurrent mutations in GNAS and the PI3K–AKT
pathway. Genes, Chromosomes & Cancer, 56, 11–17.
Wechselberger, G., Schoeller, T., & Piza-Katzer, H. (2002).
Juvenile fibroadenoma of the breast. Surgery,
132, 106–107.
Yasir, S., Gamez, R., Jenkins, S., Visscher, D. W., &
Nassar, A. (2014). Significant histological features dif-
ferentiating cellular fibroadenoma from phyllodes
tumor on core needle biopsies. American Journal of
Clinical Pathology, 142, 362–369.
Fibrocystic Breast Changes
Isabella Castellano1 and Jasna Metovic2
1
Department of Medical Sciences, University of
Turin, Turin, Italy
2
Department of Oncology, University of Turin,
Turin, Italy
Synonyms
Fibrocystic condition; Fibrocystic disease; Fibro-
cystic mastopathy; Mammary dysplasia
Definition
The term “fibrocystic changes” (FCs) covers a
wide variety of clinical and pathological condi-
tions from painful breast to solid lump, multiple
cysts, or diffuse nodularity. These abnormalities
are noncancerous disorders and do not represent a
specific disease but rather a sign of response of the
breast tissue to hormone levels in different phases
of women life. Since FCs are the most frequent
breast abnormalities, the previous definition
referred as “fibrocystic breast disease” was aban-
doned in favor of “fibrocystic breast changes,” as
Fibrocystic Breast Changes
stated in a consensus meeting in New York in
1985 (Hutter et al. 1986). In addition, for some
authors this entity may be simply an “aberration of
normal development and involution of breast tis-
sue,” in which the diagnostic definition of FCs is
more quantitative than qualitative (Tot et al.
2014). However, it is necessary to underline that
the term FCs is used occasionally in a redundant
way, including also other benign breast entities
such as fibroadenoma (▶ Fibroadenoma), ductal
hyperplasia (▶ Usual Ductal Hyperplasia (UDH)),
papilloma (▶ Intraductal Papilloma), and scleros-
ing adenosis (▶ Sclerosing Adenosis).
Clinical Features
• Incidence
FCs represent the most common breast modifica-
tion. Their incidence is so high that they are
considered as a paraphysiological condition by
some authors (Tot et al. 2014). From 58% to 61%
of breast tissue examined at autopsy show micro-
scopic evidence of FCs (Bartow et al. 1982).
• Age
FCs are rarely encountered in women younger
than 21 years. Their incidence rises during the
second decade of life, with a peak in the fourth
and fifth decade during premenopause period.
Family cancer history is frequently reported
positive (Kabat et al. 2010; Shaaban
et al. 2002).
• Sex
FCs are typical of female breast, because they
classically arise in the terminal ductal lobular
unit (TDLU); thus they are only occasionally
seen in male breast tissue.
• Site
FCs tend to be bilateral and symmetrical. They
are mainly located at the upper outer quadrants,
where glandular tissue is more abundant.
Occasionally, they may produce a clinically
palpable nodule.
• Treatment
FCs mainly occur due to relative hormone
imbalance, in particular, hyperestrogenism.
This imbalance may cause gradual dilatation
of the ducts with an overgrowth of stromal
tissue and blood vessel dilatation with fluid
Fibrocystic Breast Changes
retention, resulting in swelling, edema, and
sometimes pain in the breast. Symptoms
related to FCs are generally associated with
menstrual cycles, and they may subside with
menopause. Although the relationship
between hormones and development of FCs
is clear, hormonal treatment with progestins
and tamoxifen is prescribed only for patients
with severe and prolonged pain (Faiz and
Fentiman 2000). The synthetic steroid most
commonly prescribed is Danazol, which has
high affinity for androgen receptor (AR),
moderate affinity for progesterone receptor
(PR), and poor affinity for estrogen receptor
(ER) (Mousavi et al. 2010). Its efficacy may
be explained by the presence of AR in the
apocrine epithelium that normally lines cysts
of FCs. A wide variety of non-
pharmacological interventions has been pro-
posed, such as quitting smoking and dietary
changes. In particular, lowering the intake of
tea, coffee, chocolate, and fat may cause
reduction of methylxanthines that are impli-
cated in the development of cystic formation
(Smith et al. 2004). In more painful cases,
therapeutic efficacy of vitamin E on
mastalgia, with minimal or absent side
effects, has been described (Pruthi et al.
2010). Surgical removal of the lesion is not
recommended.
• Outcome
Page et al. (1978) classified FCs into
(i) non-proliferative FCs, (ii) proliferative
FCs without atypia, and (iii) proliferative
FCs with atypia. In this chapter only the first
group will be described, because the second
includes papilloma, radial scar, or sclerosing
adenosis, while the third encompasses atypi-
cal ductal and lobular hyperplasia. Most of
the studies report that women with FCs are
not at greater risk for subsequent carcinoma
than women in the general population (Page
et al. 1978; Dupont and Page 1985) in the
absence of positive family history, while in
other studies, the relative risk is 1.6 (Wang
et al. 2004) with an increase to 1.95 in women
50 years of age and older. In one of the largest
cohorts of 9087 women affected by non-
proliferative FCs, with a median follow-up
111
of 15 years, the relative risk to develop a
cancer was of 1.27 (Hartmann et al. 2005).
On the other hand, this risk may increase to
1.62 in women with a strong family history of
breast cancer (Hartmann et al. 2005). More
recently, a study on a screening population, in
which predominated postmenopausal
women, demonstrated a higher (OR = 2.23)
relative risk to develop cancer from non-
proliferative benign breast disease (Castells
et al. 2015). The current view is that FCs per
se have no impact on cancer development. F
However, the risk of malignant differentiation
may vary depending on age, family history,
and/or the association with other lesions, such
as ductal atypical hyperplasia (▶ Atypical
Ductal Hyperplasia), papillomas
(▶ Intraductal Papilloma), radial scars
(▶ Radial Scar), etc.
Macroscopy
FCs may be palpable, generally in the form of a
nodule or plaque. Radiologically, FCs can mimic
other pathological conditions forming nodular
thickening, microcalcifications, or cystic lesions.
Ultrasound examination is the most accurate
method to detect cystic lesions, which appear
commonly as well-defined anechoic nodules.
Low-level echoes may be seen in cysts
containing inflammatory reactive tissue, blood
clots, and dense protein. FCs at magnetic reso-
nance (MR) appear as non-mass enhancement,
mainly due to apocrine cysts, and share the same
features with ductal carcinoma in situ (▶ Ductal
Carcinoma In Situ) leading sometimes to unnec-
essary biopsy (Milosevic et al. 2017).
Dense white stromal tissue with a number of
blue-greenish cysts of different size characterizes
the cut surface of breast surgical specimens (Fig. 1).
Microscopy
FCs are characterized by histological tetrad
consisting of fibrosis, cysts, adenosis, and epithe-
lial hyperplasia: (i) Areas of fibrosis with
hyalinized stroma are prominent and cause
112 Fibrocystic Breast Changes

Fibrocystic Breast
Changes, Fig. 1 FCs in a
breast nodule: white stromal
tissue with cystic structures
is visible on cut surface

Fibrocystic Breast
Changes, Fig. 2 (H&E)
(a) Vacuum-assisted biopsy
sampling of FCs.
(b) Cluster of variably
enlarged cystic acini
containing amorphous
material and bluish
calcifications

permanent atrophy of the glandular breast tissue.
(ii) Cysts are the most frequent condition, proba-
bly due to obstruction of the duct by the exuberant
fibrosis that causes dilatation of terminal ducts
and acini. Cysts may vary in size from very large
to microscopic. Often multiple cysts occupy an
entire lobule and contain amorphous secretion
rich in proteins and microcalcifications (Fig. 2).
Microcalcifications are present in form of calcium
phosphate, appearing as basophilic and non-
birefringent round deposits forming psammoma
bodies easily recognizable at routine staining or
Fibrocystic Breast Changes
Fibrocystic Breast
Changes, Fig. 3 Single
cyst containing many
psammoma bodies (H&E)
Fibrocystic Breast
Changes,
Fig. 4 Micropapillae of
apocrine cells protrude
within the cyst (H&E)
calcium oxalate, characterized by birefringent
crystals, sometimes missed at morphological
evaluation. This type of crystals, radiologically
recognized as calcifications, have been described
only in benign cysts and were never associated
with carcinoma or epithelial hyperplasia (Radi
1989). Metaplastic apocrine epithelium usually
covers the surface of cysts as a single layer but
sometimes forms papillae and/or micropapillae.
Apocrine cells are cuboidal and monomorphic,
their cytoplasm is large and contains eosinophilic
granules, and the nucleus is roundish and contains a
single eosinophilic nucleolus. An outer layer of
myoepithelial cells is usually present and detectable
around the cysts with classical immunohistochem-
ical markers (such as p63, smooth muscle actin
(SMA), and calponin). However, in benign apo-
crine lesions, myoepithelial cells may be missing
(Cserni 2012; Tramm et al. 2011). In some cases,
rupture of cysts induces pericystic inflammatory
reaction with lymphocytes and granulocytes. (iii)
Adenosis (▶ Adenosis, Other Types), characterized
113
by an increase in the size and number of
lobules, frequently appears as sclerosing
adenosis (▶ Sclerosing Adenosis). (iv) Epithelial
hyperplasia of usual type (▶ Usual Ductal Hyper-
plasia (UDH)) is a proliferation of epithelial
cells within TDLU characterized by hetero-
geneity in term of shape and size of cells and it is
not associated with risk of subsequent malignancy.
FCs may be associated to any type of epithelial and
stromal lesions (Figs. 3 and 4).
Immunophenotype
AR is usually detected in the apocrine epithelium
of cystic lesions, while ER and PR are absent.
Apocrine epithelium is rich in gross cystic disease
fluid protein (GCDFP)-15. GCDFP-15, 24 and
44 are present at high concentration in cystic
fluid. In vitro studies suggested that presence of
GCDFP-15 may be stimulated by androgens
(Simard et al. 1989) and inhibited by estrogens.
114
Fibrocystic Breast Changes, Fig. 5 (IHC) (a) Nuclei of apocrine cells in a cyst are positive for AR and negative for
(b) ER, (c) PR, (d) IHC of GCDFP-15
GCDFP-15 is usually not expressed in normal
non-apocrine breast epithelium (Fig. 5).
Molecular Features
Molecular profile of FCs was rarely analyzed.
High levels of ER gene transcripts (Boyd et al.
1996) and ER aberrant promoter methylation have
been described (Parrella et al. 2004). The molec-
ular origin of apocrine epithelium remains contro-
versial. Washington et al. (2000) showed loss of
heterozygozity (LOH) in the apocrine compo-
nents of FCs, as well as in associated carcinoma,
indicating possible common clonal precursors. In
line with these findings, IHC screening of a vari-
ety of apocrine lesions from benign to malignant
showed similar protein signature characterized by
positive or negative expression of the following
proteins: 15-PGDH, HMGCR, S110A7, S100A9,
and p53 (Celis et al. 2006). Thus, so far, available
protein markers are not sufficiently specific to
differentiate benign apocrine lesions without
Fibrocystic Breast Changes
aggressive potential from those at risk to become
malignant (Gromov et al. 2015).
Differential Diagnosis
Concomitant presence of fibrosis, cysts with
apocrine metaplasia, (sclerosing) adenosis, and
ductal hyperplasia of usual type is patho-
gnomonic of FCs. However, each singular histo-
logic pattern is subjected per se to differential
diagnosis with other lesions. Validated criteria
used to differentiate benign from atypical or
neoplastic non-apocrine lesions are not readily
applicable to apocrine lesions. For example,
sclerosing adenosis with apocrine epithelium
may simulate an apocrine-invasive carcinoma
(▶ Apocrine Carcinoma) and may require the
use of myoepithelial markers (such as p63,
Calponin, SMA, CK5/6). Nevertheless, as men-
tioned above, pathologists should be aware that
benign apocrine papillary lesions, which may be
placed nearby to foci of sclerosing adenosis, may
Fibrocystic Breast Changes
lack myoepithelial layer (Cserni 2012) and should
not be confused with invasive lesions. Apocrine
epithelium should be differentiated from atypical
apocrine adenosis, atypical apocrine hyperplasia,
and/or apocrine ductal carcinoma in situ. The
presence of nuclear atypia (threefold nuclear
enlargement with presence of large nucleolus or
with multiple small nucleoli) seems to be the
major diagnostic criteria. In addition to nuclear
atypia, the extent of the apocrine proliferation,
architectural features, and presence of necrosis
have been emphasized to differentiate non-atypical
from atypical apocrine proliferations or in situ car-
cinomas (Tavassoli and Norris 1994; O’Malley and
Bane 2008). Finally, foci of epithelial hyperplasia
of usual type (▶ Usual Ductal Hyperplasia (UDH))
in FCs should be differentiated from atypical
hyperplasia and low-grade ductal in situ carcinoma.
Briefly, epithelial hyperplasia of usual type is a
non-monoclonal proliferation of cells filling
lumens of ducts or acini with irregular fenestrations
at the periphery and expresses both low and high
molecular weight cytokeratins (CK), such as
CK8/18 and CK5/6 and 14. In addition at differ-
ence with atypical hyperplasia (▶ Atypical Ductal
Hyperplasia) and low-grade ductal carcinoma in
situ (▶ Ductal Carcinoma In Situ), ER expression
is heterogeneous.
Reference and Further Reading
Bartow, S. A., Black, W. C., Waeckerlin, R. W., &
Mettler, F. A. (1982). Fibrocystic disease:
A continuing enigma. Pathology Annual, 2, 93–111.
Boyd, M., Hildebrandt, R. H., & Bartow, S. A. (1996).
Expression of the estrogen receptor gene in developing
and adult human breast. Breast Cancer Research and
Treatment, 37, 243–251.
Castells, X., Domingo, L., Corominas, J. M.,
Torá-Rocamora, I., Quintana, M. J., Baré, M.,
Vidal, C., Natal, C., Sánchez, M., Saladié, F.,
Ferrer, J., Vernet, M., Servitja, S., Rodríguez-Arana, A.,
Roman, M., Espinàs, J. A., & Sala, M. (2015). Breast
cancer risk after diagnosis by screening mammography
of nonproliferative or proliferative benign breast dis-
ease: A study from a population-based screening pro-
gram. Breast Cancer Research and Treatment, 149,
237–244.
Celis, J. E., Gromova, I., Gromov, P., Moreira, J. M.,
Cabezón, T., Friis, E., & Rank, F. (2006). Molecular
pathology of breast apocrine carcinomas: A protein
115
expression signature specific for benign apocrine meta-
plasia. FEBS Letters, 580, 2935–2944.
Cserni, G. (2012). Benign apocrine papillary lesions of the
breast lacking or virtually lacking myoepithelial cells-
potential pitfalls in diagnosing malignancy. Acta
Pathologica, Microbiologica, et Immunologica
Scandinavica, 120, 249–252.
Dupont, W. D., & Page, D. L. (1985). Risk factors for
breast cancer in women with proliferative breast dis-
ease. New England Journal of Medicine, 312, 146–151.
Faiz, O., & Fentiman, I. S. (2000). Management of breast
pain. International Journal of Clinical Practice, 54,
228–232.
Gromov, P., Espinoza, J. A., & Gromova, I. (2015). Molec-
ular and diagnostic features of apocrine breast lesions. F
Expert Review of Molecular Diagnostics, 15,
1011–1022.
Hartmann, L. C., Sellers, T. A., Frost, M. H., Lingle, W. L.,
Degnim, A. C., Ghosh, K., Vierkant, R. A.,
Maloney, S. D., Pankratz, V. S., Hillman, D. W., Suman,
V. J., Johnson, J., Blake, C., Tlsty, T., Vachon, C. M.,
Melton, L. J., 3rd, & Visscher, D. W. (2005). Benign
breast disease and the risk of breast cancer. The New
England Journal of Medicine, 353, 229–237.
Hutter, R. V. P., Albores-Saavedra, J., & Anderson, E. et al.
(1986). Is ‘fibrocystic disease’ of the breast precancer-
ous? Consensus meeting, New York, October 1985.
Archives of Pathology & Laboratory Medicine, 110,
121.
Kabat, G. C., Jones, J. G., Olson, N., Negassa, A.,
Duggan, C., & Ginsberg, M. (2010). A multi-center
prospective cohort study of benign breast disease and
risk of subsequent breast cancer. Cancer Causes and
Control, 21, 821–828.
Milosevic, Z. C., Nadrljanski, M. M., Milovanovic, Z. M.,
Gusic, N. Z., Vucicevic, S. S., & Radulovic, O. S.
(2017). Breast dynamic contrast enhanced MRI: Fibro-
cystic changes presenting as a non-mass enhancement
mimicking malignancy. Radiology and Oncology, 51,
130–136.
Mousavi, S. R., Mousavi, S. M., Samsami, M., &
Mahdikhah, Z. (2010). Comparison of tamoxifen with
danazol in the management of fibrocystic disease.
International Journal of Medicine and Medical Sci-
ences, 2, 329–331.
O’Malley, F. P., & Bane, A. (2008). An update on apocrine
lesions of the breast. Histopathology, 52, 3–10.
Page, D. L., Vander Zwaag, R., Rogers, L. W.,
Williams, L. T., Walker, W. E., & Hartmann, W. H.
(1978). Relation between component parts of fibrocys-
tic disease complex and breast cancer. Journal of the
National Cancer Institute, 61(4), 1055–1063.
Parrella, P., Poeta, M. L., Gallo, A. P., Prencipe, M.,
Scintu, M., Apicella, A., Rossiello, R., Liguoro, G.,
Seripa, D., Gravina, C., Rabitti, C., Rinaldi, M.,
Nicol, T., Tommasi, S., Paradiso, A., Schittulli, F.,
Altomare, V., & Fazio, V. M. (2004). Nonrandom dis-
tribution of aberrant promoter methylation of cancer-
related genes in sporadic breast tumors. Clinical Can-
cer Research, 10, 5349–5354.
116
Pruthi, S., Wahner-Roedler, D. L., Torkelson, C. J.,
Cha, S. S., Thicke, L. S., Hazelton, J. H., & Bauer,
B. A. (2010). Vitamin E and evening primrose oil for
management of cyclical mastalgia: A randomized pilot
study. Alternative Medicine Review, 15, 59–67.
Radi, M. J. (1989). Calcium oxalate crystals in breast biop-
sies. An overlooked form of microcalcification associ-
ated with benign breast disease. Archives of Pathology &
Laboratory Medicine, 113(12), 1367–1369.
Shaaban, A. M., Sloane, J. P., West, C. R., Moore, F. R.,
Jarvis, C., & Williams, E. M. I. (2002). Histopathologic
types of benign breast lesions and the risk of breast
cancer: case-control study. American Journal of Surgi-
cal Pathology, 26, 421–430.
Simard, J., Hatton, A. C., Labrie, C., Dauvois, S.,
Zhao, H. F., Haagensen, D. E., & Labrie, F. (1989).
Inhibitory effect of estrogens on GCDFP-15 mRNA
levels and secretion in ZR-75-1 human breast cancer
cells. Molecular Endocrinology, 3, 694–702.
Smith, R. L., Pruthi, S., & Fitzpatrick, L. A. (2004). Eval-
uation and management of breast pain. Mayo Clinic
Proceedings, 79, 353–372.
Fibrocystic Breast Changes
Tavassoli, F. A., & Norris, H. J. (1994). Intraductal apo-
crine carcinoma: A clinicopathologic study of 37 cases.
Modern Pathology, 7, 813–818.
Tot, T., Tabàr, L., & Dean, P. B. (2014). Practical breast
pathology. Normal breast tissue or fibrocystic change?
(pp. 2–23). Stuttgart: Thieme Publishing Group.
Tramm, T., Kim, J. Y., & Tavassoli, F. A. (2011).
Diminished number or complete loss of myoepithelial
cells associated with metaplastic and neoplastic apo-
crine lesions of the breast. American Journal of Surgi-
cal Pathology, 35, 202–211.
Wang, J., Costantino, J. P., Tan-Chiu, E.,
Wickerham, D. L., Paik, S., & Wolmark, N. (2004).
Lower-category benign breast disease and the risk of
invasive breast cancer. Journal of the National Cancer
Institute, 96, 616–620.
Washington, C., Dalbègue, F., Abreo, F.,
Taubenberger, J. K., & Lichy, J. H. (2000). Loss of
heterozygosity in fibrocystic change of the breast:
Genetic relationship between benign proliferative
lesions and associated carcinomas. American Journal
of Pathology, 157, 323–329.
G
Glycogen-Rich Clear Cell
Carcinoma
Noëlle Weingertner and Jean-Pierre Bellocq
Department of Pathology, Strasbourg University
Hospital, Strasbourg, France
Definition
Glycogen-rich clear cell carcinoma (GRCCC)
occurs in many organs. GRCCC of the breast is
an exceptionally rare subtype of infiltrative carci-
noma in which more than 90% of the neoplastic
cells have abundant clear cytoplasm containing
glycogen (Eusebi et al. 2012). Extraction of the
water-soluble glycogen during tissue processing
gives the cytoplasm an optically clear, vacuolated
appearance on tissue sections. It was first
described by Hull in 1981 (Hull et al. 1981), and
since then, fewer than 200 cases have been
reported. According to Hull et al., the features of
GRCCC are very similar to the morphology of the
developing mammary gland in 13-week-old fetus.
The clinical features of GRCCC are similar to
those of invasive carcinoma NST (▶ Invasive
Carcinoma NST).
Clinical Features
• Incidence
According to the 2012 WHO classification, the
incidence is estimated to be 1–3% of breast
© Springer Nature Switzerland AG 2020
A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
carcinoma cases when strict criteria are applied
(Eusebi et al. 2012). In everyday practice, the
frequency seems to be much lower.
• Age
Patients are 37–78 years old (median age
of 57).
• Treatment
Patients with GRCCC are treated according to
routine guidelines for breast cancer in general.
• Outcome
Opinions differ concerning the prognosis of
GRCCC. Most reports suggest more aggres-
sive behavior than carcinoma NST, but Hayes
et al. contend that prognosis is not different
once tumors are matched by size, grade, and
lymph node status (Hayes et al. 1995).
Macroscopy
The tumor size ranges from 1 to 15 cm.
Microscopy
Histologically, GRCCC shows clusters of clear
cells (Figs. 1 and 2 H&E) and must have more
than 90% of cells containing intracytoplasmic
glycogen, stained by periodic acid stain (PAS)
but not stained by diastase-periodic acid stain
(Fig. 3 PAS staining). The tumor cells tend to
have sharply defined borders and polygonal con-
tours. The cytoplasm is clear or finely granular.
118
Glycogen-Rich Clear Cell Carcinoma, Fig. 1 GRCCC –
microscopic features (H&E x0.5). Circumscribed invasive
carcinoma. (Courtesy of Gaëtan MacGrogan)
Glycogen-Rich Clear Cell Carcinoma, Fig. 2 GRCCC –
microscopic features of the same case (H&E x10). Broad
nests of polygonal cells with distinct cell borders and clear
cytoplasm. (Courtesy of Gaëtan MacGrogan)
The nuclei are hyperchromatic, sometimes with
clumped chromatin and prominent nucleoli
(Fig. 2 H&E).
The lesions have the architectural features of
carcinoma NST and rarely those of lobular
(▶ Invasive Lobular Carcinoma), medullary
(▶ Invasive Carcinoma with Medullary Features),
or tubular carcinoma (▶ Tubular Carcinoma). An
intraductal component may be present with the
same cytological characteristics.
Immunophenotype
The tumor cells are positive for cytokeratin 7,
GCDFP-15 and negative for cytokeratin 20. Positiv-
ity for chromogranin and synaptophysin has been
reported (Markopoulos et al. 2008). Tumor cells
express estrogen receptor (ER) in 50% of the cases.
Glycogen-Rich Clear Cell Carcinoma
Glycogen-Rich Clear Cell Carcinoma, Fig. 3 GRCCC –
microscopic features of the same case (PAS x20). Glyco-
gen is stained magenta on the PAS stained slide and will be
absent on the PAS/Diastase stained slide. (Courtesy of
Gaëtan MacGrogan)
Progesterone receptor (PR) is generally not expressed
but in rare instances has been reported positive (Kim
et al. 2012). Cases that are positive for HER2 and
negative for ER and PR have been described, as well
as triple-negative cases (Kim et al. 2012).
Molecular Features
This subject has not been discussed in the litera-
ture so far.
Differential Diagnosis
GRCCC has to be differentiated first and foremost
from metastases of clear cell carcinoma, particu-
larly of renal or gynecologic origin. Other diag-
noses should also be considered: lipid-rich
or histiocytoid breast carcinoma, adenomyoe-
pithelioma (▶ Adenomyoepithelioma), clear cell
hidradenoma, pecoma, and xanthogranulomatous
mastitis.
Clear-cell appearance of carcinoma can be an
artifact of the extraction of intracytoplasmic sub-
stances during tissue processing, but in this case,
PAS staining will be negative.
References and Further Reading
Eusebi, V., Ichihara, S., Vincent-Salomon, A., Sneige, N., &
Sapino, A. (2012). Exceptionally rare types and variants.
In S. R. Lakhani, I. O. Ellis, S. J. Schnitt, P. H. Tan, &
Granular Cell Tumor
M. J. van de Vijver (Eds.), WHO classification of
tumours of the breast (pp. 74–75). Lyon: IARC.
Hayes, M. M. M., Seidman, J. D., & Ashton, M. A. (1995).
Glycogen rich clear cell carcinoma of the breast.
A clinicopathologic study of 21 cases. American
Journal of Surgical Pathology, 19, 904–911.
Hull, M. T., Priest, J. B., Broadie, T. A., Ransburg, R. C., &
Mc Carthy, L. J. (1981). Glycogen-rich clear cell car-
cinoma of the breast: A light and electron microscopic
study. Cancer, 48, 2003–2009.
Kim, Z. E., Koo, J. S., & Jung, W. H. (2012).
Immunophenotypes of glycogen rich clear cell carci-
noma. Yonsei Medical Journal, 53(6), 1142–1146.
Markopoulos, C., Mantas, D., Philipidis, T., Kouskos, E.,
Antonopoulou, Z., Hatzinikolaou, M. L., & Gogas, H.
(2008). Glycogen-rich clear cell carcinoma of the
breast. World Journal of Surgical Oncology, 6, 44.
Granular Cell Tumor
Maria P. Foschini and Luca Morandi
Department of Biomedical and Neuromotor
Sciences (DIBINEM), Unit of Anatomic
Pathology at Bellaria Hospital, University of
Bologna, Bologna, Italy
Synonyms
Abrikossoff’s tumor, Granular cell myoblastoma
Definition
Granular cell tumor (GCT) is a rare tumor, of
neurogenic derivation, composed of cells with
pale and granular cytoplasm.
Clinical Features
• Incidence
GCT usually arises in the tongue, but all the
organs can be affected. About 6% of GCT
arises in the breast (Damiani et al. 1992;
Sanguinetti et al. 2016; Rexeena et al. 2015).
• Age
Breast GCT most frequently presents in middle
aged women, but age can vary from puberty to
119
elderly ladies aged more than 70 years (Torous
et al. 2017).
• Sex
Breast GCT affects more frequently female
patients, but rare cases have been reported in
males (Damiani et al. 1992). African-American
women are more frequently affected than Cau-
casian women (Torous et al. 2017).
• Site
GCT is usually located in the upper-internal
quadrant of the breast, even if all the breast
quadrants can be affected, comprising the axil-
lary tail (Damiani et al. 1992, Torous et al.
2017). GCT of the breast can be located both G
in the deep parenchyma and in the subcutane-
ous tissue. Cases deeply located and infiltrating
the pectoralis muscle are on record (Damiani
et al. 1992). Cases arising in the retro-areolar
region can cause nipple retraction. Subcutane-
ous lesions can cause skin retraction.
• Treatment
GCT is more frequently benign; therefore it is
usually treated with tumor resection, with clear
margins. Sentinel lymph node dissection is not
needed. Correct treatment largely depends on
correct preoperative diagnosis. As GCT fre-
quently mimics malignancy both on clinical
and histological grounds (Torous et al. 2017),
sometimes an erroneous aggressive treatment
is performed.
Aggressive treatment is needed in those rare
cases showing malignant features.
• Outcome
Most of breast GCT follow a benign clinical
course. Recurrences can appear when initial
surgical excision has not achieved free
margins.
Macroscopy
On macroscopy GCT presents as a firm nodule,
gray-whitish in color. Margins are more fre-
quently invasive, therefore simulating a breast
carcinoma. Rare cases with well-defined margins,
simulating fibroadenoma have been described
(Damiani et al. 1992). Size varies, but it is usually
smaller than 3 cm.
120
Microscopy
On histology breast GCT is similar to GCT of other
body sites. It is characterized by a proliferation of
cells with wide, pale eosinophilic granular cyto-
plasm (Figs. 1 and 2). Nucleus is centrally located,
small, with delicate chromatin, and inconspicuous
nucleolus (Fig. 3a, b). Cytoplasmic granules are
positive with PAS after diastase reaction. No in
situ carcinoma or lymph-vascular invasion is seen.
GCT has invasive margins, therefore infiltrat-
ing the surrounding breast and fat tissue.
Mitoses, cellular atypia, and necrosis are usually
absent, as most of the GCT are benign. These latter
features can be encountered in those rare cases of
malignant GCT (Sanguinetti et al. 2016; Rexeena
et al. 2015).
Granular Cell Tumor,
Fig. 1 GCT of the breast
shows infiltrative margins
(H&E)
Granular Cell Tumor,
Fig. 2 GCT of the breast is
composed of granular cells;
there is no evidence of in
situ carcinoma (H&E)
Granular Cell Tumor
Immunophenotype
GCT cells are typically strongly and diffusely immu-
noreactive with S-100 protein. In addition, CD68,
carcino-embryonic antigen (CEA), vimentin, and
calretinin have been described as positive
(Sanguinetti et al. 2016; Rexeena et al. 2015). Epithe-
lial markers as low and high molecular weight
cytokeratins, epithelial membrane antigen, and apo-
crine marker GCDFP-15 are negative. Estrogen, Pro-
gesterone and Androgen receptors are negative as
well as HER2 does not show features of amplification.
Proliferative index, as evaluated with Ki67, is low.
On electron microscopy the GCT cells show
numerous membrane-bound vesicles, mostly
filled with flocculent and solid electron-dense
material (Damiani et al. 1992).
Granular Cell Tumor
Granular Cell Tumor,
Fig. 3 (a) and (b) GCT is
composed of cells with
granular cytoplasm, bland
nuclei, and inconspicuous
nucleolus (H&E)
Molecular Features
No molecular data have been reported on GCT of
the breast, to the best of our knowledge. One case
of multiple GCT has been described in association
with LEOPARD Syndrome caused by mutation in
PTPN11 (Schrader et al. 2009).
Differential Diagnosis
The breast can harbor a great variety of neoplastic
lesions, characterized by granular and eosinophilic
cells (Eusebi et al. 1995; Damiani et al. 1999).
The more frequent and most important differen-
tial diagnosis is invasive lobular carcinoma
(▶ Invasive Lobular Carcinoma), particularly the
lobular histiocytoid variant. GCT simulates malig-
nancy on clinical, radiological, and pathological
features, and sometimes the differential diagnosis
121
can be difficult. Difficulty may be enhanced during
frozen section examination or in preoperative
diagnosis.
On histological examination, GCT differs from
invasive carcinoma NST for the bland cytological
features, absence of nuclear atypia and of mitotic
figures. In addition, invasive carcinoma is usually
associated with in situ carcinoma that is lacking in
GCT cases (Torous et al. 2017). When paraffin
embedded sections are under examination, immu-
nohistochemistry can be of great help, evidencing
the typical profile, with S-100 protein positivity
and negativity for epithelial markers.
Benign stromal spindle cell tumors (BSST) of
the breast (Tavassoli and Eusebi 2009), with pre-
dominant myofibroblastic differentiation, can, on
occasion, present granular cytoplasm. The typical
immunophenotype, characterized by positivity for
CD34, BCL2, smooth muscle actin, desmin, is
useful to differentiate the two lesions.
122
Once the diagnosis of GCT is achieved, it is
important to differentiate benign from malignant
lesions.
Malignant GCT is diagnosed when nuclear
atypia (vesicular nuclei with evident nucleoli),
presence of mitotic figures (more than 2 per
10 high power fields), and necrosis are observed
(Rexeena et al. 2015).
References
Damiani, S., Koerner, F. C., Dickersin, G. R., Cook, M. G.,
& Eusebi, V. (1992). Granular cell tumour of the breast.
Virchows Archiv. A, Pathological Anatomy and
Histopathology, 420(3), 219–226.
Damiani, S., Dina, R., & Eusebi, V. (1999). Eosinophilic
and granular cell tumors of the breast. Seminars in
Diagnostic Pathology, 16(2), 117–125.
Eusebi, V., Foschini, M. P., Bussolati, G., & Rosen, P. P.
(1995). Myoblastomatoid (histiocytoid) carcinoma of
the breast. A type of apocrine carcinoma. The American
Journal of Surgical Pathology, 19(5), 553–562.
Rexeena, B., Paul, A., Nitish, R. A., Kurian, C., &
Anila, R. K. (2015). Granular cell tumor of breast:
A case report and review of literature. Indian Journal
of Surgical Oncology, 6(4), 446–448.
Sanguinetti, A., Polistena, A., Lucchini, R., Monacelli, M.,
Galasse, S., Avenia, S., Bugiantella, W., Triola, R.,
Cirocchi, R., Rondelli, R., & Avenia, N. (2016).
Myoblastoma of the breast: Our experience and review
of literature. International Journal of Surgery Case
Reports, 20S, 5–7.
Schrader, K. A., Nelson, T. N., De Luca, A.,
Huntsman, D. G., & McGillivray, B. C. (2009). Multi-
ple granular cell tumors are an associated feature of
LEOPARD syndrome caused by mutation in PTPN11.
Clinical Genetics, 75(2), 185–189.
Tavassoli, F. A., & Eusebi, V. (2009). Benign soft tissue
lesions. In Tumors of the mammary gland (FIP Atlas of
tumor pathology, series 4, p. 281). Washington, DC:
American Registry of Pathology in collaboration with
the Armed Forces Institute of Pathology.
Torous, V., Schnitt, S. J., & Collins, L. C. (2017). Benign
breast lesions that mimic malignancy. Pathology, 49(2),
181–196.
Granulomatous Mastitis
Noëlle Weingertner and Jean-Pierre Bellocq
Department of Pathology, Strasbourg University
Hospital, Strasbourg, France
Granulomatous Mastitis
Synonyms
Granulomatous lobular mastitis; Idiopathic
granulomatous mastitis (IGM)
Definition
Granulomatous mastitis is a benign condition,
defined by a granulomatous inflammation in the
breast, specifically an inflammatory infiltrate com-
posed of histiocytes, sometimes epithelioid, accom-
panied by multinucleated giant cells. Other types of
inflammatory cells may be associated with it: lym-
phocytes, plasma cells, neutrophils, and eosinophils.
Granulomatous mastitis is a heterogeneous con-
dition, and its etiology includes infectious and non-
infectious processes as well as unknown factors.
The term idiopathic granulomatous mastitis
(IGM) was first used by Kessler and Wolloch in
1972 (Kessler and Wolloch 1972). This is a diag-
nosis of exclusion, and other causes of mammary
granuloma formation must be ruled out. There must
be no extra-mammary lesion and no biologic
inflammatory syndrome, but association with ery-
thema nodosum is possible. Current hypotheses on
the etiology of IGM include extravasation of lacta-
tional secretions during breastfeeding, response to
local trauma, metabolic or hormonal processes, and
underlying autoimmune or infectious processes
(principally Corynebacteria infection) that cannot
be detected by usual techniques (Bani-Hani et al.
2004). Idiopathic granulomatous mastitis can
mimic breast malignancy, clinically, radiographi-
cally (Fig. 1), and cytologically upon fine-needle
aspiration (Al-Khaffaf et al. 2008; Oran et al. 2013).
Clinical Features
• Incidence
IGM is rare, encountered in less than 0.5% of
breast samples (Fazzio et al. 2016).
• Age
IGM mainly affects childbearing age women,
most often in postpartum or breastfeeding
mothers (Fazzio et al. 2016). The age at
Granulomatous Mastitis 123

Granulomatous Mastitis,
Fig. 1 Idiopathic
granulomatous mastitis –
mammographic features.
Mammography shows
nodular opacities (stars).
Courtesy of Dr Sébastien
Molière, Department of
Radiology, Strasbourg
University Hospital

diagnosis is generally 20–50 years (age range,
11–83 years) (Seo et al. 2012).
• Sex
Mainly females. Males may rarely be affected
(Seo et al. 2012).
• Site
IGM equally affects the right or left breast,
bilaterality being exceptionally rare. Oran
et al. found the most frequent site of the lesion
was the upper outer quadrant, followed by the
inferior outer quadrant, the areola, the inferior
inner quadrant, and the upper inner quadrant
(Oran et al. 2013).
• Treatment
Spontaneous resolution occurs in 50%
of patients after a mean duration of 14.5 months
(Lai et al. 2005). Treatment of IGM
is not standardized, but corticosteroids and
methotrexate are generally used, as primary
treatment or after surgery to prevent recur-
rences. Steroids can be used before surgery to
shrink the mass (Cheng et al. 2015). Topical
corticosteroids may be effective (Tahmasebi
et al. 2016) and prevent systemic adverse
effect. Antibiotics are sometimes used in com-
bination with these treatments (D’Alfonso
et al. 2015). Surgery is controversial due to
poor wound healing, fistula formation, and dis-
ease recurrence (Tahmasebi et al. 2016), with
reported recurrence rates after surgery as high
as 50% (Pereira et al. 2012). It is usually
reserved for refractory or aggressive cases. It
124
is recommended that implants not be used if
breast reconstruction is undertaken (Pereira
et al. 2012), because the implant may act as a
foreign body and trigger further granulomatous
inflammation. Clinical follow-up is also
recommended.
• Outcome
Variable recurrence rates (5.5–50%) are
reported in the literature (Seo et al. 2012)
with complications including sinuses requiring
draining and abscess formation. The patients
often have to undergo multiple surgical pro-
cedures. Upon resolution, common sequelae
include scarring, retraction of skin and nipple,
and shrinkage of breast tissue (Pereira et al.
2012). Therefore, IGM is disfiguring and pain-
ful but does not pose a threat to general health.
There is no evidence that this condition
increases the incidence of breast carcinoma
(Pereira et al. 2012).
Macroscopy
The most common clinical/macroscopic presenta-
tion is one or multiple firm, unilateral, and palpa-
ble breast mass(es), often associated with
inflammation of the overlying skin, with “peau
d’orange” appearance being possible. The mass
can vary in size from 1 to 10 cm (Pereira et al.
2012) and is gray-tan and irregular. The lesion is
painful in approximately 25% of cases (Korkut
et al. 2015). Skin ulceration, nipple discharge
or nipple retraction, abscesses, sinus formation,
fistulas, and axillary lymphadenopathy may be
seen, this latter in approximately 15% of patients
(Seo et al. 2012; Korkut et al. 2015). Bilateral
involvement has been described. Rare patients
are asymptomatic, with an abnormality detected
on mammography (Fazzio et al. 2016).
Mammography may show nodular opacities
(Fig. 1).
Microscopy
IGM can mimic breast malignancy cytologically
(Al-Khaffaf et al. 2008; Oran et al. 2013).
Granulomatous Mastitis
Therefore, tissue core biopsy with histologic
evaluation is the most reliable diagnostic method.
Histologic evaluation demonstrates non-
necrotizing granuloma, with an infiltrate of multi-
nucleated giant cells, epithelioid histiocytes,
plasma cells, and lymphocytes. A neutrophilic
infiltrate may also occur with formation of micro-
abscesses (Pereira et al. 2012). A histological
pattern of neutrophil aggregates surrounding
microcystic spaces associated with the granulo-
matous inflammation has been called “cystic neu-
trophilic granulomatous mastitis”. This subset of
granulomatous mastitis is reported to be linked to
Corynebacterium species infection in some cases
(Gautham et al. 2019) (Figs. 2 and 3). Eosinophils
can also be seen. The inflammation is centered on
lobules (Fig. 4), but extensive inflammation may
obliterate this feature.
The diagnosis of IGM should be made after
exclusion of all other possibilities and specific
etiological features (Differential Diagnosis).
Necrosis (apart from microabscesses occasion-
ally), foreign body material, infective agents, or
vasculitis should not be present. Proper evaluation
of the specimen requires special stains to search
for mycobacteria and a variety of other organisms
and also requires that samples for microbial exam
and cultures are obtained in specific conditions.
Immunophenotype
There are no particular immunohistochemical
features in IGM. A pankeratin immunostaining
may be helpful to exclude underlying breast
carcinoma.
Molecular Features
To date, no particular molecular feature has been
described for IGM.
Differential Diagnosis
One of the most important clinical differential
diagnoses of IGM is breast carcinoma. Indeed, in
Granulomatous Mastitis 125

Granulomatous Mastitis,
Fig. 2 Cystic neutrophilic
granulomatous mastitis –
microscopic features
(microbiospy, H&E  10):
inflammatory infiltrate with
epithelioid cells,
macrophages and
neutrophil leucocytes
forming non-necrotizing
granulomas (stars). This
type of granulomatous
mastitis has association
with Corynebacteria

Granulomatous Mastitis, Fig. 3 Cystic neutrophilic
granulomatous mastitis – microscopic features
(microbiospy, H&E  20). The inflammatory infiltrate is
in contact with a lobule and shows a cyst-like space
surrounded by neutrophil leucocytes
more than 50% of cases, the initial diagnosis was
suspected to be breast cancer (Seo et al. 2012).
Furthermore, a granulomatous inflammation may
occasionally accompany an infiltrating carci-
noma, and this situation must be ruled out before
a diagnosis of granulomatous mastitis is made,
particularly in postmenopausal women.
Once malignancy is excluded, pathologists
have to think about other causes of mammary
granulomatous inflammation before a diagnosis
of IGM can be made.
Granulomatous Mastitis, Fig. 4 Idiopathic granuloma-
tous mastitis – microscopic features (microbiospy,
H&E  20): Multinucleated giant-cells (arrow)
Non-tuberculous Infectious Granulomatous
Mastitis
Infection is the first possibility to consider when
faced with an inflammatory granulomatous
infiltrate of the breast. Infectious granulomatous
mastitis can be due to mycobacteriosis,
bartonellosis (cat scratch disease), brucellosis,
corynebacteriosis, and salmonella typhi, as well
as fungal agents such as histoplasma and parasites
such as filariasis. These granulomatous inflamma-
tions are often necrotizing. Therefore, special
stains are essential in considering granulomatous
mastitis, including PAS, Grocott, Ziehl-Neelsen,
126
and Gram. When possible, some tissue should be
sent to bacteriology, mycology, and parasitology
laboratories.
Tuberculosis of the Breast
Tuberculosis of the breast is rare in Western coun-
tries, accounting for less than 1% of tuberculous
cases, and is most frequent in endemic zones.
Its incidence can increase in immunosuppressed
patients. Patients are mostly female, 20 to 50 years
old. Breast tuberculosis is most frequently sec-
ondary to a generalized tuberculous infection
(Korkut et al. 2015). It may infrequently be
primary, due to main galactophorous duct lesion,
linked to a trauma during pregnancy or lactation.
Patients present in general with a breast mass, or
an abscess, sometimes associated with satellite
axillary lymphadenopathy. Histological aspects
are similar to its appearance in other organs,
with an inflammatory infiltrate of epithelioid his-
tiocytes, with Langhans-type multinucleated giant
cells accompanied by lymphocytes and occasion-
ally by neutrophils. Caseous necrosis is character-
istic and is the main pathologic aspect
differentiating IGM from tuberculous mastitis
(Pereira et al. 2012). As in other organs, Ziehl-
Neelsen staining rarely identifies acid-fast bacilli.
Granulomatous Mastitis Associated with
Systemic Diseases
Granulomatous mastitis can be part of systemic
diseases such as sarcoidosis, granulomatosis with
polyangiitis (Wegener’s granulomatosis), giant-
cell arteritis (Horton disease), rheumatoid arthri-
tis, necrobiotic xanthogranuloma, etc. Extranodal
Rosai-Dorfman disease of the breast has also been
reported (Chen et al. 2016) and may appear as a
granulomatous process.
The histological features of systemic disease-
associated granulomatous mastitis are quite clas-
sic, similar to the histology seen in other organs.
Sarcoidosis-related mastitis is rare (less than
1% of sarcoidosis) and, in the large majority of
cases, occurs in the context of generalized disease
with pulmonary, cutaneous, lymph node, articular,
and ocular manifestations (Pereira et al. 2012).
Patients present with one or several breast
masses. Histology is characterized by small,
Granulomatous Mastitis
well-circumscribed, non-necrotizing granulomas
with epithelioid histiocytes and multinucleated
giant cells, which may contain asteroid or
Schaumann bodies.
Mammary localization of vasculitis is rare,
with approximately 40 cases described in the
literature. Suggestive clinical context is often
present. Nevertheless, patients often present a
breast mass, and biopsies of these lesions are
therefore taken to exclude malignancy. With
microbiopsies, when the vasculitis is not known,
the diagnosis is very difficult to ascertain and can
often only be suggested. Therefore, pathologists
have to analyze the vessels carefully in cases of
granulomatous mastitis.
Granulomatosis with polyangiitis mainly
affects the respiratory tract and the kidneys, but
rarely the breast. Patients are mostly females, aged
40 to 50. In general, breast lesions are accompa-
nied by respiratory tract and kidney involvement,
associated with biological inflammatory syn-
drome and ANCA antibodies. Breast lesions pre-
sent as one or multiple breast lump(s), uni- or
bilaterally, measuring 2–6 centimeters (Pereira
et al. 2012). The skin may be retracted, ulcerated,
or with “peau d’orange” effect, and axillary
lymphadenopathy may be present.
Histologically, non-well-circumscribed epithe-
lioid and giant-cell granulomas are associated
with large geographic zones of “blue necrosis”
(due to the large amounts of basophilic nuclear
debris) and vasculitis of small- and medium-sized
vessels. Eosinophils may be encountered.
Giant-cell arteritis (Horton’s disease) has been
described in all branches of the subclavicular
artery. The breast is vascularized by the internal
mammary artery and lateral thoracic artery, which
are branches of the subclavicular artery.
Patients are 50 to 80 years old. It presents as
one or several, frequently painful breast lumps
(Pereira et al. 2012). Bilaterality is encountered
in approximately 50% of cases. General symp-
toms are often present, with arthralgias, anorexia,
asthenia, fever, myalgia, biological inflammatory
syndrome, and headache. Histologically, an
inflammatory infiltrate centered on small- and
medium-sized arterial vessels is composed of
macrophages and giant cells with lymphocytes
Granulomatous Mastitis
and neutrophils. The inflammatory infiltrate is
segmental and focal, with fragmentation of
the internal elastic lamina.
Necrobiotic xanthogranuloma displays degen-
eration of collagen fibers and foam cells besides
the granulomas (Cheng et al. 2015). Benign
monoclonal gammopathy or myeloma is associ-
ated with 80% of cases.
Granulomatous Mastitis Associated with
Trauma, Surgery, or Foreign Body Material
Cytosteatonecrosis (▶ Breast Fat Necrosis) is in
general secondary to a trauma or a surgery
(Pereira et al. 2012), but may be spontaneous,
especially in older women. Clinical presentation
may be worrisome, particularly if the trauma is not
known or forgotten. The forms of trauma are
many: traumas of everyday life, massage, pressure
related to mammography, cyst aspiration, core
biopsy, mammoplasty, implant removal, radiation
therapy, etc. The lesion may persist several
months or years after the trauma. Women with
large (adipous) breasts are particularly at risk.
Fat necrosis presents as a breast mass, sometimes
with skin retraction. Cystic zones may be seen on
ultrasonography, and there may be calcifications
on mammography (D’Alfonso et al. 2015).
The macroscopic aspect is characteristic, with
adipose tissue appearing pale yellow. Fibrosis,
pseudocysts, and calcifications are seen in
old lesions. Histologically, an inflammatory infil-
trate is centered on adipose tissue, composed of
foamy macrophages, multinucleated giant cells,
lymphocytes, and plasma cells. Hemorrhage may
be seen in the acute phase. Immunohistochemistry
can be helpful to rule out a carcinoma (particularly
a lipid-rich carcinoma or a carcinoma with
“histiocytoid” morphology), which would be pos-
itive in fat necrosis for histiocytic markers such
as CD163 and CD68 and negative for pankeratin
(D’Alfonso et al. 2015). Lipid pseudocysts, calci-
fications, and ossifications can be seen in old
lesions. When cytosteatonecrosis is secondary to
radiotherapy, cytological atypia in fibroblasts,
endothelial cells, or mammary epithelial cells
may be seen.
Foreign body granulomas may be encountered
and associated with surgical thread (which is
127
often refracting under polarized light) or second-
ary to macrobiopsy or to breast implant (Oran
et al. 2013).
Breast implants are in general composed of
silicone. A fibrous capsule develops surrounding
the implant. The pocket of the implant can fissure
with a clinical aspect of skin fixation and retrac-
tion. Axillary lymphadenopathy may be encoun-
tered. Periprosthetic capsules may be addressed
to the pathologists. The inflammatory infiltrate
is composed mainly of macrophages, with a
“pseudo-synovial” palisaded disposition on the
internal side of the capsule. Multinucleated for-
eign body giant cell may be seen sometimes asso- G
ciated with optically clear holes corresponding to
silicone, which is non-refracting. Lymphocytes
may be associated. Pathologists have to examine
these specimens carefully, to exclude a carcinoma
and a breast implant-associated lymphoma
(▶ Breast Implant-Associated Malignant Lym-
phoma), the latter being recently described
(Laurent et al. 2016).
Rarely, nodular deposition of amyloid can
cause granulomatous reaction in the breast,
which will be diagnosed with special stains
(Cheng et al. 2015).
Other Conditions
Other conditions may be associated with a granu-
lomatous inflammation of the breast tissue, such
as subareolar abscesses, duct ectasia, or
hidradenitis suppurativa.
Subareolar abscess (SA) is also known as
Zuska’s disease, mastitis obliterans, or lactiferous
fistula (Pereira et al. 2012). It results from obstruc-
tion, distension, inflammation, and rupture of the
lactiferous ducts. SA occurs when the normal
epithelium of the distal ducts undergoes squa-
mous metaplasia and keratin obstructs the duct
lumen. The duct may then rupture, and release of
keratin into the breast parenchyma leads to an
inflammatory response. Granulomatous inflam-
mation is a common histologic feature in the
chronic stage of SA. Nipple discharge is common,
usually non-bloody, whereas it is not a common
feature in IGM. Smoking is a major risk factor for
SA, in contrast to IGM, which is often associated
with pregnancy and lactation. The SA abscess
128
involves the main lactiferous ducts and occurs just
below the nipple and areola, whereas IGM involves
the breast lobules at the periphery of the breast.
Fistulas from SA involve the nipple and areola,
whereas fistulas from IGM can occur in any part
of the breast. Histologically, keratinizing squamous
epithelium can be observed in SA, and the inflam-
mation is localized around the ducts. These features
are not observed in IGM.
In duct ectasia, subareolar ducts are dilated,
full of milk-like or butter-like secretion,
surrounded by fibrosis of variable intensity, and
accompanied by a chronic inflammatory infiltrate
also of variable intensity that may sometimes
become granulomatous (periductal mastitis,
comedomastitis).
Hidradenitis suppurativa can involve the
breast, but the breast localization is usually asso-
ciated with axillary and inguinal involvement
(Pereira et al. 2012). Granulomatous inflamma-
tion is present in the chronic stages.
In conclusion, when dealing with a granulo-
matous inflammation in breast specimens, pathol-
ogists have to:
• Rule out an underlying breast carcinoma
• Search for foreign body material
• Think about a possible infection, and therefore
search for necrosis and use special stains or,
more especially, microbiologic analyses on
fresh tissue if possible
• Analyze vessels carefully, searching for
vasculitis
• Of course be aware of the clinical context
References and Further Reading
Al-Khaffaf, B., Knox, F., & Bundred, N. J. (2008).
Idiopathic granulomatous mastitis: A 25-years experi-
ence. Journal of the American College of Surgeons,
206, 269–273.
Bani-Hani, K. E., Yaghan, R. J., Matalka, I. I., &
Shatnawi, N. J. (2004). Idiopathic granulomatous mas-
titis: Time to avoid unnecessary mastectomies. The
Breast Journal, 10, 318–322.
Chen, Y. P., Jiang, X. N., Lu, J. P., Zhang, H., Li, X. Q., &
Cheng, G. (2016). Clinicopathologic analysis of extra-
nodal Rosai-Dorfman disease of breast: a report of 12
cases. Zhonghua Bing Li Xue Za Zhi. 45, 556–60.
Granulomatous Mastitis
Cheng, L., Reddy, V., Solmos, G., Watkins, L.,
Cimbaluk, D., Bitterman, P., Ghai, R., & Gattuso,
P. (2015). Mastitis, a radiographic, clinical, and Histo-
pathologic review. The Breast Journal, 21, 403–409.
D’Alfonso, T. M., Ginter, P. S., & Shin, S. J. (2015).
A review of inflammatory processes of the breast
with a focus on diagnosis in Core biopsy samples.
Journal of Pathology and Translational Medicine,
49, 279–287.
Fazzio, R. T., Shah, S. S., Sandhu, N. P., &
Glazebrook, K. N. (2016). Idiopathic granulomatous
mastitis: Imaging update and review. Insights Imaging,
7, 531–539.
Gautham, I., Radford, D. M., Kovacs, C. S., Calhoun, B.
C., Procop, G. W., Shepardson, L. B., Dawson, A. E.,
Downs-Kelly, E. P., Zhang, G. X., Al-Hilli, Z., Fan-
ning, A. A., Wilson, D.A., Sturgis, C. D. (2019) Cystic
neutrophilic granulomatous mastitis: The Cleveland
Clinic experience with diagnosis and management.
The Breast Journal, 25, 80–85.
Kessler, E., & Wolloch, Y. (1972). Granulomatous masti-
tis: A report of seven cases. American Journal of Clin-
ical Pathology, 58, 642–646.
Korkut, E., Akcay, M. N., Karadeniz, E., Subasi, I. D., &
Gursan, N. (2015). Granulomatous mastitis: A ten-year
experience at a university hospital. The Eurasian Jour-
nal of Medicine, 47, 165–173.
Lai, E. C., Chan, W. C., Ma, T. K., Tang, A. P., Poon, C. S.,
& Leong, H. T. (2005). The role of conservative treat-
ment in granulomatous mastitis. The Breast Journal.
11, 454–456.
Laurent, C., Delas, A., Gaulard, P., Haioun, C.,
Moreau, A., Xerri, L., Traverse-Glehen, A., Rousset,
T., Quintin-Roue, I., Petrella, T., Emile, J. F., Amara,
N., Rochaix, P., Chenard-Neu, M. P., Tasei, A. M.,
Menet, E., Chomarat, H., Costes, V., Andrac-Meyer,
L., Michiels, J. F., Chassagne-Clement, C.,
De Leval, L., Brousset, P., Delsol, G., & Lamant,
L. (2016). Breast implant-associated anaplastic large
cell lymphoma: Two distinct clinicopathological vari-
ants with different outcomes. Annals of Oncology, 27,
306–314.
Oran, E. S., Gürdal, S. Ö., Yankol, Y., Öznur, M., Calay, Z.,
Tunaci, M., & Soybir, G. R. (2013). Management of
idiopathic granulomatous mastitis diagnosed by core
biopsy: A retrospective multicenter study. The Breast
Journal, 19, 411–418.
Pereira, F. A., Mudgil, A. V., Macias, E. S., &
Karsif, K. (2012). Idiopathic granulomatous lobular
mastitis. International Journal of Dermatology, 51,
142–151.
Seo, H. R., Na, K. Y., Yim, H. E., Kim, T. H., Kang, D. K.,
Oh, K. K., Kang, S. Y., An, Y. S., Chun, M., Kim, W.,
Park, R. W., Jung, Y. S., & Kim, K. S. (2012).
Differential diagnosis in idiopathic granulomatous
mastitis and tuberculous mastitis. Journal of Breast
Cancer, 15, 111–118.
Tahmasebi, S., Karami, M. Y., & Maalhagh, M. (2016).
Granulomatous mastitis: Time to introduce new
weapons. World Journal of Surgery, 40, 2827–2828.
Gynecomastia
Gynecomastia
Celien Vreuls and Paul J. van Diest
Department of Pathology, University Medical
Center Utrecht, Utrecht, The Netherlands
Definition
Gynecomastia is derived from the Greek terms
“gyne” meaning feminine and “masto” meaning
breasts. Gynecomastia is defined as an increase in
the size (hypertrophy) of male breast tissue.
Gynecomastia is subdivided into a “genuine”
form with increase in glandular tissue and a
“pseudo” form with increase in fat or a benign
tumor (pseudogynecomastia).
Clinical Features
Gynecomastia presents as a benign uni- or bilat-
eral swelling of the breast and is often seen in
newborn male infants, adolescent, and elderly
men. Gynecomastia is not a separate disease entity
but rather a symptom. Hormonal imbalance
between stimulation of estrogens and inhibition
of androgens is the key factor in the pathogenesis
of gynecomastia, although the most common
cause for this is idiopathic (Braunstein 1993).
Underlying medical conditions such as obesity,
hypogonadism, adrenal disease, thyroid disease,
cirrhosis, renal failure, and malnutrition may con-
tribute to this condition. Tumors of the adrenal
glands, pituitary, lungs, and testicles can induce
hormonal changes resulting in imbalances and
ultimately gynecomastia. Medications that have
been shown to contribute to this condition include
digoxin, thiazides, estrogens, phenothiazines, and
theophylline (Sansone et al. 2017).
• Incidence
At least 30% of all males will be affected
during their life. Gynecomastia is seen in up
to 90% of newborns, 40–70% during puberty,
and 30–40% of the general adult male
population, usually mild manifestations.
129
Approximately 50% of adult are affected, pre-
dominantly by pseudogynecomastia.
• Age
In general gynecomastia there are three peaks
described during life, the neonatal, pubertal,
and aging gynecomastia. In neonates,
estrogen levels are high due to exposure to
maternal estrogens. In puberty there is a
relative increase in estrogen production, and
in aging men there is an imbalance with
increasing estrogen and decreasing testos-
terone levels.
• Sex and Site
Gynecomastia by definition occurs only in G
men. The breast region is the preferred site of
occurrence, although very rare cases of axillary
gynecomastia have been described (Vega
et al. 2015).
• Treatment and Outcome
In male patients with new onset of gynecomas-
tia, the underlying cause (medications, occu-
pational exposure to estrogens or
hyperthyroidism) should be determined and
treated. Usually, within a few weeks there is
improvement of the gynecomastia. If there is
no improvement after several months, medical
treatment for gynecomastia can be tried
(Narula and Carlson 2014).
Medical treatment is probably most effec-
tive in the early stage (florid type) of gyneco-
mastia, since in the later stage the stroma
becomes fibrotic, making medical therapy
largely ineffective in men with long-standing
gynecomastia. Medical therapy for gyneco-
mastia is based on decreasing estrogen pro-
duction and/or increasing the levels of
androgens.
Surgery can be considered in men with
long-standing, symptomatic gynecomastia, if
the patient does not respond to medical ther-
apy, or if the patient prefers surgery for cos-
metic reasons or wants immediate correction of
gynecomastia (Narula and Carlson 2014). Sur-
gery may consist of suction lipectomy or
removal of glandular breast tissue through a
periareolar or axillary incision. If the underly-
ing cause of gynecomastia is not ruled out,
recurrence is possible after surgery.
130
Macroscopy
The tissue is soft, firm, and gray/white on the cut
surface. The specimens have a unifying shape of a
head, body, and tail. The head is semicircular in
shape and is located more medially toward the
sternum. The majority of the glandular tissue con-
sists of a body located immediately deep to the
nipple areolar complex. The tail appears to taper
off of the body more laterally and toward the
insertion of the pectoralis major muscle onto the
humerus (Blau et al. 2016).
Microscopy
The male breast is composed of rudimentary ducts
usually without lobule formation. If exposed to
high levels of endogenous or exogenous estrogen,
for example, in male-to-female transsexuals in
whom progestative chemical castration is com-
bined with feminizing estrogen therapy, full aci-
nar and lobular formation occurs with hormonally
stimulated nuclei and pseudolactational changes
(Kanhai et al. 2000).
Gynecomastia, Fig. 1 (H&E) Low-power hematoxylin
and eosin stains illustrate the three types of gynecomastia.
The florid type shows edematous increased periductal stro-
mal cellularity concentrically forming around the rudimen-
tary ducts that show ductal epithelial hyperplasia (a). The
Gynecomastia
Gynecomastia can be divided into three types,
reflecting stages of development: the florid type,
reflecting recent onset; the fibrous (quiescent or
inactive) type, probably the end stage of gyneco-
mastia (>6–12 months); and the intermediate
type, with features of both florid and fibrous types.
The florid type shows increased periductal
stromal cellularity, with often prominent vascular-
ity and edema (Fig. 1a), concentrically forming
around the rudimentary ducts that show ductal
epithelial hyperplasia; this can be of usual type
or with papillary projections. In the intermediate
type, radially expanding concentric fibrosis
around individual ducts starts to merge (Fig. 1b).
In the fibrous (end stage) type, usually after
12 months, the lesion is quiescent, and the ubiq-
uitously confluent fibrous collagen-rich compo-
nent dominates, and edema and epithelial
proliferation are less prominent (Fig. 1c).
Pseudoangiomatous stromal hyperplasia
(PASH) (▶ Pseudoangiomatous Stromal Hyper-
plasia) is often present in gynecomastia, particu-
larly in the florid type (Milanezi et al. 1998).
PASH has a characteristic growth pattern of
inter-anastomosing clefts that are, as the name
intermediate type shows increasing concentric fibrosis
around the individual ducts which start to merge (b). The
fibrous type shows confluent fibrous collagen-rich stroma
and less prominent epithelial proliferation (c)
Gynecomastia
Gynecomastia, Fig. 2 Medium-power hematoxylin and
eosin stain illustrates pseudoangiomatous stromal hyper-
plasia (PASH). The inter-anastomosing clefts are angulated
and slit-like, lined by myofibroblasts and surrounded by
wavy, acellular collagenous stroma (H&E)
suggests, lined by myofibroblasts and not by
endothelium, thereby positive for stromal markers
like vimentin only and not for (lympho)vascular
markers. The spaces are angulated and slit-like
and surrounded by wavy, acellular collagenous
stroma. The myofibroblasts are spindle to ovoid
but are not atypical (Fig. 2). Multinucleated giant
cells can be seen.
The rudimentary ducts in gynecomastia are
lined by at least three cell layers: an outer layer
of myoepithelial cells and two layers of epithelial
cells. The myoepithelial cells may have clear
cytoplasm. The intermediate luminal layer con-
sists of cuboidal to columnar vertically orientated
cells, with regular oval nuclei and occasional
small nucleoli. The cytoplasm is eosinophilic
with indistinct cell borders, and these cells often
show luminal tufts. The inner luminal layer com-
prised slightly smaller and more horizontally ori-
entated cells, most often arranged in a single layer,
with regular to slightly irregular small nuclei and
sporadic small nucleoli (Kornegoor et al. 2012b).
More layers may be present, resembling the
sloppy ductal hyperplasia of usual type of the
female breast, with flat peripheral layers or a mildly
cribriform architecture with irregular lumina with
regard to spacing, shape, and size, or a central sea
of epithelium with slit-like peripheral residual
lumina. Some tufting into the lumina may be pre-
sent, and micropapillae showing a pyramid shape
instead of the rod shape of micropapillae of clonal
female breast epithelial proliferations usually
denoted gynecomastoid hyperplasia (Fig. 3).
Microcalcifications and secretions are very rare.
131
Gynecomastia, Fig. 3 High-power hematoxylin and
eosin stain illustrates gynecomastoid hyperplasia. The
duct is lined by several layers that tuft into the lumina;
note the pyramid shape of the tufts (H&E)
Atypical ductal hyperplasia (ADH) G
(▶ Atypical Ductal Hyperplasia) and ductal carci-
noma in situ (DCIS) (▶ Ductal Carcinoma In
Situ), two known clonal precursor lesions for
breast cancer in females, have rarely been
reported in male breasts with gynecomastia
(Hamady et al. 2005; Doebar et al. 2017). DCIS
is the most commonly observed precursor lesion
in male breast cancer, and its presence seems to be
associated with favorable outcome (Doebar et al.
2017). It usually concerns the papillary variant or
low-grade DCIS (▶ Intraductal Papillary Carci-
noma), although all the subtypes described in
women can occur in men. DCIS is mainly associ-
ated with invasive breast cancer.
The presence of lobular carcinoma in situ
(▶ Lobular In Situ Neoplasia) has also been
described but is very rare, in line with the rarity
of invasive lobular cancer (▶ Invasive Lobular
Carcinoma) in men (Doebar et al. 2005).
Gynecomastia and Invasive Cancer
The role of gynecomastia in the development of
male breast cancer (▶ Male Breast Cancer)
remains uncertain. Gynecomastia is often seen
alongside invasive breast cancer, but gynecomas-
tia is also frequently encountered in healthy men
(Braunstein 1993; Fentiman et al. 2006). How-
ever, other studies found a significant correlation
between gynecomastia and male breast cancer
(Brinton et al. 2010).
It has been suggested that there is a difference
in carcinogenesis between male and female breast
132
cancer. One of the largest series of male breast
cancers demonstrates that luminal type A is by far
the most common breast cancer subtype in males.
Luminal type B breast cancer is less common and
represents a subgroup of ER-positive tumors with
highly malignant phenotype. HER2-driven, basal-
like, and unclassifiable triple-negative breast can-
cers in men seem to be very rare. This distribution
of breast cancers subtypes in men is different
compared with females (Kornegoor 2012a).
Immunophenotype
Epithelium
The normal ductal male breast epithelial cells are
very often ER and Bcl-2 positive (>69%), and PR
and AR expression is also common (>39%). As
described above, gynecomastia appears to show a
consistent three-layered pattern. The immunohis-
tochemical pattern is distinctive as the outer
myoepithelial layer shows expression of CK5,
CK14, and p63. The two epithelial cell layers
differ from each other. The intermediate luminal
layer, consisting of vertically oriented cuboidal to
columnar cells, is hormone receptor positive and
expresses Bcl-2 and CyclinD1. The inner luminal
layer is composed of smaller cells expressing CK5
and often CK14 but are usually negative for hor-
mone receptors and Bcl-2. All epithelial cells
show strong staining with CK7 and E-cadherin.
HER2 staining is completely negative in the epi-
thelium, and BRST2 and EGFR are also almost
always negative. Only wild-type p53 staining is
seen in ductal epithelium (Kornegoor
et al. 2012b).
Male DCIS is consistently ER positive and
CK5/CK14 negative. Ki67-positive cells are
rarely seen in the intermediate and inner luminal
layers (Kornegoor et al. 2012a).
Stroma
The immunophenotype of periductal connective tis-
sue stroma in gynecomastia appears to parallel the
phenotype of normal breast stroma. In male breast
carcinoma the stromal cell immunophenotype is
similar to that of its female counterpart showing
myofibroblastic differentiation. However, alpha-
Gynecomastia
SMA+ and CD34- staining are not specific to malig-
nancy because such findings are also encountered in
reactive fibrosis (Kalekou et al. 2005).
In most cases moderate to strong Bcl-2
staining is seen in stromal cells, especially in
florid and intermediate types. p21 shows spo-
radic positive cells in the surrounding stroma,
and p53 shows wild-type expression. Prominent
stromal staining is often seen for EGFR, espe-
cially in the presence of PASH (Kornegoor et al.
2012a). PASH areas do not stain with (lympho)
vascular makers like D2–40 (podoplanin),
LYVE-1, and CD31.
Molecular Features
Until now no chromosomal abnormalities have been
detected in cases of gynecomastia with no other
concomitant breast disease. For male DCIS and
invasive cancer, however, a clonal relationship has
been described, based on similar copy number pro-
file for 21 out of 22 interrogated breast cancer-related
genes, underlining that DCIS is a true precursor for
male invasive breast cancer (▶ Male Breast Cancer)
(Vermeulen et al. 2017). Doebar et al. showed iden-
tical genomic aberrations, including PIK3CA,
GATA3, TP53, and MAP2K4 mutations, based on
next-generation sequencing (Doebar et al. 2017). For
male breast cancer it has been suggested that the
X chromosome gain plays a role in the neoplastic
transformation of male breast epithelial cells and that
the gain of chromosome 5, loss of the
Y chromosome, loss of chromosome 17, and del
(18)(q21) are described as nonrandom abnormalities
(Di Oto et al. 2015).
Differential Diagnoses
The main most important differential diagnosis is to
discriminate gynecomastia from male breast cancer
(▶ Male Breast Cancer), especially if it is a unilat-
eral, fixed palpable mass with nipple discharge
(Johnson and Murad 2009). Mammography and
high-resolution ultrasound can be helpful to distin-
guish between these breast lesions (Munoz
Carrasco et al. 2010). Also pseudogynecomastia
Gynecomastia
and other benign lesions, such as lipoma, hema-
toma, fat necrosis (▶ Breast Fat Necrosis), dermoid
cyst, sebaceous cyst, or lymphoplasmacytic inflam-
mation, should be considered.
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H
Hamartoma
Catherine N. Chinyama
Department of Pathology, Princess Elizabeth
Hospital, St Martins, Guernsey,
Channel Islands, UK
Brighton and Sussex Medical School,
Brighton, UK
Synonyms
Adenolipofibroma; Adenolipoma; Fibroade-
nolipoma; Lipofibroadenoma
Definition
Hamartoma is from Greek hamartia meaning
“fault, defect” and -oma denoting a tumor or
neoplasm. (Seth 2017). The pathological
definition of a hamartoma, irrespective of
site of origin, is an abnormal proliferation
of tissue indigenous to the organ to create a
mass or tumor. In the breast, the constitu-
ents of the mass include fat, fibrous tissue,
and epithelial elements. Although previously
described, Arrigoni and colleagues are given
credit for increasing the awareness of the
existence of a breast hamartoma (Arrigoni
et al. 1971).
© Springer Nature Switzerland AG 2020
A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
Clinical Features
• Incidence
In the premammographic era, breast hamar-
tomas went largely unrecognized. With the
introduction of screening mammography, the
realization that a hamartoma is a stand-alone
pathological entity is on the rise. The incidence
of hamartomas is reported to be between 0.4
and 1.15% and constitutes about 4.8% of all
benign breast tumors (Wu et al. 2003).
Hamartomas have been reported in Cauca-
sians, Asian, and African patients (Herbert
et al. 2002).
• Age
The age of patients with mammary
hamartomas ranges from 18 to 89 years with
a mean age of 45 years and a median age of
43 years (Daya et al. 1995); typical presenta-
tion is in the third to fifth decade.
• Sex
Mammary hamartomas affect predominantly
women although a case has been reported in a
man (Amir and Sheikh 2016).
• Presentation
When symptomatic, a hamartoma presents with
a painless soft to firm palpable lump with the
clinical diagnosis of a fibroadenoma but not as
firm as a fibroadenoma (Tse et al. 2002). The
lump is usually present for a long duration with
little or no change in size. Screen-detected
136 Hamartoma

hamartomas tend to be small and

asymptomatic. However, there are reported
cases of hamartomas that grow slowly to pro-
duce giant lesions associated with breast asym-
metry and pressure symptoms such as
discomfort and lymphedema as in the case
reports of giant hamartomas which weighed
450 g and 1497 g, (Cazorla and Arentz 2015).
Most patients present with single lesions but a
patient with two hamartomas has been reported
(Herbert et al. 2002).
• Site
Hamartomas affect the left and right breasts
equally; however, some reports document a
higher prevalence in the right breast than the
left (Amir and Sheikh 2016).
• Mammographic Features
The mammographic features of a hamartoma
are considered “fairly characteristic.” The
lesion is well-defined, oval shaped, with a
smooth margin and consists of a mixture of
fat and fibroglandular tissue with or without a Hamartoma, Fig. 1 A mammorgram of a 41-year-old
pseudocapsule (Wu et al. 2003). Lobulated woman shows relatively well-circumscribed mass
densities may be present within the encapsu- 100 mm in diameter. There is little or no variation in the
lated fat and are referred to as “slices of salami hormogencity of the lesion. The histology showed a
harmatoma consisting of predominantly fibrous compo-
or sausages.” These densities may be associ- nent with minimal fat depostion
ated with benign round microcalcification
(Erdem et al. 2011). The main defining feature
is the presence of fat which gives the lesion. The histology showed a hamartoma
hamartoma a heterogeneous appearance. with a predominantly fibrous component with
Because the constituents of the hamartoma minimal fat deposition. In contrast a screen-
resemble normal breast tissue, the lesion is detected hamartomas tend to be small as illus-
sometimes referred to as a “breast in breast” trated in Fig. 2 in a 50-year-old woman. The
(Erdem et al. 2011). The hamartoma can con- lesion was 19 mm in diameter and located
tain excess fat, equal mixture of fat and above the nipple with a typical fatty halo.
fibroglandular tissue or minimal fat with This was a follow-up mammogram 6 months
excess fibroglandular tissue. The mammo- later and the lesion had not increased in size.
graphic density varies according to the amount Microcalcification is rare in hamartomas
of fat and fibroglandular tissue in the lesion; and when present raises the possibility of
more fat will induce radiolucency to the lesion. malignancy. However, benign dystrophic cal-
The different mammographic features are cification has been reported in some
illustrated in Figs. 1 and 2. Figure 1 is a mam- hamartomas (Park et al. 2003).
mogram of a 41-year-old woman who pre- • Sonographic Features
sented with a mass in the right breast, The characteristic sonographic feature of a
clinically suspicious of a large fibroadenoma hamartoma is compressibility with transducer
(▶ Fibroadenoma) or phyllodes tumor pressure (Park et al. 2003; Chao et al. 2007).
(▶ Phyllodes Tumor). The mammogram This gives the tumors a longer transverse dimen-
shows a 10 cm dense well-circumscribed sion than the anteroposterior diameter i.e. an
Hamartoma 137

Hamartoma, Fig. 3 Ultrasonogrphic features of screen- H

detected hamartoma in a 50-year-old woman; the charac-
teristic oval shape is due to the compressibility of the lesion

Hamartoma, Fig. 2 Screen-detected hamartoma in a

50-year-old woman. The lesion is 19 mm in diameter
with a characteristic fatty halo. This was a repeat
mammogramm at 6 months and the lesion had not grown
in size

‘oval shaped’ or ‘lens shaped’ appearance. The

oval shape of the hamartoma due to compress-
ibility under ultrasound scan is illustrated in
Fig. 3 in a screen-detected lesion. The majority
of hamartomas have well-circumscribed smooth
margins. The internal echo texture is variable
consisting of hyperechoic, mixed heteroge-
neous echogenicity or isoechoic. Some tumors
have heterogenous echogenicity with mixed
isoechogenecity and hyperechogenicity. The
variable echo texture depends on the proportion Hamartoma, Fig. 4 Symptomatic 20 mm hamartoma in
of fat and fibroglandular tissue in the a 88-year-old woman illustrating variable echogenecity on
hamartoma. Variable echogenicity is illustrated ultrasonography; note the irregular border
in Fig. 4 in a symptomatic hamartoma in an
88-year-old woman. The hamartoma in charac- phenomenon which is a feature in a malignant
terized by irregular borders and heterogeneous lesion. Cystic areas are frequent in sonographic
internal contents. Echogenic halos or anechoic images (Wu et al. 2003).
halos are present in some hamartomas due to • Magnetic Resonance Imaging (MRI)
compression between the hamartoma and the Features
surrounding breast tissue. The majority of Because hamartomas generally display benign
hamartomas lack retro-tumor acoustic features on mammography and ultrasound,
138
patients are rarely referred for MRI. Conventional
T1 and T2 weighted MRI of mammographically
and sonographically proven hamartomas demon-
strates heterogeneous intensities due to the fatty
and fibroglandular content of the lesions plus a
thin capsule. Enhancement of lesions is grad-
ual on dynamic contrast-enhanced (DCE)-
MRI. Although not routinely used in the work
up of hamartomas, MRI can be a useful ancil-
lary investigation where the mammographic
and sonographic features are inconclusive,
and there is need to exclude cancer (Erdem
et al. 2011).
• Diagnosis
Similar to any other breast lesion, the definitive
diagnosis of a hamartoma should be attained
following triple assessment consisting of clin-
ical examination, radiological assessment, and
pathological evaluation. Fine needle aspiration
cytology is rarely diagnostic in hamartomas,
because the material yield is usually inade-
quate or may sample normal breast epithelium
with no diagnostic features. Needle core biop-
sies can be diagnostic if supported by radiolog-
ical findings. Because of the resemblance to
normal breast tissue, pathologists can easily
overlook this lesion as normal breast tissue.
Figure 5 illustrates a needle core from a
mammographically detected hamartoma
showing a variable mixture of fibroglandular
tissue and fat. In the absence of a localized
radiological abnormality, this can be errone-
ously reported as nonspecific fibrosis or nor-
mal breast tissue.
Hamartoma, Fig. 5 A needle core biopsy from a
mammographically detected hamartoma showing a mix-
ture of fibrofatty tissue with benign ducts and lobular units
resembling normal breast tissue (H&E)
Hamartoma
• Treatment
Asymptomatic, screen-detected biopsy con-
firmed hamartomas can be left in situ and the
patient is subjected to close surveillance.
Symptomatic patients are offered surgery
because the diagnosis is not always conclusive.
• Outcome
Surgery is usually curative and patients have
an excellent prognosis; however a patient with
recurrent hamartoma has been reported. The
recurrence was due to incomplete surgical
excision (Tse et al. 2002).
Macroscopy
Hamartomas tend to be single, well-
circumscribed lesions ranging in size from 1 to
10 cm (McGuire and Cohn 1991). The cut surface
may be grey-white in color. The surface may be
glistening. The lesion may be encapsulated. There
is no hemorrhage or necrosis. Fat may or may not
be readily apparent on naked eye examination.
There is no lobulation usually seen in
fibroadenoma (▶ Fibroadenoma). Small cysts
may be present.
Microscopy
When supported by mammographic and sono-
graphic features, the needle core biopsy of a
hamartoma can be diagnostic and this can spare
the patient surgery in screen-detected lesions. As
illustrated in Fig. 5, the needle core biopsy from a
hamartoma consists of a variable mixture of fat
and fibrous tissue containing benign ducts and
lobular units.
The true characteristics of a hamartoma are
better appreciated in the excised specimen. The
proliferation of mostly fibrous stroma obliterates
the normal interlobular architecture. The fibrous
stroma can exhibit variable degrees of
hyalinization and may resemble scar tissue. The
most common feature which differentiates
hamartomas from other well-circumscribed
benign lesions is the presence of fat in the fibrous
stroma. The amount of fat is variable. The fat can
Hamartoma
be present as isolated adipocytes, in clusters or as
diffusely in a large area. The epithelial component
can also be heterogeneous. The ducts and lobular
units can be normal depending on the age of the
patient, hence the “breast in breast” concept. The
epithelial component can be atrophic or exhibit
hyperplasia without atypia, cystic change with or
without apocrine metaplasia. Figure 6 illustrates
the heterogeneous microscopic features in an
excised hamartoma, but with a predominantly
fibrous component, sparsely distributed benign
ducts, lobular units, cystic change, mucin filled
ducts, and myxoid degeneration of the stroma.
Rare adipocytes are scattered in the stroma.
Pseudoangiomatous hyperplasia (PASH)
(▶ Pseudoangiomatous Stromal Hyperplasia) in
the stroma is characterized by irregular slit-like
spaces which resemble capillaries but are nega-
tive for endothelial markers such as factor VIII
Hamartoma, Fig. 6 Symptomatic hamartoma consisting
of a predominantly dense hyalinized stroma with atrophic
sparsely distributed ducts and lobular units (H&E)
Hamartoma, Fig. 7 Pseudoangiomatous hyperplasia in a
needle core biopsy from a hamartoma in Fig. 6 which could
have led to erroneous diagnosis of primary PASH (H&E)
139
and CD31. Pseudoangiomatous hyperplasia is a
common feature in the stroma of hamartomas
(Tse et al. 2002). Figure 7 illustrates pseudo-
angiomatous hyperplasia in a needle core biopsy
from the same patient in Fig. 6. The needle core
biopsy was reported as suspicious of PASH.
However, on excision the lesion was a
hamartoma with pseudoangiomatous changes in
the stroma. Other features noted in hamartomas
on microscopic examination include micro-
calcification. Smooth muscle can also be present
in hamartomas and when present in excess, the
lesion is termed a myoid hamartoma (Amir and
Sheikh 2016).
H
Pathogenesis
The pathogenesis of hamartomas is unclear. It is
thought to be a developmental abnormality rather
than a true neoplasm. Initially the abnormality
was thought to be related to pregnancy and lacta-
tion (Hogamen and Ostberg 1968). However, sub-
sequent studies did not support this hypothesis as
hamartomas also arise in nulliparous women.
Although pregnancy and lactation may influence
the growth of a hamartoma, there is no evidence of
pathogenetic relationship.
Immunophenotype
One of the characteristic immunophenotypic fea-
tures of hamartomas is that both the stroma and
epithelial elements are positive for estrogen recep-
tors and progesterone receptors, i.e., ER and PR
positive (Herbert et al. 2002). This differentiates
hamartomas from normal breast tissue which is
usually ER and PR positive in the epithelium, but
ER and PR negative in the stroma. This suggests
simultaneous response to hormonal stimulation of
the constituents of the hamartoma (Fig. 8). As
expected the epithelial elements are positive for
cytokeratins and the stroma for vimentin similar to
normal breast tissue. Hamartomas do not express
HER2 or p53 and the Ki67 proliferation activity is
usually low (Herbert et al. 2002). Markers such as
desmin highlight smooth muscle fibers in the
140
Hamartoma, Fig. 8 The hamartoma from the patient in Fig. 6 expresses estrogen receptors (a) and progesterone
receptors (b) in the stroma and epithelial components. The PR appears stronger than the ER
hamartoma or support the diagnosis of a myoid
hamartoma.
Genetic Aberrations
As the breast hamartoma is not considered neo-
plastic there are very few genetic studies on this
lesion. Aberrations involving 12q12-15 in a breast
hamartoma were reported independently by dif-
ferent authors (Dietrich et al. 1994 and Rohen
et al. 1995). Using FISH studies, the authors
reported aberrations involving 12q12-15 which
was mapped to the multiple aberration region
(MAR). The MAR is a major cluster region of
chromosome 12 breakpoints of benign solid
tumors such as uterine leiomyoma, lipoma and
pleomorphic adenoma of the salivary gland. The
authors identified the aberrations in the stroma
and not the epithelial cells and concluded that
hamartomas arose due to mutated mesenchymal
stromal cells, and therefore adenolipomas or
hamartomas of the breast were not due to
entrapped epithelial cells and mesenchymal cells
with proliferating adipocytes but mutated mesen-
chymal cells capable of differentiating into stro-
mal cells as well as adipocytes.
Breast hamartomas have also been linked to
Cowden disease. Cowden disease also termed
Cowden syndrome or multiple hamartoma syn-
drome is an autosomal dominant condition with
variable expression associated with the mutation
of the PTEN suppressor gene on 10q23.3
(Liaw et al. 1997). Cowden disease causes
hamartomatous neoplasms of the skin, mucosa,
Hamartoma
gastrointestinal tract, bone, central nervous sys-
tem, eyes and genitourinary tract (Fiala (2016)
Medscape). Cowden syndrome is associated with
malignancy in particular breast cancer and thyroid
cancer. Gomez et al. (2012) reported a carcinoma
of the breast arising in a calcified hamartoma. The
case was unusual in that although Cowden syn-
drome is a multiple hamartoma syndrome, breast
hamartomas are not even in the minor criteria for
diagnosis of this condition, but breast cancer is a
major diagnostic criterion. Furthermore, the patient
had bilateral breast microcalcification which on
mammography involved over two-thirds of the
breasts. Massive calcification is not one of the
features of hamartomas. This link between PTEN
mutations and breast hamartoma confirmed an ear-
lier study by the same authors (Sabate et al. 2006)
which reported hamartomas in two patients with
Cowden syndrome.
Differential Diagnosis
The most common lesion which mimics a
hamartoma clinically is a fibroadenoma
(▶ Fibroadenoma). Fibroadenomas tend to affect
younger women in the 20–30 age groups. Although
clinically and radiologically fibroadenomas resem-
ble hamartomas, pathologically the two lesions are
very different, more significantly, fibroadenomas
lack fat infiltration. Furthermore the epithelial com-
ponent of a fibroadenoma can be very heteroge-
neous to include: sclerosing adenosis (▶ Sclerosing
Adenosis), fibrocystic change (▶ Fibrocystic Breast
Changes) with apocrine metaplasia, columnar cell
Hamartoma
change (▶ Columnar Cell Lesions), epithelial
hyperplasia of usual type (▶ Usual Ductal Hyper-
plasia (UDH)) without atypia. The fibroadenoma
is lobulated and the epithelial proliferation exhibits
the so called intracanalicular or pericanalicular
growth patterns. In older patients, fibroadenomas
become hyalinized with reduced cellularity but
with preservation of the lobular architecture. The
stroma in fibroadenoma is also prone to myxoid
degeneration. If these features are present, the diag-
nosis of hamartoma would be questionable.
Fibroadenomatoid hyperplasia is thought to be
a harbinger of a fibroadenoma and can be difficult
to differentiate from a hamartoma on a needle core
biopsy. This lesion consists of small lobules of
hyalinized stroma admixed with benign ducts and
lobular units. Inclusion of fat in the needle core
biopsy may give rise to erroneous diagnosis of
hamartoma. However, the lobulated architecture
of a fibroadenomatoid hyperplasia plus the radio-
logical findings should exclude a hamartoma.
Tubular adenoma (▶ Tubular Adenoma of the
Breast) which belongs to the same family as
fibroadenoma can mimic a hamartoma clinically
and radiologically, but the histological appearance
of crowded tubules usually with luminal secre-
tions with no intervening stroma has no resem-
blance to a hamartoma. Coincidentally, a patient
with a tubular adenoma of the breast and Cowden
disease was reported in the same study which
reported two patients with PTEN mutation in
hamartomas (Sabate et al. 2006).
Phyllodes tumors (▶ Phyllodes Tumor) arise in
the same age groups as hamartomas. A giant
hamartoma (Cazorla and Arentz 2015) would be
clinically indistinguishable from a phyllodes
tumor. However, histologically the increase in
cellularity of the stroma with associated clefting
would distinguish a phyllodes tumor from a
hamartoma (▶ Phyllodes Tumor).
Fibromatosis of the breast may clinically and
radiologically mimic a hamartoma, but the pre-
dominance of a cellular infiltrative fibrous prolif-
eration with no epithelial elements is
characteristic of this lesion and clearly differenti-
ates it from a hamartoma.
Fibrous mastopathy or fibrous tumor can be
present symptomatically or mammographically
141
detected. The well-circumscribed lesions could
be difficult to differentiate from a hamartoma
radiologically. However, the lack of sonographic
compressibility in the fibrous tumor should dis-
tinguish this lesion from a hamartoma. Fibrous
tumors can be clinically palpable but radiologi-
cally occult, which is not the case with a
hamartoma. In the absence of appropriate radio-
logical studies, a fibrous tumor can be difficult to
differentiate from a hamartoma in a needle core
biopsy (Fig. 9). In the presence of fat, a fibrous
tumor can mimic a hamartoma with a predomi-
nantly fibrous component. The cause of a fibrous
tumor is unknown but transforming growth factor
beta (TGF-beta) is implicated in promoting spin-
dle cell proliferation (Gold 1999). H
Diabetic mastopathy can mimic a hamartoma
radiologically. Histologically, the diagnosis
should be clear because of the presence of lobular
mastitis in the background of fibrotic stroma with
or without islands of mature adipocytes
(▶ Diabetic Mastopathy).
Pseudoangiomatous stromal hyperplasia
(PASH) (▶ Pseudoangiomatous Stromal Hyper-
plasia) can be present as a primary lesion of the
breast but can arise in the stroma of other breast
lesions such as gynecomastia or hamartoma. The
main pathological appearance of PASH is the
presence of slit-like structures which resemble
capillaries in the stroma. If a needle core biopsy
samples the pseudoangiomatous component in a
hamartoma, as illustrated in Fig. 7, it is almost
impossible to exclude primary PASH; more so
Hamartoma, Fig. 9 Needle core biopsy from a palpable
but mammorgraphically and sonographically occult
fibrous tumor. The stroma is hyalinized with a scar-like
appearance. The presence of fat and benign ducts and
lobular units resembles a hamartoma (H&E)
142
Hamartoma, Fig. 10 A symptomatic choristoma, 6 mm
in diameter excised from a 31-year-old woman; a well-
circumscribed lesion showing a mixture of mature adipo-
cytes, islands of cartilage with foci of ossification. Breast
tissue was present in the background (H&E)
because both hamartoma and PASH are ER and
PR positive (Bowman et al. 2012).
A choristoma is an abnormal proliferation of
tissue foreign to the organ. In the breast, the lesion
can consist of normal breast tissue, dense fibrous
stroma, mature hyaline cartilage fat and smooth
muscle (Metcalf and Ellis 1985). The presence of
cartilage should distinguish a choristoma from a
hamartoma (Fig. 10).
Breast Cancer Risk
Hamartomas have no documented risk of progres-
sion to malignancy nor are they a marker for
breast cancer. A review of the literature
documented several case reports of breast cancers
arising in patients with known hamartomas on a
surveillance program or cancer arising in a
hamartoma identified during the investigation of
mass, either radiologically or pathologically
(Choi and Ko 2010). The important message
from this review is for the clinician to take heed
of changing radiological features during surveil-
lance of a biopsy proven hamartoma in particular,
the presence of new calcification. Breast cancer
arising in a calcifying hamartoma in patients with
Cowden disease was previously described in this
chapter (Gomez et al. 2012). In this case, the
Hamartoma
Cowden disease was the main risk factor for
breast cancer rather than the hamartoma.
References and Further Reading
Amir, R. A., & Sheikh, S. S. (2016). Breast hamartoma:
A report of 14 cases of an under-recognised and under-
reported entity. International Journal of Surgery Case
Reports, 22, 1–4.
Anani, P. A., & Hessler, C. (1996). Breast hamartoma with
invasive ductal carcinoma: Report of two cases and
review of the literature. Pathology, Research and Prac-
tice, 192, 1187–1194.
Arrigoni, M. G., Dockerty, M. B., & Judd, E. S. (1971). The
identification and treatment of mammary hamartomas.
Surgery, Gynecology & Obstetrics, 133, 577–582.
Bowman, E., Gabriela, O., Okolı, J., Gundry, K., Rizzo, M.,
Gabram-Mendola, S., Manne, U., Smith, G.,
Pambuccian, S., & Bumpers, H. L. (2012). Pseudo-
angiomatous stromal hyperplasia (PASH) of the breast:
A series of 24 patients. The Breast Journal, 18, 242–247.
Cazorla, S., & Arentz, C. (2015). Breast hamartomas-
differential consideration in slow developing breast
asymmetry. JPRAS Open, 3, 17–21. www.jprasopen.
com/article/S2352-5878(14)00009-6/pdf . Accessed
11/11/17.
Chao, T., Chao, H., & Chen, M. (2007). Sonographic
features of breast hamartomas. Journal of Ultrasound
in Medicine, 26, 447–452.
Choi, N., & Ko, E. S. (2010). Invasive ductal carcinoma in
a mammary hamartoma: Case report and review of the
literature. Korean Journal of Radiology, 11, 687–691.
Daya, D., Trus, T., D'Souza, T. J., Minuk, T., & Yemen, B.
(1995). Hamartoma of the breast, an underrecognized
breast lesion: A clinicopathologic and radiographic
study of 25 cases. American Journal of Clinical Pathol-
ogy, 103, 685–689.
Dietrich, C. U., Pandis, N., Andersen, J. A., & Heim, S.
(1994). Chromosome abnormalities in adenolipomas of
the breast: Karyotypic evidence that the mesenchymal
component constitutes the neoplastic parenchyma.
Cancer Genetics and Cytogenetics, 72, 146–150.
Erdem, G., Karakas, H. M., Isik, B., & Firat, A. K. (2011).
Advanced MRI findings in patients with breast
hamartomas. Diagnostic and Interventional Radiology,
17, 33–37.
Fiala, K. H. (2016) Cowden disease (multiple hamartoma
syndrome). emedicine.medscape.com/article/1093383-
overview. Accessed 18 Nov 2017.
Gold, L. I. (1999). The role for transforming growth factor-
beta (TGF-beta) in human cancer. Critical Reviews in
Oncogenesis, 10, 303–360.
Gómez García, E. B., Lobbes, M. B., van de Vijver, K.,
Keymeulen, K., van der Ent, F., Yntema, H. G., et al.
(2012). Occult breast cancer due to multiple calcified
hamartomas in a patient with Cowden syndrome. Case
Reports Radiology, 638725.
Hemangioma of the Breast
Herbert, M., Sandbank, J., Liokumovich, P., Yanai, O.,
Pappo, I., Karni, T., et al. (2002). Breast hamartomas:
Clinicopathological and immunohistochemical studies
of 24 cases. Histopathology, 41, 30–34.
Hogamen, K., & Ostberg, G. (1968). Three cases of post-
lactational breast tumour of peculiar type. Acta
Pathologica et Microbiologica Scandinavica,
73, 169–176.
Liaw, D., Marsh, D. J., Li, J., Dahia, P. L., Wang, S. I.,
Zheng, Z., et al. (1997). Germline mutations of the
PTEN gene in Cowden disease, an inherited breast
and thyroid cancer syndrome. Nature Genetics,
16, 64–67.
McGuire, L.I., & Cohn, D. (1991). Hamartoma of the
breast. Aust NZ J Surg, 61, 713–716.
Metcalf, J. S., & Ellis, B. (1985). Choristoma of the breast.
Human Pathology, 16, 739–740.
Park, S. Y., Oh, K. K., Kim, E. K., Son, E. J., &
Chung, W. H. (2003). Sonographic findings of breast
hamartoma: Emphasis on compressibility. Yonsei
Medical Journal, 44, 847–854.
Rohen, C., Caselitz, J., Stern, C., et al. (1995).
A hamartoma of the breast with an aberration of 12q
mapped to the MAR region by fluorescence in situ
hybridization. Cancer Genetics and Cytogenetics,
84, 82–84.
Sabaté, J. M., Gómez, A., Torrubia, S., Blancas, C.,
Sánchez, G., Alonso, M. C., et al. (2006). Evaluation
of breast involvement in relation to Cowden syndrome:
A radiological and clinicopathological study of patients
with PTEN germ-line mutations. European Radiology,
16, 702–706.
Seth, R. Hamartoma. emedicine.medscape.com/article/
1254012-overview. Accessed 27 Oct 2017.
Tse, G. M. K., Law, B. K. B., Ma, T. K. F., Chan, A. B. W.,
Pang, L. M., Chu, W. C. W., & Cheung, H. S. (2002).
Hamartoma of the breast: A clinicopathological review.
Journal of Clinical Pathology, 55, 951–954.
Wu, C. Y., Lin, S. H., Tu, S. H., Huang, C. S., & Jeng,
C. M. (2003). Hamartoma of the breast. Chinese
Journal of Radiology, 28, 143–148.
Hemangioma of the Breast
Anikó Kovács1 and Ute Krüger2
1
Department of Clinical Pathology, Sahlgrenska
University Hospital, Gothenburg, Sweden
2
Department of Pathology, County Hospital,
Kalmar, Sweden
Synonym
Angioma
143
Definition
Hemangioma is a benign proliferation of endothe-
lial cells that tend to vasoformation, a generic term
for a variety of hamartomatous lesions comprising
vascular tissue. Hemangiomas in the breast are a
benign group of lesions with a broad morphologic
spectrum (Table 1).
Clinical Features
• Incidence
Breast hemangiomas are rare entities,
accounting for 0.4% of all breast tumors,
and occur more often in the breast skin. H
They have to be differentiated from atypical
vascular lesions (▶ Atypical Vascular
Lesions). Coexistence of hemangiomas with
other breast lesions (e.g., ▶ Fibroadenoma)
can occur.
• Age
At any age, from birth to late age. Younger
patients mainly have capillary hemangiomas
in the breast skin.
• Sex
Slight female predilection. Estrogens may be
implicated in its development.
• Site
Most often in the breast skin, followed by
hemangiomas in the subcutaneous fatty tissue.
They can also develop in the breast paren-
chyma, including the intralobular and peri-
ductal connective tissue. Perilobular
hemangiomas can be bilateral (Tavassoli and
Eusebi 2009).
• Size
From a microscopic size up to 18 cm large
mass over 1000 g in weight. Angiomatosis
may measure 9–22 cm. Microscopic heman-
giomas are incidental histological findings
which represent capillary hemangiomas any-
where in the breast, even in the perilobular
and periductal stroma. These lesions can be
unifocal or mutifocal, which usually remain
clinically occult and unapparent. Macro-
scopic hemangiomas are mostly cavernous
hemangiomas that can reach a palpable size
144
Hemangioma of the Breast, Table 1 Classification of mammary hemangiomas
Hemangiomas
of the breast:
localized:
nonparenchymal:
cutaneous
hemangiomas
cavernous:
• sinusoidal
• atypical
and can be revealed by mammography
(Fig. 1. Radiogram, ultrasound, and histolog-
ical features of cavernous hemangioma).
Hemangiomas of larger size may cause swell-
ing and deformity of the breast simulating
inflammatory carcinoma.
• Diagnostics
Difficult to diagnose preoperatively using
conventional imaging modalities since breast
hemangiomas lack pathognomonic character-
istics. A high percentage of hemangiomas
are diagnosed incidentally during imaging
analysis. The diagnosis of hemangioma
should be verified by histopathological exam-
ination after a clinical diagnosis made by
ultrasound and mammography, along with
magnetic resonance imaging (MRI). They
are diagnostically challenging in small core
biopsies (Howitt and Nascimento 2012).
Hemangiomas in the breast parenchyma
produce round opacities and lobular-shaped
masses with circumscribed, microlobulated,
and well-circumscribed margin on
Hemangioma of the Breast
diffuse:
angiomatosis
parenchymal:
non-cavernous: complex:
• perilobular • cavernous
• capillary and capillary
• venous
• epitheloid
• atypical
mammograms and with high density or
equal to the density of the breast parenchyma.
At ultrasonography, hemangiomas appear as
hypoechoic, oval, lobulated masses with
circumscribed and sharp margins. MRI of
breast hemangioma may show a lesion with
internal slow flow and draining vessels,
areas of hemorrhage, thrombosis, and
venous lakes. The differentiation from
angiosarcomas (▶ Angiosarcoma of the
Breast) can be difficult. Minority of vascular
neoplasms contain microcalcification,
phleboliths, and thrombosis. Anamnesis
about previous irradiation of the breast is
important.
• Treatment
Local excision or follow-up with imaging
examination. A complete excision is
recommended for angiomatosis, as it has
a potential for local recurrence. In
children, both surgery and radiotherapy of
cutaneous breast hemangiomas may result
in mammary hypoplasia (Tavassoli and
Hemangioma of the Breast
Hemangioma of the Breast, Fig. 1 A 10 mm large
cavernous hemangioma of the breast in a 52-year-old
female patient. The tumor is composed of dilated, blood-
filled spaces of different sizes and shape with thin fibrous
Eusebi 2009). Any vascular lesion with
atypical morphology on a needle core
biopsy should be completely excised,
regardless of the degree of Ki-67, to exclude
an underlying angiosarcoma. Treatment of
hemangiomas should avoid hemodynamic
145
septa between them (c H&E, 100
magnification). Mam-
mography (a) and ultrasonography picture (b) by courtesy
of Dr. Eva Molnar, Department of Radiology, Sahlgrenska
University Hospital, Gothenburg, Sweden
instability or ulceration and should prevent
or correct deformity.
• Outcome
Favorable, but hemangiomas can grow over time.
Malignant transformation is rare; they are not
likely precursors of angiosarcoma.
146
Macroscopy
Hemangiomas are usually soft, lobulated, well-
circumscribed lesions, albeit unencapsulated
with red or dark-brown, spongy, and hemorrhagic
appearance on cut surface. Discoloration of the
skin may occur if the lesion is near the skin surface
or it is located in the subareolar region.
Microscopy
All vascular lesions of the skin and soft
tissue can be diagnosed in the breast. Mammary
hemangiomas represent benign vascular lesions
which are well circumscribed and lack endothelial
hyperplasia and atypia without interanastomos-
ing vascular channels like in angiosarcoma.
Hemangioma of the Breast, Fig. 2 (a, b) Perilobular
hemangioma as an incidental finding in a 57-year-
old female patient. The coexistence of perilobular
hemangioma and lobular carcinoma in situ (LCIS)
Hemangioma of the Breast
In patients with Kasabach-Merritt syndrome
(hemangioma-thrombocytopenia syndrome),
hemangiomas can be multiple and of variable
size. Moreover, they may become progressively
larger over time.
Perilobular hemangioma is the most common
vascular lesion in the breast comprising incidental
microscopic findings smaller than 5 mm with
a reported frequency of 1–12%. These capillary
hemangiomas in the intra- or the extralobular
stroma form vessels as delicate capillary-
like spaces (Fig. 2a, b H&E) Rarely, perilobular
hemangioma is associated with lobular carcinoma
in situ (LCIS) (Fig. 2c and 2d). The endothelial
cells lining the spaces are flat without hyper-
chromasia or atypia. Hemangiomas are not encap-
sulated and sometimes show anastomosing small
vessels. These features may produce diagnostic
(H&E staining, 40
and 100
magnification). (c) Neg-
ative E-cadherin immunostaining in LCIS (200
magnifi-
cation). (d) Positive 34bE12 immunostaining in LCIS
(100
magnification)
Hemangioma of the Breast
pitfalls. Furthermore, some vascular channels
may show a dissecting growth pattern (Howitt
and Nascimento 2012). Perilobular hemangiomas
may be multiple and bilateral, which require no
treatment (Tavassoli and Eusebi 2009; Howitt and
Nascimento 2012).
Capillary hemangiomas are composed of
proliferating capillary-sized blood vessels and
usually remain clinically occult. They are charac-
terized by compact or lobular collections of
small blood vessels that resemble a pyogenic
granuloma.
Cavernous hemangiomas are composed of
dilated, blood-filled spaces of different sizes and
shapes with thin fibrous septa between them
(Fig. 3 Cavernous Hemangioma: (a) Ultrasono-
graphic picture; (b) H&E). Areas of thrombosis,
infarction, and revascularization may be present.
Within these areas, an increase in the number of
mitoses and calcification may be present. Micro-
papillary structures are consistent with recanaliza-
tion. These findings hamper the diagnosis of
preexisting hemangioma and can lead to the diag-
nosis of an intravascular papillary endothelial
hyperplasia (Masson’s tumor) (Howitt and
Nascimento 2012).
Complex hemangiomas are composed of a
mixture of both dilated vessels and small vessels,
as seen in cavernous and capillary hemangiomas,
respectively.
Hemangioma of the Breast, Fig. 3 A 3 mm large
cavernous hemangioma in a 64-year-old female
patient, in the mastectomy scar (b H&E staining,
100
magnification). Ultrasonography picture (a) by
147
Sinusoidal hemangioma is a distinctive variant
of acquired cavernous hemangioma (Calonje and
Fletcher 1991). It is a well-circumscribed tumor in
the deep dermis and the subcutaneous tissue
which shows intercommunicating vascular chan-
nels arranged in sinusoidal patterns and back-to-
back arrangements without much intervening
stroma and with pseudopapillary growth. Vessel
walls are lined by flattened endothelial cells with
focal pleomorphism and hyperchromatic nuclei.
Interconnected blood vessels with the presence of
pseudopapillae has been described not only in
sinusoidal hemangiomas but focally in spindle
cell hemangioma and juvenile hemangioma.
Venous hemangiomas consist of large venous
channels with variably thickened muscular walls H
lined by a flat endothelial layer without atypia
(Rosen et al. 1985).
Epithelioid hemangioma (angiolymphoid
hyperplasia with eosinophilia) shows a prolifera-
tion of blood vessels surrounded by varying
amounts of inflammatory cells that encircle
but do not destroy the native breast epithelium.
The endothelial cells can be cuboidal or dome-
shaped with papillary tufting (Brodie and
Provenzano 2008).
Atypical hemangiomas show conspicuous
vascular anastomoses, papillary endothelial
hyperplasia, ill-defined borders, cytological
abnormalities with mild degree of pleomorphism,
courtesy of Dr. Bronislava Vályová, Department of
Radiology, Sahlgrenska University Hospital, Gothenburg,
Sweden
148
occasional mitoses, and microthrombi. They can
be categorized into four groups according to their
growth pattern: (a) cavernous, (b) compact capil-
lary, (c) capillary budding type, and (d) combined
atypical hemangiomas with a combination of cav-
ernous (a) and compact capillary subtype (b).
There are no signs of destructive invasion, solid
areas, hemorrhage, or necrosis. Atypical heman-
giomas have no greater risk to develop into
angiosarcoma.
Angiomatosis is an extensive, acquired, or
congenital vascular lesion in young women,
which may involve large areas (9–22 cm) in the
breast growing as non-anastomosing cystic
spaces in between but not infiltrating the breast
glandular structures. The vascular spaces are
lined by flat endothelial cells without atypia and
mitotic activity. The presence of pericytes can be
detected by a-smooth muscle actin (a-SMA)
positivity. Because of lacking the circumscrip-
tion that characterizes mostly the other benign
vascular lesions, distinction from a low-grade
angiosarcoma can be difficult. However,
angiomatosis surrounds the ducts and the lobules
without invading them. Hormonal replacement
therapy with the use of exogenous estrogen may
favor the appearance of angiomatosis.
Immunophenotype
Endothelial markers are overexpressed for CD31,
CD34, factor VIII, and Fli-1. However, Fli-1 is a
marker for both benign and malignant vascular
tumors. The Ki-67 proliferation marker is rarely
>5% in breast hemangiomas, whereas in
angiosarcomas, it is usually >20%. Ki-67 may
help to highlight proliferative activity in border-
line vascular lesions. However, increased Ki-67
immunoreactivity can be seen in a hemangioma at
the site of a prior core biopsy and in thrombi;
therefore, fields with these reactive lesions should
be avoided during assessment of Ki-67 index. The
absence of cell cycle regulatory protein Skp2 can
be used in combination with Ki-67 for hemangi-
oma diagnoses. Androgen receptor expression
may be seen in hemangiomas.
Hemangioma of the Breast
Erythrocyte-type glucose transporter protein
1 (GLUT1) immunoreactivity is found in
all phases of hemangiomas and can be helpful
for differential diagnosis. Pericytes are a-SMA-
positive, whereas most angiosarcomas lack this
marker.
Differential Diagnosis
Hemangiomas should be differentiated from
angiosarcoma, atypical vascular lesions (AVLs),
pseudoangiomatous stromal hyperplasia
(PASH), Mondor’s disease, angiolipoma,
papillary endothelial hyperplasia (Masson’s
tumor), Kaposi-form hemangioendothelioma,
hemangiopericytoma, epithelioid hemangioen-
dothelioma, benign lymphangioendothelioma,
and lymphangioma.
Cutaneous hemangioma should be differenti-
ated from low-grade, postradiation cutaneous
angiosarcoma in the breast (▶ Angiosarcoma of
the Breast). Angiosarcomas are located usually in
the breast parenchyma and are usually larger than
3 cm (Howitt and Nascimento 2012). They appear
as hemorrhagic masses which involves both the
mammary parenchyma and the overlying skin.
Angiosarcomas usually lack a-SMA. MYC gene
amplification has been detected in secondary,
postradiation angiosarcomas but not in AVLs.
Amplification of FLT4 gene (which encodes
VEGFR-3 and belongs to the tyrosine kinase
receptor family) was found in 25% of secondary
angiosarcomas but not in AVLs.
Atypical vascular lesions (AVLs) (▶ Atypical
Vascular Lesions) are limited to the upper dermis
in patients with prior exposure to radiation ther-
apy. Two distinct morphological patterns exist: a
lymphatic type and a vascular type. Occasionally,
both types may be seen simultaneously within
the same lesion. The vascular type of the lesion
shows round to linear, capillary-sized vessels
which grow irregularly within the superficial or
deep dermis. Moderate nuclear atypia may be
encountered, but no mitotic figures. The lesions
frequently show endothelial hobnailing and anas-
tomosing vascular channels.
Hemangioma of the Breast
Pseudoangiomatous stromal hyperplasia
(PASH) (▶ Pseudoangiomatous Stromal Hyper-
plasia) is frequently a microscopic incidental
finding mimicking a vascular lesion. In a dense
collagenous stroma, there are slit-like, elongated,
and regular interanastomosing spaces without
red blood cells. Fibroblasts at the edges of these
spaces resemble endothelial cells. They can be
flat or plump, sometimes multinucleated, or can
aggregate into fascicles. Typically, PASH shows
immunostaining for vimentin and CD34, nuclear
staining for progesterone receptor, but not for
estrogen receptor, factor VIII, and CD31. In
more cellular fascicular lesions, the stromal
cells acquired a-SMA and desmin positivity.
PASH can be seen in male patients with
gynecomastia.
Mondor’s disease appears as a cord-like, tender
subcutaneous mass that comprises a phlebitis of the
vena thoracoepigastrica accompanied by peri-
phlebitis and thrombosis (Fig. 4. (a, b) H&E.
(c, d, e) Masson trichrome).
Angiolipomas are diagnosed mostly in the skin
as often painful and multiple lesions (Tavassoli
and Eusebi 2009). Histologically, they are an
admixture of mature adipose tissue and capillary
hemangioma often with hyaline microthrombi. As
hemangiomas, they also lack cellular atypia and
show low mitotic activity. Vascular-predominant
cellular angiolipoma may be mistaken for heman-
giomas, but hemangioma shows vessels of vari-
ous calibers with no fibrin microthrombi (Howitt
and Nascimento 2012).
Papillary endothelial hyperplasia (Masson’s
tumor) is composed of vascular spaces lined by
endothelial cells without atypia, necrosis, or
mitotic activity that surrounds hyalinized cores
representing organized and recanalized thrombus,
measuring usually less than 2 cm in diameter with
circumscribed margins. The papillary appearance
results from numerous elongated and branching
papillary fronds composed of dense and relatively
acellular collagenous stroma. Papillary endothe-
lial hyperplasia arising in an irradiated breast has
been described.
Kaposi-form hemangioendothelioma is a
locally aggressive vascular tumor with “borderline
149
malignant” behavior, often associated with
Kasabach-Merritt syndrome in children. The lesion
shows endothelial-derived spindle cell prolifera-
tion with dense hyaline stromal response, forming
irregular nodules which contain glomeruloid nests
of rounded or epithelioid endothelial cells with
abundant eosinophilic cytoplasm. A lymphatic ori-
gin is evidenced by the expression of VEGFR-3
and D2–40.
Hemangiopericytoma shows irregular,
staghorn, and slit-like vascular channels within a
cellular stroma composed of mildly pleomorphic
round, oval, or elongated spindle cells with infre-
quent mitoses. The lesion may be partially encap-
sulated (Brodie and Provenzano 2008).
Epithelioid hemangioendothelioma comprises H
epithelioid pleomorphic cells in cords and short
strands with infiltrative margins within a
myxohyaline matrix. Intracytoplasmic lumina
are present, occasionally containing erythro-
cytes. These tumors express not only vascular
antigens such as CD31, CD34, and factor VIII,
but even cytokeratin 7 and 18, but not
cytokeratin 14 (Brodie and Provenzano 2008).
A cutaneous form of epithelioid hemangioen-
dothelioma presented as an ulcerated areolar
mass with recurrence 1 year after surgery.
CAMTA1 is useful for diagnosing epithelioid
hemangioendothelioma.
Benign lymphangioendothelioma shows large
irregular empty spaces within stromal collagen and
adipose tissue with lymphoid aggregates around the
vascular spaces (Tavassoli and Eusebi 2009).
Mammary lymphangiomas are uncommon,
and they can occur both in children and adults,
involving most commonly the upper-outer quad-
rant of the breast or the axillary tail.
Lymphangiomas constitute malformations with
congenital weakness of lymphatic vessel walls
causing blockage of the lymphatic channels
that are unable to communicate with the
venous network. They are poorly demarcated
vascular lesions in the breast parenchyma with
irregular spaces containing lymph and lympho-
cytes. The vascular spaces are lined by a single
layer of D2–40-positive flattened endothelial
cells.
150
Hemangioma of the Breast, Fig. 4 Mondor’s disease.
A 48-year-old female patient with abscess in the right
breast. There was thrombophlebitis at the periphery of the
References and Further Reading
Brodie, C., & Provenzano, E. (2008). Vascular prolifera-
tions of the breast. Histopathology, 52, 30–44.
Calonje, E., & Fletcher, C. D. M. (1991). Sinusoidal hem-
angioma. A distinctive benign vascular neoplasm within
the group of cavernous hemangiomas. The American
Journal of Surgical Pathology, 15, 1130–1135.
Hemangioma of the Breast
lesion. (a, b) H&E staining (200
magnification). (c–e)
Masson trichrome staining (100
, 200
and
100
magnification)
Howitt, B., & Nascimento, A. F. (2012). Vascular lesions
of the breast. Surgical Pathology, 5, 645–659.
Rosen, P. P., Jozefczyk, M. A., & Boram, L. H. (1985).
Vascular tumors of the breast. IV. The venous heman-
gioma. The American Journal of Surgical Pathology, 9,
659–665.
Tavassoli, F. A., & Eusebi, V. (2009). Tumors of the mammary
gland (AFIP atlas of tumor pathology, series 4, fascicles
10, pp. 283–290). Silver Spring, Maryland, USA.
HER2 in Breast Cancer
HER2 in Breast Cancer
Laura Annaratone2, Ivana Sarotto1 and
Caterina Marchiò1,2,3
1
Unit of Pathology, Candiolo Cancer Institute
FPO-IRCCS, Candiolo, Italy
2
Department of Medical Sciences,
University of Turin, Turin, Italy
3
Institut Curie, Paris, France
Synonyms
ERBB2
Definition
HER2, whose official name is “erb-b2 receptor
tyrosine kinase 2,” is a tyrosine kinase receptor
belonging to the human epidermal growth factor
receptor family. It represents the second member
of this family (and therefore called HER2), and it
is an orphan receptor, meaning that no specific
ligands are known for this receptor.
Features
About 15% of all invasive breast carcinomas pre-
sent HER2 overexpression and/or HER2 gene
amplification, thus identifying a subset of breast
carcinomas that can be treated in a targeted fash-
ion. It has been shown that HER2-positive breast
carcinomas are often poorly differentiated and
of no special types (NST) (▶ Invasive Carcinoma
NST).
Ductal carcinoma in situ (DCIS) of high
nuclear grade with comedonecrosis (▶ Ductal
Carcinoma In Situ) is frequently HER2-positive
and may be associated with an invasive carci-
noma. However, HER2 overexpression in DCIS
is not considered for anti-HER2 therapy. Cells
of Paget disease of the nipple (▶ Paget Disease
of the Nipple) are typically HER2-positive.
The monoclonal antibody trastuzumab
(Herceptin ®) directed against HER2 is currently
administered together with chemotherapy in
151
patients affected by an invasive carcinoma in
the neoadjuvant, adjuvant, and metastatic set-
tings. Other agents have been developed over
the years and are used in the metastatic setting
or within the context of randomized clinical
trials.
After more than 15 years of translational
research in HER2-positive breast cancer, several
markers with prognostic value have been identi-
fied; however, the best predictive factor for
likeliness of response to anti-HER2 agents
remains HER2 overexpression/amplification.
Recently, the NRG trial B-47 (ClinicalTrials.gov
identifier: NCT01275677) has confirmed the lack
of benefit from adjuvant trastuzumab for patients
whose tumors show a score 1+ or 2+ in immuno- H
histochemistry and lack of gene amplification
(Fehrenbacher et al. 2018). Therefore, as stated
by the American Society of Clinical Oncology
(ASCO) and College of American Pathologists
(CAP) 2018 recommendations (Wolff et al.
2018), HER2 gene amplification assessed by in
situ hybridization (ISH) and protein over-
expression assessed by immunohistochemistry
(IHC) remain the primary predictors of respon-
siveness to HER2-targeted therapies in breast
cancer.
More recently, studies based on massively
parallel sequencing have unveiled the presence
of activating mutations affecting regions coding
for the tyrosine kinase domain or for the trans-
membrane domain. More frequently these muta-
tions are found in the context of breast
carcinomas lacking HER2 overexpression
and/or amplification. Currently the potential
benefit of targeted anti-HER2 therapies is being
explored in clinical trials (Hyman et al. 2018; Ma
et al. 2017).
Application
Current HER2 Testing
Approach
Each newly diagnosed invasive breast cancer is
subjected to HER2 testing, and so are relapses and
metastatic deposits. Identification of patients with
a HER2-positive tumor relies on the identification
152
of the target (HER2) by either frontline in situ
hybridization (ISH) or immunohistochemistry
(IHC) followed by ISH in borderline cases.
When applying a two-step approach, IHC is
applied first and scored according to a three-tier
scoring system according to the ASCO/CAP 2018
guidelines (score 0/1+, score 2+, score 3+; see
Fig. 1a–c, respectively) (Wolff et al. 2018). When-
ever an equivocal overexpression (score 2+) is
encountered, the sample must be subjected to
ISH to verify the presence of HER2 gene
amplification.
Cleared Methods
Three methods of ISH have been introduced in
breast pathology and are FDA approved for HER2
gene assessment in breast cancer: fluorescence
ISH (FISH), chromogenic ISH (CISH), and silver
HER2 in Breast Cancer, Fig. 1 HER2 immunohisto-
chemistry. (a) weak, incomplete membrane staining in
>10% of tumor cells (score 1+). (b) moderate, complete
HER2 in Breast Cancer
ISH (SISH). ISH tests, either in dark or in bright
field, can be performed with a single-color probe
(HER2 gene probe) or with a dual-color probe
(probes for the HER2 gene and the centromere
of the chromosome 17 (CEP17)).
Alternative probes mapping to the chromo-
some 17 have been used and proposed by several
groups; however, it is important to note that chro-
mosome 17 is highly recurrently altered in breast
cancers (Arriola et al. 2008; Isola et al. 2004;
Marchio et al. 2009; Rondon-Lagos et al. 2014);
therefore this approach should be strongly
discouraged.
Alternative techniques to assess the HER2 sta-
tus, such as mRNA assays (e.g., RT-PCR), did not
reach sufficient evidence to warrant inclusion, at
least when dealing with unselected patients (Wolff
et al. 2018).
membrane staining in >10% of tumor cells (score 2+). (c)
strong, complete membrane staining in the vast majority of
tumor cells (score 3+)
HER2 in Breast Cancer 153

Methodology of ISH Scoring HER2/CEP17 ratio is calculated, and then the

The evaluation of HER2 expression by immuno-
histochemistry or HER2 gene status by ISH is not
univocal, and slight differences can apply
depending on the use of American or European
recommendations. However, the majority of
countries agreed upon those edited by the
ASCO/CAP. The 2013 ASCO/CAP guidelines
have introduced the so-called ISH algorithm
(Table 1), and this has been confirmed by the
recently updated recommendations (Wolff et al.
2013, 2018). By following the algorithm, first the
HER2 copy number values are examined. For
each category of ISH results, additional work-
ups may be needed to adjudicate the final result.
Here below, following the ASCO/CAP 2018 rec-
ommendations, categories for positive and nega-
tive test results are illustrated.
HER2 Positive
By IHC: score 3+, circumferential membrane
staining that is complete, intense, and in >10%
of tumor cells (this is readily appreciated using a

HER2 in Breast Cancer, Table 1 Summary of changes of HER2 evaluation by ISH over the ASCO/CAP guideline
updates (2007, 2013, 2018). FDA-recommended thresholds are also reported H
NOT
Guideline Method AMP/positive Equivocal AMP/negative
FDA/ HER2/ 2 // <2
EMA CEP17
ratio
HER2 >4 4
copy
number
ASCO/ HER2/ >2.2 1.8–2.2 <1.8
CAP CEP17
2007 ratio
HER2 >6 4–6 <4
copy
number
ASCO/ ISH (a) HER2/CEP17 ratio 2, regardless of HER2/CEP17 <2 with HER2/CEP17
CAP algorithm HER2 copy number HER2 copy number 4 and <2 with HER2
2013 (b) HER2/CEP17 <2 but HER2 copy <6 copy number
dual- number 6 <4
color
ASCO/ HER2 6 4 and <6 <4
CAP copy
2013 number
single-
color
ASCO/ ISH (a) HER2/CEP17 ratio 2, regardless of HER2/CEP17 <2 with HER2/CEP17
CAP algorithm mean HER2 copy number (but additional HER2 copy number 4 and <2 with HER2
2018 work-up needed in case HER2 copy <6 (additional work-up copy number
dual- number mean is <4) needed) <4
color (b) HER2/CEP17 <2 but HER2 copy
number 6 (but additional work-up
needed)
ASCO/ HER2 6 4 and <6 (additional <4
CAP copy work-up needed)
2018 number
single-
color
AMP Amplified, ASCO American Association of Clinical Oncology, CAP College of American Pathologists, EMA
European Medicines Agency, FDA Food and Drug Administration, NOT AMP Not Amplified
154 HER2 in Breast Cancer

low power objective and observed within a homo- Additional work-up for scenarios in which the
geneous and contiguous invasive cell population). tumor cell population shows HER2/CEP17 ratio
2.0 and average HER2 copy number <4.0 sig-
By ISH:
nals/cell.
This is a challenging scenario in which, for
– Dual-probe assay: HER2/CEP17 ratio 2.0
instance, tumors harboring monosomy of chro-
and average HER2 copy number 4.0 sig-
mosome 17 easily lead to ratio values >2 despite
nals/cell (Fig. 2a).
a not high absolute HER2 copy number (mean of
– Dual-probe assay: HER2/CEP17 ratio 2.0
2 or 3). Importantly, Press and colleagues have
and average HER2 copy number <4.0 sig-
recently shown that these patients seem not to
nals/cell: additional work-up needed.
benefit from trastuzumab treatment (Press
– Dual-probe assay: HER2/CEP17 ratio <2.0
et al. 2016).
and average HER2 copy number 6 signals/
The updated guidelines suggest that, if not
cell: additional work-up needed.
already assessed by the institution or laboratory
– Single-probe assay: average HER2 copy num-
performing the ISH test, IHC testing for HER2
ber 6.0 signals/cell: concurrent score 3+ in
should be performed (using sections from the
IHC should be documented, otherwise dual
same tissue sample used for ISH) and the slides
colour ISH should be performed.

HER2 in Breast Cancer, Fig. 2 Dual-probe HER2 fluo-
rescence in situ hybridization (FISH). (a) nuclei of tumor
cells homogeneously show multiple red signals (HER2
signals) clustering together. (b) tumor cells display a
mean HER2 copy number of 4.1 (red signals) and a
CEP17 copy number of 3 (green signals) leading to a
HER2/CEP17 ratio of 1.4. (c) tumor cells harbor a mean
HER2 copy number of 2 (red signals) and a CEP17 copy
number of 1.9 with a HER2/CEP17 ratio of 1.05
HER2 in Breast Cancer
from both ISH and IHC should be reviewed
together to guide the selection of areas to score
by ISH:
(a) IHC result is 3+: diagnosis is HER2-positive.
(b) If the IHC result is 0 or 1+: diagnosis is
HER2-negative with a comment*.
(c) If IHC result is 2+, recount ISH by having an
additional observer, blinded to previous ISH
results, and count at least 20 cells that include
the area of invasive cancer with IHC 2+
staining:
– If reviewing the count by the additional
observer changes the result into another
ISH category, the result should be adjudi-
cated per internal procedures to define the
final category.
– If the count remains an average of <4.0
HER2 signals per cell and the HER2/
CEP17 ratio is >2.0, diagnosis is HER2-
negative with a comment*.
*The Expert Panel recommends the fol-
lowing comment: “Evidence is limited on the
efficacy of HER2-targeted therapy in the
small subset of cases with a HER2/CEP17
ratio of 2.0 and an average HER2 copy
number of <4.0 per cell. In the first generation
of adjuvant trastuzumab trials, patients in this
subgroup who were randomly assigned to the
trastuzumab arm did not seem to derive an
improvement in disease-free or overall sur-
vival, but there were too few such cases to
draw definitive conclusions. IHC expression
for HER2 should be used to complement ISH
and define HER2 status. If the IHC result is
not 3+ positive, it is recommended that the
specimen be considered HER2 negative
because of the low HER2 copy number by
ISH and the lack of protein overexpression.”
(Type, evidence based; evidence quality,
intermediate; strength of recommendation,
strong)
Additional work-up for scenarios in which
the tumor cell population shows HER2/
CEP17 ratio <2.0 and average HER2 copy
number 6.0 signals/cell.
155
The ISH algorithm in this case has allowed
HER2 gene amplification not to be
underestimated in a subset of tumors harbor-
ing high HER2 copy numbers together with
CEP17 gain or amplification, a scenario that
would lead to a HER2/CEP17 ratio <2 even in
the presence of a high HER2 copy number.
The phenomenon of CEP17 gain/amplifica-
tion has been demonstrated by the study of
microarray-based comparative genomic
hybridization (array CGH) (Marchio et al.
2009; Moelans et al. 2010; Yeh et al. 2009)
and further confirmed by other indirect
methods (Ercolani et al. 2017; Sapino et al.
2014). Although these carcinomas account for
a minority of cases, they are also the most H
challenging in diagnostic practice.
Now, in the 2018 updated recommenda-
tions, the recommended additional work-up
is as follows: if not already assessed by the
institution or laboratory performing the ISH
test, IHC testing for HER2 should be
performed (using sections from the same tis-
sue sample used for ISH), and the slides from
both ISH and IHC should be reviewed
together to guide the selection of areas to
score by ISH:
(a) IHC result is 3+: diagnosis is HER2-positive.
(b) If the IHC result is 0 or 1+, diagnosis is
HER2-negative with a comment**.
(c) If the IHC result is 2+, recount ISH by having
an additional observer, blinded to previous
ISH results, and count at least 20 cells that
include the area of invasion with IHC 2+
staining:
– If reviewing the count by the additional
observer changes the result into another
ISH category, the result should be adjudi-
cated per internal procedures to define the
final category.
– If the HER2/CEP17 ratio remains <2.0
with >6.0 HER2 signals per cell, diagnosis
is HER2-positive.
**The Expert Panel recommends the fol-
lowing comment: “There are insufficient data
on the efficacy of HER2-targeted therapy in
cases with a HER2 ratio of <2.0 in the
156
absence of protein overexpression because
such patients were not eligible for the first
generation of adjuvant trastuzumab clinical
trials. When concurrent IHC results are nega-
tive (0 or 1+), it is recommended that the
specimen be considered HER2 negative.”
(Type, evidence based; evidence quality,
intermediate; strength of recommendation,
strong)
An additional remark must be made regarding
HER2 heterogeneity. A matter of debate is
represented by the pattern of heterogeneity to be
considered clinically meaningful to report an ISH
result as positive featuring a heterogeneous pat-
tern of tumor population. At present, the experts
of the ASCO/CAP guidelines (Wolff et al. 2013,
2018) contend that only spatially clustered hetero-
geneity is significant and should be recorded
(Wolff et al. 2013, 2018); however, scattered
HER2-amplified cells, although of unknown clin-
ical relevance, are more frequent (Sapino et al.
2014) and usually represent a source of inter-
observer disagreement.
Regarding heterogeneity, we draw the readers’
attention to a potential pitfall in ISH testing that can
be encountered in residual carcinomas following
taxane-based neoadjuvant chemotherapy: reports
are on record on the possible presence of giant
syncytial multinucleated-looking neoplastic cells
harboring a very high number of HER2 signals
scattered within a background of tumor cells lacking
HER2 amplification. A polyploidy status induced by
chemotherapy rather than a focal amplification of
the HER2 locus has been advocated as the phenom-
enon underlying this pattern, as suggested by the
presence of additional copies of CEP17 as well as of
many regions in other chromosomes (Valent et al.
2013). A word of caution should be voiced in order
not to misinterpret this phenomenon as heteroge-
neous HER2 amplification.
HER2 Equivocal
By IHC: score 2+, weak to moderate complete
membrane staining observed in >10% of tumor
cells. In this scenario a reflex test (same specimen
using ISH) or a new test (new specimen if avail-
able, using IHC or ISH) must be ordered.
HER2 in Breast Cancer
By ISH:
– Single-probe assay: average HER2 copy num-
ber 4.0 and <6.0 signals/cell – If IHC results
score 2+ (equivocal), it is recommended to also
perform dual-probe ISH (and follow related
recommendations).
– Dual-probe assay: HER2/CEP17 ratio <2.0
and average HER2 copy number 4.0 and
<6.0 signals/cell (Fig. 2b): additional work-
up needed.
Additional work-up for scenarios in which the
tumor cell population shows HER2/CEP17 ratio
<2.0 and HER2 copy number 4 and <6.0 sig-
nals/cell.
If not already assessed, IHC testing for HER2
should be performed (using sections from the
same tissue sample used for ISH), and the slides
from both ISH and IHC should be reviewed
together to guide the selection of areas to score
by ISH:
(a) IHC result is 3+: diagnosis is HER2-positive.
(b) IHC result is 0 or 1+: diagnosis is HER2-
negative with a comment***.
(c) If IHC result remains 2+, recount ISH by
having an additional observer, blinded to pre-
vious ISH results, and count at least 20 cells
that include the area of invasion with IHC 2+
staining:
– If reviewing the count by the additional
observer changes the result into another
ISH category, the result should be adjudi-
cated per internal procedures to define the
final category.
– If the count remains a HER2/CEP17 ratio
<2.0 and average HER2 copy number
4.0 and <6.0 signals/cell, diagnosis is
HER2-negative with a comment***.
***Comment recommended by the Expert
Panel: “It is uncertain whether patients with an
average of 4.0 and <6.0 HER2 signals per
cell and a HER2/CEP17 ratio of <2.0 benefit
from HER2 targeted therapy in the absence of
protein overexpression (IHC 3+). If the spec-
imen test result is close to the ISH ratio
HER2 in Breast Cancer
threshold for positive, there is a high likeli-
hood that repeat testing will result in different
results by chance alone. Therefore, when IHC
results are not 3+ positive, it is recommended
that the sample be considered HER2 negative
without additional testing on the same
specimen.”
(Type, evidence based; evidence quality,
intermediate; strength of recommendation,
strong)
The experts also suggest that clinical correlation
with other factors in a particular case (such as grade
and special histologic subtypes) or repeat testing of
other tissue samples from the patient may also be
appropriate in this setting. In particularly challeng-
ing cases or if the results are in question, expert
consultation may be appropriate and may include
alternative probes or other genetic methods. How-
ever, alternative probes should not be used as stan-
dard practice due to limited data on outcomes for
this subset of patients. Regarding the latter, the
experts acknowledge that this group of carcinomas
has been frequently tested by ISH using multiple
chromosome 17 probes at once, many not analyti-
cally or clinically validated. Such indiscriminate
testing often results in four or more ISH ratios
being described in a single test report and a final
designation of HER2 gene amplified if just a single
ratio is >2.0. After careful consideration of this
practice and available data, the Expert Panel
strongly recommends against this as a routine test-
ing strategy.
According to this work-up, the equivocal result
is in a way “sorted out” as negative; nevertheless,
the experts acknowledge that data on this sub-
group of patients are scant. Cases as such would
be defined as HER2 double-equivocal breast car-
cinomas, i.e., breast carcinomas with an equivocal
expression of the HER2 protein (score 2+ by IHC)
and mean HER2 copy numbers in the equivocal
range (i.e., HER2/CEP17 ratio <2.0 and mean
HER2 copy numbers 4 and <6 by ISH). These
breast carcinomas fall into the luminal B subtype
when using the IHC surrogate proposed by the
St. Gallen Consensus (▶ Invasive Carcinoma
NST), as they are typically estrogen receptor pos-
itive (▶ Hormone Receptors in Breast Cancer)
157
and usually display a relatively high mean of
Ki67 indices (Ballard et al. 2017; Ragazzi et al.
2017; Sapino et al. 2014). If compared to HER2-
negative disease, these tumors display a signifi-
cantly higher prevalence of grade 3 carcinomas,
harbor significantly higher proliferation indices,
and show a significantly higher proportion of
lymph node metastases at presentation (Ballard
et al. 2017; Ragazzi et al. 2017; Sapino et al.
2014). If compared to HER2-positive disease,
HER2 double-equivocal carcinomas show a sig-
nificantly higher rate of ER positivity and a sig-
nificantly lower prevalence of histological grade
3 carcinomas (Ballard et al. 2017; Ragazzi et al.
2017; Sapino et al. 2014). Data on the efficacy of
response to anti-HER2 therapy are not available at H
present, and we only know that these carcinomas
do not do worse than HER2-negative breast car-
cinomas treated with anthracycline- and taxane-
based chemotherapy (Press et al. 2016). Recently,
an extensive genomic analysis has revealed that
double-equivocal carcinomas are preferentially
luminal B also at the transcriptomic level. In addi-
tion, in these cases, HER2 mRNA levels are more
widely overlapping with HER2-negative rather
than with HER2-positive breast carcinomas.
However, they display a high risk of recurrence
by Prosigna ® assay, even when they present good
prognostic features (unifocal, <2 cm, node nega-
tive/micrometastatic carcinomas) (Marchio et al.
2018). Interestingly, a subset of double-equivocal
cases is classified as HER2-enriched by gene
expression analysis in spite of their double-
equivocal status, opening the possibility to
explore the beneficial effect of anti-HER2 agents
in this subgroup of patients (Marchio et al. 2018).
In addition, at the mutational level, double-
equivocal carcinomas show PIK3CA and TP53
mutation rates more similar to ER-positive/
HER2-positive rather than to ER-positive/HER2-
negative carcinomas, supporting the theory that
these cases represent an aggressive subgroup of
ER-positive carcinomas (Marchio et al. 2018).
The responses to chemotherapy and
trastuzumab in this category of patients are still
unclear. In a cohort of patients treated in the neo-
adjuvant setting with trastuzumab-containing che-
motherapy, double-equivocal carcinoma patients
158
HER2 in Breast Cancer, Table 2 Prevalence of HER2
mutations in the distinct PAM50-defined molecular sub-
types (TCGA data from www.cbioportal.org). (Data
Luminal (A/B)
Luminal A
ILC Luminal A
Luminal B
HER2-enriched
Basal-like
ILC invasive lobular carcinoma, N number of cases
had low rates of pathologic complete response
(pCR), but a great proportion reached near-pCR:
when these two categories were grouped, the dif-
ference in terms of response rate was not statisti-
cally significant between double-equivocal and
HER2-positive carcinomas (Marchio et al.
2018). However, larger studies are warranted to
ascertain the real impact of chemotherapy and
anti-HER2 therapy in this specific subset of breast
carcinomas.
HER2 Negative Result
By IHC:
– Score 1+: incomplete membrane staining
that is faint/barely perceptible and in
>10% of tumor cells.
– Score 0: (i) no staining is observed or
(ii) membrane staining that is incomplete
and is faint/barely perceptible and in
10% of tumor cells.
By ISH:
– Single-probe assay: average HER2 copy
number <4.0 signals/cell: double-check
whether concurrent IHC 0, 1+ and/or con-
current dual-probe ISH with a result of
HER2 copy number <4.0 signals/cell.
– Dual-probe assay: HER2/CEP17 ratio <2.0
and average HER2 copy number <4.0 sig-
nals/cell (Fig. 2c).
HER2 Mutations
Studies based on massively parallel sequencing
have unveiled the presence of a subgroup of breast
carcinomas harboring HER2 mutations (Bose
HER2 in Breast Cancer
derived from the TCGA study by Curtis et al. (2012) and
from Ciriello et al. (2015))
Frequency of HER2 mutations
N %
5/321 1.6
3/235 1.3
4/106 4
2/133 1.5
2/58 3
0/81 0
et al. 2013; Lee et al. 2006). These cases account
for about 1.3–4% of all breast cancers, depending
on the molecular subtype and the histologic type.
They represent an important subgroup of HER2-
activated cancers that may be missed by standard
HER2 positivity assessment (IHC or ISH).
Indeed, these mutations are found in breast carci-
nomas regardless of the presence of HER2 ampli-
fication, occurring in both ER-positive/HER2-
negative diseases and HER2-enriched cancers
(Table 2) (Petrelli et al. 2017). For this reason,
they represent tumors considered to be HER2-
negative (by the routinely used methods and algo-
rithms at present) but with active HER2 signaling
that can be targeted by anti-HER2 agents.
In breast cancer, HER2 mutations are clustered
mainly in two different regions: the extracellular
domain, at exon 8, and the kinase domain, at exons
19 and 20. The majority of HER2 mutations
described so far in the context of breast cancer
affect codons belonging to the kinase domain.
The most frequent HER2 mutations are L755S,
V777L, and D769H or D769Y: all of them are
activating mutations, likely driving tumorigene-
sis. In preclinical studies, L755S is related to
resistance to the reversible HER2 inhibitor
lapatinib, but it is sensitive to the irreversible
HER2 inhibitor, neratinib (Bose et al. 2013;
Kancha et al. 2011), while the other two mutations
(V777L, and D769H or D769Y) are associated
with sensitivity to trastuzumab, lapatinib, and
neratinib (Bose et al. 2013; Petrelli et al. 2017).
Different studies have suggested that invasive
lobular carcinomas (▶ Invasive Lobular Carci-
noma) are enriched in HER2 mutations (Ciriello
et al. 2015; Lien et al. 2015; Ross et al. 2013).
HER2 in Breast Cancer
A high HER2 mutation rate has also been reported
in metastatic breast cancer. Interestingly, in this
subset of tumors, mutations are more frequent in
patient after the administration of trastuzumab
(Fang et al. 2014). In addition, HER2 mutations
can represent a marker of resistance to anti-HER2
therapy in this subset of patients (Park et al. 2015).
Using a basket-trial approach, Hyman et al.
(2018) have tested the effects of neratinib on
many patients with HER2 mutations. Sequenc-
ing analysis demonstrated that most patients
whose HER2 mutations were present in all the
tumor cells responded to neratinib, whereas
those with HER2 mutations in only a subset of
the tumor cells did not respond. Neratinib
exhibited the greatest degree of activity in
patients with breast cancer (n = 25 total, objec-
tive response rate at week 8 of 32%) with mis-
sense mutations involving the extracellular and
kinase domains, as well as insertions in the
kinase domain. These tumors were all classified
as HER2-negative (lack of amplification) at the
time of enrolment per established guidelines
(Wolff et al. 2013).
Recently, preclinical data have shown that the
co-occurrence of a HER2 mutation in HER2
amplified tumors reduces the efficacy of therapies
commonly used to treat HER2-positive breast
cancer, particularly in metastatic and previously
HER2 inhibitor-treated patients, as well as poten-
tially in patients scheduled for first-line treatment
(Cocco et al. 2018). These data may suggest the
need of clinical studies testing the efficacy of
neratinib in breast cancer patients whose tumors
carry both amplification and mutation of the
HER2 gene (Cocco et al. 2018).
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160
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Hormone Receptors in Breast
Cancer
Abeer M. Shaaban1 and Valerie Speirs2
1
Department of Cellular Pathology, Queen
Elizabeth Hospital Birmingham and University of
Birmingham, Birmingham, UK
2
Leeds Institute of Cancer and Pathology,
University of Leeds, Leeds, UK
Synonyms
AR; ER; ER b; PR
161
Definition
Estrogen receptor a, progesterone receptor,
androgen receptor, estrogen receptor b.
Description
Hormone receptors are members of the steroid
receptor family. They encompass estrogen
receptor (ERa), progesterone receptor (PR),
androgen receptor (AR), and estrogen receptor
b (ER b).
PR receptors exist in two isoforms, namely,
PRA and PRB. The levels are equally
distributed in normal breast, but during carcino- H
genesis there is often an imbalance (toward
increase in PRA).
ERb was identified 10 years after the description
of ERa. Since then five ERb isoforms have been
described, of which three (ERb1, ERb2, and
ERb5) are expressed in the breast.
Clinical Features
• Incidence of ER/PR positive carcinoma
Overall, over two thirds of breast cancers
are ER positive. Low grade no special
type cancers (▶ Invasive Carcinoma NST)
and special histological types including tubu-
lar (▶ Tubular Carcinoma), mucinous
(▶ Invasive Mucinous Carcinoma),
and classical lobular carcinoma (▶ Invasive
Lobular Carcinoma) are often positive.
Data from a UK National Biomarker audit
of over 40,000 cancers showed ER positivity
in 83.7% of primary breast cancer and 69.7%
of metastatic breast cancer. PR was positive in
68.8% and 44.6% of primary and metastatic
breast cancers, respectively (Guidelines
Working Group of the UK National Coordi-
nating Committee for Breast Pathology
2016).
• Effect of age
In the female breast, the expression of ER
in normal mammary epithelial cells increases
with age. This age effect is not seen in the
male breast.
162
• Effect of sex
The vast majority of male breast cancers
are hormone receptor positive with a
positivity rate of 82–84% for ER and
71–74% for PR (Shaaban et al. 2012;
Humphries et al. 2017) (▶ Male Breast
Cancer).
• Effect of treatment on hormone receptor
expression
Change in the level of expression and hor-
mone receptor status following neoadjuvant
chemotherapy has been observed in a small
proportion of cases (2.5–17% for ER and
5.9–51.7% for PR). This includes change
from positive to negative status and vice
versa (van den Ven et al. 2011; Gahlaut
et al. 2016). The impact on management is
not clear, but this may provide new options
for therapy in previously hormone receptor
negative tumors that switch to a positive
status.
Mechanism of Action and Function
Hormone receptors are ligand-activated transcrip-
tion factors. There are two principal modes of
activation, summarized schematically in Fig. 1
using ER as an example. The traditional mecha-
nism of action is ligand-dependent transcription.
Upon entering the cell, hormones bind to their
cognate receptors in the cytoplasm. Following
binding they dissociate from their inhibitory chap-
erone complexes and then translocate to the
nucleus. Gene activation is accomplished through
binding to consensus ER response elements
(EREs), as in the classical mode of action, or by
tethering, via Fos and Jun (components of AP-1
transcription factor), to other DNA-bound
transcription factors such as AP-1 (activator
protein 1) and SP1 (specificity protein 1)
(nonclassical pathway). Hormone receptors can
also be activated indirectly through growth factor
binding which triggers the nonclassical pathway
via activation of MAP kinase (mitogen-activated
protein kinase) signaling. Typically this involves
epidermal growth factor, insulin growth factor-1,
or transforming growth factor a (Lee et al. 2001).
Hormone Receptors in Breast Cancer
While the majority of hormone receptors in their
active state reside in the nucleus, there is evidence
for a small pool (~5%) which is located in the cell
membrane (Levin and Hammes 2016). This was
described initially as non-genomic ER activity but
is now more commonly referred to as membrane-
initiated steroid signaling (MISS) (Nemere et al.
2003). MISS is also shown in Fig. 1. Here, ligand-
receptor binding at the cell membrane initiates a
rapid activation of the nonclassical signaling path-
way, typically occurring in minutes. The impact of
extranuclear hormone receptor signaling via
MISS is still at an experimental stage and has yet
to translate into the clinic.
Immunohistochemical Interpretation
Hormone receptors are expressed in the nuclei of
cancer cells. Cytoplasmic and/or membranous
staining should be discarded. Normal breast tissue
shows scattered positive luminal cells among a
majority of negative cells. These serve as a posi-
tive internal control.
It is essential that all laboratories providing
immunohistochemical staining and reporting of
ER/PR as predictive/prognostic markers
should participate in an appropriate external
quality assurance program, an example of
which is the UK National External Quality
Assessment Scheme for Immunocytochemistry
and in situ hybridization (UK NEQAS ICC
and ISH).
Scoring
There are several recognized systems for ER/PR
scoring with variation in the cutoff value for
ER/PR positivity internationally. The current
CAP/ASCO/RCPath guidelines by the College
of American Pathologists, American Society
of Clinical Oncology, and the Royal College
of Pathologists, UK, respectively, recommend a
cutoff value of 1% of any intensity to indicate
positivity (Guidelines Working Group of the UK
National Coordinating Committee for Breast
Pathology 2016; Hammond et al. 2010).
Hormone Receptors in Breast Cancer 163

Growth factor

E2

ER ER

HSP MAP kinase

activation
ER Inactive

Cytoplasm

ER
ER P
Fos
Foss JJun
un
n
H
Nucleus AP1/SP1
P P
ER ER ER
ER P
Fos
Foss Jun
n
ERE

Classical pathway AP1/SP1

Non-classical pathway

mRNA

Protein

Estrogen action

Hormone Receptors in Breast Cancer, traditional ligand- dependent transcription pathway and
Fig. 1 Mechanism of action of estrogen receptor. The the indirect activation through growth factor binding
receptor can be activated via two mechanisms; the

The most widely used scoring system is the
Allred (Quick) score. The score is a sum of the
intensity (0, 1, 2, 3) and percentage (scores 0, 1, 2,
3, 4, 5) scores giving a final score ranging from
zero (negative) to 8/8 (strongly positive) (Harvey
et al. 1999). Another commonly used system is
the H-score which is obtained by adding the sum
of multiplying the percentage by intensity scores
(including different staining intensities within
the tumor, thus accounting for heterogeneity).
The final score ranges from 0 to 300. Another
possibility is to evaluate the percentage of any
nuclear staining, independently from the intensity.
Relevance for Breast Pathology
ER is routinely assessed on all newly diagnosed
primary breast cancers, and this is mandated
in the pathology and management guidelines
(Guidelines Working Group of the UK National
Coordinating Committee for Breast Pathology
164
2016; National Institute for Health and Care
Excellence 2009). Depending on the guidelines,
PR assessment is optional or mandatory
(American Society of Clinical Oncology/College
of American Pathologists guideline 2010). Both
receptors are increasingly tested in recurrent
and metastatic breast cancers to aid management
decisions. AR and ERb are not analyzed in the
routine setting.
Traditionally, testing for ER/PR was
performed on surgical resection specimens. With
increasing demands for early availability of
results to help select patients for neoadjuvant ther-
apy and preoperative trials, testing is currently
performed on core biopsies in the majority of
cases. Studies have shown excellent concordance
of receptor results between core and excision
samples (Hodi et al. 2007).
Repeat testing on surgical specimens is advised
in the presence of multiple tumors, tumor hetero-
geneity, if tumor cells on core biopsy were scanty,
or if the staining on core sections was technically
suboptimal/failed.
ER/PR as Predictive and Prognostic Markers
ER/PR status is a predictor for response to endo-
crine therapy. Tumors that express the highest
protein content are most likely to respond to
anti-hormonal treatment such as tamoxifen
(Harvey et al. 1999).
The aromatase inhibitor “anastrozole” has
been shown to be superior to tamoxifen in the
management of postmenopausal breast cancer
(Howell et al. 2005; Riemsma et al. 2010). More-
over, the protective effect of endocrine therapy
has been shown to last well beyond the 5 years of
standard therapy. Hormone receptor-positive
breast cancers are often indolent and relapse
late. A proportion of those tumors, however,
develop resistance to endocrine therapy during
the course of treatment.
Prognostic Significance of Other Hormone
Receptors
It has recently been shown that a high PRA/PRB
ratio is associated with early relapse on
tamoxifen in the ATAC trial cohort (Mote
et al. 2015).
Hormone Receptors in Breast Cancer
The prognostic significance of ERb protein
and mRNA expression in breast carcinoma
has been conflicting. A recent meta-analysis
of 21 studies of 6769 patients for ERb1, 2295
patients for ERb2, and 2271 patients for ERb5
concluded that ERb1 protein expression corre-
lated with favorable survival (DFS, OS)
and ERb2 with improved DFS only, whereas
ERb5 was not associated with DFS (Liu
et al. 2016).
AR has been shown to be an independent
prognosticator (when tumor size, grade, and
nodal status were included in the model) of favor-
able outcome not only in ER-positive breast car-
cinoma but also in ER-negative tumors
(Aleskandarany et al. 2016).
A prognostic index (ERPI) was created using
AR status (positive or negative) together with
tumor size and lymph node status that clearly
separated patients with luminal-A and luminal-B
breast cancer into good and poor prognosis groups
(Castellano et al. 2013).
References and Further Reading
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Elmouna, A., Jerjees, D., Ali, S., Buluwela, L.,
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breast cancer: Transcriptomic and protein expression
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Goia, M., Donadio, M., Arisio, R., Muscara, F.,
Durando, A., Viale, G., Cassoni, P., & Sapino, A.
(2013). A simple and reproducible prognostic index in
luminal ER-positive breast cancers. Annals of Oncol-
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Sharma, N., Velikova, G., Perren, T., Dodwell, D.,
Lansdown, M., & Shaaban, A. M. (2016). Effect of
neoadjuvant chemotherapy on breast cancer pheno-
type, ER/PR and HER2 expression – Implications for
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Hormone Receptors in Breast Cancer
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I
Infarct of Breast Tissue
Peter Regitnig
Diagnostic- and Research Institute of Pathology,
Medical University of Graz, Graz, Austria
Definition
An infarct is a coagulative necrosis of (breast-)
tissue, caused by ischemia. This is mostly not a
primary event in breast tissue but rather a sec-
ondary one, typically occurring after an invasive
procedure or within a breast lesion such as a
fibroadenoma, papilloma, or large neoplasm. In
rare events, it can occur during late pregnancy or
lactation.
Clinical Features
• Incidence
Primary breast infarction is rare. Only a
few case reports exist about breast infarction
during the third trimester of pregnancy or lacta-
tion (Han et al. 2015; Hasson and Pope 1961).
Secondary breast infarction sometimes
occurs as a complication following core needle
biopsy, fine needle aspiration biopsy (FNAB),
or a surgical procedure by altering the blood
vessels of a breast lesion, which then undergoes
infarction.
© Springer Nature Switzerland AG 2020
A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
• Age
Wide age distribution depending on underlying
lesion. Primary infarction is more typical in
pregnant women.
• Sex
Only females, no reported male case.
• Site
No site preference.
• Treatment
Due to clinical presentation of an infarct, core
needle biopsy is most often performed. Local
excision of the infarcted area is necessary most
of the time due to pain and depending on the
underlying lesion itself.
• Outcome
It depends on the infarcted lesion and the pri-
mary cause.
Macroscopy
Infarction typically presents as a palpable mass
that may be painful and varies between soft and
hard in consistency. In this case, it can be mistaken
for a carcinoma due to the firm consistency of the
lesion. Infarcts usually occur as single lesions,
localized to a breast lesion, or to hyperplastic
lactating breast tissue during the puerperal period.
The infarcted area can be well circumscribed (Han
et al. 2015). Hemorrhage can be seen within most
infarcts and sometimes a hyperemic outer border
can also be observed.
168
Microscopy
On routine H&E sections, infarcted tissue is, like in
other areas of the body, typically recognizable by the
loss of nuclear staining with ghostlike nuclear con-
tours in an early phase, independent of the underly-
ing structures. Epithelial structures are more affected
compared to mesenchymal areas. Structural integ-
rity of an underlying breast lesion is in most cases
still preserved. Localized hemorrhages and small
groups of granulocytes and lymphocytes can be
included, and thrombotic small vessels can be seen.
After days to weeks, the infarcted area can
undergo different changes depending on the
remaining surrounding tissue and its capability to
repair the infarcted area. This mainly depends on
the cause of the infarct and whether the surrounding
tissue is well oxygenized by blood vessels. In the
latter case, the infarct will be organized by a typical
granulation tissue, which contains macrophages,
fibroblasts, and capillaries, finally resulting in a
fibrotic scar with more or less remaining macro-
phages or siderophages. In the opposite case, if the
surrounding tissue is less oxygenized, then the
infarcted area will undergo a more acellular, long-
lasting degenerative process leading to a pseudo-
cyst with macro- or microcalcifications.
In a chronic ischemic healing process, epithe-
lial structures can be entrapped and can be
distorted within marked fibrosis, which might
be mistaken for a carcinoma. The appearance of
squamous metaplasia has also been described
(Flint and Oberman 1984).
When an infarct in the breast is seen, it is most
important to think about a possible infarcted neo-
plasm, which might be recognized only in its sil-
houettes. Therefore, a thorough clinical history or
additional information is also very important. In
every infarcted area, it is critical to also evaluate
the general architectural aspects within the infarct
and to evaluate the margin toward unaffected areas.
These two steps may lead to the recognition of an
underlying lesion or neoplasm, respectively. Find-
ings of the core needle biopsy should be cautiously
interpreted if the sample size is small and only
central areas are visible. Ultimately surgical exci-
sion should be performed to confirm the diagnosis
of an underlying breast lesion.
Infarct of Breast Tissue
Typical breast lesions that tend to undergo
(partial) infarction are fibroadenoma
(▶ Fibroadenoma), papilloma (▶ Intraductal Pap-
illoma), adenosis (▶ Adenosis, Other Types), and
highly proliferative breast carcinoma, mostly
basal-like carcinoma.
Similar to an infarct is hemorrhagic necrosis of
the skin and subcutis, which can occur as a side effect
or complication of anticoagulant therapy. Most often,
this situation occurs subsequent to thrombophlebitis
treated with warfarin. A hypersensitivity reaction
affecting small vessels might be the pathogenic rea-
son. Another explanation could be heterozygous
protein C deficiency promoting paradoxical coagu-
lation under warfarin (Isenberg et al. 1996).
Immunophenotype
Although not applicable to an infarct by itself, it
can be helpful to reconstruct infarcted breast
lesions. Sometimes myoepithelial markers can
be helpful, even in less preserved areas.
Molecular Features
Not applicable
Differential Diagnosis
Clinically, a breast infarct can simulate a carci-
noma through its tenderness, and even enlarged
axillary lymph nodes may coexist due to the reac-
tive inflammatory process as a result of the infarct.
Nipple discharge of an infarcted papilloma is
bloody and thus raises suspicion. In FNAB,
infarcted areas can show highly reactive and thus
atypical cells, which may be misleading.
On H&E, highly fibrotic areas containing high
collagen content and low cellularity can be mistaken
for an infarct, but there are still some remaining
bland fibroblasts and typical collagen bundles.
Difficulties sometimes arise because of the
presence of complete necrotic material of a highly
proliferative carcinoma or another breast lesion in
the background.
Inflammatory Myofibroblastic Tumor of the Breast
References and Further Reading
Flint, A., & Oberman, H. A. (1984). Infarction and squa-
mous metaplasia of intraductal papilloma: A benign
breast lesion that may simulate carcinoma. Human
Pathology, 15, 764–767.
Han, B., Zhang, H., Jiang, P., Zheng, C., Bi, L., Lu, L. U.,
& Fan, Z. (2015). Breast infarction during pregnancy
and lactation: A case report. Experimental and Thera-
peutic Medicine, 10, 1888–1892.
Hasson, J., & Pope, C. H. (1961). Mammary infarcts asso-
ciated with pregnancy presenting as breast tumors.
Surgery, 49, 313–316.
Isenberg, J. S., Tu, Q., & Rainey, W. (1996). Mammary
gangrene associated with warfarin ingestion. Annals of
Plastic Surgery, 37, 553–555.
Inflammatory Myofibroblastic
Tumor of the Breast
Gaetano Magro and Lucia Salvatorelli
Department of Medical and Surgical Sciences and
Advanced Technologies, G.F. Ingrassia, Azienda
Ospedaliero-Universitaria “Policlinico-Vittorio
Emanuele,” Anatomic Pathology Section, School
of Medicine, University of Catania, Catania, Italy
Synonyms
Inflammatory pseudotumor; Plasma cell
granuloma
Definition
Inflammatory myofibroblastic tumor (IMT) is
currently classified by WHO as a soft tissue
tumor composed of spindly myofibroblasts
admixed with inflammatory cells such as plasma
cells, lymphocytes, and eosinophils (Coffin and
Fletcher 2013). IMT can occur in adults at sev-
eral anatomic sites, including the breast.
Although initially thought to be an exaggerated
inflammatory local response to various stimuli,
and thus variably labeled as “inflammatory
pseudotumor (IP) or plasma cell granuloma,”
there is growing evidence that a subset of these
lesions are truly neoplastic in nature with the
169
tendency to recur in up to 25% of the cases and
with a slight risk of distant metastasis. This is
especially true if IMT typically arises in the lung
and abdomen of children/adolescents (Coffin
and Fletcher 2013). As future studies are needed
to better define the boundaries between a reac-
tive and a neoplastic process, the combined
diagnosis of “inflammatory pseudotumor/
inflammatory myofibroblastic tumor,” specify-
ing the presence or not of ALK-1 expression
(see below), seems actually to be more appropri-
ate for these lesions.
Clinical Features
• Incidence
I
The terms IMT or IP of the breast have been
used interchangeably over time, and only
24 cases have been reported in English litera-
ture so far (Haj et al. 2003; Vecchio et al. 2011;
Zhao et al. 2013; Bosse et al. 2014; Choi et al.
2015; Markopoulos et al. 2015; Talu
et al. 2016).
• Age
IMT/IP can occur at any age including adoles-
cents (16–86 years), but it is more frequently
observed between the third to sixth decades.
• Sex
The majority of cases seems to occur sponta-
neously in women. Only rarely IMT has been
described in male patients, following local
mechanical trauma (Vecchio et al. 2011).
• Clinical presentation
Patients usually present with a painless nodule
ranging in size from 1.0 to 8 cm in its greatest
diameter, without associated constitutional
symptoms (fever, malaise, weight loss) as usu-
ally seen in pediatric patients with lung and
abdominal tumors.
• Radiographic findings
Imaging features (ultrasound; mammogra-
phy) are non-specific and usually reveal a
solitary, less frequently multifocal, round to
oval mass which may show either well-
circumscribed (Zhao et al. 2013) or ill-defined
margins with the suspicion of malignancy
(Haj et al. 2003).
170
• Treatment
Complete surgical excision is the adequate treat-
ment. Most cases have an indolent clinical
course (Vecchio et al. 2011), but local recurrence
can be documented in a minority of cases
(15–20% of cases) (Zhao et al. 2013; Choi
et al. 2015). Only rarely IMT of the breast may
show metastatic potential (Zhao et al. 2013;
Choi et al. 2015). However, some tumors
labeled as “inflammatory myofibroblastic
tumors” are not convincing based on the
illustrations provided by the authors, and they
could represent low- to intermediate-grade
myofibroblastic sarcomas (Choi et al. 2015).
Patients with IMT/IP of the breast need a long-
term follow-up.
Macroscopy
Grossly, IMT/IP presents as a round to oval mass,
sometimes lobulated, with well or often ill-
defined margins. The size is variable, ranging
from 1.5 to 8.0 cm (average tumor size of
3.1 cm). The cut surface reveals a tumor mass
firm in consistency and gray whitish in color.
Necrosis and hemorrhage are absent.
Microscopy
IMT/IP shows morphological and immunohisto-
chemical features similar to those reported at other
sites (Table 1). At low magnification, a tumor
mass with infiltrative margins into the surround-
ing fibro-fatty breast tissue is observed. It consists
of a proliferation of plump, bland-looking spindle
cells with the features of myofibroblasts, showing
pale to slightly eosinophilic cytoplasm and ovoid
to tapering vesicular nuclei with inconspicuous
nucleoli (Fig. 1a, b H&E). These cells are usually
arranged in interlacing short bundles with
focal swirling and/or storiform growth pattern
(Fig. 1a, b H&E). Mitotic count is extremely
variable, ranging from few (1–2) to 10 mitoses
per 10 high power fields. Characteristically the
spindle cells are closely admixed with inflamma-
tory cells, especially lymphocytes (Fig. 2a H&E),
plasma cells (Fig. 2b H&E), and eosinophils.
Inflammatory Myofibroblastic Tumor of the Breast
Inflammatory Myofibroblastic Tumor of the Breast,
Table 1 Clinicopathologic features
Inflammatory myofibroblastic tumor/inflammatory
pseudotumor
Clinical features
Females (only rarely males)
Age: 16–86 years
Painless nodule (1–8 cm) arising spontaneously
Imaging
Nodule with well-circumscribed or ill-defined
margins
Gross pathology
Poorly circumscribed mass
Firm in consistency
Gray whitish in color
Histological features
Margins: Well- or poorly circumscribed
Cells: Plump, bland-looking spindle cells
admixed with lymphocytes, plasma cells, and
eosinophils
Growth pattern: Interlacing short fascicles; focal
storiform or swirling pattern
Mitotic count: 0–3 mitoses per 10 high power field
Stroma: Fibrous to focally edematous
Immunohistochemistry
Positive markers: Vimentin and a-smooth muscle
actin
Variable expression: Desmin; ALK-1 (40–50% of
cases)
Negative markers: Cytokeratins, EMA, CD34, S-100
protein, b-catenin, STAT6
Cytogenetics
FISH analysis: ALK-gene rearrangements/
amplification
Cellularity is quite variable and tumor stroma is
fibrous to loose. A minority of cases shows exten-
sive hypocellular and hyalinized areas, closely
resembling scar-like tissue. Rarely the tumor
cells may exhibit moderate/severe cytological
atypia consisting of large vesicular or hyper-
chromatic nuclei (Fig. 2c H&E) with one or two
prominent nucleoli. Necrosis and atypical mitoses
are absent. Macrophages and a few multi-
nucleated giant cells can be occasionally seen.
Immunophenotype
IMT/IP shows a myofibroblastic profile with
immunoreactivity for vimentin, a-smooth muscle
actin (Fig. 2d Immunostaining with a-smooth
muscle actin), and variably with desmin. The
Inflammatory Myofibroblastic Tumor of the Breast
Inflammatory Myofibroblastic Tumor of the Breast, Fig. 1 (a) Proliferation of bland-looking spindle cells with
fascicular and swirling growth patterns. (b) Higher magnification showing the cytological details
expression of ALK-1 protein has been demon-
strated in three cases (Zhou et al. 2013; Bosse
et al. 2014), proving that, at least, a subset of
these lesions could represent true IMT. Occasion-
ally immunostaining for cytokeratins has been
described. No immunoreactivity is reported for
CD34, CD21, CD35, S100, and estrogen/proges-
terone receptors (Table 1).
Molecular Features
The role of ALK gene is still unclear in the path-
ogenesis of IMT. The distinction between IMT
and IP still remains arbitrary, especially in the
absence of a proven immunohistochemical
expression of ALK-1 or rearrangements of ALK
gene by means of FISH. Some investigators prefer
the diagnosis of IP when dealing with ALK-
negative lesions arising at unusual sites, including
the breast, of adult patients (Vecchio et al. 2011).
Among the cases of IMT/IP of the breast tested by
FISH, only four cases have been found to be
ALK-rearranged. Notably ALK1 expression
171
and/or ALK gene rearrangement does not seem
to predict clinical course. In this regard, only a
few cases, regardless of ALK-1 expression and/or
ALK rearrangements, develop local recurrence or
more rarely distant metastases (Zhao et al. 2013;
Bosse et al. 2014; Choi et al. 2015; Markopoulos
et al. 2015; Talu et al. 2016).
Differential Diagnosis
The diagnosis of IMT/IP arising in the breast is
challenging, especially on a core needle biopsy.
The pathologists facing with a bland-looking
spindle cell lesion of the breast should keep in
mind a wide variety of benign and malignant
lesions, including reactive spindle cell nodule,
nodular fasciitis, IgG4-related sclerosing mastitis,
myofibroblastoma (▶ Mammary Myofibro-
blastoma), solitary fibrous tumor, desmoid-type
fibromatosis, low-grade (fibromatosis-like) spin-
dle cell carcinoma (▶ Invasive Metaplastic Carci-
noma), low-grade myofibroblastic sarcoma, and
172
Inflammatory Myofibroblastic Tumor of the Breast,
Fig. 2 Proliferating spindle cells are closely admixed with
lymphocytes (a) (H&E) and plasma cells (b) (H&E). In
dermatofibrosarcoma protuberans (Table 2).
A history of a previous biopsy or fine-needle
aspiration (FNA), as well as the recognition of
entrapped/displaced epithelial mammary struc-
tures, stromal hemosiderin deposition, foamy
and hemosiderin-laden macrophages, lympho-
cytes and plasma cells, fat necrosis, and foreign
body giant cell reaction, favors the diagnosis of
reactive spindle cell nodule.
Nodular fasciitis shares with IMT/IP irregular
margins, at least focally, and the presence of var-
iable myxoid matrix, mitoses, and inflammatory
cells. However lymphocytes and plasma cells in
the latter are more prominent and closely
intermingling with the spindle cells. Unlike nod-
ular fasciitis, IMT/IP lacks the typical tissue-
culture/granulation-like appearance.
Inflammatory Myofibroblastic Tumor of the Breast
some areas the spindle cells may exhibit moderate nuclear
atypia (c) (H&E). Immunostaining with alpha-smooth
muscle actin is a common finding (d)
Immunoglobulin (IgG)4-related sclerosing
mastitis is rare with only a few cases reported in
the breast to date (Cheuk et al. 2009). Histologi-
cally the breast masses usually contain prominent
stromal sclerosis with a variable number of
spindle fibroblast-like cells, a dense lympho-
plasmacytic infiltrate, and loss of breast lobules
(Cheuk et al. 2009). This lesion differs from
IMT/IP in that fibrosis and inflammation predom-
inate over the spindle cell component. Diagnostic
clue is the presence of numerous (range from
272 to 495 per high power field) IgG4-expressing
plasma cells (Cheuk et al. 2009).
Myofibroblastoma (▶ Mammary Myofibro-
blastoma), a benign tumor of the mammary
stroma which presents as a nodule with well-
circumscribed margins, is usually composed of
Inflammatory Myofibroblastic Tumor of the Breast 173

Inflammatory Myofibroblastic Tumor of the Breast, Table 2 Differential diagnosis

Differential diagnosis of inflammatory myofibroblastic tumor/inflammatory pseudotumor
Inflammatory Imaging features: Well-circumscribed or ill-defined margins
myofibroblastic tumor/ Histology: Interlacing short fascicles of spindle cells, closely intermingling with
inflammatory lymphocytes, plasma cells, and eosinophils
pseudotumor Immunohistochemistry: Staining with vimentin and a-smooth muscle actin; variable
staining with desmin and ALK-1; CD34, CD21,CD35, b-catenin, and STAT6 are
negative
Reactive spindle cell Imaging features: Nodule with circumscribed margins, following biopsy or FNAC
nodule Histology: Short fascicles; focal storiform pattern; hemosiderin deposition; foamy and
hemosiderin-laden macrophages, lymphocytes, and plasma cells; fat necrosis and foreign
body giant cell reaction
Immunohistochemistry: Staining with a-smooth muscle actin; CD34, desmin,
b-catenin, and pancytokeratins are negative
Nodular fasciitis Imaging features: Ill-defined margins, at least focally
Histology: Short, focally intersecting fascicles; foci of extravasated red blood cells and
lymphocytes; tissue culture-like appearance
Immunohistochemistry: Staining with a-smooth muscle actin; CD34, desmin,
b-catenin, and pancytokeratins are negative
IgG4-related sclerosing
mastitis
Imaging features: Multiple nodular masses with ill-defined or circumscribed margins
Histology: Fibro-sclerotic tissue with prominent inflammation of lymphocytes (nodular
I
aggregate of lymphoid cells; lymphoid follicle formation) and plasma cells; variable
number of fibroblast-like cells
Immunohistochemistry: IgG4-expressing plasma cells
Myofibroblastoma Imaging features: Well-circumscribed nodule
Histology: Short, haphazardly intersecting fascicles interrupted by keloid-like collagen
fibers
Immunohistochemistry: Staining with desmin, CD34, estrogen, and progesterone
receptors; variable expression of a-smooth muscle actin, bcl2, CD10, CD99;
pancytokeratins, S100 protein, b-catenin, and STAT6 are negative
Solitary fibrous tumor Imaging features: Well-circumscribed nodule
Histology: Short fibroblast-like spindle to round/ovoid cells, haphazardly arranged; focal
storiform pattern
Immunohistochemistry: Staining with CD34 and STAT6; desmin, a-smooth muscle
actin, and pancytokeratins are negative
Desmoid-type Imaging features: Ill-defined, often infiltrative margins
fibromatosis Histology: Long fascicles, focally intersecting; fibrous stroma
Immunohistochemistry: Staining with a-smooth muscle actin and b-catenin; CD34,
desmin, pancytokeratins, and STAT6 are negative
Low-grade Imaging features: Ill-defined or frankly infiltrative margins
(fibromatosis-like) Histology: Proliferation of spindle cells with, at least focally, mild to moderate nuclear
spindle cell carcinoma atypia; scattered clusters of epithelioid to polygonal cells; occasionally small squamous-
glandular structures and/or foci of in situ or invasive carcinoma
Immunohistochemistry: Staining with pancytokeratins and p63; variable expression of
a-smooth muscle actin and desmin; CD34, b-catenin, and STAT6 are negative
Low-grade Imaging features: Poorly circumscribed nodule
myofibroblastic sarcoma Histology: Proliferation of spindle cells with fascicular arrangement; low to focally
moderate nuclear pleomorphism; occasionally severe nuclear pleomorphism
Immunohistochemistry: Staining with a-smooth muscle actin; desmin,
pancytokeratins, b-catenin, CD34, and STAT6 are negative
Dermatofibrosarcoma Imaging features: Ill-defined margins
protuberans Histology: Proliferation of spindle cells with diffuse storiform pattern; infiltration of
adipose tissue in a “honeycomb” pattern
Immunohistochemistry: Staining with CD34 and STAT6; desmin, a-smooth muscle
actin, b-catenin, and pancytokeratins are negative
174
eosinophilic spindle cells arranged in short, hap-
hazardly intersecting fascicles with interspersed
keloid-like collagen fibers. Unlike IMT/IP,
myofibroblastoma contains mast cells but not
lymphocytes, plasma cells, or eosinophils in the
stroma. In addition myofibroblastoma usually
co-expresses diffusely CD34, desmin, and
a-smooth muscle actin, while ALK1 immunore-
activity is absent.
In contrast to IMT/IP, solitary fibrous tumor
characteristically shows short fibroblast-like cells
haphazardly arranged and medium-sized blood
vessels with hyalinized walls and branching con-
figuration. In addition solitary fibrous tumor is
diffusely positive for CD34 and STAT6, which
are not expressed in IMT/IP.
wDesmoid-type fibromatosis usually exhibits
extensive infiltrative margins with fingerlike pro-
jections into the adjacent fibro-fatty tissue and
breast parenchyma. The diagnosis of desmoid-
type fibromatosis is based on the presence of
long, sweeping fascicles set in a variable fibrous
stroma. Spindle cells are aligned parallel and their
nuclei are spaced, without overlapping. Inflamma-
tory cells admixed with the proliferating spindle
cells are lacking in desmoid-type fibromatosis.
Although desmoid-type fibromatosis may
share with IMT/IP the immunohistochemical
expression of a-smooth muscle actin, the former
is typically positive for b-catenin in about 80% of
cases.
Low-grade (fibromatosis-like) spindle cell car-
cinoma (▶ Invasive Metaplastic Carcinoma) is
included in the differential diagnosis because neo-
plastic cells adopt a spindle cell morphology.
Detection of epithelioid-polygonal cells arranged
in small cohesive clusters, in addition to spindle
cell component, and immunoreactivity for
cytokeratins and myoepithelial markers, espe-
cially p63, supports the diagnosis of carcinoma.
Low-grade myofibroblastic sarcoma shares with
IMT/IP the expression of a-smooth muscle actin.
However, its presentation (nodule with well-
circumscribed margins); presence, at least focally,
of moderate nuclear atypia; and high mitotic count
(from 7 to 35 mitoses per 10 HPF), along with
absence of inflammatory cells, favor the diagnosis
of low-grade myofibroblastic sarcoma.
Inflammatory Myofibroblastic Tumor of the Breast
Finally, dermatofibrosarcoma protuberans may
share with IMT/IP the storiform/swirling growth
pattern which can be focally encountered in the
latter. Unlike IMT/IP, dermatofibrosarcoma pro-
tuberans exhibits a diffuse storiform pattern and is
diffusely positive for CD34, while myogenic
markers (desmin, a-smooth muscle actin) are
absent.
References and Further Reading
Bosse, K., Ott, C., Biegner, T., Fend, F., Siegmann-Luz,
K., Wallwiener, D., & Hahn, M. (2014). 23-year-old
female with an inflammatory Myofibroblastic tumour
of the breast: A case report and a review of the
literature. Geburtshilfe und Frauenheilkunde, 74,
167–170.
Cheuk, W., Chan, A. C., Lam, W. L., Chow, S. M.,
Crowley, P., Lloydd, R., Campbell, I., Thorburn, M.,
& Chan, J. K. (2009). IgG4-related sclerosing mastitis:
Description of a new member of the IgG4-related scle-
rosing diseases. The American Journal of Surgical
Pathology, 33, 1058–1064.
Choi, E. J., Jin, G. Y., Chung, M. J., Moon, W. S., &
Youn, H. J. (2015). Primary inflammatory
myofibroblastic tumors of the breast with metastasis:
Radiographic and histopathologic predictive factors.
Journal of Breast Cancer, 18, 200–205.
Coffin, C. M., & Fletcher, J. A. (2013). Inflammatory
myofibroblastic tumour. In C. D. M. Fletcher, J. A.
Bridge, P. C. W. Hogendoorn, & F. Mertens (Eds.),
WHO classification of tumours of soft tissue and bone
(4th ed., pp. 83–84). Lyon: WHO Press.
Haj, M., Weiss, M., Loberant, N., & Cohen, I. (2003).
Inflammatory pseudotumor of the breast: Case report
and literature review. The Breast Journal, 9, 423–425.
Markopoulos, C., Charalampoudis, P., Karagiannis, E.,
Antonopoulou, Z., & Mantas, D. (2015). Inflammatory
myofibroblastic tumor of the breast. Case Reports in
Surgery, 2015, 705127.
Talu, C. K., Çakır, Y., Hacıhasanoğlu, E., Leblebici, C.,
Aksoy, Ş., & Nazlı, M. A. (2016). Inflammatory
myofibroblastic tumor of the breast coexisting with
pseudoangiomatous stromal hyperplasia. The Journal
of Breast Health, 12, 171–173.
Vecchio, G. M., Amico, P., Grasso, G., Vasquez, E., La
Greca, G., & Magro, G. (2011). Post-traumatic inflam-
matory pseudotumor of the breast with atypical mor-
phological features: A potential diagnostic pitfall.
Report of a case and a critical review of the literature.
Pathology, Research and Practice, 207, 322–326.
Zhao, H. D., Wu, T., Wang, J. Q., Zhang, W. D., He, X. L.,
Bao, G. Q., Li, Y., Gong, L., & Wang, Q. (2013).
Primary inflammatory myofibroblastic tumor of the
breast with rapid recurrence and metastasis: A case
report. Oncology Letters, 5, 97–100.
Intraductal Papillary Carcinoma
Zhou, Y., Zhu, J., Zhang, Y., Jiang, J., & Jia, M. (2013).
An inflammatory myofibroblastic tumour of the breast
with ALK overexpression. BMJ Case Reports,
2013. https://doi.org/10.1136/bcr-07-2011-4474, pii:
bcr0720114474.
Intraductal Papillary
Carcinoma
Emma Josephine Groen and Jelle Wesseling
Department of Pathology, The Netherlands
Cancer Institute-Antoni van Leeuwenhoek
Hospital, Amsterdam, The Netherlands
Synonyms
Noninvasive papillary carcinoma; Papillary duc-
tal carcinoma in situ
Definition
In literature, an unambiguous definition and uni-
form criteria of intraductal papillary carcinoma
is lacking. Often, it is described as a luminal
epithelial neoplastic proliferation of the breast
confined to the mammary ducts and lobules
(also known as ductal carcinoma in situ, DCIS
(▶ Ductal Carcinoma In Situ)), characterized by
a papillary growth pattern. It is considered a
potential precursor lesion for breast cancer.
Whether these lesions represent de novo malig-
nant papillary epithelial proliferations or malig-
nant epithelial populations transforming and
replacing benign papillomas (▶ Intraductal Pap-
illoma) remains unclear.
Clinical Features
As intraductal papillary carcinoma is a morpho-
logical subtype of DCIS, the following features
are derived from literature based on DCIS in gen-
eral, combined with data specifically focusing on
intraductal papillary carcinoma (also known as
papillary DCIS).
175
• Incidence
The incidence of DCIS has dramatically
increased since the introduction of population-
based breast cancer screening. Nowadays,
approximately 20–25% of all breast neoplastic
lesions are DCIS. A pure or predominant papil-
lary growth pattern is however rare.
• Age
The reported age range of the patients with
malignant papillary lesions in general is
27–89 years with a mean age of 60 (Tse 2005).
• Sex
Predominantly in women.
• Site
The vast majority is asymptomatic and
is detected by screening mammography. Symp-
toms such as nipple discharge, Paget’s disease of
I
the nipple, or a palpable mass sometimes occur.
There is no preferential site for intraductal pap-
illary carcinoma.
• Treatment
Treatment is similar to DCIS in general. Cur-
rently almost all lesions are being treated to
prevent the development of breast cancer.
Breast conserving treatment followed by radio-
therapy or in case of extensive lesions a mas-
tectomy with or without immediate
reconstruction are generally recommended.
There is no consensus on the value of adjuvant
hormonal treatment.
• Outcome
The natural course of intraductal papillary car-
cinoma or papillary DCIS is largely unknown,
as almost all lesions are treated. Fifteen years
after DCIS diagnosis, including all subtypes,
cumulative incidence of ipsilateral breast can-
cer was 1.9% after mastectomy, 8.8% after
breast conservative surgery (BCS) plus radio-
therapy, and 15.4% after BCS alone (Elshof
et al. 2016).
Despite the increased detection and treat-
ment of these potential precursor lesions for
breast cancer, the incidence of breast cancer
has not declined, suggesting overdiagnosis
exists resulting in overtreatment. Unfortu-
nately, we cannot, at present, distinguish inno-
cent from aggressive DCIS lesions regarding
their capacity to progress to invasive breast
176
cancer. Therefore, biomarker studies in order
to enable risk stratification and prospective
trials investigating the safety of a wait-and-
see strategy for low-risk ductal carcinoma in
situ have emerged.
Macroscopy
As DCIS in general, intraductal papillary
carcinoma is a segmental disease that can be asso-
ciated with an impeccable breast parenchyma.
Occasionally, dilated mammary ducts filled with
necrotic debris and calcifications with or without
fibrosis can be seen.
Microscopy
Intraductal papillary carcinoma is characterized
by a segmental disease distribution. Involved
spaces show intraluminal arborizing fibrovascular
cores covered by neoplastic epithelium (Fig. 1a,
Fig. 2-plate A1). In 1962, delicate and relatively
inconspicuous fibrovascular cores were described
as characteristic for malignant lesions such as
intraductal papillary carcinoma (Kraus and
Neubecker 1962). More recently, however, others
have refuted this statement, as they found broad
fibrovascular cores even more often in malignant
papillary lesions and concluded this morphologic
feature was not a helpful feature to distinguish
between benign and malignant lesions (Kraus
Intraductal Papillary Carcinoma, Fig. 1 Intraductal papillary carcinoma, haemotoxylin-eosin stain (H&E),
(a) magnification 25; (b) magnification 200
Intraductal Papillary Carcinoma
and Neubecker 1962; Yamaguchi et al. 2014).
The neoplastic epithelium often consists of one
or more layers of uniform cuboidal to columnar
epithelium with hyperchromatic nuclei of low
to intermediate grade (Fig. 1b, Fig. 2-plate A2).
Myoepithelial cells are absent within the fibrovas-
cular cores but are seen at the periphery of the
involved spaces, in line with an in situ process. It
should be noted that a pure papillary architecture
is rarely seen; often it is seen intermixed with
other growth patterns, such as micropapillary,
cribriform, or solid DCIS.
Pitfalls
In some cases, intraductal papillary carcinoma
constitutes of a dimorphic epithelial cell popula-
tion, in which an often basally located second
population of cells with abundant pale cytoplasm
(“globoid cells”) is seen. These cells may be
incorrectly interpreted as myoepithelial cells
(Collins and Schnitt 2007). Immunohistochemical
staining for epithelial and myoepithelial cells can
resolve this issue and confirm the epithelial nature
of these cells.
Dislodgement and displacement of fragments
from papillary lesions into the surrounding
breast stroma or even within lymphatic vascular
spaces, especially after a biopsy procedure, is
a well-known occurrence and should be
interpreted with caution (Collins and Schnitt
2007; Kraus and Neubecker 1962; Ni and Tse
2015). In case of displacement into the surround-
ing breast stroma, epithelial components with
Intraductal Papillary Carcinoma
Intraductal Papillary Carcinoma, Fig. 2 (a) Intraductal
papillary carcinoma: A1 – H&E 50; A2 – H&E 400;
A3 – p63 400, showing presence of myoepithelial cells at
the periphery of the involved space but not within the
fibrovascular structure; A4 – ER 400, strong diffuse
homogeneous ER expression. (b) Intraductal benign pap-
illoma: B1 – H&E 50; B2 – H&E 400; B3 – p63 400,
showing presence of myoepithelial cells both within the
fibrovascular structures and at the periphery of the
some degree of degenerative changes are present
within the confines of the biopsy tract with
concomitant reactive changes such as reactive
fibrous stroma, signs of associated hemorrhage,
177
involved space; B4 – ER 400, heterogeneous ER expres-
sion (mosaic pattern). (c) Encapsulated papillary carci-
noma: C1 – H&E 50; C2 – H&E 400; C3 – p63
400, showing no myoepithelial cells; C4 – ER 400,
strong diffuse homogeneous ER expression. (d) Solid
papillary carcinoma: D1 – H&E 50; D2 – H&E 400;
D3 – p63 400, showing sporadic myoepithelial cells at
the periphery of the nodules; D4 – ER 400, strong diffuse
homogeneous ER expression
fat necrosis, and some degree of inflammation.
Invasion should only be considered when epithe-
lial structures are found well away from the
biopsy site and show morphological features
178
consistent with invasive cancer. Likewise, the
presence of epithelial fragments in lymphatic
vascular spaces or even lymph nodes should
be doubted when no convincing invasive cancer
is found elsewhere within the breast.
Immunohistochemistry to verify the presence
or absence of myoepithelial cells in the distinction
between true invasion and displacement is only
useful when myoepithelial cells can be detected,
because often only the luminal epithelial cells
are displaced. Especially in intraductal papillary
carcinoma where myoepithelial cells are only
found at the periphery, immunohistochemistry is
of limited value (Collins and Schnitt 2007; Ni and
Tse 2015).
Immunophenotype
The neoplastic epithelial compartment often
shows strong homogeneous staining for estrogen
receptor (ER). To confirm the absence of
myoepithelial cells within the papillary fibrovas-
cular structures and the presence at the periphery
of the involved spaces, a p63 stain is advised (see
also below) (Fig. 2-plate A3, A4).
Molecular Features
Few studies have evaluated molecular alterations in
intraductal papillary carcinoma specifically, in line
with its rarity and the uncertainty regarding what
can be considered as such a lesion. In addition,
most studies have looked at only small
and nonuniform series, variably including atypical
papillomas, papillomas with DCIS, intraductal pap-
illary carcinomas, or even invasive papillary carci-
nomas. Taking this into account, numerical or
structural alterations in chromosome 17 and
the accumulation of numerical alterations in
chromosomes 3, 7, and X have been detected in a
low percentage of the cases of papillary carcinoma,
but not in papillomas (Tsuda et al. 1997).
A higher PIK3CA and AKT1 mutation
frequency was found in papillomas compared to
papillary carcinomas, which might suggest
a different molecular origin of at least some
papillary carcinomas (Troxell et al. 2009).
Intraductal Papillary Carcinoma
Whereas LOH at loci 16p13 and 16q21 could
be detected in malignant as well as paired benign
papillary lesions as obtained from adjacent tissue,
LOH at locus 16q23 and at the TP53 locus was
limited to malignant lesions, suggesting a role
for the latter two in malignant transformation
(Di Cristofano et al. 2005; Lininger et al. 1998).
LOH at loci 16q12.2 and 16q21 was found
exclusively in malignant intraductal papillary
lesions in core needle biopsies. Therefore, these
loci of LOH might be potential biomarkers in
the differential diagnosis with benign lesions
(Yoshida et al. 2012).
Differential Diagnosis
Other Forms of Ductal Carcinoma In Situ
(▶ Ductal Carcinoma In Situ)
There is no evidence to date that the papillary
growth pattern as seen in intraductal papillary
carcinoma implicates relevant differences in
terms of clinical or radiological features and out-
come compared to DCIS lesions comprising other
growth patterns. Of note, as described above,
DCIS with a pure papillary growth pattern
is rarely seen, but a clear definition of when to
call a DCIS lesion “intraductal papillary carci-
noma” as a whole is lacking (e.g., which percent-
age of the lesion should consist of a papillary
growth pattern). Finally, labeling DCIS with
a papillary growth pattern as intraductal papillary
carcinoma may be relevant when considering
a differential diagnosis with other papillary
lesions; it can also be confusing as DCIS showing
other growth patterns are simply diagnosed
as DCIS.
Benign Papilloma (▶ Intraductal Papilloma)
Benign papillomas are either localized centrally
(solitary) or in the periphery (multiple) and show
a similar papillary growth pattern with variable
degrees of cell proliferation. In benign papillo-
mas, however, one cannot only appreciate the
presence of myoepithelial cells along the periph-
ery of involved lumina but within the fibrovascu-
lar structures as well. Also in the proliferative
areas, a mixture of luminal epithelial cells and
myoepithelial cells is seen, consistent with
Intraductal Papillary Carcinoma
a hyperplastic process (Fig. 2-plate B1, B2, B3).
A heterogeneous ER expression pattern is often
seen (Fig. 2-plate B4), but homogeneous ER
expression does not rule out benignancy, espe-
cially when epithelium with columnar cell type
change is encountered (Ni and Tse 2015). Other
useful findings are the presence of apocrine meta-
plasia within a papillary lesion and ▶ usual ductal
hyperplasia and ▶ sclerosing adenosis in the adja-
cent breast tissue, which are suggestive of
a benign papilloma (Collins and Schnitt 2007;
Kraus and Neubecker 1962).
When an undoubtedly neoplastic epithelial
population with papillary growth has been identi-
fied one should keep in mind the following.
A recognizable architecture of a benign papilloma
in some part of the lesion precludes the diagnosis
of intraductal papillary carcinoma and should
rather be considered an atypical papilloma or
a papilloma with DCIS depending on the
classification used.
Encapsulated Papillary Carcinoma and Solid
Papillary Carcinoma
Encapsulated Papillary Carcinoma (▶ Encapsu-
lated Papillary Carcinoma) often have
a symptomatic presentation with a subareolar
mass and/or nipple discharge mostly occurring
in elderly women. Microscopically, one or several
nodules of often but not exclusively low to inter-
mediate grade papillary neoplasms can be seen
originating in a cystically dilated duct surrounded
by a thick fibrous capsule (Collins and Schnitt
2007; Ni and Tse 2015). In contrast to intraductal
papillary carcinoma, these lesions do not show
a rim of myoepithelial cells at the periphery and
ER is homogeneously and strongly expressed
(Fig. 2-plate C1, C2, C3, C4).
Solid papillary carcinoma (▶ Solid Papillary
Carcinoma) also tends to present in elderly
women as a circumscribed mass. As in
intraductal papillary carcinoma a papillary
ground structure can be appreciated in solid pap-
illary carcinoma. In the latter, however, fibrovas-
cular cores are often completely surrounded by a
solid epithelial cell proliferation. These epithelial
cells often show ovoid to spindle bland cells and
can show neuroendocrine features, both morpho-
logically and immunohistochemically, with the
179
expression of neuroendocrine markers such as
synaptophysin and chromogranin A. Mucin pro-
duction or even a mucinous invasive component
can be seen in association with these lesions.
Myoepithelial cells can be present or absent
at the periphery of these lesions while ER is
homogeneously expressed in epithelial cells
(Fig. 2-plate D1, D2, D3, D4).
The true nature of both these entities is uncer-
tain. Historically, these lesions were considered
variants of DCIS but given the often lack of
myoepithelial cells, these lesions may perhaps be
better classified as low grade invasive carcinomas
with pushing growth or intermediates during the
progression from in situ to invasive breast cancer.
In the absence of a component of frank invasive
growth or high-grade morphology, the outcome is
I
excellent.
As described above, the presence of
myoepithelial cells both at the periphery
(DD encapsulated/solid papillary carcinoma)
and in the fibrovascular structures and/or cell
proliferation (DD benign papilloma) is a key
distinguishing feature. One should be careful
interpreting immunohistochemical stains for
myoepithelial cells as both stromal fibroblasts
and pericytes can show cross-reactivity, and all
stains have their inherent sensitivity and specific-
ity. A combination of more than one marker
is therefore advised. P63 is superior to other
myoepithelial markers in the classification of pap-
illary lesions, as it is a nuclear stain with only
minimal cross-reactivity and high sensitivity.
For evaluating the nature of solid epithelial
proliferations often seen in papillary lesions,
cytokeratin 5/6 is recommended, as among the
high molecular weight cytokeratins (HMWCKs),
it has the highest sensitivity and specificity
(Ni and Tse 2015; Tse et al. 2009).
Classifying papillary lesions on fine-needle
aspiration is challenging and should generally
be discouraged, given the necessity to visualize
not only the presence of myoepithelial cells but
also their exact location within the lesion.
Immunohistochemical Biomarkers
Several studies have evaluated the effectivity
of new immunohistochemical biomarkers to
distinguish benign from malignant papillary
180
lesions. The absence of staining for stem cell
markers CD44 and CD133 may be useful in iden-
tifying malignant papillary lesions. Positive CD44
expression has been proposed as a marker to dif-
ferentiate between benign and malignant papillary
lesions with a reported sensitivity of 45% and
a specificity of 92% (Tse 2005) and CD133
expression was significantly lower in papillary
carcinomas than in benign or atypical papillomas
(p < 0.001) (Lin et al. 2014).
Cell cycle markers cyclin B1 and cyclin D1
have been shown to be independently associated
with malignancy in papillary lesions. Positive
staining for cyclin B1 and cyclin D1 was found
to be helpful for identifying malignant papillary
lesions with a sensitivity of 80% and a specificity
of 72.7% for cyclin B1 and a sensitivity of 86.4%
but only a specificity of 32.6% for cyclin D1 (Loh
et al. 2015). The expression was however fre-
quently heterogeneous and only focal, limiting
its usefulness in clinical practice.
References and Further Reading
Collins, L. C., & Schnitt, S. J. (2007). Papillary lesions of
the breast: Selected diagnostic and management issues.
Histopathology, 52, 20–29. https://doi.org/10.1111/
j.1365-2559.2007.02898.x.
Di Cristofano, C., Mrad, K., Zavaglia, K., Bertacca, G.,
Aretini, P., Cipollini, G., et al. (2005). Papillary lesions
of the breast: A molecular progression? Breast Cancer
Research and Treatment, 90, 71–76. https://doi.org/
10.1007/s10549-004-3003-3.
Elshof, L. E., Schaapveld, M., Schmidt, M. K.,
Rutgers, E. J., Leeuwen, F. E., & Wesseling,
J. (2016). Subsequent risk of ipsilateral and contralat-
eral invasive breast cancer after treatment for ductal
carcinoma in situ: Incidence and the effect of
radiotherapy in a population-based cohort of 10,090
women. Breast Cancer Research and Treatment, 159,
553–563. https://doi.org/10.1007/s10549-016-3973-y.
Kraus, F. T., & Neubecker, R. D. (1962). The differential
diagnosis of papillary tumors of the breast. Cancer, 15,
444–455.
Lin, C.-H., Liu, C.-H., Wen, C.-H., Ko, P.-L., & Chai, C.-Y.
(2014). Differential CD133 expression distinguishes
malignant from benign papillary lesions of the breast.
Virchows Archiv, 466, 177–184. https://doi.org/
10.1007/s00428-014-1695-2.
Lininger, R. A., Park, W. S., Man, Y. G., Pham, T.,
MacGrogan, G., Zhuang, Z., & Tavassoli, F. A.
(1998). LOH at 16p13 is a novel chromosomal alter-
ation detected in benign and malignant microdissected
papillary neoplasms of the breast. Human Pathology,
29, 1113–1118.
Intraductal Papilloma
Loh, S. F., Cooper, C., Selinger, C. I., Barnes, E. H.,
Chan, C., Carmalt, H., et al. (2015). Cell cycle marker
expression in benign and malignant intraductal papil-
lary lesions of the breast. Journal of Clinical Pathol-
ogy, 68, 187–191. https://doi.org/10.1136/jclinpath-
2014-202331.
Ni, Y.-B., & Tse, G. M. (2015). Pathological criteria and
practical issues in papillary lesions of the breast –
A review. Histopathology, 68, 22–32. https://doi.org/
10.1111/his.12866.
Troxell, M. L., Levine, J., Beadling, C., Warrick, A.,
Dunlap, J., Presnell, A., et al. (2009). High prevalence
of PIK3CA/AKT pathway mutations in papillary neo-
plasms of the breast. Modern Pathology, 23, 27–37.
https://doi.org/10.1038/modpathol.2009.142.
Tse, G. M. K. (2005). CD44s is useful in the differentiation
of benign and malignant papillary lesions of the breast.
Journal of Clinical Pathology, 58, 1185–1188. https://
doi.org/10.1136/jcp.2005.026906.
Tse, G. M., Tan, P. H., & Moriya, T. (2009). The role of
immunohistochemistry in the differential diagnosis of
papillary lesions of the breast. Journal of Clinical
Pathology, 62, 407–413. https://doi.org/10.1136/
jcp.2008.063016.
Tsuda, H., Takarabe, T., Inazawa, J., &
Hirohashi, S. (1997). Detection of numerical alterations
of chromosomes 3, 7, 17 and X in low-grade intracystic
papillary tumors of the breast by multi-color fluores-
cence in situ hybridization. Breast Cancer, 4, 247–252.
Yamaguchi, R., Tanaka, M., Tse, G. M., Yamaguchi, M.,
Terasaki, H., Nomura, Y., et al. (2014). Broad
fibrovascular cores may not be an exclusively benign
feature in papillary lesions of the breast: A cautionary
note. Journal of Clinical Pathology, 67, 258–262.
https://doi.org/10.1136/jclinpath-2013-201749.
Yoshida, M., Tsuda, H., Yamamoto, S., Kinoshita, T., Akashi-
Tanaka, S., Hojo, T., & Fukutomi, T. (2012). Loss of
heterozygosity on chromosome 16q suggests malignancy
in core needle biopsy specimens of intraductal papillary
breast lesions. Virchows Archiv, 460, 497–504. https://doi.
org/10.1007/s00428-012-1200-8.
Intraductal Papilloma
Ales Ryska and Folakemi A. Torgersen
The Fingerland Department of Pathology, Charles
University Medical Faculty and University
Hospital, Hradec Kralove, Czech Republic
Synonyms
Ductal adenoma; Large duct papilloma; Major
duct papilloma; Microscopic papilloma; Small
duct papilloma
Intraductal Papilloma
Definition
Intraductal papillomas are benign intraluminal
neoplastic proliferations characterized by the
presence of arborizing fibrovascular cores lined
by bilayered populations of basal (myoepithelial)
and luminal (epithelial) cells (O’Malley et al.
2012). Papillomas may be centrally or peripher-
ally located in the breast. Central papillomas with
predominant glandular differentiation are also
known as ductal adenomas (▶ Ductal Adenoma).
Large, often complex papillomas containing a
cystic component are sometimes called papillary
cystadenomas (Wei 2016).
Clinical Features
• Incidence
Intraductal papillomas account for less than
10% of all benign breast tumors. They are
however the most common papillary lesions
of the breast.
• Age
Though there is a wide age distribution, most
intraductal papillomas occur in the fourth and
fifth decades. While central lesions are more
common in perimenopausal women, periph-
eral papillomas typically affect slightly youn-
ger patients.
• Sex
Vast majority of cases are diagnosed in
females. Intraductal papillomas in the male
breast are extremely rare. Isolated case reports
exist in the literature of intraductal papillomas
occurring in males ranging in age from 11 to
73 years.
• Site
Central papillomas are more common (about
75% of all papillomas) and arise in the
lactiferous ducts in the subareolar region of
the breast. They are usually solitary but less
frequently may also be multiple. Peripheral
or small duct papillomas on the other hand
arise in smaller branches or even in the
terminal ductolobular units and are fre-
quently multiple. Some papillomas grow
within cystically dilated ducts (intracystic
papillomas).
181
• Clinical symptoms
Patients with central papillomas frequently
present with serous or serosanguinous nipple
discharge (Wei 2016). Small retroareolar pap-
illomas can be occult on mammography
because of the breast density in the area. Larger
lesions on the other hand appear as well-
circumscribed round or oval masses. Up to a
quarter of central papillomas are associated
with benign appearing mammographic calcifi-
cations. On ultrasound, cystic lesions with
solid components may be observed.
Galactography (ductography) shows well-
defined filling defects and may be useful in
identifying affected ducts prior to excision
(MacGrogan and Tavassoli 2003).
Sclerosing papillomas may mimic malig-
I
nancy both clinically and on imaging. Patients
may present with a palpable mass fixed to the
skin. Radiographically these lesions may pre-
sent as stellate soft tissue densities, sometimes
with microcalcifications.
Peripheral papillomas are usually clinically
occult and nipple discharge is rare. Patients
may present with a palpable mass.
• Treatment
Papillary lesions may be heterogeneous; there-
fore, papillomas with atypia (focal atypical epi-
thelial proliferation usually with low-grade
nuclei) diagnosed on core needle biopsy are
usually recommended for excision as the likeli-
hood of discovering malignancy on excision is
up to 67%. Complete surgical excision is also
recommended for papillomas without atypia as
no features predictive of upgrading on examina-
tion of the entire lesion have been identified
(Shiino et al. 2015). Imaging-guided large-
volume vacuum-assisted percutaneous biopsy
has been suggested as a possible alternative to
surgical excision (Bianchi et al. 2015). When a
papilloma without atypia is diagnosed with vac-
uum biopsy, there is a high likelihood that it is
benign; however, if surgical excision is not
performed, long-term follow-up is still required.
Patients with multiple papillomas are at
increased risk of developing malignancy thus
long-term follow-up is appropriate. As no sig-
nificant increase of risk of malignancy devel-
opment has been demonstrated in patients with
182 Intraductal Papilloma

solitary papillomas, their regular follow-up is

not justified.
• Outcome
Intraductal papillomas with no other changes
in the surrounding breast tissue are associated
with a slight increase in relative risk of subse-
quent invasive breast carcinoma, equivalent to
that of florid ductal hyperplasia.
In a study of 193 papillomas diagnosed on
core needle biopsy, Cyr et al. reported that 12%
of the papillomas were upgraded to malignant
on excision; these carcinomas were early stage
and usually hormone receptor positive and thus
likely to have favorable prognosis (Cyr Intraductal Papilloma, Fig. 1 (H&E) Arborizing struc-
ture of intraductal papilloma
et al. 2011).

Macroscopy

Macroscopically, central papillomas may appear

as exophytic shagged masses attached to the wall
within dilated ducts. Papillomas vary greatly in
size, ranging from a few millimeters to several
centimeters. Peripheral papillomas are macro-
scopically unidentifiable.

Microscopy
Cytologically, smears from papillomas are
moderately cellular. The fronds of intraductal
papillomas show sharp delineation and cells
in tissue fragments are more cohesive. The papil-
lae feature fibrovascular stalks lined by
columnar cells. Frequently, epithelial cells
arranged in a honeycomb pattern are seen.
Alternatively, columnar cells can be arranged
in small papillae and/or can be seen isolated.
The presence of apocrine metaplasia and
bipolar naked nuclei is very frequent (Gomez-
Aracil et al. 2002).
Histologically intraductal papillomas are
characterized by the presence of a complex
arborizing structure comprised of fibrovascular
cores lined by myoepithelial (basally located)
and epithelial (luminal) cell layers (Fig. 1
(H&E) (Fig. 2 (H&E). The epithelial cell nuclei
vary in shape and size but are lacking
Intraductal Papilloma, Fig. 2 (H&E) Intraductal papil-
loma with complex structure and signs of bleeding
hyperchromasia (O’Malley et al. 2012). Regressive
changes may frequently occur in papillomas, mak-
ing them difficult to assess when only a limited
amount of tissue is available for histological exam-
ination (▶ Infarct of Breast Tissue). Such changes
include bleeding and infarction. These are typically
seen in large central lesions and may occur as a
result of torsion of fibrovascular cores or prior
sampling. When no residual vital tissue is present,
the lesion should be simply called an infarcted
papillary lesion (Wei 2016).
Stromal fibrosis or sclerosis is another feature
commonly associated with intraductal papillomas.
The sclerosis may distort the tissue to such an
extent that a pseudo-infiltrative pattern is observed
(Fig. 3 (H&E). In these sclerosing intraductal
Intraductal Papilloma 183

Intraductal Papilloma, Fig. 3 (H&E) Pseudo-infiltra- Intraductal Papilloma, Fig. 4 (H&E) Peripheral papil-
tive pattern in intraductal papilloma with stromal sclerosis loma with apocrine metaplasia and microcalcifications in
adjacent TDLU

papillomas, immunohistochemistry can be useful

I
for demonstrating the presence of myoepithelial
cells (Tse et al. 2009). Ductal adenomas (▶ Ductal
Adenoma), which are quite rare, show an epithelial
proliferation surrounding a central scar. They are
thought to be sclerosing intraductal papillomas.
Some cases of ductal adenoma may appear in the
context of Carney complex.
Inflammatory cell infiltrate as well as epithelial
and myoepithelial hyperplasia may also be
observed in intraductal papillomas. Metaplastic
changes are quite common, especially apocrine
metaplasia. Squamous-, clear cell-, sebaceous-,
osseous-, chondroid- and mucinous metaplasia Intraductal Papilloma, Fig. 5 p63 stain showing
may also occur. Squamous metaplasia may be pre- myoepithelial cells within papillary fronds
sent more frequently in the vicinity of infarction.
Compared with central papillomas, peripheral
papillomas (Fig. 4 (H&E) are more commonly and uneven in distribution. The myoepithelial
associated with other proliferative changes of the cells may be identifiable at high power, but immu-
breast such as usual- and atypical ductal hyper- nohistochemical staining for myoepithelial markers
plasia (▶ Usual Ductal Hyperplasia (UDH), may be necessary in some cases (Fig. 5 p63 stain).
▶ Atypical Ductal Hyperplasia) and ductal carci- Smooth muscle actin, p63, p40, CD10, calponin,
noma in situ (▶ Ductal Carcinoma In Situ). and high molecular weight keratins like CK 5/6,
CK14, and HMW-CK may be used (Tse et al.
2009). Among these, smooth muscle actin and
Immunophenotype CD10 are the least specific as their expression can
be seen also in some stromal cells. Thus, they have
Demonstration of a continuous myoepithelial cell only limited value in lesions with a pseudo-invasive
layer within the papillary fronds as well as in the growth pattern.
periphery of the duct wall distinguishes benign CK5/6 may also be useful for confirming het-
papillary lesions from the malignant ones. This erogeneity of cell population in a benign lesion
myoepithelial layer may however be attenuated when a patchy staining pattern is observed (Fig. 6.
184
CK5/6 immunostaining) (Tse et al. 2009). Lack of
CyclinB1 expression was described as a feature of
papillomas, while lack of CD133 expression was
found almost exclusively in malignant papillary
lesions (Ni and Tse 2016).
Molecular Features
Molecular studies are not relevant for routine
diagnosis and assessment of papillary lesions.
However, Volckmar et al. described recurrent mis-
sense mutations affecting AKT1, GNAS, and
PIK3CA in ductal adenomas (▶ Ductal Adenoma)
(Volckmar et al. 2017). They concluded that muta-
tions in so-called cancer-related genes do not nec-
essarily indicate malignant behavior but are also
present in benign tumors.
Differential Diagnosis
Papillomas frequently contain foci of benign epi-
thelial proliferation showing features of usual
ductal hyperplasia (UDH) (▶ Usual Ductal
Hyperplasia (UDH)). This includes the presence
of nuclei of variable shape, often elongated or
spindled, without atypia. The cells grow in a
lace-like pattern with irregular unevenly shaped
lumina. The cells demonstrate the phenomenon of
nuclear streaming (Bianchi et al. 2015).
Immunohistochemically, it is possible to demon-
strate a mosaic co-expression of low (e.g., CK18)
and high (e.g., CK5/6) molecular weight
cytokeratins with variable intensity of staining in
individual cells (Wei 2016).
Atypical epithelial proliferations (▶ Atypical
Ductal Hyperplasia and ▶ Ductal Carcinoma In
Situ) may involve intraductal papillomas, and
they are usually of low grade. They are typically
characterized by the presence of small, evenly
spaced cells with round, bland, uniform nuclei.
Intraductal papilloma with ADH and intraductal
papilloma with DCIS are distinguished from one
another using quantitative criteria; when the atyp-
ical proliferation is smaller than or equal to 3 mm,
it is classified as ADH within a papilloma. Atyp-
ical proliferations larger than 3 mm fulfill criteria
Intraductal Papilloma
Intraductal Papilloma, Fig. 6 CK5/6 stain demonstrat-
ing the presence of myoepithelial cells in papillary fronds
as well as a mosaic staining pattern in benign hyperplastic
luminal epithelium
for intraductal papilloma with low-grade DCIS
(O’Malley et al. 2012).
Intraductal papillary carcinoma (▶ Intraductal
Papillary Carcinoma) is one of the architectural
patterns of DCIS (▶ Ductal Carcinoma In Situ). It
is not associated with intraductal papillomas. The
neoplastic intraductal proliferations in intraductal
papillary carcinomas (papillary DCIS) show slen-
der, delicate fibrovascular cores lined by stratified
columnar epithelial cells with palisading nuclei
arranged perpendicular to the fibrovascular
cores. When diagnosed cytologically, smears
from malignant papillary lesions are usually
more cellular than those from papillomas
(Gomez-Aracil et al. 2002).
The state of the myoepithelial cell layer is a
useful indicator of the nature of the papillary
lesion. Atypical papillomas show reduced num-
bers of myoepithelial cells, while in intraductal
papillary carcinomas, there is a paucity or com-
plete absence of myoepithelial cells in the papil-
lary fronds. However, it should be kept in mind
that the sole absence of demonstrable
myoepithelial cells does not automatically mean
a diagnosis of malignancy, as these may be
completely or almost completely absent in papil-
lomas with apocrine metaplasia (Cserni 2012).
During different diagnostic interventions for
intraductal papillomas (such as fine-needle aspi-
ration cytology, core-cut biopsy, wire placement,
etc.), so-called epithelial displacement may occur
Invasive Carcinoma NST
(Nagi et al. 2005). This phenomenon – although
relatively rare – is well known and represents an
important diagnostic pitfall. Displaced benign
epithelial structures are usually represented by
small isolated clusters of cells present in the
stroma or lymphatic channels. Unlike truly inva-
sive nests of neoplastic cells, displaced epithelial
clusters are always located within the biopsy tract
and lack desmoplastic stromal reaction (Ueng
et al. 2009). Though the biologic significance of
epithelial displacement is unknown, preliminary
studies suggest that displaced cells most probably
do not survive the preceding trauma or eventually
die as time progresses (Nagi et al. 2005).
References and Further Reading
Bianchi, S., Bendinelli, B., Saladino, V., Vezzosi, V.,
Brancato, B., Nori, J., & Palli, D. (2015). Non-
malignant breast papillary lesions – b3 diagnosed on
ultrasound – guided 14-gauge needle core biopsy:
Analysis of 114 cases from a single institution and
review of the literature. Pathology and Oncology
Research, 21, 535–546.
Cserni, G. (2012). Benign apocrine papillary lesions of the
breast lacking or virtually lacking myoepithelial cells-
potential pitfalls in diagnosing malignancy. Acta
Pathologica, Microbiologica, et Immunologica
Scandinavica, 120, 249–252.
Cyr, A. E., Novack, D., Trinkaus, K., Margenthaler, J. A.,
Gillanders, W. E., Eberlein, T. J., Eberlein, T. J., Ritter,
J., & Aft, R. L. (2011). Are we overtreating papillomas
diagnosed on core needle biopsy? Annals of Surgical
Oncology, 18, 946–951.
Gomez-Aracil, V., Mayayo, E., Azua, J., & Arraiza, A.
(2002). Papillary neoplasms of the breast: Clues in
fine needle aspiration cytology. Cytopathology, 13,
22–30.
MacGrogan, G., & Tavassoli, F. A. (2003). Central atypical
papillomas of the breast: A clinicopathological study of
119 cases. Virchows Archiv, 443, 609–617.
Nagi, C., Bleiweiss, I., & Jaffer, S. (2005). Epithelial
displacement in breast lesions: A papillary phenome-
non. The Archives of Pathology and Laboratory Med-
icine, 129, 1465–1469.
Ni, Y. B., & Tse, G. M. (2016). Pathological criteria and
practical issues in papillary lesions of the breast – a
review. Histopathology, 68(1), 22–32. https://doi.org/
10.1111/his.12866.
O’Malley, F., Visscher, D., MacGrogan, G., & Tan, P. H.
(2012). Intraductal papilloma. In S. R. Lakhani, I. O.
Ellis, S. J. Schnitt, P. H. Tan, & M. J. van de Vijver
(Eds.), WHO classification of tumours of the breast
(pp. 100–102). Lyon: IARC Press.
185
Shiino, S., Tsuda, H., Yoshida, M., Jimbo, K., Asaga, S.,
Hojo, T., & Kinoshita, T. (2015). Intraductal papillo-
mas on core biopsy can be upgraded to malignancy on
subsequent excisional biopsy regardless of the presence
of atypical features. Pathology International, 65,
293–300.
Tse, G. M., Tan, P. H., & Moriya, T. (2009). The role of
immunohistochemistry in the differential diagnosis of
papillary lesions of the breast. Journal of Clinical
Pathology, 62, 407–413.
>Ueng, S. H., Mezzetti, T., & Tavassoli, F. A. (2009).
Papillary neoplasms of the breast: A review. The
Archives of Pathology and Laboratory Medicine, 133,
893–907.
Volckmar, A. L., Leichsenring, J., Flechtenmacher, C.,
Pfarr, N., Siebolts, U., Kirchner, M., Budczies, J.,
Bockmayr, M., Ridinger, K., Lorenz, K., Herpel, E.,
Noske, A., Weichert, W., Klauschen, F., Schirmacher,
P., Penzel, R., Endris, V., & Stenzinger, A. (2017).
Tubular, lactating, and ductal adenomas are devoid
of MED12 Exon2 mutations, and ductal
adenomas show recurrent mutations in GNAS and I
the PI3K-AKT pathway. Genes, Chromosomes &
Cancer, 56, 11–17.
Wei, S. (2016). Papillary lesions of the breast: An update.
The Archives of Pathology and Laboratory Medicine,
140, 628–643.
Invasive Carcinoma NST
Ian Ellis
Department of Histopathology, City Hospital
Campus, Nottingham University Hospitals,
Nottingham City Hospital, Nottingham, UK
Synonyms
Carcinoma simplex; Ductal carcinoma NST; Infil-
trating ductal carcinoma; Invasive carcinoma of
no specific type (NST); Invasive ductal carcinoma
not otherwise specified (ductal NOS); Scirrhous
carcinoma; Spheroidal cell carcinoma
Definition
Invasive breast carcinoma of no special type
is also commonly known as invasive ductal
carcinoma not otherwise specified, comprises
the largest group of invasive breast cancers. It
186
is a morphologically heterogeneous group which
does not exhibit the features or purity of tumors
of recognized special types of breast cancer,
such as classical invasive lobular (▶ Invasive
Lobular Carcinoma) or tubular carcinoma
(▶ Tubular Carcinoma).
Clinical Features
• Incidence
Invasive carcinoma NST forms a large propor-
tion of mammary carcinomas and its epidemio-
logical characteristics are similar to those of
breast cancer as a whole. The WHO currently
identifies that breast cancer is the most frequent
cancer among women, impacting 2.1 million
women each year, and also causes the greatest
number of cancer-related deaths among women.
In 2018, it is estimated that 627,000 women die
from breast cancer – that is approximately 15%
of all cancer deaths among women. While
breast cancer rates are higher among women in
more developed regions, rates are increasing in
nearly every region globally.
• Age
It is rare below the age of 40 years, but
the proportion of tumors classified as such in
young women with breast cancer is in general
similar to that in older women.
• Sex
Breast cancer of NST is a disease predomi-
nantly of females with male breast cancer
being very rare. Less than 1% of all breast
cancer cases develop in men, and only one in
a thousand men will ever be diagnosed with
breast cancer.
• Site
Breast cancer of NST occurs in the parenchyma
of the breast or very rarely in extra mammary
ectopic breast tissue. Approximately 50% of
breast cancers arise in the upper outer quadrant
of the breast, 15% in the inner upper quadrant,
and <10% in the inner lower and outer lower
quadrants respectively.
• Treatment
The management of breast cancer of NST
depends on the prognostic characteristics of
Invasive Carcinoma NST
the tumor including the histological grade
(or growth fraction), size, lymph node stage,
vascular invasion, hormone receptor, and
HER2 receptor status of the cancer. Treatments
are more aggressive when the prognosis is
worse or there is a higher risk of recurrence of
the cancer following treatment. Surgery with or
without radiation therapy is the usual initial
treatment in early stage disease, which may
be followed by adjuvant systemic therapy
such as endocrine therapy, chemotherapy, and
targeted anti HER2 therapy where appropriate.
Approximately, 70–80% of NST breast can-
cers are estrogen receptor (ER)-positive and
12–20% of cases are HER2 positive.
Neoadjuvant chemotherapy (NACT) has
been shown to be effective in downstaging
breast cancer and is now commonly used as
primary therapy (Early Breast Cancer Trialists’
Collaborative Group 2018). NACT for early
breast cancer can make breast-conserving sur-
gery more feasible. Patients with high-grade,
hormone receptor-negative tumors are most
likely to achieve a complete clinical response
of the primary tumor after NACT. Pathological
complete response (pCR) of the axilla can
be achieved in 41–75% of patients with
HER2-positive or triple-negative cancer
receiving NACT.
• Outcome
Outcomes for breast cancer vary depending on
the extent of disease, prognostic characteristics
and response to treatment. Survival rates have
improved significantly in recent years due to
multiple variables including early detection,
screening and an increasing range of effective
treatment options. Survival rates in the devel-
oped world are now high, with between 80%
and 90% of those in Europe and the United
States alive for at least 5 years. In developing
countries survival rates are poorer.
Tools and methods have been developed to
assist in predicting patient outcome and to sup-
port clinical decision making in breast cancer
management. Examples of such methods
include the Nottingham Prognostic Index (NPI)
(Blamey et al. 2007), St Gallen consensus
criteria, the National Comprehensive Cancer
Invasive Carcinoma NST
Network (NCCN) guidelines, and Predict
(https://www.predict.nhs.uk).
The NPI is based on a combination of
histopathological examination of tumor size,
lymph node stage, and tumor grading assem-
bled in a prognostic index formula. Prognosis
worsens as the NPI numerical value increases
and by using cut-off points patients may be
stratified into good, moderate and poor prog-
nostic groups. The NPI has been confirmed
after long-term follow-up, validated indepen-
dently in large multi-center studies, and revised
in order to stratify patients into 5 prognostic
groups (Blamey et al. 2010).
Macroscopy
Due to their morphological, biological, and
behavioral diversity, these tumors have no specific
macroscopic features. They can range in size from
<10 mm to >100 mm. They can have a rounded,
irregular, stellate, diffuse, or nodular configura-
tion. The invasive border is variable in appearance
but usually moderately or ill-defined and lacks
sharp circumscription. Classically, NST carcino-
mas form a mass lesion and are firm or even hard
on palpation, and may have a “gritty” feel when
cut with a blade. The cut surface appearance is
varied but is usually pale and grey to cream white.
Microscopy
Assignment of a tumor to the NST histological
type of breast cancer is essentially through a pro-
cess of exclusion of recognized special types. As
a consequence, morphological features vary con-
siderably from case to case. All types of tumor
margins can be observed, from highly infiltrative,
invading nonspecialized mammary stroma,
and disrupting the normal parenchymal lobular
architecture to continuous pushing margins.
Architecturally, the tumor cells may be arranged
in cords, clusters, and trabeculae, while some
tumors are characterized by a predominantly
solid or syncytial infiltrative pattern with little
associated stroma (Fig. 1a, b, c: all the figures
187
in this chapter illustrate examples of NST histo-
logical type, please note the ranges of non
specific appearances). In many of cases, glandular
differentiation may be apparent as tubular or
acinar structures with central lumina formed by
the tumor cell population. Occasionally,
areas with single-file infiltration or targetoid
features mimicking invasive lobular carcinoma
(▶ Invasive Lobular Carcinoma) occur but
lacking its distinct cytomorphological character-
istics. NST carcinoma cells have a variable
appearance. Their cytoplasm may be abundant
and eosinophilic. Nuclei may be regular and uni-
form or highly pleomorphic with prominent, often
multiple, nucleoli. Mitotic activity ranges from
virtually absent to frequent. In up to 80% of
cases, foci of associated ductal carcinoma in situ
I
(DCIS) (▶ Ductal Carcinoma In Situ) will be pre-
sent. Any associated DCIS is usually of same
nuclear grade as the invasive carcinoma. Occa-
sionally lobular neoplasia, either ALH or LCIS
may be present (▶ Lobular In Situ Neoplasia).
The stromal component is extremely variable.
There may be a highly cellular fibroblastic prolif-
eration, a scanty element of connective tissue or
marked hyalinization. Foci of elastosis may also
be present in a periductal or perivenous distribu-
tion. Focal necrosis may be present and this is
occasionally extensive with secondary formation
of cysts. In a minority of cases, a distinct
lymphoplasmacytoid infiltrate can be identified.
Vascular tumor emboli can be observed within or
adjacent to the tumor.
Carcinoma of Mixed Histological Type
The current UK (Ellis et al. 2016), European
(Perry et al. 2006) and WHO (Lakhani et al.
2012) classification systems promote use the
mixed tumor type category for tumors which
lack the purity of a specific special type but
show prominent or dominant but not pure special
type characteristics. For a tumor to be typed as
breast carcinoma NST, it must have a non-
specialized pattern in >50% of its mass as
judged by thorough examination of representa-
tive sections. If the NST pattern comprises
between 10% and 49% of the tumor, the rest
being of a recognized special type, then it
188
Invasive Carcinoma NST, Fig. 1 (H&E) (a, b, c) Exam-
ples of three invasive carcinomas of NST type showing no
specific characteristics and a range of morphological
appearances. Note the lack of special characteristic
exhibited by each tumor and also the range of
will fall into one of the mixed groups:
mixed NST and special type (Fig. 2) or
mixed NST and lobular carcinoma. Apart
from these considerations, there are very
few lesions that should be confused with NST
carcinomas.
Rare Morphological Variants of NST
Carcinoma
The 2012 WHO classification of breast tumors
(Lakhani et al. 2012) recognizes a number of
morphological forms of breast cancer that are
not currently recognized as distinct special types
of invasive breast cancer but as variants of
NST breast cancer. These include pleomorphic
Invasive Carcinoma NST
morphological appearances seen in the NST tumor type.
Please note that all the figures in this chapter are of NST
tumors, with the exception of Fig. 2 which shows a tumour
of mixed type with both NST and Tubular features
carcinoma, carcinoma with osteoclast-like stro-
mal giant cells, carcinoma with choriocarci-
nomatous features, and carcinoma with
melanotic features. There is also a current debate
whether to include medullary like cancers within a
group of NST cancers with associated
lymphocyte-rich stroma rather than as a distinct
separate morphological type.
Pleomorphic carcinoma. The 2012 WHO
classification defines pleomorphic carcinoma
as a rare variant of high-grade NST carcinoma,
which is characterized by a proliferation of
pleomorphic and bizarre, sometimes multi-
nucleated, tumor giant cells comprising
>50% of the tumor cells in a background
Invasive Carcinoma NST
Invasive Carcinoma NST, Fig. 2 (H&E) (a, b) An
example of a tumor of mixed type with focal (>50% and
<90%) tubular carcinoma characteristics with background
(<50%) non specialised, NST, features. Please note that
this tumour shows grade 1 histological characteristics.
of adenocarcinoma or adenocarcinoma with
metaplastic spindle and squamous differentia-
tion. The tumors are typically of grade 3 with
a high mitotic frequency and central necrosis.
Carcinoma with osteoclast-like stromal giant
cells. The 2012 WHO classification defines
these carcinomas by the presence of osteoclas-
tic giant cells (OGCs) in the stroma. The giant
cells are generally associated with an inflam-
matory, fibroblastic, hypervascular stroma,
with extravasated erythrocytes, lymphocytes,
and monocytes, along with mononucleated
and binucleated histiocytes, some containing
hemosiderin. The giant cells vary in size and
contain a variable number of non-atypical
nuclei. The carcinomatous part of the lesion is
most frequently a well – to moderately differ-
entiated infiltrating breast carcinoma NST
but all the other histological types have been
observed particularly invasive cribriform car-
cinoma (▶ Invasive Cribriform Carcinoma),
and also tubular (▶ Tubular Carcinoma),
mucinous (▶ Invasive Mucinous Carcinoma),
papillary, lobular (▶ Invasive Lobular Carci-
noma), squamous, and other metaplastic
(▶ Invasive Metaplastic Carcinoma) patterns
and pleomorphic carcinoma.
Carcinoma with choriocarcinomatous features.
The 2012 WHO classification defines these as
189
Note the presence of a normal lobular unit (b) for compar-
ison of tumor cells’ nuclear size. The carcinoma has similar
sized nuclei and score 1 for nuclear pleomorphism. There
is marked tubule/gland formation, score 1 and no visible
mitoses, score 1, giving a total score of 3 (grade 1)
I
NST carcinoma associated with elevated levels
of serum human chorionic gonadotropin. Up to
60% of NST carcinomas have been found to
contain HCG-positive cells. Histological evi-
dence of choriocarcinomatous differentiation,
however, is exceptionally rare with only a few
cases reported.
Carcinoma with melanotic features. The 2012
WHO classification defines this as an excep-
tionally rare tumor which appears to represent
combinations of NST carcinoma and malignant
melanoma and in some of these cases exhibits
a transition from one cell type to the other.
The mere presence of melanin in breast cancer
cells should not be construed as evidence of
melanocytic differentiation, since pigmenta-
tion of carcinoma cells with melanin can
occur when breast cancers invade the skin
and involve the dermoepidermal junction.
In addition, care must be taken to distinguish
tumors showing melanocytic differentiation
from breast carcinomas with prominent cyto-
plasmic deposition of lipofuscin. It should also
be noted that most melanotic tumors of the
breast represent metastases from malignant
melanomas originating in extra-mammary
sites. Primary melanomas may arise anywhere
in the skin of the breast, but an origin in the
nipple-areola complex is extremely rare.
190
Additional Classification Systems
Histological Grade
One of the most fundamental aspects of oncological
pathology, which has undoubtedly stood the test of
time, has been the recognition that the detailed
morphological structure of tumors can be correlated
with their degree of malignancy. Greenhough in
1928, in Boston, USA, undertook the first formal
study of the grading of breast cancer. Scarff and his
colleagues at the Middlesex Hospital in London
re-examined Greenhough’s method and decided
that only three factors, tubule formation, nuclear
pleomorphism, and hyperchromatism were of
importance. Scarff’s method has formed the basis
of all subsequent grading systems. The perceived
poor reproducibility and consistency has been
largely resolved by use of semi objective scoring
systems and adherence to written criteria. These
studies have highlighted the need for grading to be
carried out by trained histopathologists who work to
an agreed protocol.
The Nottingham method, outlined in
Tables 1 and 2, is the most widely used method.
Three characteristics of the tumor are evaluated
according to semi quantitative criteria, tubule
formation as an expression of glandular differen-
tiation, nuclear pleomorphism and mitotic counts.
It has been validated through long term follow
up of a large series of patients confirming
conclusively the highly significant relationship
between histological grade and prognosis; sur-
vival worsens with increasing grade (Elston and
Invasive Carcinoma NST, Table 1 Semiquantitative
method for assessing histological grade in breast
carcinoma
Feature Score
Tubule formation
Majority of tumor (>75%) 1
Moderate degree (10–75%) 2 morphonuclear leukocytes are excluded.
Little or none (<10%) 3 6. One section (4–5 mm, magnification
Nuclear pleomorphism
Small, regular uniform cells 1 ered to be sufficient.
Moderate increase in size and variability 2 7. Full sections are preferred over biopsies
Marked variation 3 whenever possible.
Mitotic counts
Dependent on microscope field area 1–3
(see Table 2)
Invasive Carcinoma NST
Ellis 1991). The method has now been shown to
have good reproducibility in other centres and it
has been adopted for use in the pathological data
set of the United Kingdom NHS BSP and in the
USA and Europe (Rakha et al. 2010). Examples
of grade 1, grade 2, and grade 3 carcinomas
are shown in Figs. 2a, b, 3, 4, and 5.
Tumor Infiltrating Lymphocytes
It has been recognized that some types of breast
cancer such as medullary like, NST, triple negative
and HER2 positive, are associated with tumor-
infiltrating lymphocytes (TILs) (Fig. 6). Formal
evaluation of TILs is gaining momentum as evi-
dence strengthens for the clinical relevance of phe-
nomenon which is regarded as an immunological
biomarker. The extent of lymphocytic infiltration in
tumor tissue can be assessed as by evaluation of
hematoxylin and eosin (H&E)-stained tumor sec-
tions and has been shown to provide prognostic
and potentially predictive value, particularly in the
triple-negative and HER 2 positive settings.
A standardized methodology for evaluating
TILs has been developed for visual assessment
on H&E sections (Salgado et al. 2015) by the
International TILs Working Group. Their key rec-
ommendations are:
1. TILs should be reported for the stromal com-
partment (=% stromal TILs).
2. TILs should be evaluated within the borders
of the invasive tumor.
3. Exclude TILs outside of the tumor border and
around DCIS and normal lobules.
4. Exclude TILs in tumor zones with crush arti-
facts, necrosis, regressive hyalinization as
well as in the previous core biopsy site.
5. All mononuclear cells (including lymphocytes
and plasma cells) should be scored, but poly-
200–400) per patient is currently consid-
8. A full assessment of average TILs in the
tumor area by the pathologist should be
used. Do not focus on hotspots.
Invasive Carcinoma NST 191

Invasive Carcinoma NST, Table 2 Assignment of points for mitotic counts according to the field area
Number of mitoses corresponding to
Field diameter in mm Score 1 Score 2 Score 3
0.40 Up to 4 5–8 9 or more
0.41 Up to 4 5–9 10 or more
0.42 Up to 4 5–9 10 or more
0.43 Up to 4 5–10 11 or more
0.44 Up to 5 6–10 11 or more
0.45 Up to 5 6–11 12 or more
0.46 Up to 5 6–11 12 or more
0.47 Up to 5 6–12 13 or more
0.48 Up to 6 7–12 13 or more
0.49 Up to 6 7–13 14 or more
0.50 Up to 6 7–13 14 or more
0.51 Up to 6 7–14 15 or more
0.52 Up to 7 8–14 15 or more
0.53 Up to 7 8–15 16 or more
0.54 Up to 7 8–16 17 or more I
0.55 Up to 8 9–16 17 or more
0.56 Up to 8 9–17 18 or more
0.57 Up to 8 9–17 18 or more
0.58 Up to 9 10–18 19 or more
0.59 Up to 9 10–19 20 or more
0.60 Up to 9 10–19 20 or more
0.61 Up to 9 10–20 21 or more
0.62 Up to 10 11–21 22 or more
0.63 Up to 10 11–21 22 or more
0.64 Up to 11 12–22 23 or more
0.65 Up to 11 12–23 24 or more
0.66 Up to 11 12–24 25 or more
0.67 Up to 12 13–25 26 or more
0.68 Up to 12 13–25 26 or more
0.69 Up to 12 13–26 27 or more
0.70 Up to 13 14–27 28 or more

9. TILs should be assessed as a continuous
parameter.
10. No formal recommendation for a clinically
relevant TIL threshold(s) can be given at
this stage.
Immunophenotype
Being a heterogeneous form of breast
cancer tumors of NST type have not distinct
immunephenotypic characteristics. The majority
of NST tumors are positive for GCDFP-15 and
low molecular weight cytokeratin, including CK’s
7, 8 and 18. All of the major gene expression
molecular classes (luminal, basal/triple negative
and HER2 positive) are represented in the NST
group with the luminal ER positive tumors
predominating, approximately 70–80% of NST
breast cancers are ER-positive (▶ Hormone
Receptors in Breast Cancer). The basal/triple neg-
ative for ER, progesterone receptor (PR)
and HER2 group occur at a lower frequency
(10–20%), as does the HER2 positive/ER positive
and negative subgroups, with 12–20% of cases
being HER2 positive (▶ HER2 in Breast Cancer).
192
Invasive Carcinoma NST, Fig. 3 Example of a grade
1 carcinoma. The tumour shows prominent tubule/gland
formation (score 1), moderate to high nuclear pleomor-
phism (score 3) and no mitotic figures (score 1). Final
garde score 5 indicating a grade 1 invasive carcinoma.
The differential diagnosis would be with a pure tubular
carcinoma but the degree of nuclear pleomorphism
exhibited preclude a diagnosis of pure tubular carcinoma
and classification as grade 1 NST carcinoma is appropriate
(H&E)
Invasive Carcinoma NST, Fig. 4 Example of a grade
2 invasive carcinoma. There is over 10% tubule/gland
formation, score 2, moderate nuclear pleomorphism,
score 2 and on assessment of 10 calibrated high power
fields a mitotic frequency score of 2. Total grade score 6,
indicating a grade 2 tumor (H&E)
Molecular Features
NST breast cancer shows high genetic varia-
tion comparable to breast cancer as a whole.
Historically breast cancer was regarded as a
Invasive Carcinoma NST
Invasive Carcinoma NST, Fig. 5 Example of a grade
3 tumor. There is no evidence of tubule/gland formation,
score 3, a high degree of nuclear pleomorphism and
increase in nuclei size, score 3, assessment of 10 calibrated
high power fields showed a high frequency of mitosis,
score 3. The total grade score is 9 indicating a grade
3 tumor (H&E)
single disease with variable histology and clin-
ical course. Recently high-throughput molecu-
lar biology analytical methods such as cDNA
microarray analysis when applied to breast
cancer as a whole and to the NST class
revealed unexpectedly large-scale molecular
differences between ER-positive cancers and
ER-negative cancers (Fig. 7) (Allison 2012;
Rakha and Green 2017). In addition these
molecular biology studies have shown specific
genetic lesions or regions of alteration associ-
ated with some histological special types or
grade, for example the low nuclear grade
tumors including invasive lobular (▶ Invasive
Lobular Carcinoma) and tubular carcinoma
(▶ Tubular Carcinoma) cluster in the luminal
A intrinsic class and have distinct similar
alterations of chromosomes 1 and 16. In con-
trast, the group of NST breast cancers harbors
all the molecular intrinsic classes and has
genetic alterations across the genome. These
results imply that breast cancer overall and the
NST group appear to develop via multiple
different genetic evolutionary pathways. As a
consequence, NST breast cancer is viewed not
as a single disease but as a collection of sev-
eral biologically distinct neoplastic diseases
that arise from the breast epithelium.
Invasive Carcinoma NST 193

Invasive Carcinoma NST,

Fig. 6 A high grade
invasive carcinoma with
some medullary like
features showing marked
stromal infiltration by
lymphocytes and plasma
cells (TILs) (H&E)

St Gallen 2017 division of subtypes

Clinical grouping
Triple negative
Hormone receptor-
negative and HER2-
positive
Hormone receptor-positive
and HER2-positive
Hormone receptor-positive
and HER2-negative
– a spectrum of ER+/
HER2-negative
High receptor, low
Invasive Carcinoma NST, Fig. 7 An example of a triple proliferation, low grade
negative, for ER, PR and HER2, grade 3 invasive carci- (luminal A-like)
noma of NST type showing undifferentiated basal like
characteristics (H&E)
Intermediate
All four different molecular types of breast
cancer can be observed in NST breast cancer:
• Luminal A type – low proliferation
ER-positive
• Luminal B type – highly proliferative ER-
Low receptor, high
positive, PR low or negative proliferation, high grade
• Basal/triple negative – ER/PR-negative and (luminal B-like)
HER-2-negative
• HER-2 amplified breast cancer
a
Basal like breast cancer and HER2-enriched subtype can
However, for clinical purposes, these have
be defined by genomic assay only.
been further refined by the St Gallen consensus b
No role for gene testing in clinical pathologic low risk
conference (Curigliano et al. 2017): cases (pT1a, pT1b, G1, ER high, pN0).
I
Notesa
Negative ER, PR and
HER2
International guidelines
International guidelines
ER and/or PgR positive
1%
Multi-parameter
molecular marker ‘good’
if available.b High ER/PR
and clearly low Ki-67 or
grade.
Multi-parameter
molecular marker
‘intermediate’ if available.
Uncertainty persists about
degree of risk and
responsiveness to
endocrine and cytotoxic
therapies.
Multi-parameter
molecular marker ‘bad’
if available. Lower ER/
PR with clearly high
Ki-67, histological
grade 3.
194
Differential Diagnosis
The principle differential diagnosis relates to dis-
tinction from invasive mammary carcinomas of
recognized pure special types such as invasive
lobular carcinoma (▶ Invasive Lobular Carci-
noma), tubular (▶ Tubular Carcinoma)/invasive
cribriform carcinoma (▶ Invasive Cribriform Car-
cinoma), mucinous carcinoma (▶ Invasive
Mucinous Carcinoma), medullary-like carcinoma
(▶ Invasive Carcinoma with Medullary Features),
and other rarer special types. Such distinction
requires knowledge and application of the defin-
ing features of each type which are predominantly
morphological and detailed elsewhere in the rele-
vant sections. However, a very high proportion of
invasive lobular carcinomas (▶ Invasive Lobular
Carcinoma) have alterations in the E-Cadherin
gene with resultant loss of E-Cadherin protein
expression. Immunohistochemical staining for
E-Cadherin can therefore be a helpful supporting
adjunct test to differentiate the lobular class from
the NST group of cancers.
The UK, EU, and WHO classification systems
highlight the need for >90% purity of special
type characteristics to define most special types
of cancer to ensure their prognostic characteristics
will be manifest. Tumors exhibiting between
50% and 90% special type characteristics are
recommended to be designated as mixed special
and NST type (see above).
Tumors of unusual morphological appearance,
particularly if ER negative and lacking an accom-
panying in situ component such as DCIS, may
represent a metastatic tumor deposit in the breast
rather than a primary NST mammary carcinoma.
Clinical information relating to past medical his-
tory of a malignancy elsewhere, clinical investi-
gation, and immunophenotype of the tumor can
help distinguish a primary from a metastatic tumor
(Lee 2007).
References and Further Reading
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cancer: What a pathologist needs to know. American
Journal of Clinical Pathology, 138, 770–780.
Blamey, R. W., Ellis, I. O., Pinder, S. E., Lee, A. H.,
Macmillan, R. D., Morgan, D. A., Robertson, J. F.,
Invasive Carcinoma NST
Mitchell, M. J., Ball, G. R., Haybittle, J. L., &
Elston, C. W. (2007). Survival of invasive breast cancer
according to the Nottingham Prognostic Index in cases
diagnosed in 1990–1999. European Journal of Cancer,
43, 1548–1555.
Blamey, R. W., Hornmark-Stenstam, B., Ball, G., Blichert-
Toft, M., Cataliotti, L., Fourquet, A., Gee, J., Holli, K.,
Jakesz, R., Kerin, M., Mansel, R., Nicholson, R.,
Pienkowski, T., Pinder, S., Sundquist, M.,
van de Vijver, M., & Ellis, I. (2010). ONCOPOOL –
A European database for 16,944 cases of breast cancer.
European Journal of Cancer, 46, 56–71.
Carlson, R. W., Brown, E., Burstein, H. J., Gradishar, W. J.,
Hudis, C. A., Loprinzi, C., Mamounas, E. P.,
Perez, E. A., Pritchard, K., Ravdin, P., Recht, A.,
Somlo, G., Theriault, R. L., Winer, E. P., &
Wolff, A. C. (2006). NCCN Task Force report: Adju-
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Comprehensive Cancer Network, 4(Suppl 1), S1–S26.
Curigliano, G., Burstein, H. J., Winer, E. P., Gnant, M.,
Dubsky, P., Loibl, S., Colleoni, M., Regan, M. M.,
Piccart-Gebhart, M., Senn, H.-J., Thürlimann, B.,
André, F., Baselga, J., Bergh, J., Bonnefoi, H.,
Brucker, S. Y., Cardoso, F., Carey, L., Ciruelos, E.,
Cuzick, J., Denkert, C., Di Leo, A., Ejlertsen, B.,
Francis, B., Galimberti, V., Garber, J., Gulluoglu, B.,
Goodwin, P., Harbeck, N., Hayes, D. F., Huang, C. S.,
Huober, J., Khaled, H., Jassem, J., Jiang, Z.,
Karlsson, P., Morrow, M., Orecchia, R.,
Osborne, K. C., Pagani, O., Partridge, A. H.,
Pritchard, K., Ro, J., Rutgers, E. J. T., Sedlmayer, F.,
Semiglazov, V., Shao, Z., Smith, I., Toi, M., Tutt, A.,
Viale, G., Watanabe, T., Whelan, T. J., & Xu, B. (2017).
De-escalating and escalating treatments for early-stage
breast cancer: The St. Gallen International Expert
Consensus Conference on the Primary Therapy of
Early Breast Cancer 2017. Annals of Oncology, 28,
1700–1712.
Early Breast Cancer Trialists’ Collaborative Group
(EBCTCG). (2018). Long-term outcomes for neo-
adjuvant versus adjuvant chemotherapy in early breast
cancer: Meta-analysis of individual patient data from
ten randomised trials. Lancet Oncology, 19, 27–39.
Ellis, I. O., Al-Sam, S., Anderson, N., Carder, P., Deb, R.,
Girling, A., Hales, S., Hanby, A., Ibrahim, M.,
Lee, A. S. H., Liebmann, R., Mallon, E., Pinder, S. E.,
Provenzano, E., Quinn, C., Rakha, E., Rowlands, D.,
Stephenson, T., & Wells, C. A. (2016). Pathology
reporting of breast disease in surgical excision speci-
mens incorporating the dataset for histological
reporting of breast cancer. The Royal College of Pathol-
ogists, London. file:https://www.rcpath.org/profession/
guidelines/cancer-datasets-and-tissue-pathways.html#
Elston, C. W., & Ellis, I. O. (1991). Pathological prognostic
factors in breast cancer. I. The value of histological
grade in breast cancer: Experience from a large
study with long-term follow-up. Histopathology, 19,
403–410.
Lakhani, S. R., Ellis, I. O., Schnitt, S. J., Tan, P. H., &
van de Vijver, M. J. (2012). WHO classification of
tumours of the breast (4th ed.). Lyon: IARC Press.
Invasive Carcinoma with Medullary Features
Lee, A. H. (2007). The histological diagnosis of metastases
to the breast from extramammary malignancies.
Journal of Clinical Pathology, 60, 1333–1341.
Perry, N., Broeders, M., de Wolf, C., Törnberg, S.,
Holland, R., & von Karsa, L. (2006). European guide-
lines for quality assurance in breast cancer screening
and diagnosis (4th ed.). Luxembourg: Office for
Official Publications of the European Communities.
Rakha, E. A., & Green, A. R. (2017). Molecular classifi-
cation of breast cancer: What the pathologist needs to
know. Pathology, 49, 111–119.
Rakha, E. A., Reis-Filho, J. S., Baehner, F., Dabbs, D. J.,
Decker, T., Eusebi, V., Fox, S. B., Ichihara, S.,
Jacquemier, J., Lakhani, S. R., Palacios, J.,
Richardson, A. L., Schnitt, S. J., Schmitt, F. C.,
Tan, P. H., Tse, G. M., Badve, S., & Ellis, I. O.
(2010). Breast cancer prognostic classification in the
molecular era: The role of histological grade. Breast
Cancer Research, 12, 207.
Salgado, R., Denkert, C., Demaria, S., Sirtaine, N.,
Klauschen, F., Pruneri, G., Wienert, S., Van den
Eynden, G., Baehner, F. L., Penault-Llorca, F.,
Perez, E. A., Thompson, E. A., Symmans, W. F.,
Richardson, A. L., Brock, J., Criscitiello, C.,
Bailey, H., Ignatiadis, M., Floris, G., Sparano, J.,
Kos, Z., Nielsen, T., Rimm, D. L., Allison, K. H.,
Reis-Filho, J. S., Loibl, S., Sotiriou, C., Viale, G.,
Badve, S., Adams, S., Willard-Gallo, K., Loi, S., &
International TILs Working Group 2014. (2015). The
evaluation of tumor-infiltrating lymphocytes (TILs)
in breast cancer: Recommendations by an International
TILs Working Group 2014. Annals of Oncology, 26,
259–271.
Invasive Carcinoma with
Medullary Features
Cecily Quinn1,2 and Clare D’Arcy1
1 morphology in 75% of the tumor and the remain-
Department of Histopathology, Irish National
Breast Screening Programme and St. Vincent’s
University Hospital, Dublin, Ireland
2 A subset of invasive carcinoma NST that dis-
School of Medicine, University College Dublin,
Dublin, Ireland
Synonyms
Atypical medullary carcinoma (atypical MC);
Carcinoma with medullary features (CMF); Clas-
sical medullary carcinoma (classical MC); Inva-
sive carcinoma of no special type (NST) with
medullary characteristics
195
Definition
The 2012 WHO Classification of Tumors of the
Breast recommends the use of the collective term
“Carcinoma with Medullary Features” to encom-
pass tumors previously diagnosed as classical
medullary carcinoma (classical MC), atypical
medullary carcinoma (atypical MC), and a sub-
group of invasive breast carcinoma of no special
type (NST) with medullary characteristics
(Lakhani et al. 2012).
These tumors are characterized by the follow-
ing histological features:
1. An expansile or pushing border
2. A syncytial growth pattern
3. High cytonuclear grade
I
4. A prominent lymphoplasmacytic infiltrate
These diagnostic criteria are less strict than the
original criteria proposed by Ridolfi et al. for a
diagnosis of classical MC which requires com-
plete circumscription, a syncytial growth pattern
in at least 75% of the tumor, a moderate to marked
mononuclear stromal infiltrate, high nuclear
grade, no intraduct component, and no micro-
glandular features (Ridolfi et al. 1977).
Atypical MC displays some but not all of
the features of classical MC and permits lack
of complete circumscription, a less prominent
lymphoid infiltrate, accompanying intraduct
carcinoma and focal glandular differentiation.
A well-circumscribed tumor with classical MC
der composed of invasive carcinoma NST also
qualifies as atypical MC.
plays medullary characteristics, including circum-
scription, high nuclear grade, and a prominent
lymphoplasmacytic stromal infiltrate, has been
observed, particularly in women with inherited
BRCA1 gene mutations.
In view of the need to recognize the latter
tumor subgroup and the considerable lack of
reproducibility in the diagnosis of classical and
atypical MC, the WHO group has taken the prag-
matic approach to combine these three groups
emphasizing their common characteristics and
196
propose the collective term, “Carcinoma with
Medullary Features,” abbreviated to CMF for the
remainder of this chapter (Lakhani et al. 2012).
Clinical Features
• Incidence
Classical MC, as defined by Ridolfi et al. in
1977, is generally considered to be a rare breast
tumor accounting for <1% of all breast cancers
(Ridolfi et al. 1977). Rates of up to 7% have
been reported and this is likely attributable to
interobserver and inter-institutional variation
in the application of the histological criteria
used to make the diagnosis.
In reported series, MC is less common
than atypical MC but the incidence is
largely unknown due to variation in defi-
nition and lack of and/or inconsistent coding
documentation.
CMF has a broader, more inclusive, defini-
tion and includes a subset of tumors with med-
ullary characteristics that would previously
have been categorized as invasive carcinoma
NST. It is difficult to obtain precise figures on
overall incidence, but it is estimated that CMF
accounts for between 10% and 20% of invasive
breast tumors (Hicks and Lester 2017).
• Age
The age at diagnosis of women with CMF ranges
from 21 to 95 years, with an average age at
presentation of between 45 and 50 years. The
latter is approximately 10 years younger than the
average age profile of women diagnosed with
other types of invasive breast carcinoma. One
in four diagnoses of CMF occurs in women
under the age of 35 years. This is likely to be
due to the association of CMF with inherited
Breast Cancer susceptibility gene 1 (BRCA1)
germline mutation (Eisinger et al. 1998).
• Sex
CMF is predominantly reported in females in
line with all other forms of breast carcinoma.
The literature is scarce on histological tumor
type in men. Most breast tumors in men are
luminal A or triple negative. MC has been
reported in male patients. Male patients with
Invasive Carcinoma with Medullary Features
BRCA1 gene mutations are also at increased
risk of developing breast cancer. BRCA2
mutations confer a higher risk of breast cancer
in men than in women.
• Site and Presentation
Patients may present with a discrete palpable
breast mass or may be diagnosed through
mammographic screening, population based
or high-risk surveillance programs. CMF is
typically well circumscribed and may have a
soft consistency due to the lack of a stromal
desmoplastic reaction. In view of these fea-
tures and the relatively young age at presen-
tation, these tumors may mimic benign
lesions both clinically and on imaging studies.
The overlying skin may be red. Bilateral syn-
chronous MCs have been reported, more com-
monly in patients with a positive family
history.
CMF may be associated with a rapid growth
rate and may also come to medical attention as
an interval screening breast cancer.
Axillary lymph node involvement may occur
but is relatively less common in CMF compared
with invasive carcinoma NST (▶ Invasive Car-
cinoma NST). Concomitant enlarged axillary
lymph nodes are more likely to be reactive than
involved by metastatic CMF and presentation as
axillary lymph node involvement is rare (Hicks
and Lester 2017). Presentation as distant metas-
tases is also rare.
• Treatment Surgery
The primary goal of treatment is complete sur-
gical excision with clear margins. Conservation
surgery is clearly desirable and is feasible in
most cases due to the absence of ductal carci-
noma in situ (▶ Ductal Carcinoma In Situ).
Mastectomy may be necessary to treat large
and some centrally located tumors.
A diagnosis of CMF, in some countries, will
lead to genetic testing in women who have not
been previously tested. The results of this
may lead to consideration of additional breast
and other prophylactic surgery. This requires
careful evaluation by the patient in consulta-
tion with her/his clinical team.
• Chemotherapy
Invasive Carcinoma with Medullary Features
CMF is typically triple negative although cases
of hormone receptor positive MC have been
reported. In view of the more favorable prog-
nosis associated with CMF, it has been
suggested that patients with lymph node nega-
tive disease may possibly avoid chemotherapy.
In general, this tumor type tends to occur in
younger women and the constellation of mor-
phological features is usually associated with
triple negative status. At the present time it is
recommended that adjuvant or neoadjuvant
chemotherapy treatment recommendations for
patients with CMF should take account of the
clinical, pathological, and biological character-
istics as for all invasive breast cancers. PARP
inhibitors and platinum agents are reported to
be more effective in the treatment of BRCA1-
related tumors.
• Immunotherapy
Several clinical trials are in progress to investi-
gate the efficacy of immunotherapy agents in
the treatment of triple negative breast carci-
noma (TNBC) (Dua and Tan 2017). This relates
to the discovery that approximately 25% of
TNBCs express the T-cell inhibitory molecule
PD-L1 (programmed death ligand-1), particu-
larly in tumors with a high lymphocyte count.
PDL1 is expressed on cancer cells, tumor infil-
trating lymphocytes (TILs), and immune cells
(Tung et al. 2016). The binding of PD-L1 to the
PD-1 (programmed death 1) checkpoint recep-
tor on T cells is one mechanism for tumor
evasion of the immune response. As detailed
in subsequent sections, CMF is characterized
by a prominent inflammatory cell infiltrate with
a high TIL count. CMF is also associated with a
high level of genomic instability leading to
increased production of neoantigens and greater
immunogenicity (Weigelt et al. 2010). These
features suggest that CMF is likely to be a can-
didate tumor type for targeted immunotherapy.
Adjuvant Radiotherapy: Recommenda-
tions for post-surgical radiotherapy should be
made in accordance with those for other pri-
mary invasive breast carcinomas.
• Outcome
In the original report from Ridolfi et al., clas-
sical MC, diagnosed using their strict criteria,
197
was associated with a significantly higher sur-
vival rate at 10 years, estimated at 84% for
patients with classical MC compared with
63% for patients with non-medullary invasive
breast carcinoma (Ridolfi et al. 1977). This
also pertained to patients with
positive axillary lymph nodes when the
two groups were compared. In addition to
57 patients with classical MC, the study popu-
lation included 79 patients with AMC and
56 with non-medullary carcinoma (invasive
carcinoma NST, using modern terminology).
Patients with AMC also had an improved prog-
nosis with a 10-year survival rate of 74% over-
all. Interestingly, AMC with a sparse lymphoid
infiltrate was associated with a relatively poor
prognosis. Apart from this observation, the
I
authors were unable to draw any firm conclu-
sions regarding the prognostic effect of the
other morphological features of AMC.
In a more recent study, Mateo et al.
reviewed the outcome of patients diagnosed
with MC (n = 3,688) and AMC (n = 288)
registered with the National US Cancer Data-
base (NCDB) during the period 2004 to 2013
(Mateo et al. 2016). Cases are reported to
the NCDB using codes from the International
classification of diseases for Oncology
(ICD-O-3). During the study period 918,870
cases of non-medullary breast carcinoma
were registered. Over 20% of tumors diag-
nosed as MC or AMC were recorded as hor-
mone receptor positive. The study did not
include a review of histopathological slides
and the number of AMC tumors was rela-
tively small. Notwithstanding these limita-
tions the authors found no significant
difference between MC and AMC in terms
of clinicopathological characteristics and
clinical outcome.
Subsequent studies from several institutions
have also reported a more favorable outcome in
patients with MC compared with grade matched
invasive carcinoma NST. In a compilation of
data from 13 International Breast Cancer Study
Group (IBCSG) trials, Huober et al. found that
patients with MC diagnosed on morphology
alone had an improved prognosis in terms of
198
disease free and overall survival at 14 years
(Huober et al. 2012). Restricting the diagnosis
to patients with hormone receptor negative dis-
ease was associated with an even more favor-
able outlook.
In the last decade, the role of TILs in medi-
ating response to chemotherapy and improving
clinical outcomes in all subtypes of breast can-
cer has been recognized. TNBCs are associated
with a greater degree of lymphoid infiltration
than luminal tumors and survival benefit
increases with each 10% increase in TILs
(Stanton and Disis 2016). The survival advan-
tage associated with TILs appears to be more
powerful in TNBCs than in HER2 positive
tumors that may also feature lymphoid infiltra-
tion. Considering that a prominent lymphoid
infiltrate is one of the key morphological
criteria for a diagnosis of CMF, it appears likely
that the improved prognosis in CMF is related
to the host immune response, particularly in
triple negative tumors. Gene expression profil-
ing studies (GEP) have also demonstrated that
the expression levels of immune response genes
are independent predictors of outcome in highly
proliferative breast cancers. A high TIL count
also has implications for targeted immunother-
apy as discussed above.
In the context of prognosis and treatment,
the decision by the WHO to broaden the defi-
nition and to create the designation of CMF
(to include MC, AMC, and invasive carcinoma
NST with specific histological appearances)
takes account of the compelling data regarding
the improved outcome associated with specific
MC morphology and that reported in relation
to a high TIL count in TNBC.
Macroscopy
CMF, by definition, is a well-circumscribed tumor
with an expansile or pushing border and may
resemble a fibroadenoma on gross inspection. The
cut surface is fleshy and the consistency is soft,
attributed to the absence of a stromal desmoplastic
reaction. The color varies from tan to grey-white.
Invasive Carcinoma with Medullary Features
Foci of hemorrhage and necrosis may be evi-
dent but are not extensive.
Ridolfi et al. observed an average tumor size of
2.9 cm (Ridolfi et al. 1977). Some studies report
an average tumor size of up to 4 cm but in
most studies the recorded median size is in the
range of 2– 3 cm.
The imaging characteristics of CMF, including
those observed on mammography and ultrasound
examination, may resemble a fibroadenoma.
Magnetic resonance imaging (MRI) does not
differentiate between CMF and other breast
tumor types.
Calcification is rare in CMF due to the lack of
stromal desmoplasia and to the absence or low
volume of accompanying DCIS.
Microscopy
The original criteria for a diagnosis of classical
MC included complete tumor circumscription
with a pushing border and no extension of tumor
cells into adjacent stroma, a syncytial growth
pattern in at least 75% of the tumor, a moderate
to marked mononuclear stromal infiltrate, high
nuclear grade, no glandular features and no
intraduct component (DCIS). The last criterion
was shown to be less important with a DCIS
component having no impact on prognosis.
A tumor showing the majority of these features
can be diagnosed as CMF. This approach should
facilitate recognition and identification of CMF.
However, due to the inherent flexibility in the
application of the diagnostic criteria (“some but
not all of the features of MC”), interobserver
variability and reproducibility of diagnosis con-
tinue to be a challenge.
Despite these limitations, tumors categorized
as CMF share the following morphological
features:
Outline: CMF is a well-delineated tumor
with a predominant pushing or expansile margin
(Figs. 1 and 2).
Syncytial growth pattern: This refers to the
arrangement of tumor cells in solid, broad anasto-
mosing sheets with minimal intervening stroma.
In classical MC, this pattern is present in at least
Invasive Carcinoma with Medullary Features
Invasive Carcinoma with Medullary Features, Fig. 1
(H&E  4) Low-power view of CMF showing the classical
well-circumscribed outline with an expansile edge
Invasive Carcinoma with Medullary Features, Fig. 2
(H&E  10) CMF at higher magnification showing the
classical well-circumscribed outline with an expansile edge
75% of the tumor. Although the latter is not a
requirement for diagnosis, CMF shows a predom-
inant solid growth pattern with scant intervening
stroma. The relative paucity of stroma and lack of
a desmoplastic reaction confer a soft consistency
on these tumors which, together with the typical
pushing border, may give a false impression of a
benign lesion on gross examination.
High nuclear grade: CMF is composed of
cells with high nuclear grade and prominent
nucleoli that may be multiple. Tumor giant cells
are commonly seen. Mitotic figures, including
atypical forms, are frequent (Fig. 3).
199
Invasive Carcinoma with Medullary Features, Fig. 3
(H&E  20) Tumor cells of CMF show a syncytial growth
pattern, high nuclear grade and mitotic activity
Invasive Carcinoma with Medullary Features, Fig. 4
(H&E  10) CMF showing a prominent lymphoplas-
macytic infiltrate
Lymphoplasmacytic infiltrate: This is
usually a prominent feature of CMF (Fig. 4). The
infiltrate tends to be more marked at the periphery
of the tumor and comprises a mixed population of
CD3+ T lymphocytes, cytotoxic CD8+ T lympho-
cytes, and plasma cells.
The presence of a prominent lympho-
plasmacytic infiltrate is associated with an
improved prognosis related to the host lymphocyte
response.
Gland formation: The complete absence of
gland formation is a strict requirement for a
200
diagnosis of classical MC. Although CMF may
show some gland formation, this should be
minimal.
DCIS: Accompanying DCIS is usually absent
or low volume in CMF.
Lymphovascular invasion: This is uncom-
mon in CMF.
Other features: Hemorrhage and necrosis may
be present within the tumor. Breast tissue in the
vicinity of CMF may show lymphocytic lobulitis.
Histological grading: Opinion is divided
regarding the role of histological tumor grading
of CMF. Some authorities advise against grading
as the morphological characteristics of CMF will
conform to a grade 3 carcinoma and not reflect the
improved prognosis of CMF relative to a grade
matched invasive carcinoma NST (▶ Invasive
Carcinoma NST). RCPath UK guidelines recom-
mend grading all special type carcinomas in addi-
tion to invasive carcinoma NST (Ellis et al. 2016).
The reasons cited include the diagnostic difficulty
that may be encountered in separating a special
type carcinoma from invasive carcinoma NST
where knowledge of histological grade may
inform further treatment planning.
Immunophenotype
At the present time, CMF is defined based on the
constellation of morphological characteristics
outlined above. While CMF is associated with a
classical immunohistochemical profile, these are
not the defining properties of this tumor type and
some variation in the expression of the following
proteins will occur.
CMF is one of the morphological subtypes
of invasive breast carcinoma with an immuno-
phenotype that correlates with the specific
so-called basal-like tumor gene expression profile
(Flucke et al. 2010; Jacquemier et al. 2005; Rakha
and Green 2017). There is no internationally
accepted definition of a basal-like tumor.
Immunohistochemical marker expression profiles
that have been proposed to define basal-like
breast cancers include (a) triple negative for estro-
gen (ER) and progesterone (PR) receptors
and HER2 expression, (b) expression of one or
Invasive Carcinoma with Medullary Features
more high-molecular-weight/basal cytokeratins
(CK5/6, CK14, and CK17) and (c) triple negative
(ER, PR, HER2 negative) immunophenotype
combined with expression of CK5/6 and/or epi-
dermal growth factor receptor (EGFR) (Badve
et al. 2010).
CMF is negative for ER, PR, and HER2 in the
majority of cases. However, expression of these
biomarkers has been reported in small numbers of
CMF indicating that tumors with this light micro-
scopic morphology are heterogeneous at cellular
level (Matkovic et al. 2008; Mateo et al. 2016).
Notwithstanding this if any of these biomarkers is
positive one should at least consider alternative
tumor types in the differential diagnosis.
In addition to triple negative status, CMF has
been shown to express basal type cytokeratins, in
particular CK5/6, with greater frequency than non
CMF breast tumors. Reported rates of CK5/6
expression vary, attributed to variation in anti-
bodies used and the inclusion of hormone receptor
positive tumors with classical CMF/MC morphol-
ogy in some studies. CK 14 expression has also
been reported but appears to be less commonly
expressed than CK5/6. Up to 70% of CMF tumors
have been shown to express EGFR.
Expression of other immunomarkers associ-
ated with basal-like tumors has been documented
in CMF including P-cadherin, p63, smooth mus-
cle actin, S100, and caveolin.
The majority of CMF tumors are immunohis-
tochemically p53 positive due to the high rate of
TP53 mutation (see Molecular Features) (Silwal-
Pandit et al. 2014).
In keeping with the morphology, CMF is a
highly proliferative tumor with a high Ki67 index.
TILs are now known to play a key role
in mediating response to chemotherapy and
improving clinical outcomes in invasive breast
carcinoma, particularly in TNBC. The dense lym-
phoid infiltrate that is a key criterion for the diag-
nosis of CMF typically contains a high proportion
of CD8+ cytotoxic T lymphocytes that likely
accounts for the improved prognosis associated
with this morphological variant of breast cancer.
Although CMF shows morphological similar-
ities to Epstein Barr Virus (EBV) associated
Invasive Carcinoma with Medullary Features
lymphoepithelioma-like carcinoma of the breast,
expression of EBV protein is rare.
Molecular Features
Molecular Classification
Gene expression profiling (GEP) studies, using
unsupervised cluster analysis, has led to the classi-
fication of breast cancer based on molecular char-
acteristics (Perou et al. 2000). The vast majority of
CMF tumors segregate as basal-type, which are
typically characterized by lack of expression of
ER, PR, and HER2 and by positive expression of
genes that are expressed in the basal-like cells of the
normal breast and those associated with high pro-
liferative activity. Further transcriptional analysis
of the basal-like TNBC group has led to the recog-
nition of heterogeneity within this group of tumors
and the identification of basal-like TNBC molecu-
lar subtypes (Lehmann and Pietenpol 2013).
CMF tumors display a unique gene expression
profile (Bertucci et al. 2006). CMF tumors are
characterized by upregulation of genes involved
in the immune response including those that con-
trol interleukin, interferon, and cytokine produc-
tion. Genes involved in activation of the apoptosis
pathway are also over-expressed compared with
non-CMF basal-like tumors. In contrast, genes
that are involved in remodeling of the cytoskeleton
and those that control cell invasiveness are under-
expressed in CMF (Weigelt et al. 2010). This pro-
file correlates with the immunomodulatory subtype
of TNBC tumors, associated with an improved
response to chemotherapy, a more favorable prog-
nosis and potential for treatment with
immunotherapy.
Genetic Alterations
BRCA1, located at chromosome 17q12–21, is a
tumor suppressor gene. Germline mutations of
BRCA1 account for 30–40% of hereditary breast
carcinomas. Most breast tumors that develop in
patients with BRCA1 germline mutations are of
CMF type. A diagnosis of CMF may, therefore,
signify a BRCA1 mutation and consideration of
genetic testing. However, not all patients with
CMF have a BRCA1 mutation. It is estimated
201
that approximately 20% of patients with CMF
test positive for BRCA1 mutation. CMF is
uncommon in patients with BRCA2 mutations.
Somatic BRCA1 mutations and BRCA1 pro-
moter hypermethylation have also been reported
in CMF. Promoter hypermethylation may lead to
inactivation of the BRCA1 gene and contribute to
breast carcinogenesis.
The most common somatic mutation in CMF is
TP53, which occurs at a higher rate than in non
CMF tumors. TP53 mutations are common in all
forms of breast cancer and overall are associated
with a worse prognosis. However, the prognostic
impact appears to vary with molecular subtype
and may be limited to ER positive tumors.
In keeping with the high rate of TP53 mutations
in CMF, high-density array comparative genomic
I
hybridization (CGH) studies have demonstrated a
high level of genomic instability in these tumors.
Gains of 1q and 8q are common to all basal-like
carcinomas and are observed in CMF. CMF
tumors also show a specific pattern of genetic
alteration including recurrent gains at 3p, 9p,10p,
and 16q and losses at 4p and amplicons of 1q, 8p,
and 10p (Vincent-Salomon et al. 2007).
Differential Diagnosis
When confronted with a well-circumscribed inva-
sive breast tumor with no associated DCIS and
triple negative for ER, PR, and HER2, it is always
wise to maintain a broad differential diagnosis.
Recognition of CMF is important due to its
association with the BRCA1 germline mutation.
A diagnosis of CMF, particularly in a younger
patient, will lead to consideration of genetic test-
ing for the patient and her/his family. CMF also
has a more favorable prognosis than a grade
3 invasive carcinoma NST. These characteristics
emphasize the importance and value of careful
assessment of breast tumor morphology, even in
this era of sophisticated genetic methodologies.
The main alternative diagnosis is invasive car-
cinoma NST (▶ Invasive Carcinoma NST). To
date there has been considerable interobserver var-
iation in the diagnosis of MC and AMC. Applica-
tion of the more relaxed histological criteria
202
proposed by the WHO and outlined above should
improve observer agreement in recognizing CMF
and distinguishing it from NST. In view of the
clinical relevance, it is more important to entertain
the diagnosis than to assign these tumors to the
NST category. The preferential expression of basal
type immunohistochemical markers may be help-
ful in making a diagnosis of CMF.
The possibility of a metastasis from an alternative
primary site or an intramammary lymph node
replaced by metastatic tumor should be borne in
mind. This is less likely when dealing with a single
tumor. Tumors that metastasize to the breast include
melanoma, which may be pigmented, ovarian carci-
noma, lung carcinoma, sarcomatoid carcinoma, and
sarcoma and primary sarcoma. Thorough evaluation
of tumor morphology and consideration of the clin-
ical history and radiological findings are key to
reaching a correct diagnosis. In the case of an
intramammary lymph node replaced by tumor, a
search for lymph node capsule and any residual
normal lymph node architecture should assist the
diagnosis. Comparison with previous histology
and the use of immunohistochemistry will also assist
accurate diagnosis of an intramammary metastasis.
Lymphoma of the breast is a rare condition that
should also be considered in the differential diag-
nosis. Breast lymphoma (mostly diffuse large
B-cell lymphoma) may occur as a primary process
or represent breast involvement by known sys-
temic lymphoma. It usually forms a solid mass
and may mimic carcinoma both radiologically
and histologically. On close inspection, it lacks
the syncytial growth pattern observed in CMF.
Consideration of the diagnosis and the use of
immunohistochemistry will clarify the diagnosis.
References and Further Reading
Badve, S., Dabbs, D., Schnitt, S., Baehner, F., Decker, T.,
Eusebi, V., et al. (2010). Basal-like and triple-negative
breast cancers: A critical review with an emphasis
on the implications for pathologists and oncologists.
Modern Pathology, 24, 157–167.
Bertucci, F., Finetti, P., Cervera, N., Charafe-Jauffret, E.,
Mamessier, E., Adélaïde, J., et al. (2006). Gene expres-
sion profiling shows medullary breast cancer is a sub-
group of basal breast cancers. Cancer Research, 66,
4636–4644.
Invasive Carcinoma with Medullary Features
Dua, I., & Tan, A. R. (2017). Immunotherapy for triple-
negative breast cancer: A focus on immune checkpoint
inhibitors. American Journal of Haematology and
Oncology, 13, 20–27.
Eisinger, F., Noguès, C., Birnbaum, D., Jacquemier, J., &
Sobol, H. (1998). BRCA1 and medullary breast cancer.
Journal of the American Medical Association, 280,
1227–1228.
Ellis, I. O., Al-Sam, S., Anderson, N., Carder, P., Deb, R.,
Girling, A., et al. (2016). Pathology reporting of breast
disease in surgical excision specimens incorporating
the dataset for histological reporting of breast cancer.
(2016). Rcpath.org. Available from: http://www.rcpath.
org. Accessed Sept 2017.
Flucke, U., Flucke, M., Hoy, L., Breuer, E., Goebbels, R.,
Rhiem, K., et al. (2010). Distinguishing medullary car-
cinoma of the breast from high-grade hormone receptor-
negative invasive ductal carcinoma: An immunohisto-
chemical approach. Histopathology, 56, 852–859.
Hicks, D. G., & Lester, S. C. (2017). Carcinoma with
medullary features. Available from: https://app.
expertpath.com. Accessed Sept 2014.
Huober, J., Gelber, S., Coates, A. S., Viale, G.,
Ohlschlegel, C., et al. (2012). Prognosis of medullary
breast cancer: Analyses of 13 international breast can-
cer study group (IBCSG) trials. Journal of Clinical
Oncology, 11, 2843–2851.
Jacquemier, J., Padovani, L., Rabayrol, L., Lakhani, S.,
Penault-Llorca, F., Denoux, Y., et al. (2005). Typical
medullary breast carcinomas have a basal/myo-
epithelial phenotype. The Journal of Pathology, 207,
260–268.
Lakhani, S., Ellis, I. O., Schnitt, S. J., Tan, P. H., & van de
Vijver, M. J. (2012). WHO classification of tumours of
the breast (pp. 46–47). Lyon: International Agency for
Research on Cancer.
Lehmann, B., & Pietenpol, J. (2013). Identification and use
of biomarkers in treatment strategies for triple-negative
breast cancer subtypes. The Journal of Pathology, 232,
142–150.
Mateo, A., Pezzi, T., Sundermeyer, M., Kelley, C.,
Klimberg, V., & Pezzi, C. (2016). Chemotherapy
significantly improves survival for patients with
T1c-T2N0M0 medullary breast cancer: 3739 cases
from the National Cancer Data Base. Annals of Surgi-
cal Oncology, 24, 1050–1056.
Matkovic, B., Juretic, A., Separovic, V., Novosel, I.,
Separovic, R., Gamulin, M., et al. (2008). Immunohis-
tochemical analysis of ER, PR, HER-2, CK 5/6,
p 63 and EGFR antigen expression in medullary breast
cancer. Tumori, 94, 838–844.
Perou, C. M., Sorlie, T., Eisen, M. B., van de Rijn, M.,
Jeffrey, S. S., Rees, C. A., et al. (2000). Molecular
portraits of human breast tumors. Nature, 406,
474–452.
Rakha, E., & Green, A. (2017). Molecular classification of
breast cancer: What the pathologist needs to know.
Pathology, 49, 111–119.
Ridolfi, R., Rosen, P., Port, A., Kinne, D., & Miké, V.
(1977). Medullary carcinoma of the breast.
Invasive Carcinoma with Neuroendocrine Differentiation
A clinicopathologic study with 10 year follow-up.
Cancer, 40, 1365–1385.
Silwal-Pandit, L., Vollan, H., Chin, S., Rueda, O.,
McKinney, S., Osako, T., et al. (2014). TP53 mutation
Spectrum in breast cancer is subtype specific and has
distinct prognostic relevance. Clinical Cancer
Research, 20, 3569–3580.
Stanton, S., & Disis, M. (2016). Clinical significance
of tumor-infiltrating lymphocytes in breast cancer.
Journal for Immunotherapy of Cancer, 4, 59.
Tung, N., Garber, J., Hacker, M., Torous, V., Freeman, G.,
Poles, E., et al. (2016). Prevalence and predictors of
androgen receptor and programmed death-ligand 1 in
BRCA1-associated and sporadic triple-negative breast
cancer. Breast Cancer, 2, 16002.
Vincent-Salomon, A., Gruel, N., Lucchesi, C.,
MacGrogan, G., Dendale, R., Sigal-Zafrani, B., et al.
(2007). Identification of typical medullary breast carci-
noma as a genomic sub-group of basal-like carcinomas,
a heterogeneous new molecular entity. Breast Cancer
Research, 9, R24.
Weigelt, B., Geyer, F., & Reis-Filho, J. (2010). Histological
types of breast cancer: How special are they?
Molecular Oncology, 4, 192–208.
Invasive Carcinoma with
Neuroendocrine
Differentiation
Ewa Chmielik
Tumor Pathology Department, Maria
Sklodowska-Curie Memorial Cancer Center and
Institute of Oncology, Gliwice, Poland
Synonyms
Carcinoid tumor of the breast; Endocrine
carcinoma
Definition
Invasive carcinoma with neuroendocrine
(NE) differentiation presents microscopic features
similar to NE neoplasms of other organs.
Bussolati and Badve (2012) classifies
invasive carcinomas with NE differentiation
into three subtypes: well-differentiated NE
tumors, poorly differentiated neuroendocrine
203
carcinomas/small cell carcinomas, and invasive
carcinomas with NE differentiation.
Clinical Features
• Incidence
Invasive breast carcinomas with NE features
are rare and represent less than 5% of breast
cancers (Wang et al. 2014).
• Age
Most patients are in the sixth or seventh
decades of life.
• Sex
There is a female predilection. Single case
reports of invasive breast carcinomas with
NE features in male patients were occasionally
I
described.
• Site
Usually, invasive breast carcinomas with NE
differentiation present unilaterally, neverthe-
less a single case report with bilateral primary
breast NE carcinoma in a young woman has
been described (Zhang and Chen 2011). The
central and subareolar region of the breast or
the upper outer quadrant are the most frequent
locations where this type of carcinoma arises.
Rarely, multicentric forms were reported.
• Treatment
Surgery is the standard initial treatment for early
invasive carcinomas with NE features. Patients
with locally advanced cases or with inoperable
carcinomas are treated with neoadjuvant ther-
apy. Patients with luminal A or B carcinomas
are candidates for adjuvant endocrine therapy. In
hormone receptor positive cases with high
Ki-67 proliferation index, adjuvant chemother-
apy in addition to endocrine therapy may be
beneficial. Anti-HER2 therapy is an option for
patients with HER2-positive carcinomas with
NE features, which is a quite rare event. Peptide
receptor radionuclide therapy (PPRT) has been
reported in patients with carcinomas expressing
somatostatin receptors (Inno et al. 2016).
Breast NE carcinomas can metastasize to
multiple organs even years after treatment of
the primary tumor, and therefore long-term
follow-up is advisable (Inno et al. 2016).
204 Invasive Carcinoma with Neuroendocrine Differentiation

• Outcome
Well-differentiated NE tumors have a favorable
prognosis and have significantly less frequent
lymph node metastases compared with those with
partial NE differentiation (Sapino et al. 2001a).
Mucinous differentiation, estrogen receptor
(ER) expression, and progesterone receptor
(PR) expression are important parameters for
favorable prognosis in invasive carcinomas
with NE features (Sapino et al. 2001a).
However, as a group, patients with breast car-
cinomas showing NE differentiation have worse
overall survival (OS) and disease-free survival
(DFS) than those without (Kwon et al. 2014).
In particular, poorly differentiated/small cell
carcinomas are aggressive with poor prognosis
(Sapino et al. 2001a). The most frequent meta-
static sites of breast NE carcinomas are bone,
lungs, bone marrow, liver, pleura, skin, adrenal
gland, and pancreas (Lavigne et al. 2017) and
less frequently in other organs.
Invasive Carcinoma with Neuroendocrine Differenti-
ation, Fig. 1 Mammography shows a stellate lesion
Macroscopy which was histologically a well-differentiated NE breast
tumor with microcalcifications, BI-RADS 5, ACR 2
Invasive breast carcinomas with NE differentia-
tion may be grossly well circumscribed or with
infiltrative border (Fig. 1 radiogram of invasive
breast carcinoma with NE differentiation).

Microscopy

Like NE tumors of other organs, well-differentiated

NE tumors of the breast are composed by polygo-
nal, plasmacytoid, or spindle cells with eosino-
philic granular cytoplasm. Nuclei show low
pleomorphism varying from ovoid to round, they
may be centrally or eccentrically located, and chro-
matin is finely punctuated. Nucleoli are inconspic- Invasive Carcinoma with Neuroendocrine Differenti-
uous. The number of mitoses is very low. ation, Fig. 2 Carcinoid-like pattern with rosettes (H&E,
The following growth patterns have been 20)
described: solid cohesive, solid papillary, alveo-
lar, and cellular mucinous (Sapino et al. 2000).
In solid cohesive or carcinoid-like patterns, The solid papillary (▶ Solid Papillary Carci-
neoplastic cells are organized in glandular or noma) growth pattern shows plasmacytoid, spin-
rosette-like structures (Figs. 2 and 3 H&E) and dle, or signet-ring cells. Intracellular (signet ring)
form peripheral palisading similar to typical or extracellular mucin is a common finding. For
carcinoid tumors. this reason, it has been postulated that this variant
Invasive Carcinoma with Neuroendocrine Differentiation 205

Invasive Carcinoma with Neuroendocrine Differenti- Invasive Carcinoma with Neuroendocrine Differenti-
ation, Fig. 3 Carcinoid-like pattern with rosettes (H&E, ation, Fig. 4 Strongly and diffusely positive
40) immunostaining for synaptophysin (10)

I
is the preinvasive counterpart of mucinous carci-
noma with NE differentiation.
The mucinous variant of NE carcinoma shows
lakes of mucin populated by large clusters of cells
unlike non-NE mucinous carcinoma (▶ Invasive
Mucinous Carcinoma).
In alveolar growth pattern, large clear cells are
separated by scanty dense stroma. The number of
mitoses can be higher than in the other
histotypes.
Within poorly differentiated NE carcinomas
of the breast, the small cell variant is character-
ized by high nuclear/cytoplasmic ratio, dark Invasive Carcinoma with Neuroendocrine Differenti-
chromatin, inconspicuous nucleoli, and scant ation, Fig. 5 Carcinoma in situ component of NE breast
eosinophilic cytoplasm. The mitotic activity is carcinoma positive for Chromogranin A (40)
brisk (approximately 10 mitoses/10HPF). Zones
of necrosis or hemorrhage are often encountered.
The presence of an intraductal component of differentiation detected only by immunohistochem-
small cell carcinoma supports the breast origin. istry occurs in up to 30% of invasive carcinomas
NST (▶ Invasive Carcinoma NST) or other special
types. CD56 immunostaining and TTF-1 (20% of
Immunophenotype cases) have been documented in primary breast
small cell carcinoma.
All invasive carcinomas with NE differentiation ER are expressed in all of well-differentiated NE
express NE markers. Synaptophysin (Fig. 4) and tumors (Lavigne et al. 2017) or nearly in all (95%)
chromogranin A (Fig. 5) are considered as the cases (Bogina et al. 2016). The vast majority of
most sensitive and specific NE markers. cases (89%) express PR (Lavigne et al. 2017).
Seventy percent of NE carcinomas express Only few cases show immunophenotype
chromogranin A, 96% express synaptophysin, and ER+/HER2+, ER /HER2+, or lack ER and
66% express both markers (Lavigne et al. 2017). NE HER2 expression (Bogina et al. 2016).
206
According to molecular classification, carcino-
mas with NE differentiation belong to luminal
A or luminal B subtypes.
Androgen receptors are positive in 45%
of carcinomas with NE differentiation and up to
35% of carcinomas express somatostatin recep-
tors (Righi et al. 2010). Well-differentiated NE
carcinoma may co-express NE and apocrine
(GCDFP-15) markers and androgen receptors
together with ER and PR (Sapino et al. 2001b).
Nearly all (96–98%) NE breast carcinomas
express FOXA1, GATA3, and CK8/18 (Lavigne
et al. 2017).
Molecular Features
Cytogenetics
NE breast carcinomas are characterized by chromo-
somal numerical aberrations and/or structural aber-
rations. Numerical aberrations like trisomy 7 and
12 recently detected in NE breast carcinomas are
known as cytogenetic abnormalities of carcinoid
tumors of the lung and gastrointestinal tract. Clonal
structural chromosomal aberrations involved chro-
mosomes 1, 3, 6q, and 17q. Complex karyotypes
including both numerical and structural aberrations
per cell were identified in 57.1% of intermediate-
and high-grade NE breast carcinomas.
Chromothripsis (chromosomal shattering) of chro-
mosome 8 was rarely observed (Xiang et al. 2014).
Molecular Genetics
Breast carcinomas with NE differentiation harbor
similar number of somatic mutations as luminal
B breast carcinomas but significantly higher than
that of luminal A breast carcinomas. GATA3,
FOXA1, TBX3, and ARID1A are mutated in 17%
of cases (Marchiò et al. 2017). PIK3CA mutations
were less frequent than in luminal A carcinomas and
invasive lobular carcinomas (▶ Invasive Lobular
Carcinoma). Similarly to NE neoplasms of lung
and colon, breast NE carcinomas are characterized
by lack of TP53 mutations. Comparative study
performed by Marchiò et al. (2017) suggested that
NE differentiation in invasive mucinous carcinomas
(▶ Invasive Mucinous Carcinoma) and invasive
lobular carcinomas may develop after the
Invasive Carcinoma with Neuroendocrine Differentiation
acquisition of the genetic/epigenetic features typical
of these histotypes.
Differential Diagnosis
Differential diagnosis includes alveolar variant of
infiltrating lobular carcinoma (▶ Invasive Lobular
Carcinoma), solid variant of mammary adenoid
cystic carcinoma (▶ Adenoid Cystic Carcinoma),
and metastatic neuroendocrine tumor.
Alveolar variant of infiltrating lobular carci-
noma consists of groups of monotonous cells sep-
arated by bands of fibrous stroma. Coexistence of
lobular neoplasia and infiltrating lobular carci-
noma, classical variant, is typical. Chromogranin
positivity can be focal and weak. As for all vari-
ants of lobular carcinomas, ER is generally posi-
tive and E-cadherin is negative.
Solid variant of mammary adenoid cystic carci-
nomas usually presents as a discrete, palpable, lob-
ulated mass located in the sub-/periareolar region in
approximately 50% of cases. Adenoid cystic carci-
nomas are composed of epithelial and myoepithelial
cells. On higher power view, adenoid cystic carci-
nomas show moderate to marked nuclear atypia and
high mitotic rate. Pseudoglandular structures can
occasionally be seen within the tumor nests. Ade-
noid cystic carcinomas are negative for NE markers
and frequently positive for c-kit.
Metastatic NE tumors in the breast show the
typical architectural patterns (trabecular, acinar,
etc.) and cytologic features (“salt-and-pepper”
chromatin) (Fig. 6 H&E). The neoplastic cells
are obviously positive for NE markers; however,
markers such as CDX2 (gastrointestinal) and thy-
roglobulin (thyroid) can help in defining the pri-
mary site of origin. NE carcinomas of small
bowel, lung, and ovary are those most frequently
spreading to the breast. Sometimes a breast mass
can be the first manifestation of the disease
because the primary tumor, e.g., in gastrointesti-
nal tract, may be very small and undetected. ER
and PR are usually negative in metastatic NE
cancer. The most important feature of metastases
to the breast is the absence of an in situ compo-
nent. It is important to differentiate primary NE
breast carcinoma from metastatic NE carcinoma
Invasive Carcinoma with Signet Ring Cell Differentiation
Invasive Carcinoma with Neuroendocrine Differenti-
ation, Fig. 6 Metastatic neuroendocrine tumor to the
breast from gastrointestinal tract (H&E)
to the breast due to the differences in management
and prognosis. Patients with single metastatic NE
tumor to the breast should undergo wide local
excision alone without axillary dissection.
References and Further Reading
Bogina, G., Munari, E., Brunelli, M., Bortesi, L.,
Marconi, M., Sommaggio, M., Lunardi, G., Gori, S.,
Massocco, A., Pegoraro, M. C., & Zamboni, G. (2016).
Neuroendocrine differentiation in breast carcinoma:
Clinicopathological features and outcome.
Histopathology, 68, 422–432.
Bussolati, G., & Badve, S. (2012). Carcinoma with neuro-
endocrine features. In S.R. Lakhani, I.O. Ellis, S. J.
Schnitt, P. H. Tan, M. J. van de Vijver (Eds). WHO
Classification of Tumours of the Breast (pp 62–63)
Lyon: IARC
Inno, A., Bogina, G., Turazza, M., Bortesi, L., Duranti, S.,
Massocco, A., Zamboni, G., Carbognin, G., Alongi, F.,
Salgarello, M., & Gori, S. (2016). Neuroendocrine
carcinoma of the breast: Current evidence and future
perspectives. The Oncologist, 21, 28–32.
Kwon, S. Y., Bae, Y. K., Gu, M. J., Choi, J. E., Kang, S. H.,
Lee, S. J., Kim, A., Jung, H. R., Kang, S. H., Oh, H. K.,
& Park, J. Y. (2014). Neuroendocrine differentiation
correlates with hormone receptor expression and
decreased survival in patients with invasive breast
carcinoma. Histopathology, 64, 647–659.
Lavigne, M., Menet, E., Tille, J. C., Lae, M., Fuhrmann, L.,
Bonneau, C., Deniziaut, G., Melaabi, S., Ng, C. C. K.,
Marchiò, C., Rouzier, R., Bièche, I., & Vincent-
Salomon, A. (2017). Comprehensive clinical and
molecular analyses of neuroendocrine carcinomas of
the breast. Modern Pathology. https://doi.org/10.1038/
modpathol.2017.107. [Epub ahead of print].
207
Marchiò, C., Geyer, F. C., Ng, C. K., Piscuoglio, S., De
Filippo, M. R., Cupo, M., Schultheis, A. M., Lim, R. S.,
Burke, K. A., Guerini-Rocco, E., Papotti, M., Norton, L.,
Sapino, A., Weigelt, B., & Reis-Filho, J. S. (2017). The
genetic landscape of breast carcinomas with neuroendo-
crine differentiation. The Journal of Pathology, 241,
405–419.
Righi, L., Sapino, A., Marchiò, C., Papotti, M., &
Bussolati, G. (2010). Neuroendocrine differentiation
in cancer: Established facts and unresolved problems.
Seminars in Diagnostic Pathology, 27, 69–76.
Sapino, A., Righi, L., Cassoni, P., Papotti, M., Pietribiasi, F.,
& Bussolati, G. (2000). Expression of the neuroendo-
crine phenotype in carcinomas of the breast. Seminars in
Diagnostic Pathology, 17, 127–137.
Sapino, A., Papotti, M., Righi, L., Cassoni, P., Chiusa, L.,
& Bussolati, G. (2001a). Clinical significance of
neuroendocrine carcinoma of the breast. Annals of
Oncology, 12(Suppl 2), S115–S117.
Sapino, A., Righi, L., Cassoni, P., Papotti, M., Gugliotta, P.,
& Bussolati, G. (2001b). Expression of apocrine differ-
entiation markers in neuroendocrine breast carcinomas I
of aged women. Modern Pathology, 14, 768–776.
Wang, J., Wei, B., Albarracin, C. T., Hu, J., Abraham, S. C.,
& Wu, Y. (2014). Invasive neuroendocrine carcinoma
of the breast: A population-based study from the sur-
veillance, epidemiology and end results (SEER) data-
base. BMC Cancer, 4(14), 147–156.
Xiang, D. B., Wei, B., Abraham, S. C., Huo, L.,
Albarracin, C. T., Zhang, H., Babiera, G.,
Caudle, A. S., Akay, C. L., Rao, P., Zhao, Y. J., Lu,
X., & Wu, Y. (2014). Molecular cytogenetic character-
ization of mammary neuroendocrine carcinoma.
Human Pathology, 45, 1951–1956.
Zhang, J.-Y., & Chen, W.-J. (2011). Bilateral primary
breast neuroendocrine carcinoma in a young woman:
Report a case. Surgery Today, 41, 1575–1578.
Invasive Carcinoma with
Signet Ring Cell
Differentiation
Ian Ellis
Department of Histopathology, City Hospital
Campus, Nottingham University Hospitals,
Nottingham City Hospital, Nottingham, UK
Synonyms
Mucinous carcinoma; Signet ring cell carcinoma;
Signet ring cell carcinoma arising in invasive no
special type (ductal) carcinoma; Signet ring cell
variant of invasive lobular carcinoma
208
Definition
The definition of primary mammary invasive signet
ring cell carcinoma (SRCC) varies in the limited
number of published series to date. Some restrict
the definition to lobular carcinoma (Merino and
Livolsi 1981), with a population of signet ring
cells present and exclude signet ring cell variant
of invasive ductal/NST carcinoma or vica versa.
Others recognize signet ring cell tumor cell mor-
phology in invasive ductal, lobular, and mucinous
carcinoma, and one recent study has shown no
difference between these variants (Ohashi et al.
2016). The current 2012 WHO classification of
breast tumors (Lakhani et al. 2012) includes
SRCC as a subcategory of invasive mucinous car-
cinoma (▶ Invasive Mucinous Carcinoma) and
uses the following definition, “Carcinomas with
signet-ring-cell differentiation are characterized by
abundant intracellular mucin that pushes the
nucleus to one side, creating the characteristic
signet-ring-cell morphology.” The published series
differ on the number of signet cells that must be
present to label a carcinoma as SRCC, but generally
require >10–20% signet ring cells as a minimum
requirement.
Clinical Features
• Incidence
Primary SRCC carcinoma of the breast is a
very rare tumor subtype with few series
published to date. It is exceptionally rare as a
pure form but presence of SRCC cells have
been reported to occur in between 1% and 4%
of primary breast carcinomas; however, there
are no detailed epidemiological or comparative
studies available.
• Age
No large series exist but the average age at
presentation appears to be older than that for
breast cancer as a whole.
• Sex
Marked female predominance.
• Site
Breast but exclusion of metastatic SRCC from
distant sites particularly GI tract needs to be
excluded.
Invasive Carcinoma with Signet Ring Cell Differentiation
• Treatment
These tumors are generally recognized to have
an aggressive behavior with higher frequency
of vascular invasion and lymph node involve-
ment. Treatment will be governed but the char-
acteristics of the individual patient and based
on tumor size, grade, lymph node stage, hor-
mone receptor (▶ Hormone Receptors in
Breast Cancer), and HER2 (▶ HER2 in Breast
Cancer) status.
• Outcome
Most but not all of the published series recog-
nize SRC to be more aggressive than mucinous
carcinoma (▶ Invasive Mucinous Carcinoma),
invasive ductal carcinoma of no special type
(▶ Invasive Carcinoma NST), and classic
invasive lobular carcinoma (▶ Invasive Lobu-
lar Carcinoma) of the breast, with frequent
metastasis to regional lymph nodes and distant
metastasis to the lung, liver, and bone but also
with unusual sites of metastasis including the
stomach, endometrium, cervix, serosa, gastro-
intestinal tract, urinary tract, and spleen.
Macroscopy
There are no specific macroscopic features.
Microscopy
SRCC has been defined as a lesion with diffuse
infiltration of the stroma by mucin containing signet
ring cells where mucin fills the cytoplasm and dis-
places nucleus. Prominent signet-ring-cell differen-
tiation is most common in invasive lobular
carcinomas but may also be seen in invasive carci-
noma NST and other special type cancers, particu-
larly mucinous carcinoma. Pure SRCC is
exceptionally rare, and it has been argued that car-
cinomas with signet-ring-cell differentiation do not
represent a distinct entity. The current 2012 WHO
classification of breast tumors (Bussolati and
Sapino 2012) describes two cytological types of
carcinomas with signet-ring-cell differentiation.
One type characterized by large intracytoplasmic
vacuoles, with a “target” appearance owing to the
presence of large intracytoplasmic lumina
Invasive Carcinoma with Signet Ring Cell Differentiation
Invasive Carcinoma with
Signet Ring Cell
Differentiation,
Fig. 1 Signet ring cell
carcinoma of the breast
showing the characteristic
appearance of the tumor
cells with pushed aside
nuclei and mucin filled
cytoplasm (H&E high
power)
containing a periodic acid Schiff (PAS)/Alcian blue
and HMFG2-positive central globule. This cytolog-
ical pattern is typically observed in lobular neopla-
sia, in classic ▶ invasive lobular carcinoma, and it
has also been associated with the pleomorphic var-
iant of lobular carcinoma (▶ Pleomorphic Lobular
Carcinoma). The other cytological type is similar to
the cells of diffuse gastric carcinoma (Fig. 1) and is
characterized by acidic muco-substances that dif-
fusely fill the cytoplasm and dislodge the nucleus to
one pole of the cell. This type of signet-ring cell has
also been described as a variant of DCIS.
Immunophenotype
Primary breast SRCC are usually GCDFP-15 pos-
itive and approximately 80% are positive for
estrogen receptor. HER2 status frequency is not
well described but HER2 positive cases occur but
at a lower frequency than breast cancer as a whole.
These tumors typically have a luminal type
cytokeratin profile being low molecular weight
cytokeratin CK8/18 and CK7 positive. Lobular
variants are usually E-Cadherin negative.
Molecular Features
There are no known specific genetic or molecular
features.
209
I
Differential Diagnosis
The differential diagnosis includes mucinous
carcinomas and clear cell carcinomas and metas-
tasis from other sites. It is important to differen-
tiate from these carcinomas as the treatment
options and the outcome varies considerably.
Metastases will lack an accompanying in situ
carcinoma (DCIS or LCIS) component.
A variety of immunohistochemical markers
have been applied to distinguish SRCC from
metastasis from different organs. SRCCs of the
breast are generally immunohistochemically
positive for GCDFP-15, whereas SRCCs of the
gastrointestinal tract are negative. ER is very
often positive in primary SRCC of the breast,
but commonly negative in gastric and colonic
SRCC. Adenocarcinomas of the breast, stomach,
and colon also show different CK7 and CK20
expression patterns (Tot 2000). While primary
SRCC of the breast is typically positive for
CK7 but negative for CK20, the gastrointestinal
SRCCs are commonly positive for CK20 but
usually negative for CK7. In combination with
ER staining, CK7 and CK20 expression patterns
can be used to distinguish gastrointestinal SRCC
from SRCC of the breast but it should be borne in
mind that approximately 20% of SRCCs of the
breast are negative for ER (Tot 2000). Mucin
secretion type may also be helpful (Chu and
Weiss 2004). Adenocarcinomas of the breast
210 Invasive Cribriform Carcinoma

usually express MUC1 but not MUC2, whereas

gastrointestinal adenocarcinomas frequently Invasive Cribriform
express MUC2 but less frequently express Carcinoma
MUC1. The combination of immunomarkers
can substantially increase the sensitivity and Emad Rakha
specificity for diagnosing SRCCs of these Department of Histopathology, Division of
organs. SRCC of the breast can be distinguished Cancer and Stem Cells, University of
from gastrointestinal SRCC, if ER and MUC1 Nottingham, Nottingham, UK
are used as markers for SRCC of the breast, and
MUC2 and CDX2 can be used as markers for
gastric and colon SRCCs. To distinguish SRCCs Synonyms
of gastric versus colonic origin, Hep Par1 and
CDX2 strongly favor a gastric primary site, Invasive cribriform carcinoma; Pure invasive
whereas Hep Par1 negativity and MUC2 positiv- cribriform carcinoma
ity strongly favor a colonic primary site (Fan
et al. 2003). E-Cadherin is less useful and lacks
sensitivity. Definition

A special type of invasive carcinoma with an

References and Further Reading
Bussolati, G., & Sapino, A. (2012). Carcinomas with sig-
net ring cell differentiation. In S. R. Lakhani, I. O. Ellis,
S. J. Schnitt, P. H. Tan, & M. J. van de Vijver (Eds.),
WHO classification of tumours of the breast (4th ed.,
p. 61). Lyon: IARC Press.
Chu, P. G., & Weiss, L. M. (2004). Immunohistochemical
characterization of signet-ring cell carcinomas of the
stomach, breast, and colon. American Journal of Clin-
ical Pathology, 11, 884–892.
Fan, Z., van de Rijn, M., Montgomery, K., & Rouse,
R. V. (2003). Hep par 1 antibody stain for the differ-
ential diagnosis of hepatocellular carcinoma:
676 tumors tested using tissue microarrays and con-
ventional tissue sections. Modern Pathology, 16,
137–144.
Lakhani, S. R., Ellis, I. O., Schnitt, S. J., Tan, P. H., & van
de Vijver, M. J. (2012). WHO classification of tumours
of the breast (4th ed.). Lyon: IARC Press.
Merino, M. J., & Livolsi, V. A. (1981). Signet ring carci-
noma of the female breast: A clinicopathologic analysis
of 24 cases. Cancer, 48, 830–837.
Ohashi, R., Hayama, A., Yanagihara, K., Yamashita, K.,
Sakatani, T., Takei, H., & Naito, Z. (2016). Prognostic
significance of mucin expression profiles in breast car-
cinoma with signet ring cells: A clinicopathological
study. Diagnostic Pathology, 11, 131.
Tot, T. (2000). The role of cytokeratins 20 and 7 and
estrogen receptor analysis in separation of metastatic
lobular carcinoma of the breast and metastatic signet
ring cell carcinoma of the gastrointestinal tract. APMIS,
11, 467–472.
excellent prognosis that grows in a pattern similar
to that seen in intraductal cribriform carcinoma.
Clinical Features
• Incidence
Invasive cribriform carcinoma accounts for
0.3–0.8% of breast carcinomas (Venable et al.
1990; Li et al. 2005; Louwman et al. 2007);
however, a frequency of up to 4% has been
reported in some series (Page et al. 1983;
Venable et al. 1990).
• Age
Mean patient age is 53–58 years (Venable
et al. 1990).
• Sex
Female; rare in male as for other forms of
breast cancer.
• Site
Anywhere in the breast but most frequent in the
upper outer quadrant like other types of breast
cancer.
• Treatment
Local control and hormone therapy are the
main treatment options. Even when patients
have axillary metastases from pure invasive
Invasive Cribriform Carcinoma
cribriform carcinoma, the prognosis is good.
The use of systemic adjuvant chemotherapy is
typically not needed in pure early-stage inva-
sive cribriform carcinomas.
• Outcome
Invasive cribriform carcinoma, like tubular car-
cinoma (▶ Tubular Carcinoma), has a favorable
outcome with 10-year overall survival of 90%
(Ellis et al. 1992) to 100% (Page et al. 1983;
Louwman et al. 2007). The outcome of mixed
invasive cribriform carcinoma is less favorable
than that of the pure form but better than that of
no special type ▶ (NST) carcinoma (Page et al.
1983). Axillary node metastases occur in 14%
of cases (Page et al. 1983) and rarely involve
more than one or two axillary lymph nodes.
Macroscopy
There is no specific macroscopic feature that dis-
tinguishes invasive cribriform carcinoma from no
special type (NST) or mixed types. Mean tumor
size is 3 cm (Page et al. 1983). The consistency is
generally hard, but foci of hemorrhage may be
seen. Necrosis is not a feature of cribriform carci-
noma. Calcification is common and may be the
presenting sign on mammography.
Microscopy
Pure invasive cribriform carcinoma consists of an
invasive cribriform pattern in more than 90% of
the lesion (Fig. 1). The tumor is arranged as, often
angulated, invasive islands, in which well-defined
cribriform spaces are formed by arches of cells
(sieve-like pattern). Apical snouts are common.
Mucin-positive secretion bearing micro-
calcifications can be present within the lumina
(Page et al. 1983; Wells and Ferguson 1988).
Tumor cells are small to moderate in size with
mild or moderate degree of pleomorphism. Mito-
ses are rare. A prominent fibroblastic stroma is
common; in occasional cases, osteoclast-like
giant cells of histiocytic origin are found.
211
DCIS, generally of cribriform architecture, is
frequent (80%) (Page et al. 1983). If axillary
metastasis develops, the cribriform pattern is typ-
ically retained. Invasive cribriform carcinoma can
show prominent tubular component similar to that
of ▶ tubular carcinoma in up to 50% of the tumor
(Page et al. 1983). Cases with a 10–40% compo-
nent of another morphological type (other than
tubular carcinoma) are regarded as mixed type
(Page et al. 1983; Venable et al. 1990).
Immunophenotype
Invasive cribriform carcinoma typically displays a
luminal A phenotype with high expression of
hormone receptors, luminal cytokeratins, and
E-cadherin. Pure invasive cribriform carcinoma I
does not express basal cytokeratins and lacks
HER2 gene amplification and p53 expression.
Molecular Features
Invasive cribriform carcinoma and tubular carci-
noma have similar genomic and transcriptomic
features.
Differential Diagnosis
Invasive cribriform carcinoma should be differenti-
ated from cribriform DCIS (▶ Ductal Carcinoma In
Situ), ▶ adenoid cystic carcinoma, and other types of
breast carcinoma with cribriform areas. Invasive
cribriform carcinoma is distinguished from cribri-
form DCIS by the lack of a myoepithelial cell layer
around its invasive islands and its haphazard distri-
bution and irregular configuration. Adenoid cystic
carcinoma (▶ Adenoid Cystic Carcinoma) has a sec-
ond population of cells as well as intracystic secre-
tory and basement membrane-like (e.g., laminin
positive) material (Wells and Ferguson 1988). The
presence of osteoclast-like giant cells in the stroma is
mostly seen in ICC, but such giant cells may be seen
in other types of invasive mammary carcinoma and
are not diagnostic of invasive cribriform carcinoma.
212
Invasive Cribriform Carcinoma, Fig. 1 (H&E) a) A
case of invasive cribriform carcinoma showing irregular
infiltrating islands of low-nuclear-grade malignant cells
References
Ellis, I. O., Galea, M., Broughton, N., Locker, A.,
Blamey, R. W., & Elston, C. W. (1992). Pathological
prognostic factors in breast cancer. II. Histological
type. Relationship with survival in a large study with
long-term follow-up. Histopathology, 20, 479–489.
Li, C. I., Uribe, D. J., & Daling, J. R. (2005). Clinical
characteristics of different histologic types of breast
cancer. British Journal of Cancer, 93, 1046–1052.
Louwman, M. W., Vriezen, M., van Beek, M. W.,
Nolthenius-Puylaert, M. C., van der Sangen, M. J.,
Roumen, R. M., Kiemeney, L. A., & Coebergh, J. W.
(2007). Uncommon breast tumors in perspective: Inci-
dence, treatment and survival in the Netherlands. Inter-
national Journal of Cancer, 121, 127–135.
Page, D. L., Dixon, J. M., Anderson, T. J., Lee, D., &
Stewart, H. J. (1983). Invasive cribriform carcinoma
of the breast. Histopathology, 7, 525–536.
Venable, J. G., Schwartz, A. M., & Silverberg, S. G. (1990).
Infiltrating cribriform carcinoma of the breast:
A distinctive clinicopathologic entity. Human Pathology,
21, 333–338.
Wells, C. A., & Ferguson, D. J. (1988). Ultrastructural and
immunocytochemical study of a case of invasive crib-
riform breast carcinoma. Journal of Clinical Pathology,
41, 17–20.
Invasive Lobular Carcinoma
Maria P. Foschini and Luca Morandi
Department of Biomedical and Neuromotor
Sciences (DIBINEM), Unit of Anatomic
Pathology at Bellaria Hospital, University of
Bologna, Bologna, Italy
Invasive Lobular Carcinoma
arranged in cribriform pattern and desmoplastic stroma.
Higher-power view is shown in Fig. 1b
Definition
Invasive lobular carcinoma (ILC) is characterized
by noncohesive cells, usually E-cadherin negative,
that are dispersed or arranged in single-file linear
pattern, but can show several additional architec-
tural patterns (Tavassoli and Eusebi 2009; Lakhani
et al. 2012). ILC is frequently associated with
lobular carcinoma in situ (LCIS).
Clinical Features
• Incidence
ILC is the second most common type of breast
cancer and constitutes 5–15% of all invasive
breast tumors (Lakhani et al. 2012), although
incidence varies according to the criteria
applied for diagnosis. The incidence of ILC is
increasing, especially among postmenopausal
women, probably as consequence of hormonal
replacement therapy and alcohol abuse (Rakha
and Ellis 2010).
• Age
ILC usually affects peri and postmenopausal
women aged 50 or more but it can be seen in a
wide age range of patients, from young, in their
third decade of life, to elderly women, aged more
than 80 years (Tavassoli and Eusebi 2009).
• Sex
ILC affects more frequently female patients
and it is rare in men.
Invasive Lobular Carcinoma
• Site
ILC arises in the breast parenchyma, affecting
any of the breast quadrants. Bilaterality and
multifocality are seen in ILC more frequently
than in other breast cancers (Rakha and Ellis
2010). Paget’s disease (▶ Paget Disease of the
Nipple) is not associated with ILC.
ILC may present as a palpable breast mass
of variable size. Mammographic features are
often difficult to interpret, and this may impair
early diagnosis. ILC is the most common
type of cancer among mammographically
undetected cancers (Tavassoli and Eusebi
2009). Furthermore, Magnetic Resonance
Imaging (MRI) is more effective to estimate
both the size and the bilaterality of ILC than
mammography. Preoperative diagnosis, when
based on fine needle aspiration cytology can
lead to inadequate results, as a consequence
of low cellularity of ILC.
• Treatment
Surgery associated with endocrine therapy
constitutes the treatment of choice in operable
cases; however, adjuvant chemotherapy can
be useful in advanced cases.
• Outcome
ILC usually shows favorable prognostic pro-
file (low or intermediate nuclear grade, high
expression of estrogen (ER) and progesterone
receptors (PR), low proliferative index). On
the other side, ILC presents at a more
advanced stage than other types of carcinoma.
Studies focused on ILC prognosis led to
conflicting results, failing to demonstrate a
better prognosis when ILC is compared to
invasive carcinoma of no special type (NST)
(▶ Invasive Carcinoma NST). Distant metas-
tases can occur after many years suggesting a
worse long-term prognosis of ILC than of
breast carcinoma NST (Rakha and Ellis
2010; Lakhani et al. 2012). ILC metastatic
pattern shows a greater tendency toward
abdominal dissemination (comprising metas-
tases to gastro-intestinal tract, uterus, and
ovary) at presentation. In addition, brain,
meninges, bone, pleural and peritoneal sero-
sal membranes may be involved (Tavassoli
and Eusebi 2009; Lakhani et al. 2012).
213
ILC can show a great variety of morpholog-
ical variants, whose prognostic impact has
been poorly studied. According to the data
obtained by Orvieto et al. (2008), the classical
variant shows a better prognosis than other
morphological variants of ILC, due to a lower
number of recurrences and metastases.
Histological grade is related to ILC progno-
sis (Rakha and Ellis 2010). ILC grade 3 shows
more frequent aggressive prognostic parame-
ters as advanced T stage, vascular invasion,
lymph-node metastases at presentation. As
expected, these features are related to poorer
outcome, when compared with ILC grade 2.
Macroscopy
I
Macroscopic features vary according to mam-
mography and clinical presentation. About half
of the cases present as an ill-defined, firm mass.
In addition, ILC can present as multiple minute
nodules. Due to the diffuse growth pattern in
about 30% of the cases, it is very difficult to detect
any nodule, the breast parenchyma being fibrous
and firm (Tavassoli and Eusebi 2009).
Microscopy
ILC shows a wide spectrum of different architec-
tural and histological features (Tavassoli and
Eusebi 2009) that should be recognized in order
to achieve a correct diagnosis.
Architectural Variants
Architectural histological variants are often
intermingled one to the other and the predominant
pattern (over 80% of tumor structure) determines
the specific tumor type (Tavassoli and Eusebi
2009).
ILC Classical variant (ILC-C) has been recog-
nized for long time and is characterized by a
diffuse growth pattern with occasional nodules.
The cells are sparse and dissociated and invade the
stroma in a single cell file (Fig. 1a, H&E) and may
surround the residual ducts and lobules in a
targetoid fashion (Fig. 1b, cytokeratin
214
Invasive Lobular Carcinoma, Fig. 1 A: ILC-C is char-
acterized by a diffuse growth of neoplastic cells infiltrat-
ing the mammary tissue (H&E). B: Neoplastic cell, (here
Invasive Lobular Carcinoma, Fig. 2 ILC-C sometimes a solid architecture can be seen (A) (H&E). Negative
immunohistochemistry for E-cadherin helps in the differential diagnosis with invasive carcinoma of no special type (B)
immunohistochemistry (IHC)) due to invasion of
the prelymphatic channels of Hartveit (Tavassoli
and Eusebi 2009). No inflammatory reaction of
the stroma is seen. Neoplastic cells have monoto-
nous morphology, roundish central nucleus, with
delicate chromatin, and scarce cytoplasm.
Intracytoplasmic vacuoles are not infrequent and
can be highlighted by Alcian blue pH2.5/PAS
after diastase staining. On electron microscopy,
the intracytoplasmic lumina are lined by
microvilli (Tavassoli and Eusebi 2009).
ILC-C neoplastic cells can invade diffusely the
mammary gland, in a “spider–web” fashion (Tot
2016). This type of growth indicates poor
Invasive Lobular Carcinoma
stained with low molecular weight cytokeratin antibody)
are arranged around a ductule in a targetoid fashion
prognosis. Mitotic count is low and necrosis is
rarely seen in this variant.
ILC with solid architecture (ILC-S) can present
as a solid mass, of varying size, usually >2
cm. ILC-S is composed of neoplastic cells similar
to those of the ILC-C, but often showing higher
nuclear grade (Fig. 2a, H&E). Atypical mitotic
figures and necrotic areas are frequent findings in
ILC-S. Negative immunohistochemistry for
E-cadherin helps in the differential diagnosis with
invasive carcinoma of no special type (▶ Invasive
Carcinoma NST) (Fig. 2b, (IHC) E-cadherin high-
lights the epithelial cells of a residual duct. ILC
nests are negative).
Invasive Lobular Carcinoma 215

Invasive Lobular Carcinoma, Fig. 3 ILC-LA shows

neoplastic cells arranged in alveolar structures, separated
by fibrous septa (H&E)
Invasive Lobular Carcinoma, Fig. 4 ILC-H: is com-
posed of neoplastic cells with foamy cytoplasm and mild
Mucinous variant (ILC-Muc) is a rare variant nuclear atypia (H&E)
of ILC that shows abundant extracellular mucin
deposition (Cserni et al. 2017). Mucin deposition
I
can be focal or diffuse. ILC-Muc neoplastic cells
are similar to those seen in ILC-C.
Loose alveolar variant (ILC-LA) is character-
ized by neoplastic cells arranged in alveolar struc-
tures, separated by fibrous septa (Fig. 3, H&E).
The neoplastic cells show the same morphological
features of ILC-C.
Tubulo-lobular variant (ILC-TL) is character-
ized by a mixture of tubular carcinoma and ILC
(Tavassoli and Eusebi 2009).

Cytologic Variants
All these features may manifest within each his-
tologic variants.
Histiocytoid variant (ILC-H) (Tan et al. 2011)
is composed of neoplastic cells that resemble his-
tiocytes having a clear and finely foamy cyto-
plasm (Fig. 4, H&E). On electron microscopy,
the neoplastic histiocytoid cells show large clear
vesicles, typical of apocrine cells. The apocrine
nature of these neoplastic cells can be demon-
strated with positive immunohistochemical reac-
tion for the apocrine marker Gross Cystic Disease
Fluid Protein 15 (GCDFP-15).
Apocrine variant (ILC-A): the neoplastic cells
show eosinophilic and granular cytoplasm, central
nucleus with evident nucleolus. Diffuse positivity
for GCDFP-15 is usually encountered. ILC-A may
be associated with LCIS with apocrine features.
Signet ring cell variant (ILC-SR): cells with a
signet ring appearance are the predominant
neoplastic population (Fig. 5, H&E). In ILC-SR,
Invasive Lobular Carcinoma, Fig. 5 ILC-SR shows
numerous cells with intracytoplasmic vacuole (H&E)
two types of signet ring cells can be encountered
(Tavassoli and Eusebi 2009). The first and more
common type is characterized by intracytoplasmic
mucin-filled vacuoles, with microvilli seen on elec-
tron microscopy. The second type shows dilated
cisternae of the endoplasmic reticulum filled with
PAS or Alcian blue positive mucin similar to the SR
cells of the stomach.
Myoepithelial cell variant (ILC-M): rare
cases showing evidence of myoepithelial cell dif-
ferentiation are on record (Del Vecchio et al. 2005;
Tavassoli and Eusebi 2009). The cases described
by Del Vecchio et al. (2005) were composed of
cells having features intermediate between
epithelial-secretory and myoepithelial (therefore
216
the name of “myosecretory” was applied) (Del
Vecchio et al. 2005). The myosecretory features
were present both in the invasive and in situ
components.
Pleomorphic variant (ILC-P): this variant is
described in a dedicated chapter (▶ Pleomorphic
Lobular Carcinoma).
All ILC variants are frequently associated with
in situ lobular carcinoma (LCIS) (▶ Lobular In
Situ Neoplasia) or to in situ duct carcinoma
(▶ Ductal Carcinoma In Situ) (DCIS) of low
nuclear grade. LCIS is frequently multifocal and
can be localized within the invasive component or
in the surrounding parenchyma, as well as in other
quadrants or in the contralateral breast (Foschini
et al. 2006).
ILC grading: ILC is usually graded following
the Nottingham grading system applied in all
breast carcinomas (Rakha and Ellis 2010). ILC
grade can be difficult to assess due to the lack of
tubule formation and low mitotic index. The vast
majority of ILC are grade 2. Grade 3 ILC are more
frequently encountered among the special vari-
ants, as ILC-S and ILC-P.
Nevertheless, studies based on large cohort of
patients, with long-term follow-up information,
demonstrate that ILC grading might predict
prognosis.
Tumor infiltrating lymphocytes (TIL) are
scanty in ILC. Prominent TIL can be observed in
those variants showing more aggressive features,
as ILC-P, ILC-S, and in ILC grade 3 cases. On
very rare occasions TIL can be so prominent that
ILC acquire the features of lymphoepithelioma-
like carcinoma (Cristina et al. 2000).
The architectural pattern of ILC is reflected in
lymph node metastases, which are composed of
neoplastic cells dispersed among the lymph-
node parenchyma or disposed in linear files and
small clusters (Fig. 6, (IHC) cytokeratin
immunostaining of ILC metastasis in lymph
node). Specifically, the differential diagnosis
between isolated tumor cells (ITC), micro- and
macrometastases, can be a matter of subjective
interpretation. In order to achieve a reliable inter-
pretation that can give accurate information on the
risk of further axillary metastases, several
methods have been proposed. Van Deurzen et al.
(2010) demonstrated that the method proposed by
Invasive Lobular Carcinoma
Invasive Lobular Carcinoma, Fig. 6 Lymph-node
metastasis of ILC-C is characterized by single or small
groups of neoplastic cells, and sometimes it is difficult to
define the size of the metastatic deposit (cytokeratin IHC
reaction)
the European Working Group on Breast Screening
Pathology (EWGBSP) is the most accurate in
defining patients with high or low risk of further
axillary metastatic load.
Frozen section interpretation of sentinel node
metastases from ILC is difficult, as single neoplas-
tic cells intermingled with lymphocytes can be
missed on a quick intra-operative evaluation. To
this purpose, the application of rapid cytokeratin
immunohistochemical staining can be of help to
highlight the neoplastic cells.
Immunophenotype
Loss of E-cadherin expression is the most typical
immunohistochemical feature of ILC neoplastic
cells (Dabbs et al. 2013) as to be used in the
differential diagnosis between ILC and other
breast carcinoma histotypes. In ILC-C,
E-cadherin loss is almost complete; no staining
is visible along the cell membrane of the neoplas-
tic cells. In some ILC variants, E-cadherin loss
can be partial and the neoplastic cells can show a
residual, partial positivity along the cell mem-
brane (Canas-Marques and Schnitt 2016).
ILC, in addition to loss of E-cadherin expres-
sion, is characterized by altered P120 catenin
expression within the cytoplasm instead of the
membrane (Canas-Marques and Schnitt 2016).
Combined immunohistochemical reactions,
showing E-cadherin loss and P120 cytoplasmic
Invasive Lobular Carcinoma
Invasive Lobular Carcinoma, Fig. 7 Most of the ILC
neoplastic cells are ER positive (IHC, ER in red)
expression, can be of help in the correct ILC
diagnosis.
ILC cells in addition express low-molecular
weight cytokeratins, cytokeratin 34BetaE12,
GATA3, mammaglobin, GCDFP-15, Epithelial
membrane antigen (EMA), cathepsin D, and cyclin
D1 (Rakha and Ellis 2010). Myoepithelial cell
markers are usually negative with the exception
of the “hybrid” variant (Del Vecchio et al. 2005).
ER (Fig. 7, (IHC) ER positive nuclei in red) and
PR are highly expressed in the vast majority of ILC
and in most of the neoplastic cells (>80%), while
the intensity and the percentage of positive cells
can decrease in the ILC variants, especially in the
aggressive variants. Androgen receptor (AR) is
highly expressed in most ILCs (Riva et al. 2005).
HER2 overexpression or amplification is an
extremely rare event in ILC and is almost exclu-
sively seen in the pleomorphic variant of ILC
(▶ Pleomorphic Lobular Carcinoma).
Proliferative activity, evaluated immunohisto-
chemically with Ki67 antibody, is lower in ILC
than in invasive breast carcinoma NST (▶ Inva-
sive Carcinoma NST). High proliferative index is
seen in ILC grade 3 or in the special variants with
aggressive behavior.
Molecular Features
The key molecular alterations detected in ILC are
those affecting the CDH1 gene, mapped on
16q22.1, whose protein product is E-cadherin
(Dabbs et al. 2013).
217
A wide spectrum of genetic or epigenetic alter-
ations can affect the CDH1 gene, as deletions,
mutations, and methylation. The most frequent
alterations, detected in ILC, are 16q loss and
gains of 1q and 16p. In addition, several other
genetic aberrations have been found, as 8q gain
and losses at 8p23-p21, 11q14.1q25, 13q, Xq
(Rakha and Ellis 2010).
The E-cadherin transcriptional regulation can
be altered by numerous different transcription fac-
tors as activation of the TGFb pathway, SNAIL
and SLUG upregulation, and ZEB1 expression
(Dabbs et al. 2013).
The different genetic mechanisms leading to
E-cadherin inactivation and\or protein loss are
reflected by the different patterns of E-cadherin
expression detected on immunohistochemistry
I
(Dabbs et al. 2013; Canas-Marques and Schnitt
2016).
CDH1 mutations were enriched in multifocal
rather than unifocal tumors, suggesting that these
aberrations might be implicated in ILC spreading
within the breast stroma. They may be probably
related even to the peculiar pattern of metastatic
dissemination to organs such as the GI tract, ova-
ries, and peritoneum due to critical role of
cadherin in cell adhesion.
Other four key genes have been reported to
be frequently mutated in ILC: PIK3CA (~45%),
PTEN (usually LOH or mutations in ~13% of
cases), AKT1 (~13%), and HER2 (~5.1%)
(Desmedt et al. 2016).
The transcriptomic characterization of
141 cases of ILC based on a standardized molec-
ular assay revealed that 84% of samples were
classified as luminal A or luminal B (Ciriello
et al. 2015). A more recent study using immuno-
histochemistry surrogates evaluating 981 primary
ILC (Iorfida et al. 2012) confirmed those data,
where 41% and 57% of the ILC samples pertained
to the luminal A and B subtype, respectively.
Genetic studies based on clonal analyses dem-
onstrate a relation between LCIS and ILC
(Morandi et al. 2006). These data have been con-
firmed recently by an independent study (Sakr
et al. 2016), indicating that LCIS and ILC have a
similar repertoire of somatic mutations, with
PIK3CA and CDH1 being the most frequently
mutated genes.
218
Differential Diagnosis
The spectrum of differential diagnoses to be con-
sidered in cases of ILC varies according to ILC
variant.
Differential diagnosis is more frequently car-
ried out with invasive carcinoma NST (▶ Invasive
Carcinoma NST), especially in cases of ILC-S. To
this purpose, in addition to the morphological
features described above, absence or reduced
E-cadherin expression is of help. In more difficult
cases, cytoplasmic P120 expression can be added.
Differential diagnosis between ILC-C and
polymorphous (low-grade) adenocarcinoma
(PLGA) is described in a specific chapter
(▶ Polymorphous Carcinoma). Shortly, when
morphology is difficult to interpret, E-cadherin
fragmented expression and reduced CK7
expression as observed in PLGA can help in the
differential diagnosis. In addition, BCL2
positivity and ER\AR negativity are frequently
seen in PLGA. Epithelioid Myofibroblastoma
(▶ Mammary Myofibroblastoma) is extremely
rare, but may mimic ILC-C, since the epithelioid
cells are variously arranged in single cells, single
files or nests. These cells are positive for ER and
PR and unlike ILC-C are variably positive also for
vimentin, desmin, alpha-smooth muscle actin,
CD34, CD99, and CD10.
ILC-H should be differentiated from several
reactive and neoplastic conditions (Eusebi et al.
1995; Tan et al. 2011). Differential diagnosis can
be difficult especially intraoperatively on frozen
sections. Focal inflammation, rich in histiocytes,
is the most frequent condition to be considered.
Differential diagnosis can be especially difficult
when ILC-H is associated with prominent TIL.
ILC-H usually shows nuclear atypia and it is
frequently associated with in situ carcinoma. On
permanent sections, the strong positivity on
immunohistochemistry for CK7 and GATA3 epi-
thelial markers, together with the high ER, PR,
and AR expression, helps in the differential
diagnosis.
Differential diagnosis between ILC-H and
granular cell tumor is discussed in a specific chap-
ter (▶ Granular Cell Tumor). Shortly, the diagno-
sis of granular cell tumor should be considered for
those lesions lacking nuclear atypia and
Invasive Lobular Carcinoma
carcinoma in situ; on permanent sections, granular
cell tumor has a specific immunoprofile (S100
positivity) and lacks cytokeratin positivity.
ILC-H and ILC-A should be differentiated from
invasive carcinoma with apocrine changes
(▶ Apocrine Carcinoma). To this purpose, the
absence or decreased expression of E-cadherin
together with cytoplasmic P120 are the main hall-
marks of ILC.
ILC-SR can be difficult to differentiate from sig-
net ring cell carcinomas arising in different organs
especially in cases of ILC-SR presenting with gastric
of gastro-intestinal metastases. Breast ILC-SR
lesions show strong positivity for ER, PR, and AR,
and GATA3, a feature usually lacking in similar
carcinomas arising in organs different from breast.
ILC-Muc is differentiated from mucoid carci-
noma (▶ Invasive Mucinous Carcinoma) for
E-cadherin loss and cytoplasmic P120 (Cserni
et al. 2017).
ILC-M is a rare variant that should be differenti-
ated mainly from invasive carcinoma NST
(▶ Invasive Carcinoma NST). It has a bland cytol-
ogy similar to ILC-C, partial loss of E-Cadherin and
a concurring expression of epithelial and
myoepithelial cell markers (Del Vecchio et al. 2005).
ILC-P is discussed in detail in the dedicated
chapter (▶ Pleomorphic Lobular Carcinoma).
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Invasive Metaplastic
Carcinoma
Caterina Marchiò1,2,3, Suzanne Chartier3,
Guillaume Bataillon3 and
Anne Vincent-Salomon3
1
Unit of Pathology, Candiolo Cancer Institute
FPO-IRCCS, Candiolo, Italy
2
Department of Medical Sciences, University of
Turin, Turin, Italy
3
Institut Curie, Paris, France
Synonyms
Carcinoma with pseudosarcomatous metaplasia;
Carcinosarcoma; Matrix-producing carcinoma;
Sarcomatoid carcinoma; Spindle cell metaplastic
tumor
Definition
Metaplastic carcinomas represent a morphologi-
cally heterogeneous group of invasive breast
220
cancers in which a variable proportion of the
tumor shows squamous and/or mesenchymal dif-
ferentiation featuring, for instance, spindle,
chondroid, osseous, or rhabdoid cells (Lakhani
et al. 2012).
Clinical Features
• Incidence
Metaplastic carcinomas represent an uncom-
mon histologic type of breast cancer account-
ing for 0.2–5% of all breast carcinomas
(Lakhani et al. 2012).
• Age
Although the range of age at presentation is
similar to that of invasive carcinomas of
no special type (IC-NST) (▶ Invasive Carci-
noma NST), two studies have reported an older
mean age at presentation in metaplastic carci-
nomas compared to that of patients affected by
IC-NSTs (Lai et al. 2013; Pezzi et al. 2007).
• Sex
Most of the cases have been described in
female patients; however there are reports of
metaplastic carcinomas diagnosed in male
patients.
• Site
The location in the breast in which metaplastic
carcinomas arise is not dissimilar to that of any
IC-NSTs.
• Treatment
The treatment is based on a surgical approach
with sentinel node biopsy. It should be noted
that mastectomy is more common than breast-
conserving surgery in these patients, most
likely because of the large tumor size at pre-
sentation. In addition, axillary involvement is
less frequent than in IC-NSTs. Nevertheless,
axillary sentinel lymph node biopsy is a
recommended good practice. Surgery is
followed by adjuvant chemotherapy-based
regimens and radiotherapy, depending on clin-
icopathological parameters.
When considering a therapeutic approach
with neoadjuvant chemotherapy, it should be
kept in mind that these carcinomas usually
show a poor response to chemotherapy
Invasive Metaplastic Carcinoma
compared to conventional types of triple-
negative breast cancer (TNBC) (Jung et al.
2010). A recent study has demonstrated that
patients affected by a metaplastic breast carci-
noma and treated with chemotherapy in the neo-
adjuvant setting were more likely to have a
clinically progressive disease during neoadjuvant
therapy compared to other types of TNBC and
also showed a poorer disease-free survival
(Tanabe et al. 2017). There seems to be a differ-
ence in response to chemotherapy across distinct
transcriptomic subtypes (see section Molecular
Features): those cases classified as mesenchymal,
basal-like2, and luminal androgen receptor show
a lesser degree of response to neoadjuvant che-
motherapy compared to basal-like1 cases
(Lehmann et al. 2016).
• Outcome
Unlike conventional forms of TNBC, metaplas-
tic carcinomas have been reported to be resistant
to chemotherapy and to have a worse outcome
(Jung et al. 2010). Although metaplastic carci-
nomas are mostly high grade and display an
aggressive behavior, it should be acknowl-
edged that there are two low-grade forms of
metaplastic carcinoma, i.e., fibromatosis-like
metaplastic carcinoma and low-grade
adenosquamous carcinoma (Marchiò et al.
2016). Fibromatosis-like metaplastic carci-
noma still has a long-term metastatic potential,
although less than high-grade metaplastic car-
cinomas, and must be surgically treated as
carcinomas (Gobbi et al. 2003; Sneige et al.
2001). ▶ Low Grade Adenosquamous Carci-
noma tends to recur locally; nevertheless its
metastatic potential is minimal, and therefore
chemotherapy should be avoided (Marchiò
et al. 2016).
Macroscopy
The gross appearance of these tumors is not
distinctive: similarly to other types of breast can-
cer, they can show either well-circumscribed or
indistinct, irregular borders (Collins and Schnitt
2013). It should be noted however that they can
occasionally present as a cystic lesion, and this is
Invasive Metaplastic Carcinoma
particularly the case for squamous cell carcino-
mas; in addition, when heterologous elements
are abundant and predominant, the macroscopic
appearance may be more distinctive. For
instance, on cut surface, squamous or chondroid
areas may appear as pearly white to gray glisten-
ing areas.
Finally, at the time of diagnosis, they tend to be
larger than IC-NSTs (▶ Invasive Carcinoma
NST), with a reported mean size of 3.9 cm
(Collins and Schnitt 2013).
Microscopy
Histologically these tumors are most often of high
grade, with conspicuous nuclear pleomorphism
and mitotic activity; however they constitute a
heterogeneous group of lesions encompassing
several entities (Fig. 1). The 2012 WHO classifi-
cation has adopted a descriptive classification
including:
– Squamous cell carcinoma
– Metaplastic carcinoma with mesenchymal
differentiation
– Spindle cell carcinoma
– Fibromatosis-like metaplastic carcinoma
– Low-grade adenosquamous carcinoma
When diagnosing a metaplastic breast cancer,
one should clearly describe the distinct morpho-
logical components present as this may have clin-
ical implications.
Squamous Cell Carcinoma
Metaplastic squamous cell carcinomas can be
pure or admixed with an IC-NST (Lakhani et al.
2012; Collins and Schnitt 2013). Pure squamous
cell carcinomas of the breast are rare. It is impor-
tant to keep in mind that some degree of squamous
differentiation can be observed in invasive carci-
nomas of no special type (▶ Invasive Carcinoma
NST) and is more commonly seen in carcinomas
with medullary features (▶ Invasive Carcinoma
with Medullary Features) (Lakhani et al. 2012;
Collins and Schnitt 2013). It is good practice to
rule out the possibility of a metastasis from other
221
organs such as the skin and, when dealing with
male patients or whenever a patient has a history
of lung cancer or is heavy smoker, the lung (see
below for section “Differential Diagnosis”).
Squamous cell carcinomas of the breast
typically present as a cystic lesion where the cav-
ity is lined by a squamous epithelium with vari-
able nuclear atypia, and there is evidence of
neoplastic infiltration in the adjacent stroma that
usually displays a marked inflammatory infiltrate
(Lakhani et al. 2012).
The squamous differentiation of the neoplastic
cells can show well to poorly differentiated fea-
tures (Fig. 1a and b, H&E), and a spindle cell
morphology can also be appreciated, typically at
the infiltrative border of the tumor (Lakhani
et al. 2012).
I
An acantholytic variant of squamous cell car-
cinoma has also been described, featuring irregu-
lar spaces lined by squamous cells. These spaces
can be misinterpreted as vascular spaces and lead
to a wrong diagnosis of angiosarcoma (Lakhani
et al. 2012; Collins and Schnitt 2013).
Metaplastic Carcinoma with Mesenchymal
Differentiation
These lesions are defined by the presence of a
varying degree of heterologous differentiation of
mesenchymal origin (Collins and Schnitt 2013)
and can also be called “matrix-producing carcino-
mas.” The most frequent heterologous differen-
tiation encountered in metaplastic carcinomas
of the breast is either osseous or cartilaginous
(Fig. 1e and f, H&E) (Collins and Schnitt 2013).
As a general rule, the heterologous compo-
nents may appear either benign or malignant, in
the latter case resembling/mimicking a sarcoma-
tous component. Based on this, whenever the
mesenchymal component is predominant a differ-
ential diagnosis with (i) a malignant phyllodes
tumor (▶ Phyllodes Tumor) with heterologous
differentiation or (ii) a sarcoma (primary or meta-
static) has to be taken into account (Collins and
Schnitt 2013; Rakha et al. 2016).
In these cases, an extensive sampling of the
lesion is often required to look for unequivocal
epithelial elements or foci of ductal carcinoma in
situ (▶ Ductal Carcinoma In Situ) (Collins and
222
Invasive Metaplastic Carcinoma, Fig. 1 H&E. Repre-
sentative microphotographs of the heterogeneity of metaplas-
tic carcinomas. (a) squamous cell carcinoma. (b) A higher
magnification of a metaplastic carcinoma with epidermoid
features showing high mitotic count. (c) Spindle cell
Schnitt 2013; Rakha et al. 2016). As discussed in
the differential diagnosis paragraph, this is the
typical scenario in which a panel of cytokeratins
Invasive Metaplastic Carcinoma
carcinoma. (d) Fibromatosis-like metaplastic carcinoma. (e,
f) Two examples of a metaplastic carcinoma with mesenchy-
mal differentiation, one featuring chondroid differentiation
(e) and the other showing bone tissue formation (f)
is employed to demonstrate even a focal expres-
sion. It has to be stressed that not all metaplastic
carcinomas express cytokeratins and that focal
Invasive Metaplastic Carcinoma
cytokeratin expression can also be observed in
phyllodes tumors (▶ Phyllodes Tumor), thus
making the differential diagnosis particularly
challenging and, in some cases, not possible
(Collins and Schnitt 2013).
Spindle Cell Carcinoma
Metaplastic carcinomas can present as a prolifer-
ation of atypical spindle cells (Lakhani et al.
2012), thus posing important differential diagno-
sis issues with other spindle cell lesions of the
breast. The neoplastic spindle cells show a wide
morphological spectrum and may have a fasci-
cular, storiform, or haphazard growth pattern
(Fig. 1c, H&E) with infiltrative borders (Lakhani
et al. 2012). The nuclear atypia varies from mod-
erate to high grade. An inflammatory infiltrate of
lymphocytes and dendritic cells is often found
(Lakhani et al. 2012).
The presence of a carcinomatous component
in the mixed tumors makes the diagnosis rela-
tively straightforward. On the other side, the
diagnosis of high-grade spindle cell carcinoma
with no morphological evidence of epithelial dif-
ferentiation is challenging (Rakha et al. 2016).
This represents another scenario in which exten-
sive sampling and thorough immunohistochemi-
cal investigation with a panel of markers
including more than one cytokeratin are useful
(Collins and Schnitt 2013; Rakha et al. 2016). As
discussed above for metaplastic carcinomas with
mesenchymal differentiation, foci of ductal car-
cinoma in situ (▶ Ductal Carcinoma In Situ) or
small cohesive epithelial foci should be sought.
A pure spindle cell malignancy with no evidence
of these features or even focal cytokeratin
expression should prompt to consider, in the dif-
ferential diagnosis, malignant phyllodes tumor
(▶ Phyllodes Tumor), sarcomas, and metastatic
sarcomatoid tumors (Collins and Schnitt 2013;
Rakha et al. 2016).
A low-grade form of spindle cell carcinoma
has also been described and is labeled as
“Fibromatosis-like Metaplastic Carcinoma” and
is discussed here below.
Fibromatosis-like Metaplastic Carcinoma
This tumor type, described by Gobbi et al. (1999),
represents a low-grade variant of metaplastic
223
carcinoma with spindle-like features. The authors
originally described this lesion by using the term
“tumor” to avoid the word “carcinoma” because
neither the phenotype nor the behavior seemed to
be that of a carcinoma (Gobbi et al. 1999); how-
ever this entity was labeled as “carcinoma” in the
2012 WHO classification.
The microscopic growth pattern is typically
infiltrative, with finger-like projections extending
into adjacent mammary structures and fat tissue;
however lesions with ill-defined border or nodular
appearance have also been described (Gobbi et al.
1999). It is characterized by a dominant prolifer-
ation of spindle cells displaying pale eosinophilic
cytoplasm and slender nuclei with mild cytologic
atypia (Fig. 1d H&E, and Fig. 2a and b, H&E)
(Gobbi et al. 1999). The stroma shows varying
I
degree of collagenization. Focal plump fusiform
and polygonal tumor cells, with more rounded
nuclei, arranged in “epithelioid” clumps can be
observed. Spindle cells are often arranged in
wavy interlacing fascicles (Lakhani et al. 2012).
In addition, foci of glandular or squamous ele-
ments associated with the spindle cells can be
encountered posing issues in differential diagno-
sis with ▶ low grade adenosquamous carcinoma
(see below); in fibromatosis-like carcinomas, foci
of glandular or squamous elements should repre-
sent less than 5% of the overall tumor cell com-
ponent. Ductal carcinoma in situ (▶ Ductal
carcinoma in situ) can be associated (Gobbi
et al. 1999).
Cytokeratin expression is typically
found; however it is important to note that it
can be focal and occasionally restricted to the
plump spindle and more epithelioid cells.
Expression of p63 is invariably observed in
these lesions.
Low-Grade Adenosquamous Carcinoma
This is a rare histologic type of metaplastic
carcinoma showing a distinctive combination of
glandular and squamous differentiation. It is
characterized by well-developed gland/tubule
formation intimately admixed with solid
nests of squamous cells in a spindle cell back-
ground. Despite the presence of metaplastic
elements, these tumors display a low-grade
histological pattern. In agreement with their
224 Invasive Metaplastic Carcinoma

Invasive Metaplastic Carcinoma, Fig. 2 A core biopsy atypia (A,B). The neoplastic cells show mild
sample showing a spindle cell proliferation in the mam- pancytokeratin expression (C), focal CK5/6 expression
mary gland featuring fusiform cells displaying pale eosin- (D), and more pervasive and intense CK14 expression
ophilic cytoplasm and slender nuclei with bland cytologic (E). The lesion shows diffuse p63 expression (F)

low-grade morphological features, the majority lymph node metastasis (Collins and Schnitt
of low-grade adenosquamous carcinomas exhibit 2013). A proportion of cases, however, can
an excellent prognosis, with a low incidence of behave in a locally aggressive manner.
Invasive Metaplastic Carcinoma
A more detailed description of this entity can
be found in the chapter entitled ▶ Low-Grade
Adenosquamous Carcinoma.
Immunophenotype
The large majority (>90%) of these tumors
are of triple-negative phenotype, i.e., they
lack expression of estrogen receptor (ER),
progesterone receptor (PR), and HER2. The
search for an epithelial phenotype is of key
importance for the differential diagnosis. Any
positivity for an epithelial marker would sup-
port a diagnosis of metaplastic carcinoma.
A large panel of epithelial markers has to be
assessed, taking into account pancytokeratins
(such as AE1/AE3, KL1), EMA, and
E-cadherin. Luminal cytokeratins (CKs) such
as CK8/18 can be expressed but in a low
proportion of cases (Collins and Schnitt
2013; Rakha et al. 2017). Of note, expression
of high molecular weight (basal) CKs, includ-
ing CK5/6, CK5, CK14, and CK17, is fre-
quently observed (Collins and Schnitt 2013;
Rakha et al. 2017) (Fig. 2 (c) pancytokeratin;
(d) CK5/6; (e) CK14; (f) p63). Indeed, it has
been shown that 90.8% of MBCs show a
basal-like immunophenotype (Reis-Filho
et al. 2006).
Expression of markers usually expressed in
normal myoepithelial cells, such as p63 and
smooth muscle actin, is also frequently encoun-
tered and orients the diagnosis toward a
metaplastic carcinoma (Collins and Schnitt
2013; Rakha et al. 2017). The expression of
such markers should not be misinterpreted
as synonymous of a myoepithelial carcinoma
(▶ Myoepithelial Carcinoma of the Breast).
Luminal cells, in a way akin to all breast carci-
nomas, including triple-negative breast cancers,
represent the cells of origin of metaplastic
carcinomas.
A recent study has comprehensively analyzed
a wide panel of immunohistochemical markers
across a large series of metaplastic carcinomas
reported in the literature (Rakha et al. 2017), and
results are summarized in Table 1.
225
Molecular Features
In a way akin to TNBC, metaplastic carcinomas
are characterized by high levels of genetic insta-
bility showing a similar constellation of gene
copy number alterations (Hennessy et al. 2009).
Amplification of the epidermal growth factor
receptor (EGFR) gene with associated over-
expression has been reported in a subset of meta-
plastic carcinomas and seems to be prevalent
in tumors with squamous and/or spindle cell mor-
phology (Geyer et al. 2010). At the transcriptomic
level, metaplastic carcinomas preferentially per-
tain to the basal-like or claudin-low molecular
subtypes; those displaying spindle cell morphol-
ogy are the ones more likely to be classified as
claudin-low (Hennessy et al. 2009: Lien et al.
I
2004; Weigelt et al. 2009). When using the six
molecular subtype classification of TNBC pro-
posed by Lehmann and colleagues (Lehmann
et al. 2011), it has been observed that MBCs are
preferentially of mesenchymal-like and mesen-
chymal stem-like subtype (Weigelt et al. 2015).
On the other side, if the integrative clustering
approach is employed, metaplastic carcinomas
preferentially belong to IntClust 4, IntClust 1,
IntClust 8, and IntClust 9 (Weigelt et al. 2015).
Interestingly, it has also been shown that dif-
ferent histologic components of metaplastic car-
cinomas are associated with specific molecular
features (Weigelt et al. 2015). As an example,
samples exclusively or predominantly composed
of areas of spindle cells or showing chondroid
morphology are of claudin-low intrinsic mole-
cular subtype and of mesenchymal-like subtype,
respectively, whereas those samples exclu-
sively or predominantly composed of squamous
cells show a higher degree of heterogeneity.
A characterization of the landscape of somatic
genetic alterations in metaplastic breast carcino-
mas has been recently provided (Ng et al. 2017).
Although metaplastic carcinomas and common
forms of TNBC harbor a similar mutational
frequency in the TP53 gene, they seem to be
genetically distinct. Indeed, metaplastic carcino-
mas show more frequent mutations in PIK3CA,
PIK3R1, PTEN, and Wnt pathway genes, to the
extent that 57% and 51% of cases harbor somatic
226 Invasive Metaplastic Carcinoma

Invasive Metaplastic Carcinoma, Table 1 Expression carcinomas. This table has been modified and adapted
of CKs and epithelial differentiation markers in the main from Table 2 reported in Rakha et al. (2017). Number of
subgroups of metaplastic carcinomas. Data are extracted positive cases/total number of cases (percentages). LGASC
from a series of published cohorts of metaplastic low-grade adenosquamous carcinoma
Metaplastic carcinoma Fibromatosis-
Squamous with mesenchymal Spindle cell like
carcinoma differentiation carcinoma carcinoma LGASC
Cytokeratins AE1/ 11/13 (85) 36/36 (100) 99/117 (85) 30/30 (100) 13/14 (93)
AE3
CK8/18 17/18 (94) 7/13 (94) 14/54 (26) 1/2 (50) 18/21 (86)
CK7 // 4/4 (100) 0/2 (0) 0/25 (0) 21/22 (95)
CK19 // 5/7 (71) 0/2 (0) // 2/2 (100)
MNF116 // 7/10 (70) 38/40 (95) // 2/2 (100)
34bE12 // 10/15 (67) 7/9 (78) 28/28 (100) 23/23
(100)
CK5/6 59/63 (94) 41/56 (73) 25/34 (74) 6/6 (100) 25/27 (93)
CK14 17/19 (89) 38/52 (73) 35/43 (81) // 2/3 (67)
CK17 // 5/9 (56) 6/7 (86) // //
Myoepithelial p63 46/53 (87) 58/84 (69) 73/100 (73) 7/7 (100) 32/88 (84)
markers SMA 3/6 (50) 14/30 (47) 77/92 (84) 22/30 (73) 5/23 (22)
SMM // 2/16 (12) 1/10 (10) 0/24 (0) 0/19 (0)
CD10 // 9/18 (50) 14/15 (93) // 0/17 (0)
Calponin // 24/30 (80) 1/7 (14) // 0/7 (0)
S100 // 59/63 (94) 32/86 (37) 1/5 (20) //
Epithelial EGFR 95/114 47/76 (62) 35/49 (71) // //
differentiation (83)
EMA 0/3 (0) 14/15 (93) 32/101 (32) // //
E-CAD 18/20 (90) 0/19 (0) 0/10 (0) 0/3 (0) //

mutations in genes of the PI3K/AKT/mTOR path-
way and of the Wnt pathway, respectively
(Ng et al. 2017). These data are of clinical interest
as they provide a molecular basis for the recent
preclinical and clinical observations that Wnt and
PI3K/AKT/mTOR pathway inhibition may be
beneficial for a subset of patients with metaplastic
carcinoma (Ng et al. 2017).
Differential Diagnosis
Due to the rarity and the histological diversity of
metaplastic carcinoma of the breast, its diagnosis
in routine diagnostic practice can be sometimes
challenging (Rakha et al. 2017).
As a general rule, if an invasive lesion of the
breast shows mesenchymal or squamous
differentiation and is associated with conven-
tional mammary invasive or in situ carcinoma,
the diagnosis of a metaplastic carcinoma is usu-
ally straightforward. If these features are absent,
evidence for epithelial differentiation of the neo-
plastic cells should be provided by using immu-
nohistochemistry (Fig. 2) (Rakha et al. 2017).
A wide spectrum of benign, locally aggressive,
and highly aggressive lesions has to be taken
in account for the differential diagnosis (Rakha
et al. 2017). For instance, in order to render
a diagnosis of primary squamous cell carcino-
mas of the breast, a squamous cell carcinoma
of other sites, and in particular of the skin and
of the lung, should be ruled out (Lakhani
et al. 2012).
Clinical history and radiological findings
would be crucial in this scenario. However, if
Invasive Metaplastic Carcinoma
there is no evidence of an in situ carcinoma,
the differential diagnosis may be not possible.
There is no specific marker that is preferentially
expressed in lung versus breast squamous cell
carcinoma: in this scenario ER and PR cannot
be of help, and markers such as p40, p63, or basal
CKs are usually expressed by both entities.
GATA3 expression is not consistently found in
metaplastic carcinomas (Wendroth et al. 2015;
Hattori et al. 2015) and, although rarely, can be
found in lung squamous cell carcinomas (Hattori
et al. 2015). Other markers of breast origin
include mammaglobin and gross cystic disease
fluid protein-15 (GCDFP-15), an apocrine differ-
entiation marker. Mammaglobin is reported not
to be expressed by metaplastic carcinomas
(Reyes et al. 2012); GCDFP15 expression is
detected in a minority of metaplastic carcinomas
and can be occasionally encountered in squa-
mous cell carcinomas of the lung (Provenzano
et al. 2016).
Another example is given by low-grade
fibromatosis-like metaplastic carcinomas, which
have to be distinguished from desmoid-
type fibromatosis or other benign spindle
cell lesions of the breast (Marchiò et al. 2016).
Furthermore, low-grade adenosquamous carci-
nomas (▶ Low-Grade Adenosquamous Carci-
noma) may closely resemble tubular carcinomas
(▶ Tubular Carcinoma) or syringomatous tumors
of the nipple (▶ Syringomatous Tumor of the
Nipple).
It is crucial to keep in mind that no marker is
expressed consistently in all metaplastic carci-
nomas. As a consequence, it is good practice
to use a panel of markers (see Fig. 2) (Rakha
et al. 2017). Most metaplastic carcinomas
express at least one of the epithelial differentia-
tion markers. The frequency of staining may
be related to the degree of differentiation of
the tumors with fibromatosis-like spindle cell
carcinoma and low-grade adenosquamous carci-
noma showing very high rates of expression
of several markers and in a larger proportion of
tumor cells (>10%) (Table 1, see Fig. 2) (Rakha
et al. 2017).
227
References and Further Reading
Collins, L. C., & Schnitt, S. (2013). Biopsy interpretation
of the breast (2nd ed.). Philadelphia: Lippincott
Williams & Wilkins.
Geyer, F. C., Weigelt, B., Natrajan, R., Lambros, M. B.,
de Biase, D., Vatcheva, R., Savage, K., Mackay, A.,
Ashworth, A., & Reis-Filho, J. S. (2010). Molecular
analysis reveals a genetic basis for the phenotypic
diversity of metaplastic breast carcinomas. The Journal
of Pathology, 220(5), 562–573.
Gobbi, H., Simpson, J. F., Borowsky, A., Jensen, R. A., &
Page, D. L. (1999). Metaplastic breast tumors with a
dominant fibromatosis-like phenotype have a high risk
of local recurrence. Cancer, 85(10), 2170–2182.
Gobbi, H., Simpson, J. F., Jensen, R. A., Olson, S. J., & Page,
D. L. (2003). Metaplastic spindle cell breast tumors aris-
ing within papillomas, complex sclerosing lesions, and
nipple adenomas. Modern Pathology, 16(9), 893–901.
Hattori, Y., Yoshida, A., Yoshida, M., Takahashi, M., &
Tsuta, K. (2015). Evaluation of androgen receptor and I
GATA binding protein 3 as immunohistochemical
markers in the diagnosis of metastatic breast carcinoma
to the lung. Pathology International, 65(6), 286–292.
Hennessy, B. T., Gonzalez-Angulo, A. M., Stemke-Hale, K.,
Gilcrease, M. Z., Krishnamurthy, S., Lee, J. S.,
Fridlyand, J., Sahin, A., Agarwal, R., Joy, C., Liu, W.,
Stivers, D., Baggerly, K., Carey, M., Lluch, A.,
Monteagudo, C., He, X., Weigman, V., Fan, C.,
Palazzo, J., Hortobagyi, G. N., Nolden, L. K.,
Wang, N. J., Valero, V., Gray, J. W., Perou, C. M., &
Mills, G. B. (2009). Characterization of a naturally
occurring breast cancer subset enriched in epithelial-
to-mesenchymal transition and stem cell characteris-
tics. Cancer Research, 69(10), 4116–4124.
Jung, S. Y., Kim, H. Y., Nam, B. H., Min, S. Y., Lee, S. J.,
Park, C., Kwon, Y., Kim, E. A., Ko, K. L., Shin, K. H.,
Lee, K. S., Park, I. H., Lee, S., Kim, S. W., Kang, H. S.,
& Ro, J. (2010). Worse prognosis of metaplastic breast
cancer patients than other patients with triple-negative
breast cancer. Breast Cancer Research and Treatment,
120(3), 627–637.
Lai, H. W., Tseng, L. M., Chang, T. W., Kuo, Y. L.,
Hsieh, C. M., Chen, S. T., Kuo, S. J., Su, C. C., &
Chen, D. R. (2013). The prognostic significance of
metaplastic carcinoma of the breast (MCB)–A case
controlled comparison study with infiltrating ductal
carcinoma. Breast, 22(5), 968–973.
Lakhani, S. R., Ellis, I. O., Schnitt, S. R., Hoon Tan, P., &
van de Vijver, M. (2012). WHO classification of tumors
of the breast. Lyon: IARC Press.
Lehmann, B. D., Bauer, J. A., Chen, X., Sanders, M. E.,
Chakravarthy, A. B., Shyr, Y., & Pietenpol, J. A.
(2011). Identification of human triple-negative breast
cancer subtypes and preclinical models for selection of
targeted therapies. Journal of Clinical Investigation,
121(7), 2750–2767.
228
Lehmann, B. D., Jovanović, B., Chen, X., Estrada, M. V.,
Johnson, K. N., Shyr, Y., Moses, H. L., Sanders, M. E.,
& Pietenpol, J. A. (2016). Refinement of triple-negative
breast cancer molecular subtypes: Implications for neo-
adjuvant chemotherapy selection. PLoS One, 11(6),
e0157368.
Lien, H. C., Lin, C. W., Mao, T. L., Kuo, S. H., Hsiao, C. H.,
& Huang, C. S. (2004). p53 overexpression and mutation
in metaplastic carcinoma of the breast: Genetic evidence
for a monoclonal origin of both the carcinomatous and
the heterogeneous sarcomatous components. The Jour-
nal of Pathology, 204(2), 131–139.
Marchio, C., Geyer, F. C., & Reis-Filho, J. S. (2016). Pathol-
ogy and molecular pathology of breast cancer. In M. Loda
et al. (Eds.), Pathology and epidemiology of cancer
(pp. 173–232). Cham: Springer International Publishing.
Ng, C. K. Y., Piscuoglio, S., Geyer, F. C., Burke, K. A.,
Pareja, F., Eberle, C. A., Lim, R. S., Natrajan, R.,
Riaz, N., Mariani, O., Norton, L., Vincent-Salomon, A.,
Wen, Y. H., Weigelt, B., & Reis-Filho, J. S. (2017). The
landscape of somatic genetic alterations in metaplastic
breast carcinomas. Clinical Cancer Research, 23(14),
3859–3870.
Pezzi, C. M., Patel-Parekh, L., Cole, K., Franko, J.,
Klimberg, V. S., & Bland, K. (2007). Characteristics
and treatment of metaplastic breast cancer: Analysis of
892 cases from the National Cancer Data Base. Annals
of Surgical Oncology, 14(1), 166–173.
Tanabe, Y., Tsuda, H., Yoshida, M., Yunokawa, M.,
Yonemori, K., Shimizu, C., Yamamoto, S., Kinoshita, T.,
Fujiwara, Y., & Tamura, K. (2017). Pathological fea-
tures of triple-negative breast cancers that showed pro-
gressive disease during neoadjuvant chemotherapy.
Cancer Science, 108(7), 1520–1529.
Provenzano, E., Byrne, D. J., Russell, P. A., Wright, G. M.,
Generali, D., & Fox, S. B. (2016). Differential expres-
sion of immunohistochemical markers in primary lung
and breast cancers enriched for triple-negative tumours.
Histopathology, 68(3), 367–377.
Rakha, E. A., Aleskandarany, M. A., Lee, A. H., &
Ellis, I. O. (2016). An approach to the diagnosis of
spindle cell lesions of the breast. Histopathology,
68(1), 33–44.
Rakha, E. A., Coimbra, N. D., Hodi, Z., Juneinah, E.,
Ellis, I. O., & Lee, A. H. (2017). Immunoprofile of
metaplastic carcinomas of the breast. Histopathology,
70(6), 975–985.
Reis-Filho, J. S., Milanezi, F., Steele, D., Savage, K.,
Simpson, P. T., Nesland, J. M., Pereira, E. M.,
Lakhani, S. R., & Schmitt, F. C. (2006). Metaplastic
breast carcinomas are basal-like tumours. Histopathol-
ogy, 49(1), 10–21.
Reyes, C., Gomez-Fernández, C., & Nadji, M. (2012).
Metaplastic and medullary mammary carcinomas
do not express mammaglobin. American Journal of
Clinical Pathology, 137(5), 747–752.
Sneige, N., Yaziji, H., Mandavilli, S. R., Perez, E. R.,
Ordonez, N. G., Gown, A. M., & Ayala, A. (2001).
Low-grade (fibromatosis-like) spindle cell carcinoma
of the breast. American Journal of Surgical Pathology,
25(8), 1009–1016.
Invasive Micropapillary Carcinoma
Weigelt, B., Kreike, B., & Reis-Filho, J. S. (2009). Meta-
plastic breast carcinomas are basal-like breast cancers:
A genomic profiling analysis. Breast Cancer Research
and Treatment, 117(2), 273–280.
Weigelt, B., Ng, C. K., Shen, R., Popova, T., Schizas, M.,
Natrajan, R., Mariani, O., Stern, M. H., Norton, L.,
Vincent-Salomon, A., & Reis-Filho, J. S. (2015). Meta-
plastic breast carcinomas display genomic and trans-
criptomic heterogeneity. Modern Pathology, 28(3),
340–351.
Wendroth, S. M., Mentrikoski, M. J., & Wick, M. R.
(2015). GATA3 expression in morphologic subtypes
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disease fluid protein 15 and mammaglobin. Annals of
Diagnostic Pathology, 19(1), 6–9.
Invasive Micropapillary
Carcinoma
Lilla Madaras and Janina Kulka
2nd Department of Pathology, Semmelweis
University, Budapest, Hungary
Synonyms
Micropapillary carcinoma
Definition
Invasive micropapillary carcinoma (IMPC) is a
special type of invasive breast carcinoma (IBC)
characterized by cancer cells with eosinophilic or
granular cytoplasm, forming morule-like clus-
ters, surrounded by clear stromal spaces. Tumor
cells have characteristic reverse polarity, also
known as an “inside-out” growth pattern: the
apical pole of tumor cells faces the empty stromal
spaces.
Clinical Features
• Incidence
Pure IMPC is a rare subtype of invasive breast
cancer, accounting in its pure form for 0.9–2%
of IBCs. The reported incidence of IBC with a
micropapillary component is up to 8%.
Invasive Micropapillary Carcinoma
• Age
The reported median age of IMPC is from
48 to 62 years, consistent with that of
patients with estrogen receptor (ER)
positive IBC.
• Sex
IMPC usually affects women, but single cases
of male IMPC had been reported. In studies on
male breast cancer, the reported incidence of
IBC with micropapillary features varies
between 0% and 11%.
• Site
No specific site within the breast parenchyma
was identified for these tumors.
• Treatment
Currently stage I and II tumors are treated as
IBC of no special type (IBC NST) (▶ Invasive
Carcinoma NST); however there are some sug-
gestions that modification of current
locoregional treatment would be beneficial in
cases of IMPC: wider surgical margins and
more aggressive axillary and supraclavicular
management would enhance local disease con-
trol (Yu et al. 2015).
• Outcome
Since the incidence of IMPC is low, studies
on its outcome are sparse. It seems that
despite the reported unfavorable tumor char-
acteristics of IMPC (higher nuclear grade,
frequent lymphovascular invasion (LVI),
lymph node metastases (LNM), and extra-
capsular spread) (Chen et al. 2014; Yu et al.
2015) the overall prognosis of IMPC patients
in multivariate analysis – when stratified for
number of positive lymph nodes and other
prognostic factors – is comparable to that of
IBC NST patients (Yu et al. 2015).
According to Chen’s study of 624 patients
with IMPC, the prognosis is poor if the tumor
is ER negative.
Macroscopy
IMPCs do not have any particular features on
grossing. The reported mean tumor size is between
1.5 cm and 3.9 cm, not significantly different from
that of IBC NST (▶ Invasive Carcinoma NST)
(Yi-Ling et al. 2016).
229
Microscopy
IMPC is characterized by cell clusters arranged
in pseudopapillary structures, devoid of fibrovas-
cular cores and surrounded by clear stromal spaces,
delineated by delicate fibers of a fibro-collagenous
stroma (Fig. 1a. H&E: shows the low power pattern
of IMPC). The empty spaces surrounding the
tumor cell morules resemble lymphatic channels
but lack endothelial lining (Fig. 1b. H&E: lack of
endothelial lining of stromal spaces).
The amount of a micropapillary component
required for the diagnosis of IMPC in a tumor is
not yet established. Some authors have used the
diagnosis of IMPC in tumors with at least a 50%
micropapillary component, while others require
that the entire tumor should demonstrate the char-
I
acteristic micropapillary growth pattern in order
to be diagnosed as pure IMPC. For practical
reasons at least 75% of the tumor should demon-
strate the characteristic micropapillary growth in
order to be characterized as pure IMPC. There are
some suggestions that IBC with any well-defined
micropapillary carcinoma component should pro-
mpt the diagnosis of IMPC and the percentage of
the micropapillary component clearly stated in the
pathology report (Yi-Ling et al. 2016) (Fig. 2.
H&E: mixed IBC NST and IMPC).
The tumor cells of IMPC usually have eosino-
philic cytoplasm, and they demonstrate a charac-
teristic reverse polarity (“inside-out” pattern): the
apical surface of the cells facing the empty stromal
spaces and not the central pseudolumen, if pre-
sent. In some cases apocrine features can be iden-
tified. True tubule formation is lacking; nuclear
pleomorphism is only rarely pronounced. Number
of mitoses is usually low to moderate. Most
IMPCs are grade 2 or 3 lesions. Necrosis, tumor
infiltrating lymphocytes (TILs) are not common.
Peritumoral LVI is detected in up to 70% of
IMPC cases, while the LVI rate of IBC NST cases
is 20% (Gruel 2014). It seems that neither the
tumor size alone nor the extent of the micro-
papillary component but the presence of the
micropapillary pattern correlates with the agg-
ressive locoregional presentation of the tumor
(Yi-Ling et al. 2016).
The majority of patients – up to 84% – present
with axillary LNM at initial diagnosis. This rate is
230
Invasive Micropapillary Carcinoma, Fig. 1 A: Low power pattern of IMPC (H&E); B: Lack of endothelial lining of
stromal spaces around the morule-like clusters formed by tumor cells (H&E)
significantly higher than that of IBC NST patients
with LNM, and the number of lymph nodes
involved by metastatic disease is also higher in
IMPC than in IBC NST cases.
Associated intraductal carcinoma (DCIS)
(▶ Ductal Carcinoma In Situ) is usually of micro-
papillary architecture with high-grade nuclei.
Necrosis and microcalcifications may also be
present.
Immunophenotype
IMPC is frequently positive for ER (66–94%) and
progesterone receptor (PR) (50–84%). The prog-
nosis of ER-negative IMPCs is usually poor. In
reported series to date, basal cytokeratins are not
expressed in IMPCs. Pure IMPCs are likely to
have high Ki67 index, and cyclin D1 is also highly
expressed (Marchiò et al. 2008).
The reported incidence of HER2-positive IMPC
is inconsistent, which varies between 8.3% and
95% (Yi-Ling et al. 2016). The American Society
of Clinical Oncology (ASCO) and the College of
Invasive Micropapillary Carcinoma
American Pathologists (CAP) 2013 guidelines for
HER2 testing suggest that micropapillary carci-
noma with HER2 immunohistochemistry staining
that is intense but incomplete (basolateral or
U-shaped) and therefore would be considered
score 1+ may actually be amplified by fluorescent
in situ hybridization (FISH). Thus the guideline
recommends that these IMPC cases should be
reported as equivocal (score 2+), and alternative
testing should be carried out. This recommendation
of the 2013 ASCO/CAP guideline was based solely
on the results of a single study, which was
reinforced later by others.
Epithelial membrane antigen (EMA) or mucin
1 (MUC1 [CD227]) is a high-molecular weight
(>400 kDa), type I membrane-tethered glycopro-
tein that may serve to demonstrate the reverse
polarity of IMPC cells by staining the apical sur-
face of tumor cells facing the empty stromal
spaces (Fig. 3a: EMA immunohistochemistry
showing positive reaction at the periphery of
the morule-like micropapillary tumor cell clusters
highlighting their inverse polarity in a pure IMPC
case and Fig. 3b, in the IMPC component of a
Invasive Micropapillary Carcinoma
Invasive Micropapillary Carcinoma, Fig. 2 Mixed
breast carcinoma: IBC NST and IMPC (H&E)
mixed breast carcinoma). High expression of vas-
cular endothelial growth factor (VEGF)-C and
VEGF-receptor-3 by IMPC cells facilitates LNM
by increasing lymphatic vessel density.
Molecular Features
Genetic heterogeneity is a characteristic feature of
IMPCs. Some cases show duplication or deletion
of long segments of a few chromosomes, or mul-
tiple segments of duplications and deletions may
be present throughout the whole genome, or mul-
tiple amplicons on single chromosome arms may
be identified (Marchiò et al. 2008).
Microarray-based comparative genomic hybrid-
ization studies demonstrated that pure IMPCs and
IBC NST cases with micropapillary features are
remarkably similar and harbor genetic alterations
distinct from that of grade- and ER-matched cases
of IBC NST (▶ Invasive Carcinoma NST). Recur-
rent gains in regions of 8p, 8q, 17q, and 20q, while
losses of 1p, 8p, 13q, and 20q, were more prevalent
in IMPC than in IBC NST (Marchiò et al. 2009; Li
et al. 2012; Wang et al. 2015).
231
The genes SEC63 and FOXO3 were found to
be downregulated in IMPCs; their protein prod-
ucts play a role in cell polarity control. SEC63
protein also plays a role in trafficking of proteins
in ciliogenesis. FOXO3 regulates LKB1 tran-
scription. LKB1 protein has a role in maintaining
cell polarity during cell division. These findings
suggest the possible role of SEC63 and FOXO3 in
altered polarity of IMPC cells (Gruel et al. 2014).
The most frequent amplifications were found
on chromosome 17q22-q23.3. The second most
common region recurrently amplified was the
ERBB2 region (Gruel 2014). MYC amplification,
compared to IBC NST cases, is significantly more
common in pure IMPC. An interesting observa-
tion was, that despite these tumors belonging to
the luminal molecular subtype, ESR1 amplifica-
I
tion is not a common genomic alteration (Marchiò
et al. 2008).
Consistent with the frequent ER expression
observed in IMPCs, microarray-based gene
expression profiling also revealed that these
tumors frequently harbor genetic aberrations
similar to those detected in IBCs of the luminal
B subtype (Natrajan et al. 2014).
When analyzing the transcriptomes of IMPC
cases by deep sequencing, 45 microRNAs
(miRNA) were shown differently expressed in
IMPC and in IBC NST. A miRNA-specific RT
qPCR-based analysis revealed significant differ-
ences of let-7b, miR-30c, miR-148a, miR-181a,
and miR-181b expression levels between IMPCs
and IBC NSTs (Li et al. 2012).
Promoter hypermethylation of leucine zipper
putative tumor suppressor 1 (LZTS1), located on
8p – leading to downregulation of the gene – is
frequently observed in IMPCs associated with
LNM (Wang et al. 2015).
Differential Diagnosis
IMPC should be distinguished from ▶ mucinous
carcinoma, which displays abundant extracellular
mucin, absent in IMPC. Invasive micropapillary
carcinoma with mucinous differentiation (Fig. 4a
H&E) and invasive mucinous carcinoma with
micropapillary carcinoma growth pattern
232 Invasive Micropapillary Carcinoma

Invasive Micropapillary Carcinoma, Fig. 3 EMA of cancer cells and (B) of a mixed IBC NST and IMPC,
immunohistochemical reaction (A) of a pure IMPC with where the characteristic pattern of EMA positivity high-
EMA positivity at the periphery of the morule-like micro- lights the IMPC component of the tumor
papillary tumor cell clusters showing the inverse polarity

Invasive Micropapillary Carcinoma, Fig. 4 A: IMPC with mucinous differentiation (H&E); B: Invasive mucinous
carcinoma with IMPC growth pattern (IMMPC) (H&E)
Invasive Micropapillary Carcinoma
(IMMPC) (Fig. 4b H&E) are relatively newly
described entities.
Serous ovarian carcinoma metastatic to the breast
may mimic the histological features of IMPC and
usually also displays lymphatic tumor emboli. How-
ever, the presence of psammoma bodies and the
immunoreactivity for WT1 together with the clinical
history may assist to make the right diagnosis. The
caveat here is that IMPCs may express WT1, albeit
infrequently (Lee et al. 2007).
IMPC should be distinguished from IBC NST
(▶ Invasive Carcinoma NST) with widespread
lymphovascular invasion. Although the clear
spaces around the morule-like clusters of IMPC
cells resemble lymphatic channels, they are
devoid of endothelial cell lining. The characteris-
tic reverse polarity of IMPC cells is usually not
observed in IBC NST.
It is important that widespread retraction arti-
fact be not overdiagnosed as IMPC.
Fact sheet
Definition
Rare type of invasive breast cancer displaying tumor
cell clusters in empty spaces. The tumor cells have
inverse polarity.
Microscopy
The inverse polarity of tumor cells can be
demonstrated by EMA immunohistochemistry.
The cells may form morule-like clusters or
pseudotubules.
Lymphovascular invasion is a common feature.
Immunohistochemistry
IMPCs are usually ER/PR positive. Some cases belong
to the HER2-positive subtype. Few IMPCs belong to the
triple-negative non-basal group of breast carcinomas.
Molecular features
IMPCs are characterized by genetic heterogeneity.
Gains and losses of large chromosomal segments are
common. Genes responsible for cell polarity were found
to be downregulated.
Treatment
Wide excision with sentinel lymph node (▶ Sentinel
Node) biopsy. IMPCs are more likely to develop axillary
LN metastases than IBC NSTs.
Outcome
According to recent large studies with follow-up data, the
outcome is not worse than that of stage-matched ER-positive
IBC NSTs. ER-negative IMPCs have poor prognosis.
Differential diagnosis
Widespread lymphovascular invasion in IBC NST
Mucinous carcinoma with micropapillary features
Metastatic serous papillary ovarian carcinoma
Retraction artifact in poorly fixed specimens
233
References and Further Reading
Chen, A. C., Paulino, A. C., Schwartz, M. R.,
Rodriguez, A. A., Bass, B. L., Chang, J. C., &
Teh, B. S. (2014). Population-based comparison of
prognostic factors in invasive micropapillary and inva-
sive ductal carcinoma of the breast. British Journal of
Cancer, 111, 619–622.
Fisher, E. R., Palekar, A. S., Redmond, C., Barton, B., &
Fisher, B. (1980). Pathologic findings from the
National Surgical Adjuvant Breast Project (protocol
no. 4). VI. Invasive papillary cancer. American Journal
of Clinical Pathology, 73, 313–322.
Gruel, N., Benhamo, V., Bhalshankar, J., Popova, T.,
Freneaux, P., Arnould, L., Mariani, O., Stern, M. H.,
Raynal, V., Sastre-Garau, X., Rouzier, R., Delattre, O.,
& Vincent-Salomon, A. (2014). Polarity gene alter-
ations in pure invasive micropapillary carcinomas of
the breast. Breast Cancer Research, 16, R46. https://
doi.org/10.1186/bcr3653
Lee, A. H., Paish, E. C., Marchio, C., Sapino, A., I
Schmitt, F. C., Ellis, I. O., & Reis-Filho, J. S. (2007).
The expression of Wilms’ tumour-1 and Ca125 in
invasive micropapillary carcinoma of the breast.
Histopathology, 51(6), 824–828.
Li, S., Yang, C., Zhai, L., Zhang, W., Yu, J., Gu, F.,
Lang, R., Fan, Y., Gong, M., Zhang, X., & Fu, L.
(2012). Deep sequencing reveals small RNA charac-
terization of invasive micropapillary carcinomas of the
breast. Breast Cancer Research and Treatment, 136(1),
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Invasive Mucinous Carcinoma
James S. DeGaetano and Ian Said Huntingford
Pathology Department, Mater Dei Hospital,
Msida, Malta
Synonyms
Colloid carcinoma; Gelatinous carcinoma;
Mucinous adenocarcinoma; Mucoid carcinoma
Definition
Mucinous carcinoma (MC) of the breast forms part
of the special type of breast cancers and
is characterized histologically by aggregates or
clusters of typically uniform cells floating within
copious amounts of extracellular mucin (Bussolati
and Sapino 2012). In order to qualify for a
Invasive Mucinous Carcinoma
diagnosis of MC, the mucinous component should
represent over 90% of the tumor (Harris
et al. 2011).
Clinical Features
• Incidence
Pure mucinous carcinoma (PMC) of the breast
represents one of the rarest subgroups (Park
et al. 2010) and accounts for approximately
2% of all breast carcinomas (Bussolati and
Sapino 2012; Harris et al. 2011).
• Age
Compared to conventional invasive breast
carcinoma, PMC tends to affect an older pop-
ulation, typically in the postmenopausal age
group (Park et al. 2010).
• Sex
While MC of the breast primarily affects
women, isolated case reports of male breast
MC exist. Furthermore, some of these
cases of male breast MC have presented
with metastasis to axillary lymph nodes.
Metastasis to the lung has also been
documented.
• Symptoms and Imaging Findings
The presentation is similar to other breast carci-
nomas. Patients typically present with a palpable
mass. Not surprisingly, the radiological findings
can mimic those of a benign neoplasm, typically
presenting as a lobulated and well-circumscribed
lesion (Park et al. 2010). The majority of tumors
show high signal intensity on T2 weighted and
short tau inversion recovery (STIR) magnetic
resonance imaging (MRI). This is due to the
high water content owing to the copious amounts
of extracellular mucin seen in such lesions.
• Treatment
By definition, these are rare cancers hence most
of the data on management is based on smaller
case series as well as isolated case reports. Man-
agement is usually no different to the more
common invasive breast carcinoma of no spe-
cial type (IBC NST) (▶ Invasive Carcinoma
NST). Breast conserving therapy is typically
undertaken, interestingly with a similar rate of
local recurrence compared to IBC NST. Since
Invasive Mucinous Carcinoma
PMC is regarded to have a good prognosis, the
need to undergo axillary dissection was histori-
cally a rather contentious issue; although, this is
less so given that most patients undergo sentinel
node (▶ Sentinel Node) biopsy in the first
instance, ultimately dictating whether axillary
dissection is required (Dieci et al. 2014). The
National Comprehensive Cancer Network
(NCCN) guidelines state that adjuvant endo-
crine therapy should be considered if the case
is hormone receptor (HR) (▶ Hormone Recep-
tors in Breast Cancer) positive, node negative
(or nodal metastasis size is equal to or less than
2 mm), and the tumor size is less than 3 cm. If
the tumor size is less than 1 cm, then adjuvant
endocrine therapy is mainly indicated for risk
reduction. If the tumor size is equal to or greater
than 3 cm, then endocrine therapy is definitely
recommended. If the tumor is HR positive yet
there is ipsilateral axillary nodal involvement
(one or more ipsilateral metastases greater than
2 mm), then adjuvant chemotherapy may be
indicated in addition to adjuvant endocrine ther-
apy. In the context of HR negative cases, the HR
status should be re-evaluated, and if it is
reconfirmed that the case is HR negative, then
the treatment follows that of IBC NST (NCCN
2017).
• Outcome
PMC has an excellent prognosis with a low rate
of local recurrence and a 5-year disease-free
survival rate ranging from 81% to 94%. The
disease-specific survival rate is quoted at
95.3%, while the overall 5-year survival rate is
80%. Lymph node involvement plays an impor-
tant role in determining survival rates with the
overall 5-year survival rate increasing to 86% if
there is no nodal involvement (Harris et al.
2011). Case series have estimated the axillary
lymph node involvement rate at about 12%
(Di Saverio et al. 2008). The greater the nodal
involvement, the higher the likelihood of death
from malignancy and the greater the risk of
tumor recurrence (Harris et al. 2011). Tumor
size has an impact on the incidence of lymph
node involvement, with tumors less than 10 mm
displaying a low risk of lymph node metastasis,
namely, 0–4%. Some reports show that tumor
235
size does not have such an important impact on
overall prognosis, since there typically is over-
estimation of tumor size owing to the presence
of abundant extra-cellular mucin. Other studies
(Di Saverio et al. 2008) still utilize tumor size as
an independent prognostic factor, although it
has less relevance compared to nodal status
and stage. When compared to IBC NST
(▶ Invasive Carcinoma NST), MC displays bet-
ter disease-free survival; however, overall sur-
vival appears to be similar.
A study (Tseng et al. 2013) retrospectively
reviewed 93 cases of PMC and amongst other
aspects looked at the effects that the various
clinicopathological features had on disease-
free and overall survival. These factors
included age, tumor size, grade (I vs. II), HR
I
status, HER2 status, primary treatment status
(mastectomy vs. lumpectomy with and without
radiotherapy), as well as systemic therapy
(endocrine therapy alone vs. with chemother-
apy). A univariate analysis of these character-
istics interestingly revealed that none of these
factors had an impact on survival.
It is important to distinguish between PMC
and mixed mucinous carcinoma (MMC), since
the prognosis between the two is different. Stud-
ies have estimated the 10 year survival rate of
PMC to be 90.4% while that of MMC to be 66%.
The importance of this distinction is further
highlighted since MMC demonstrates a higher
rate of recurrence. The study also confirmed that
in particular MC, Type A, with a high mucin
content has a favorable prognosis. When dealing
with Type B MC, treatment should be based on
whether there is lymph node involvement or not.
As shall be eluded to later, there is no significant
difference in survival between the two main his-
tological types of PMC: Type A and Type B.
Macroscopy
The typical appearance is that of a gelatinous
lesion reflecting the high mucinous component
(Bussolati and Sapino 2012) (Fig. 1). The tumor
size typically ranges from 3 to 120 mm and has an
average dimension of 20 mm (Harris et al. 2011).
236
Invasive Mucinous Carcinoma, Fig. 1 Classic macro-
scopic appearance of mucinous carcinoma. One can
appreciate the mucinous cut surface
Microscopy
Role of Fine Needle Aspiration (FNA) Biopsy in
Diagnosis of Mucinous Carcinoma
Fine needle aspiration can play an important role
in the diagnosis of both PMC and MMC (Cyrta
et al. 2013). The most common features encoun-
tered on cytology include copious mucin and
bland nuclear cytology (regular nuclear con-
tours, small nuclear size) (Fig. 2). If the lesion
is mixed, one can expect sparser mucin content
and more pronounced nuclear cytological fea-
tures such as larger nuclei, nuclear contour irreg-
ularity, and prominent nucleoli. The presence of
necrosis is also suggestive of a mixed mucinous
component.
Invasive Mucinous Carcinoma
Histopathology
MC of the breast is characterized by copious pools
of extraceullar mucin-containing free floating
tumor cells typically arranged as nests, trabeculae,
sheets, or acini. The nuclear grade is usually low
to intermediate (Harris et al. 2011); however, rare
cases with pronounced atypia and mitoses have
been reported (Bussolati and Sapino 2012).
PMC has been traditionally subtyped into Type
A and Type B. Type A is described as the hypo-
cellular variant and displays a variety of architec-
tural pattern ranging from cribriform, tubular,
cord like, papillary, as well as micropapillary
(Fig. 3). Type B is the hypercellular variant and
grows in solid nests (Fig. 3). Type B mucinous
carcinomas often show neuroendocrine differen-
tiation (Capella et al. 1980). The morphological
similarities are also confirmed at molecular level
(Weigelt et al. 2009).
MMC is a well-described entity, and the most
common admixture is with IBC NST (▶ Invasive
Carcinoma NST) and lobular carcinoma
(▶ Invasive Lobular Carcinoma) (Fig. 3).
A particular histological variant, namely, mucin-
ous micropapillary carcinoma (▶ Invasive Micro-
papillary Carcinoma), is associated with higher
rates of lymphovascular invasion, lymph node
involvement, and greater expression of human epi-
dermal growth factor receptor 2 (HER2) positivity.
This entity is characterized by the coexistence of
mucinous and micropapillary morphology. Charac-
teristic histological features of this entity include
the presence of a micropapillary pattern, a mucin-
ous appearance, psammomatous calcifications,
hobnailing, and an intermediate/high grade nuclear
cytology. The study (Barbashina et al. 2013)
described 15 cases and found that 60% of cases
showed lymphovascular invasion, with 33%
of patients displaying synchronous axillary lymph
node involvement.
Immunophenotype
The receptor status profile of MC has also
been studied quite intensely. It is typically
Invasive Mucinous Carcinoma
Invasive Mucinous Carcinoma, Fig. 2 FNA of mucinous carcinoma (H&E, clockwise, x4, x10, x20, x40). Groups of
fairly monomorphic tumor cells float in a sea of mucinous material
associated with a higher expression rate of
Estrogen receptor (ER) and Progesterone recep-
tor (PR) compared to IBC NST with studies
suggesting prevalence rates of 73–94% and
63–90%, respectively (Fig. 4). There are also
lower rates of HER2 expression compared to
IBC NST quoted at 0–14% (Hugen et al.
2014). Both PMC and MMC express WT-1
(Bussolati and Sapino 2012). A study analyzed
the immunohistochemical profile of 40 cases of
mucinous carcinoma (De Andrade et al. 2017)
with 85% of cases expressing either GCDFP15
and mammoglobin. No cases expressed CDX-2,
while the Type B mucinous carcinomas showed
higher expression rates of Ki67 and were more
likely to express markers of neuroendocrine dif-
ferentiation (Fig. 5).
237
Molecular Features
Role of Mucins
At a cellular level, it is believed that complex
rearrangements in glycoproteins occurs in cancer-
ous mucinous cells compared to normal ductal
cells (Adsay et al. 2003). In this study, MUC1
stains highlighted a shift of glycoproteins to the
stroma facing aspects of the cancerous cells com-
pared to the typical luminal surface position
normally seen in ductal epithelial cells. This alter-
ation in position probably explains the accumula-
tion of mucin within stroma in mucinous
carcinoma. Within the neoplastic cells, mucigen
granules also adopted a clustered configuration.
The type of mucin expressed is MUC2, which
might also explain the more indolent nature of
238 Invasive Mucinous Carcinoma

Invasive Mucinous Carcinoma, Fig. 3 Types and pat- C), mucinous carcinoma solid papillary architecture (H&E,
terns of mucinous carcinoma. Mucinous carcinoma B), mucinous carcinoma with invasive breast carcinoma
Type A (H&E, A), mucinous carcinoma Type B (H&E, (H&E, D)

Invasive Mucinous Carcinoma, Fig. 4 Diffuse, strong ER positivity (A); diffuse, strong PR positivity (B); HER2
negative expression (C); unusual HER2 expression in Type B mucinous carcinoma (D)

mucinous carcinoma since it is believed that differences in MUC protein expression profiles
MUC2 has tumor suppressor activity and forms between the two types of MC. Type A breast
a rather viscid tumor environment perhaps mucinous carcinoma shows luminal and apical
inhibiting spread of cancer cells. There are even expression of MUC proteins, while the expression
Invasive Mucinous Carcinoma
Invasive Mucinous Carcinoma, Fig. 5 Mucinous
carcinoma Type A Ki67 proliferation index (A).
Mucinous carcinoma Type B Ki67 proliferation index
profile in Type B is membrano-cytoplasmic. Inter-
estingly MUC2 expression is inversely associated
with the rate of lymph node involvement and
lymphovascular invasion in non-mucinous inva-
sive carcinomas. MUC6 expression is also asso-
ciated with MC (Rakha et al. 2005).
The pathogenesis of MC is also thought to
result from altered expression of MUC2 within
normal breast tissue. The study also concluded
that out of all mucins it is MUC1 and MUC3
which have the most profound impact on out-
come. MUC1 expression appears to be associated
with a better prognosis mostly because it is
associated with more well differentiated neo-
plasms. Tumors expressing MUC3 (membranous
staining) tend to have a higher rate of lymph node
involvement and local recurrence as well as being
associated with poorer histological parameters
(such as worse grade) (Rakha et al. 2005).
Molecular Profile
MicroRNA has been the subject of intense
research and is enabling us to better understand
the molecular pathways involved in cancer. There
is downregulation of miR-143 and miR-224-5p in
239
(B). Mucinous carcinoma Type B neuroendocrine marker
expression (Synaptophysin (C) and Chromogranin (D))
breast MC, which is a similar finding in various
other types of cancers including prostate, colon,
bladder, amongst others (Feng et al. 2013).
miR-143 downregulation is also associated with
mucinous phenotype within colon cancer, hence it
is plausible to consider miR-143 downregulation
as an important common factor in the mucinous
cancer pathway. Interestingly, unlike in colonic
mucinous cancer, microsatellite instability is not
a prevalent occurrence (Hugen et al. 2014).
Studies have shown that specialized breast
cancers typically adopt a particular category of
molecular profiling with mucinous cancer
expressing a luminal phenotype (Weigelt et al.
2010). As has already been stated, there is consid-
erable overlap between Type B mucinous carci-
noma and neuroendocrine carcinoma (▶ Invasive
Carcinoma with Neuroendocrine Differentiation),
and this is mirrored at the genetic level, with both
types of tumors exhibiting identical genomic
profiles (Weigelt et al. 2009). They are also
genomically distinct from conventional IBC
NST (▶ Invasive Carcinoma NST) (Lacroix-
Triki et al. 2010). The pure variant typically
shows genetic stability and characteristically
240
lacks 1q gain and 16q loss which is typically seen
in low grade IBC NST (Lacroix-Triki et al. 2010;
Dieci et al. 2014; Hugen et al. 2014). They also
demonstrate a low incidence of PIK3CA muta-
tions (Dieci et al. 2014). Studies which carried out
hierarchical molecular clustering revealed that
even mixed mucinous carcinomas are
genomically very similar to pure mucinous carci-
noma rather than IBC NSTs (Lacroix-Triki
et al. 2010).
Differential Diagnosis
The differential diagnosis of mucinous carcinoma
typically includes the following: Mucocele-like
lesion (▶ Mucocele-like Lesion), Mucinous
DCIS, CIS with mucocele-like lesion and signet
ring cell carcinoma (▶ Invasive Carcinoma with
Signet Ring Cell Differentiation). A newly
described entity of invasive lobular carcinoma
(ILC) (▶ Invasive Lobular Carcinoma) with
extracellular mucin production certainly enters
into the differential diagnosis. This entity can be
easily confused with mucinous carcinoma
exhibiting a separate lobular component. Obvi-
ously if one overlooks the lobular component,
then an incorrect diagnosis of PMC can easily be
made. There do exist a number of useful histolog-
ical clues when making a diagnosis of this entity.
These include the presence of classical ILC
(▶ Invasive Lobular Carcinoma) around and not
necessarily within the mucinous lakes. The iden-
tification of lobular neoplasia (▶ Lobular In Situ
Neoplasia) is another helpful feature. Also impor-
tant is the lack of E-cadherin staining, and cyto-
plasmic expression of p120 by tumor cells in the
mucinous areas. One may also include solid pap-
illary carcinoma (SPC) (▶ Solid Papillary Carci-
noma) in the differential diagnosis since there may
be co-existing mucin, and it is not unusual for
SPC to demonstrate neuroendocrine differentia-
tion similar to Type B MC.
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Pierson, C. R., Cheng, J. D., Visscher, D. W.,
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Hruban, R. H., & Klimstra, D. S. (2003). Pathogenesis
of colloid (pure mucinous) carcinoma of exocrine
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production with altered cell polarity and abnormal
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noma carcinoma in the breast and pancreas. American
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Barbashina, V., Corben, A. D., Akram, M., Vallejo, C., & Tan,
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and carcinomas with signet-ring-cell differentiation.
In S. R. Lakhani, I. O. Ellis, S. J. Schnitt, P. H. Tan, &
M. J. van de Vijver (Eds.), WHO classification of
tumours of the breast (pp. 60–61). Lyon: IARC Press.
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(1980). Endocrine differentiation in mucoid carcinoma
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Bourgier, C., Mazouni, C., Mathieu, M. C.,
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De Andrade, N. R., Derchain, S. F., Pavanello, M.,
Paiva, G. R., Sarian, L. O., & Vassallo, J. (2017).
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Lin, G. (2013). MicroRNA and histopathological
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pathology: A volume in the foundations in diagnostic
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Bogers, A. J., Marijnissen-Van Zanten, M. A. J., de Wilt,
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Invasive Oncocytic Carcinoma
Dario de Biase1 and Moira Ragazzi2
1
Department of Pharmacy and Biotechnology,
University of Bologna, Bologna, Italy
2
Department of Oncology and Advanced
Technologies, Operative Unit of Pathology,
Azienda USL-IRCCS, Reggio Emilia, Italy
Synonyms
Malignant oncocytoma
Definition
Invasive oncocytic carcinoma (OC) is a “special
type” of breast carcinoma that is composed of at
least 70% of cells with oncocytic features
(so-called oncocytes) on both morphologic and
immunophenotypic grounds (Lakhani et al. 2012).
241
Oncocyte is a Greek term, first applied to sal-
ivary glands by Hamperl (1931) in 1931, which
means “swollen cell.” Under light microscope,
oncocytes are characterized by abundant granular
eosinophilic cytoplasm due to a high content of
mitochondria, demonstrable at ultrastructural
level (Roth et al. 1962). By definition, mitochon-
dria must occupy at least 60% of the total cyto-
plasmic volume (Ghadially 1985) and confer an
intense cytoplasmic granular positivity for anti-
mitochondrion antibody (Damiani et al. 1998;
Ragazzi et al. 2011). Namely, a carcinoma can
be classified as oncocytic if it shows a strong
cytoplasmic positivity for anti-mitochondrion
antibody in at least 70% of tumor cells.
I
Clinical Features
• Incidence
This tumor is considered very rare, but is
suspected to be overlooked, and probably mis-
diagnosed as apocrine carcinoma. The largest
series on record retrospectively evaluating
76 consecutive breast carcinomas using immu-
nohistochemistry for anti-mitochondrion
antibody reported an incidence of 19.6%
(Ragazzi et al. 2011).
• Age
Patient age ranges from 26 to 94 years with an
average age at presentation of 67 years (Costa
and Silverberg 1989; Damiani et al. 1998;
Ragazzi et al. 2011; Marla et al. 2013; Itagaki
et al. 2017).
• Sex
Thirty-seven cases of invasive oncocytic carci-
noma have been reported in English-language
literature. Among them, four cases occurred
in men.
• Site
All breast quadrants can be affected and a
multifocal and bilateral case has also been
reported (Itagaki et al. 2017).
• Treatment
Clinical features of oncocytic carcinomas are
similar to those of invasive carcinomas, no
special type (NST) (▶ Invasive Carcinoma
NST) (Ragazzi et al. 2011). Thus, the thera-
peutic strategies are the same. Resistance to
242
radiotherapy has been hypothesized just as it
has been reported in oncocytic tumors at other
sites, including the rectum, thyroid, and menin-
ges, but it has been never investigated in the
breast.
• Outcome
Presently, knowledge available on the prog-
nostic impact of oncocytic differentiation in
breast carcinomas is scant. According to the
largest series reported (Ragazzi et al. 2011),
prognosis depends on grading and staging
and is similar to the matched breast carcinomas
NST (▶ Invasive Carcinoma NST).
Macroscopy
Tumor size ranges from 0.8 to 9 cm (mean 3 cm).
On cut section, OCs are mainly well-defined, solid,
and firm, from whitish to tan brown nodules.
Microscopy
OC shows the spectrum of different architectural
patterns seen in invasive carcinoma NST (▶ Inva-
sive Carcinoma NST), even if a solid growth
pattern with nests, sheets, and cords is
characteristic. Tumor margins are more frequently
Invasive Oncocytic
Carcinoma,
Fig. 1 Invasive oncocytic
carcinoma (OC), low
magnification: Nodule has
typically pushing margins
and solid architecture
(H&E)
Invasive Oncocytic Carcinoma
pushing (Fig. 1). The main difference between OC
and carcinoma NST resides in cytologic features.
OCs are typically composed of large polygonal
cells with abundant granular eosinophilic cyto-
plasm, neat cytoplasmic borders, centrally located
nuclei, and prominent nucleoli (Fig. 2).
A moderate to marked nuclear pleomorphism is
often observed. Coherently, OCs are mostly grade
3 (53%) according to the Nottingham scoring
system, but they can be also grade 2 (36%),
while a minority of cases is grade 1 (11%).
A discrete lymphoid infiltrate can be also seen in
the majority of cases. Invasive carcinoma is asso-
ciated with an in situ component in a prevalence
of cases.
In a retrospective series, tumors with oncocytic
features were originally diagnosed as invasive car-
cinoma NST in the majority of patients (78%) but
special-types were also present including pure
mucinous carcinomas (▶ Invasive Mucinous Car-
cinoma), apocrine (▶ Apocrine Carcinoma), and
neuroendocrine carcinomas (▶ Invasive Carci-
noma with Neuroendocrine Differentiation)
(Ragazzi et al. 2011). One tall cell variant of pap-
illary breast carcinoma (▶ Tall Cell Variant of Pap-
illary Breast Carcinoma) was also reported in that
series (Fig. 3). In these mixed cases, aspects of both
differentiations usually coexist.
Invasive Oncocytic Carcinoma
Invasive Oncocytic Carcinoma, Fig. 2 Invasive
oncocytic carcinoma (OC), higher magnification: (a) Neo-
plastic cells have abundant eosinophilic and finely granular
cytoplasm, with neat borders, centrally located round
nuclei, and prominent nucleoli (H&E); (b)
Immunophenotype
By definition, OCs show an intense and diffuse
anti-mitochondrion antibody positivity in at least
70% of tumor cells (Ragazzi et al. 2011).
In addition, OCs have mostly a “luminal” phe-
notype with expression of CK7, EMA, and con-
sistent positivity for hormone receptors. HER2
positivity has been detected in 25% of tested
cases. Few triple-negative cases are also on
record, and in these cases, androgen receptor
(AR) should be performed to rule-out apocrine
differentiation. Most importantly, a tall cell vari-
ant of papillary breast carcinoma should be
excluded: it is AR negative and can co-express
luminal-markers (CK7, EMA, GATA 3), S100,
243
Antimitochondrion antibody shows intense and diffuse
positivity; (c) A discrete lymphocytic infiltrate is often
present at the edge of the tumour (H&E); (d) Tumour
cells forming cords in desmoplastic stroma can be seen
(H&E)
and basal-type cytokeratins (CK5 or CK5/6)
(Bhargava et al. 2017).
Molecular Features
Using the array comparative genomic hybridiza-
tion (aCGH) technique on a cohort of OCs and
mitochondrion-rich breast carcinomas compared
with matched invasive ductal carcinomas NST
(▶ Invasive Carcinoma NST), Geyer et al. found
that the formers are characterized by gains of
5p13.33, 11q13.1-q13.2, 16p13.3, 17q25.3, and
19p13 (Geyer et al. 2012). These chromosomal
regions host several nuclear genes with mitochon-
drial functions (Geyer et al. 2012). Intriguingly, in
244
Invasive Oncocytic Carcinoma, Fig. 3 Tall cell variant
of papillary breast carcinoma: (a) Follicular structures
filled with colloid-like material with scalloped borders.
Small papillae are evident as well as some calcifications
(H&E). (b) High magnification of a solid structure
the 5p13.33 region, the Telomerase Reverse Tran-
scriptase (TERT) gene has been mapped and it has
been established that TERT protein can localize to
the mitochondrion and modulate its activity
(Sahin et al. 2011). Based on these data, Geyer
et al. concluded that OCs of the breast are a group
of tumors with a distinctive pattern of chromo-
somal aberrations, previously associated with
OCs of other anatomical sites (e.g., oncocytic
tumors of the kidney and thyroid) (Geyer
et al. 2012).
A recent in vitro study, performed on six breast
cancer cell lines, investigated the role of SIRT/
FOXO/SOD2 axis of the mitochondrial unfolded
protein response in promoting breast tumor inva-
siveness. In the same paper, Kenny et al. found a
Invasive Oncocytic Carcinoma
composed of columnar cells with abundant granular cyto-
plasm and grooved nuclei (H&E); (c) Tumour cells show
intense and diffuse positivity for antimitochondrion anti-
body (Courtesy of Professor Vincenzo Eusebi)
notably increase of SOD2 immunostaining in a
series of OC breast carcinomas compared with
non-OC. These high SOD2 levels seem to be cor-
related with the high activity of the SIRT/FOXO/
SOD2 axis. Moreover, the authors observed that
patients with high SOD2 expression tumors had a
significantly worse outcome and that a SOD2 pos-
itive expression correlated with lymph nodal
involvement (Kenny et al. 2017).
Differential Diagnosis
Carcinoma with apocrine differentiation (▶ Apo-
crine Carcinoma): The differential diagnosis
between OC and carcinomas with apocrine
Invasive Oncocytic Carcinoma
features is usually difficult on morphology and
mainly relies on immunohistochemistry. Apo-
crine carcinomas are positive for GCDFP-15 and
AR, while hormone receptors are typically nega-
tive and antibodies for mitochondria are seen in
cells below 50% of the total neoplastic prolifera-
tion. Occasional cases, however, are oncocytic
and apocrine at the same time.
Acinic cell carcinoma (ACC) (▶ Acinic Cell
Carcinoma): Granular cytoplasm in ACC is due to
zymogen granules that are evidenced by PAS after
diastase digestion. Anti-mitochondrion antibodies
are negative. Tumor cells in ACC show serous
differentiation and are positive with salivary type
amylase, lysozyme, and alpha-1-antichimotrypsin
immunostains. In addition, ACC cells are typi-
cally immunoreactive for S-100 and they are triple
negative with no expression of both estrogen and
progesterone receptors and no Her2 amplification.
Neuroendocrine carcinoma (▶ Invasive Carci-
noma with Neuroendocrine Differentiation):
Well-differentiated neuroendocrine carcinoma of
the breast could be very similar to low-grade
OC. Expression of chromogranin and/or syn-
aptophysin in the majority of tumor cells is char-
acteristic of neuroendocrine differentiation.
Granular cell tumors (▶ Granular Cell Tumor):
They are composed of cells with eosinophilic
granular cytoplasm that can mimic oncocytes,
but they derive from Schwann cells of peripheral
nerves. Accordingly, neoplastic cells in granular
cell tumors are strongly and diffusely positive for
S100 and CD68 immunostains while they are
negative for keratins.
References and Further Reading
Bhargava, R., Florea, A. V., Pelmus, M., Jones, M. W.,
Bonaventura, M., Wald, A., & Nikiforova, M. (2017).
Breast tumor resembling tall cell variant of papillary
thyroid carcinoma: A solid papillary neoplasm with
characteristic immunohistochemical profile and few
recurrent mutations. American Journal of Clinical
Pathology, 147, 399–410.
Costa, M. J., & Silverberg, S. G. (1989). Oncocytic carci-
noma of the male breast. Archives of Pathology and
Laboratory Medicine, 113, 1396–1399.
Damiani, S., Eusebi, V., Losi, L., D’Adda, T., & Rosai,
J. (1998). Oncocytic carcinoma (malignant
oncocytoma) of the breast. American Journal of Surgi-
cal Pathology, 22, 221–230.
245
Eusebi, V., Damiani, S., Ellis, I. O., Azzopardi, J. G., &
Rosai, J. (2003). Breast tumor resembling the tall cell
variant of papillary thyroid carcinoma: Report of
5 cases. American Journal of Surgical Pathology, 27,
1114–1118.
Eusebi, V., Tallini, G., & Rosai, J. (2004). Nuclear alter-
ations and RET/PTC activation. American Journal of
Surgical Pathology, 28, 974–975.
Foschini, M. P., Asioli, S., Foreid, S., Cserni, G., Ellis,
I. O., Eusebi, V., & Rosai, J. (2017). Solid papillary
breast carcinomas resembling the tall cell variant of
papillary thyroid neoplasms: A unique invasive tumor
with indolent behavior. American Journal of Surgical
Pathology, 41, 887–895.
Geyer, F. C., de Biase, D., Lambros, M. B., Ragazzi, M.,
Lopez-Garcia, M. A., Natrajan, R., Mackay, A.,
Kurelac, I., Gasparre, G., Ashworth, A., Eusebi, V.,
Reis-Filho, J. S., & Tallini, G. (2012). Genomic profil-
ing of mitochondrion-rich breast carcinoma: Chromo-
somal changes may be relevant for mitochondria
accumulation and tumour biology. Breast Cancer
Research and Treatment, 132, 15–28. I
Ghadially, F. N. (1985). Diagnostic electron microscopy of
tumours (2nd ed.). London: Butterworth & Company.
Hamperl, H. (1931). Beiträge zur normalen und
pathologischen Histologie menschlieher
Speicheldriisen. Zeitschrift für Mikroskopisch-
Anatomische Forschung, 27, 1–55.
Itagaki, H., Yamamoto, T., Hiroi, A., Kawanishi, K., Nogu-
chi, E., Ohchi, T., Kamio, T., Kameoka, S., Oda, H., &
Nagashima, Y. (2017). Synchronous and bilateral
oncocytic carcinoma of the breast: A case report and
review of the literature. Oncology Letters, 13,
1714–1718.
Kenny, T. C., Hart, P., Ragazzi, M., Sersinghe, M., Chipuk,
J., Sagar, M. A. K., Eliceiri, K. W., LaFramboise, T.,
Grandhi, S., Santos, J., Riar, A. K., Papa, L., D'Aurello,
M., Manfredi, G., Bonini, M. G., & Germain,
D. (2017). Selected mitochondrial DNA landscapes
activate the SIRT3 axis of the UPRmt to promote
metastasis. Oncogene, 36, 4393–4404.
Lakhani, S. R., Ellis, I. O., Schnitt, S. J., Tan, P. H., & van
de Vijver, M. J. (2012). WHO classification of tumours
of the breast (4th ed.). Lyon: IARC.
Marla, N. J., Pai, M. R., Swethadri, G. K., & Fernandes,
H. (2013). Male breast cancer-review of literature on a
rare microscopic variant (oncocytic carcinoma). Indian
Journal of Surgery, 75(Suppl 1), 240–242.
Masood, S., Davis, C., & Kubik, M. J. (2012). Changing
the term “breast tumor resembling the tall cell variant of
papillary thyroid carcinoma” to “tall cell variant of
papillary breast carcinoma”. Advances in Anatomic
Pathology, 19, 108–110.
Ragazzi, M., de Biase, D., Betts, C. M., Farnedi, A.,
Ramadan, S. S., Tallini, G., Reis-Filho, J. S., & Eusebi,
V. (2011). Oncocytic carcinoma of the breast: Fre-
quency, morphology and follow-up. Human Pathology,
42, 166–175.
Roth, S. I., Olen, E., & Hansen, L. S. (1962). The eosino-
philic cells of the parathyroid (oxyphil cells), salivary
(oncocytes), and thyroid (Huerthle cells) glands. Light
246
and electron microscopic observations. Laboratory
Investigation, 11, 933–941.
Sahin, E., Colla, S., Liesa, M., Moslehi, J., Muller, F. L.,
Guo, M., Cooper, M., Kotton, D., Fabian, A. J.,
Walkey, C., Maser, R. S., Tonon, G., Foerster, F.,
Xiong, R., Wang, Y. A., Shukla, S. A., Jaskelioff, M.,
Martin, E. S., Heffernan, T. P., Protopopov, A.,
Ivanova, E., Mahoney, J. E., Kost-Alimova, M.,
Perry, S. R., Bronson, R., Liao, R., Mulligan, R.,
Shirihai, O. S., Chin, L., & DePinho, R. A. (2011).
Telomere dysfunction induces metabolic and mito-
chondrial compromise. Nature, 470, 359–365.
Invasive Secretory Carcinoma
Angelo Sidoni
Department of Experimental Medicine, Section of
Pathologic Anatomy and Histology, Medical
School, University of Perugia, Perugia, Italy
Synonyms
Juvenile secretory carcinoma, Juvenile breast car-
cinoma, Secretory carcinoma.
Definition
Invasive secretory carcinoma (ISC) is one of the
rarest histological subtypes of breast cancer, of
low-grade and translocation-associated. ISC
shows distinctive histological features consisting
in intracellular and extracellular production of
secretory material.
Clinical Features
• Incidence
Less than 0.15% of all breast carcinomas
(about 200 cases published in English
literature).
• Age
Originally described in children and termed
“juvenile secretory carcinoma” (McDivitt and
Stewart 1966), it appears that two thirds of the
published cases actually occur in adults and
Invasive Secretory Carcinoma
very rarely in the elderly. The age range of
the reported cases varies from 3 to 91 years.
• Sex
Mainly observed in adult female and children of
both sexes, very rare in men over the age of 30.
A case in a male-to-female transgender patient
has been described (Grabellus et al. 2005).
• Site
ISC may appear in any part of the breast; how-
ever, a subareolar location is prevalent, particu-
larly in men and children, and frequently
associated with nipple discharge. The usual clin-
ical presentation is a slow growing nodule,
mobile, often present for a long time and easily
mistaken with a fibroadenoma (▶ Fibroadenoma)
or a papilloma (▶ Intraductal Papilloma) on
imaging studies. Rare cases are reported in the
axilla, conceivably originating from ectopic
breast tissue or from skin appendage glands.
• Treatment
Treatment varies depending on the age and sex
of patients. In children, considering the favor-
able prognosis and the need to safeguard the
development of the breast, a conservative local
excision is the most advisable treatment. In post-
menarchal girls and women wide local excision,
quadrantectomy, or mastectomy are reported
based on tumor dimensions in order to obtain
negative surgical margins. In males, due to small
dimension of breast, mastectomy is the rule.
Sentinel lymph node (▶ Sentinel Node) map-
ping is suggested. No definitive conclusions are
available on the benefits of systemic adjuvant
chemotherapy and radiotherapy.
• Outcome
The clinical course of ISC is mainly character-
ized by favorable prognosis and a prolonged
survival, particularly in children and young
adults under 30 years of age, even in presence
of lymph node metastasis (rarely are involved
more than three lymph nodes). In adult women
ISC are more aggressive, especially if the
tumor is of high-grade (see below) and locally
advanced, although distant metastases are
exceptional and still correlated with long sur-
vival. Late local recurrence (even after
20 years) may occur and a prolonged follow-
up is necessary.
Invasive Secretory Carcinoma 247

Macroscopy apocrine features are polygonal with abundant

granular and eosinophilic cytoplasm, and their
ISC usually presents as a single firm nodule, with nuclei are round and uniform with discrete nucle-
well-defined smooth contour and a mean diameter oli. Mitotic activity and necrosis are
of 3 cm (range 0.5–12.5). The cut surface may be usually absent. An in situ component is often
lobulated with a central area of fibrosis and a color present with growth patterns similar to those
variable from grayish-white to yellow-tan. Occa- seen in conventional invasive carcinoma of no
sionally margins may be spiculated and the tumor special type, mainly of low grade (cribriform
may show microcystic nature with spongy consis- and papillary), but with the same cytological
tency. Multifocality is very uncommon. features of the ISC. Microcalcifications are rare
or absent.
Both intracellular and extracellular secretory
Microscopy material is diastase-PAS positive (Fig. 4 PAS
staining) and sialidase-Alcian blue (Fig. 5 Alcian
In prototypical ISCs tumor cells are arranged in blue) positive, indicating a composition rich in
varying patterns with a tubular, follicular, micro-
cystic (honeycomb) solid, and papillary architec-
I
ture (Fig. 1 H&E). Fibrous septa crossing the mass
may be present, explaining its lobulated appear-
ance. A striking feature is the presence of abun-
dant extracellular eosinophilic secretory material
reminiscent of thyroid colloid (Fig. 2 H&E).
Tumor borders are usually pushing but infiltrative
growth in the surrounding tissues may be
observed (Fig. 3 H&E).
Tumor cells show a variable combination of
secretory and apocrine features (Koerner 2014).
Secretory cells have a pale cytoplasm with numer-
ous vacuoles containing eosinophilic material.
Nuclei display low-grade features and are small Invasive Secretory Carcinoma, Fig. 2 Honeycomb pat-
and ovoid with inconspicuous nucleoli. Cells with tern resembling thyroid follicles (H&E)

Invasive Secretory Carcinoma, Fig. 1 Coexistence of Invasive Secretory Carcinoma, Fig. 3 Despite the well
solid, microcystic, follicular, tubular, and papillary patterns circumscribed appearance, invasion is present at the border
(H&E) (H&E)
248
Invasive Secretory Carcinoma, Fig. 4 Diastase-
periodic-acid-Schiff positivity of extracellular secretory
material
Invasive Secretory Carcinoma, Fig. 5 Sialidase-Alcian
blue positivity of extracellular secretory material
acidic mucins, particularly sulfated mucopolysac-
charides and sialomucins.
The above histological description is
consistent with almost all cases of ISC; however,
a small subset of patients may present morpho-
logical aspect of aggressiveness (prevalent
solid pattern, scant secretory activity, strong
nuclear atypia, high mitotic rate, necrosis,
peritumoral lymphovascular involvement, and
metastatic behavior), which seems to correlate
with a specific genomic profile (Del Castillo
et al. 2015).
At ultrastructural level tumor cells contain
secretory intracytoplasmic membrane-bound vac-
uoles, bound with desmosome and grouped in
Invasive Secretory Carcinoma
clusters partially surrounded by a basal lamina.
Large extracellular spaces are occupied by secre-
tory material.
Concluding the microscopic description of
ISCs, it is worth noting the singular resemblance
of ISC with a newly described salivary gland
tumor named “mammary analogue secretory car-
cinoma” (MASC). As the name implies, this
entity shows morphological, immunohistochemi-
cal, and genetic characteristics similar to those of
the breast counterpart. A cutaneous variant of
secretory carcinoma has been recently proposed
(Bishop et al. 2017).
Immunophenotype
Immunohistochemically most of the ISC are
triple-negative (absence of estrogen receptors,
progesterone receptors, and HER2) and positive
for cytokeratin (CK) 5/6 and/or CK14 and for
epidermal growth factor receptor (EGFR), which
confirm a basal-like phenotype. S-100 protein is
typically strongly expressed as well as the signal
transducer and activator of transcription 5A
(STAT5a). Other markers, consistently expressed,
include epithelial membrane antigen (EMA), and
lactalbumin, while variable reactivity was
observed for polyclonal CEA, gross cystic disease
fluid protein-15 (GCDFP-15), E-cadherin, and
CD117. Tumor cells may at least focally express
CKs 8/18, 19, and various CK cocktails.
Myoepithelial cells are absent thus alpha-smooth-
muscle actin, calponin, and p63 are negative.
Reported Ki67 indexes varied from less than
1–50%.
Molecular Features
The most relevant and specific molecular alter-
ation in ISC consists in a recurrent balanced chro-
mosomal translocation, t(12;15) (p13;q25) with
an ETS variant 6–neurotrophic receptor tyrosine
kinase 3 (ETV6–NTRK3) fusion gene (Tognon
et al. 2002). This translocation had already been
described in pediatric spindle cell tumors, such as
infantile fibrosarcoma and cellular congenital
Invasive Secretory Carcinoma
mesoblastic nephroma, in some myeloid acute
leukemia, and, subsequently, in mammary ana-
logue secretory carcinoma (MASC) of the sali-
vary gland.
Differential Diagnosis
If the pathologist has sufficient material, the
diagnosis of ISC, despite its rarity, does not pre-
sent any particular problems. Some difficulties
may arise in cases with predominant apocrine
aspects or against the recently described mam-
mary acinic carcinoma (▶ Acinic Cell Carci-
noma). However, looking for a typical
histological pattern of ISC, the presence of intra-
cellular and extracellular secretory material,
tumor cells with granular eosinophilic to foamy
cytoplasm and immunohistochemical features
(triple-negative and S-100-positive) are helpful
for the diagnosis. In difficult cases, FISH detec-
tion of an ETV6 rearrangement can be used to
make a correct diagnosis. On the contrary differ-
ential diagnosis with other lesions containing
secretory aspects based on core needle biopsies
or fine needle aspiration cytology may be partic-
ularly challenging given their pathologic spec-
trum and frequently subtle morphology (Toll
et al. 2016).
249
References and Further Reading
Bishop, J. A., Taube, J. M., Su, A., Binder, S. W., Kazakov,
D. V., Michal, M., & Westra, W. H. (2017). Secretory
carcinoma of the skin harboring ETV6 gene fusion.
A cutaneous analogue to secretory carcinomas of the
breast and salivary glands. American Journal of Surgi-
cal Pathology, 41, 62–66.
Del Castillo, M., Chibon, F., Arnould, L., Croce, S.,
Ribeiro, A., Perot, G., Hostein, I., Geha, S., Bozon,
C., Garnier, A., Lae, M., Vincent-Salomon, A., &
MacGrogan, G. (2015). Secretory breast carcinoma.
A Histopathologic and genomic Spectrum character-
ized by a joint specific ETV6-NTRK3 gene fusion.
American Journal of Surgical Pathology, 39,
1458–1467.
Grabellus, F., Worm, K., Willruth, A., Schmitz, K. J.,
Otterbach, F., Baba, H. A., Kimming, R., & Metz,
K. A. (2005). ETV6-NTRK3 gene fusion in a secretory
carcinoma of the breast of a male-to-female transsex-
ual. The Breast, 14, 71–74. I
Koerner, F. C. (2014). Secretory carcinoma. In S. A. Hoda,
E. Brogi, F. C. Koerner, & P. P. Rosen (Eds.), ROSEN's
BREAST pathology (4th ed., pp. 689–701). Philadel-
phia: Wolters Kluwer Lippincott Williams & Wilkins.
McDivitt, R. W., & Stewart, F. W. (1966). Breast carci-
noma in children. JAMA, 195, 388–390.
Tognon, C., Knezevich, S. R., Huntsman, D., Roskelley,
C. D., Melnyk, N., Mathers, J. A., Becker, L., Carneiro,
F., MacPherson, N., Horsman, D., Poremba, C., &
Sorensen, P. H. (2002). Expression of the ETV6-
NTRK3 gene fusion as a primary event in human
secretory breast carcinoma. Cancer Cell, 2, 367–376.
Toll, A., Joneja, U., & Palazzo, J. (2016). Pathologic spec-
trum of secretory and mucinous breast lesions. Archives
of Pathology and Laboratory Medicine, 140, 644–650.
L
Lobular In Situ Neoplasia
Gyula Pekar
Division for Laboratory medicine, Department of
Pathology, Lund University, Lund, Sweden
Synonyms
Lobular carcinoma in situ (LCIS); Lobular
intraepithelial neoplasia (LIN)
Definition
Lobular carcinoma in situ (LCIS) is character-
ized by a neoplastic proliferation of small,
uniform, dyscohesive cells that expands at
least 50% of one terminal ductal-lobular unit
(TDLU). Although the first pictures of “atypical
proliferation of acinar cells” were published in
1919 by Ewing, the term LCIS was introduced in
1941 by Foote and Stewart to describe the histo-
logical hallmarks of this lesion within breast
lobules. The description was restricted to a
well-developed example of classic LCIS
(LCIS-C) as an established histopathological
entity. In 1985, Dupont and Page described
the earlier stages of this lesion, such as
atypical lobular hyperplasia (ALH). The term
lobular neoplasia (LN) denotes the full spectrum
of proliferation of the characteristic “lobular”
cells in acini with frequent coexistence of
© Springer Nature Switzerland AG 2020
A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
ALH and LCIS (Haagensen et al. 1978).
Additionally, the lobular neoplastic
lesions have also been classified using lobular
intraepithelial neoplasia (LIN) as an alternative
nomenclature in WHO book in 2003, although
this terminology does not seem to have gained
wide acceptance. While the natural history of
lobular neoplastic lesions is debatable, LCIS
clearly increases breast cancer risk in both
breasts. LCIS is often multifocal/multicentric
and is accompanied with a variable
transformation rate into invasive carcinoma,
suggesting it both as a nonobligate precursor
and as a high-risk lesion (King et al. 2015).
In the eighth edition of the American Joint
Committee for Cancer (AJCC) staging
classification system, LCIS is considered a risk
lesion and not anymore an in situ (pTis) cancer.
However, the AJCC expert panel still debates
on the management of pleomorphic LCIS
(LCIS-P).
Clinical Features
• Incidence
0.5–4.0% of breast biopsies, depending
on diagnostic criteria, the amount of normal
breast tissue in biopsy specimens and mam-
mographic appearance. LCIS prevalence is
0.5% in “benign” breast biopsies and higher
(3.2–4.0%) in biopsies performed because of
a mammographic abnormality.
252 Lobular In Situ Neoplasia

• Age are often not at the site of core needle

The average age at diagnosis ranges from 44 to biopsy.
54 years, with the greatest incidence before – Surgical excision is suggested when any LCIS
menopause (80–90%). is associated with microcalcifications or
• Sex shows histological features of non-LCIS-C
Predominantly in women; however, very rare (e.g., LCIS-P or comedo necrosis). The find-
cases reported in men. The majority of LCIS ing of LCIS-C on surgical margins in excision
shows strong expression of estrogen receptor specimen does not require re-excision. When
(ER) and hormonal influence may play a role in LCIS-P is identified at a surgical margin, how-
neoplastic cells proliferation, but the incidence ever, a re-excision should be performed. There
is not higher in women using hormone replace- are no data on the optimal width of negative
ment therapy. margin or the benefit of radiation therapy for
• Site patients with LCIS-P.
LCIS has a propensity to develop in multiple
foci within the same or both breasts; up to 50%
of patients may have bilateral disease, and multi-
Outcome
centric foci have been described in up to 80% of
patients undergoing mastectomy for LCIS.
LCIS is an indolent lesion with very low malig-
• Presentation
nant potential, but it conveys 8–10 increased
There are no specific mammographic findings
risk for ipsilateral as well as contralateral invasive
associated with LCIS. LCIS may be associated
breast cancer comparing to general population.
with benign calcifying lesions such as atrophic
Epidemiologic studies demonstrated that the
lobules, flat epithelial atypia (FEA) (▶ Colum-
probability of developing invasive cancer is
nar Cell Lesions), sclerosing adenosis
increasing by roughly 1% per year, with a higher
(SA) (▶ Sclerosing Adenosis), and collage-
risk of developing ipsilateral than contralateral
nous spherulosis (▶ Collagenous Spherulosis)
invasive breast cancer either invasive lobular car-
are discovered coincidentally in apparently
cinoma (ILC) (▶ Invasive Lobular Carcinoma) or
normal tissue surrounding a benign (i.e.,
invasive carcinoma of no special type (NST)
▶ Fibroadenoma) or malignant tumor. LCIS
(▶ Invasive Carcinoma NST). However, mastec-
is part of the “Rosen triad” together with tubu-
tomy has never been shown to reduce mortality
lar carcinoma (TC) (▶ Tubular Carcinoma)
compared to observation alone. In some instances,
and columnar cell lesions. Calcifications are
LCIS-C cells may be clonally related to subse-
infrequently present in LCIS, but in cases of
quent ILC. LCIS-P has been more frequently
florid (LCIS-F) and pleomorphic type
associated with invasive disease and a more
(LCIS-P) comedo necrosis with calcium depo-
aggressive course (Pieri et al. 2014), with
sition frequently occur. Breast magnetic reso-
genetic similarities of synchronous pleomorphic
nance imaging (MRI) detects LCIS with higher
ILC (▶ Pleomorphic Lobular Carcinoma),
sensitivity than ultrasonography.
warranting a more aggressive therapeutic
• Treatment
approach. It is still debated whether LCIS detected
– Clinical follow-up may be an acceptable
in association with an invasive carcinoma
alternative to excisional biopsy when in
increases the risk of disease recurrence.
core needle biopsy LCIS is an incidental
finding to a target lesion and/or in cases
with limited volume lesions (less than
three TDLU involved). Likelihood of find- Macroscopy
ing cancer after excision is ~ 3% and typi-
cally it belongs to low-grade neoplasia LCIS per se usually does not form a macroscopic
group. Subsequent cancers in these patients alteration (except very rare cases with LCIS-F).
Lobular In Situ Neoplasia
Lobular In Situ Neoplasia, Fig. 1 (H&E) Proliferation
of monomorphic, evenly spaced cells that are loosely
cohesive and slightly larger than normal acinar cells. The
Microscopy
LCIS-C
Proliferation of monomorphic, evenly spaced
cells that are loosely cohesive and slightly larger
than normal acinar cells with uniform nuclei,
evenly distributed chromatin with indistinct
nucleoli (Fig. 1A H&E). LCIS-C is lacking pleo-
morphism and necrosis. Mitotic figures and
hyperchromatism are not features of LCIS-C
but may occasionally be seen. Intracytoplasmic
lumina are often present (Fig. 1B H&E) and
stain with alcian blue (AB) and/or Periodic acid-
Schiff reagent (PAS). The anatomical
distribution can involve lobules causing their
expansion (Fig. 2A H&E and 2B E-cadherin
immunostaining) or LCIS can spread along larger
ducts or even along the main lactiferous ducts,
causing cloverleaf or necklace patterns (Fig. 2C
H&E and 2D E-cadherin), usually without
intraepidermal spreading to the nipple. “Pagetoid
spread” refers to continuous growth of tumor
cells beneath adjacent terminal duct epithelium.
Additionally, LCIS-C may occur in SA (▶ Scle-
rosing Adenosis), radial scar (▶ Radial Scar),
fibroadenoma (▶ Fibroadenoma), collagenous
spherulosis (▶ Collagenous Spherulosis), or pap-
illary lesions (▶ Intraductal Papilloma).
Variants of LCIS
Rare, comprising <5% of all carcinoma in situ.
Several variants have been recognized, these
253
nuclei are uniform with evenly distributed chromatin and
indistinct nucleoli (A). Intracytoplasmic lumina are often
present (B – arrows)
include apocrine types of LCIS (Fig. 3 (A) H&E;
(B) E-Cadherin; (C) GCDFP-15 and (D) PAS),
LCIS-P, LCIS with comedo necrosis, and carci-
noma in situ with mixed ductal and lobular fea-
tures. Clear cell and signet ring cell variants of
LCIS have also been described. The natural his-
tory is unknown. Likelihood of microinvasion L
(▶ Microinvasive Carcinoma of the Breast) or
invasion is higher than in LCIS-C.
Pleomorphic LCIS (LCIS-P)
It occurs in older postmenopausal age group
compared with LCIS-C. Although the cells
appear dyscohesive as in LCIS-C, they exhibit
high nuclear grade (nuclei are more than 3
larger than lymphocytes) with multinucleation.
Occasionally, the cytoplasm can appear eosino-
philic and finely granular, giving the cells an
apocrine appearance. Central comedo necrosis
and calcifications are quite commonly associated
(Fig. 4 (A) H&E, (B) p120, (C) PAS-AB, (D) E-
cadherin).
Florid LCIS (LCIS-F)
LCIS-F shows cohesive (solid) growth of cells
with either low- or high-grade nuclear features.
Central necrosis and calcium deposition are
common. Clustered calcifications within central
necrosis are detected at mammography. Calcifica-
tions may show a “linear” shape if extralobular
duct(s) are involved.
254
Lobular In Situ Neoplasia, Fig. 2 LCIS distribution can
involve lobules causing expansion (A, H&E) and E-
cadherin immunostaining persists in myoepithelial cells
around E-cadherin–negative LCIS cells (B). LCIS can
In Situ Carcinoma with Mixed Ductal and
Lobular Features
It is very rare. This is considered collision in situ
carcinoma containing both LCIS-C and ductal car-
cinoma in situ (DCIS) within the same structure.
Immunophenotype
LCIS-C and variants of LCIS can exhibit strong
reactivity for the high-molecular-weight CK
34bE12 that is absent or weakly expressed in
DCIS. E-cadherin expression can be reliably
used as a marker to differentiate between ductal
and lobular neoplasia (>95% of cases of LCIS
lack E-cadherin). However, morphologically
unequivocal cases of LCIS may demonstrate
focal E-cadherin positivity. p120-catenin is
Lobular In Situ Neoplasia
spread along larger ducts or even along the main lactiferous
ducts, causing cloverleaf or necklace patterns (C, H&E). E-
cadherin negative LCIS cells spread along ducts between
E-cadherin positive epithelial and myopeithelial cells (D)
characteristically diffusely localized to the cyto-
plasm in cases of lobular neoplasia, whereas in
ductal lesions it remains localized to the mem-
brane. Immunoreactivity for ER and progesterone
receptor (PR) is found in virtually all LCIS-C, in
about 66% of LCIS-P and in less than 25% of
apocrine LCIS-P. PR expression is reduced in
LCIS associated with ILC (▶ Invasive Lobular
Carcinoma). LCIS-C is typically negative for
HER2 protein overexpression/gene amplification,
lacks p53 mutations, and has a low Ki67 labeling
index. Conversely, variants of LCIS and LCIS-P
may show HER2 protein overexpression/gene
amplification (especially when associated with
invasive carcinoma), p53 positivity and a moder-
ate to high Ki67 labeling index. GCDFP-15 is
positive in >90% of LCIS-C, 75% of LCIS-P,
and in virtually all cases of apocrine LCIS-P.
Lobular In Situ Neoplasia
Lobular In Situ Neoplasia, Fig. 3 Apocrine type of LCIS (A, H&E); E-Cadherin is negative in neoplastic cells (B);
GCDFP-15 (C) and PAS (D) are diffusely positive in apocrine LCIS
Molecular Features
E-cadherin alterations, low-grade neoplasia path-
way, and genetic predisposition:
E-cadherin is encoded by the CDH1 gene on
chromosome 16q22, and loss of this protein is
believed to account for the dyscohesive nature of
the cells in LCIS and ILC. As a tumor suppressor
gene, biallelic inactivation is needed by somatic
frameshift mutation (up to 50% of ILC have
CDH1 mutations), allelic deletion by loss of het-
erozygosity or aberrant promoter methylation
(Mastracci et al. 2005). Genetic studies of colum-
nar cell lesions, ALH, and LCIS proved concor-
dant genomic alterations, remarkably similar
to low-grade DCIS, NST grade 1, TC, tubulo-
lobular carcinoma, and ILC classic type,
suggesting them to be part of a morphologic con-
tinuum within the low-grade neoplasia pathway
(Simpson et al. 2005). In cases of LCIS-P, higher
255
number of DNA copy number changes and more
complex chromosomal rearrangements were
reported. Early onset of bilateral LCIS with or
without ILC can be associated with CDH1
germline genetic aberration in women without a
family history of gastric cancer.
Differential Diagnosis
ALH
Distinction between ALH and LCIS is based on
extent of lesion, and ALH is defined by its limited
extent with neoplastic cells only partially filling
the lobular acini with residual lumina. The num-
ber of acini involved is <50%.
Low-Grade DCIS, Solid Pattern
The presence of a dyscohesive growth pattern and
prominent intracytoplasmic vacuoles favors a
256 Lobular In Situ Neoplasia

Lobular In Situ Neoplasia, Fig. 4 Pleomorphic LCIS, The black arrows on pictures A-C point at the characteris-
central comedo necrosis (A, H&E); diffuse p120 cytoplas- tics multinucleation which is a distinctive feature of
mic positivity (B); PAS-AB staining (C); E-Cadherin (D). LCIS-P

diagnosis of lobular neoplasia. On the other hand, central necrosis and calcifications. The
the presence of distinct cell membranes supports a dyscohesive appearance, lack of E-cadherin
diagnosis of DCIS (▶ Ductal Carcinoma In Situ). expression and diffuse p120 staining of the cells
E-cadherin, p120 IHC can be particularly helpful. are helpful in making the LCIS-P diagnosis.

Benign Lesions Harboring LCIS Mimicking

Benign Cells
Invasive Carcinoma
Myoepithelial cells may be confused with lobu-
LCIS involving SA (▶ Sclerosing Adenosis)
lar neoplasia, particularly when these cells
can mimic invasive carcinoma. Lobulocentric
extend in a pagetoid manner into ducts and
proliferation of back-to-back ductules, often
show abundant clear cell change. IHC for spe-
with microcalcifications, is typical for SA.
cific myoepithelial markers can be helpful in
Myoepithelial markers are helpful in such cases.
problematic cases.
LCIS may grow in otherwise typical FA
(▶ Fibroadenoma), and it will not generate any
diagnostic concern.
References and Further Reading
LCIS-P Versus DCIS Haagensen, C. D., Lane, N., Lattes, R., & Bodian, C.
LCIS-P is very easily confused with high-grade (1978). Lobular neoplasia (so-called lobular carcinoma
DCIS, particularly when there is associated in situ) of the breast. Cancer, 42, 737–769.
Low-Grade Adenosquamous Carcinoma
King, T. A., Pilewskie, M., Muhsen, S., Patil, S.,
Mautner, S. K., Park, A., Oskar, S., Guerini-Rocco, E.,
Boafo, C., Gooch, J. C., De Brot, M., Reis-Filho, J. S.,
Morrogh, M., Andrade, V. P., Sakr, R. A., &
Morrow, M. (2015). Lobular carcinoma in situ:
A 29-year longitudinal experience evaluating clinico-
pathologic features and breast cancer risk. Journal of
Clinical Oncology, 33, 3945–3952.
Mastracci, T. L., Tjan, S., Bane, A. L., O’malley, F. P., &
Andrulis, I. L. (2005). E-cadherin alterations in atypical
lobular hyperplasia and lobular carcinoma in situ of the
breast. Modern Pathology, 18, 741–751.
Pieri, A., Harvey, J., & Bundred, N. (2014). Pleomorphic
lobular carcinoma in situ of the breast: Can the
evidence guide practice? World Journal of Clinical
Oncology, 5, 546–553.
Simpson, P. T., Reis-Filho, J. S., Gale, T., & Lakhani, S. R.
(2005). Molecular evolution of breast cancer. Journal
of Pathology, 205, 248–254.
Low-Grade Adenosquamous
Carcinoma
Angelo Sidoni
Department of Experimental
Medicine, Section of Pathologic Anatomy
and Histology, Medical School,
University of Perugia, Perugia, Italy
Synonyms
Adenosquamous carcinoma; Infiltrative syringomatous
adenoma; Syringomatous squamous tumor
Definition
Low-grade adenosquamous carcinoma (LGASC)
of the breast is exceedingly uncommon, and it is
characterized by well-developed gland formation
mixed with solid nests of squamous cells in a
spindle cell background.
Clinical Features
• Incidence
LGASC belongs to the family of “metaplastic
breast cancers,” (▶ Invasive Metaplastic Car-
cinoma) representing 0.2 to 5% of all breast
257
carcinomas. Such a variability of incidence is
due to a plethora of terminologies used by
different authors to designate these tumors.
Consequently, it is not surprising that there
are series of metaplastic carcinomas that do
not even report a single case of LGASC,
while other authors estimate their incidence
around 0.58% of the total of invasive breast
cancers. The real prevalence of this histotype is
probably underestimated due to the diagnostic
difficulties in recognizing it correctly. In any
case this entity has to be considered exception-
ally uncommon and no more than 130 cases
have been published in English literature
until now.
• Age
In the original series of Rosen and Ernsberger
(1987) the age of patients affected by LGASC
ranged from 42 to 76 years with a mean age of
59. In later studies the extent of age range was
19–88 years, with prevalence in the peri-
meopausal or postmenopausal age.
• Sex L
Female. No cases of LGASC in males have
been reported so far.
• Site
LGASC may appear in any part of the breast
parenchyma not infrequently in peria-
reolar location. The most frequent clin-
ical presentation is a palpable mass followed
by mammographic abnormalities or nipple dis-
charge. Due to the frequent association with
other lesions imaging studies can be inconclu-
sive or confounding.
• Treatment
Because of the paucity of reported cases, there
is no consensus on the optimal treatment of
LGASC. On the other hand, when compared
with the majority of metaplastic carcinomas,
which are also triple negative but highly
aggressive and chemoresistant, LGASC por-
tends an indolent course with a low metastatic
potential and thus a complete local excision or
mastectomy to achieve clear margins appear
appropriate.
Lymph node metastases are exceedingly
rare and routine sentinel node biopsy and axil-
lary dissection may not be necessary. There is
258 Low-Grade Adenosquamous Carcinoma

no unequivocal evidence of the usefulness of
both adjuvant radiotherapy and chemotherapy.
• Outcome
Unlike the aggressive tumor behavior and poor
clinical outcomes seen in other forms of meta-
plastic mammary carcinomas, the majority of
LGASC have been described to have an excel-
lent prognosis with greater predilection
towards local recurrence, even multiple,
which can occur within 2–3 years especially
in patients with excisional biopsy alone. Usu-
ally all patients with recurrences remain dis-
ease free after definitive re-excision. The only
particularly aggressive examples reported in
the literature are: one lethal case due to a recur-
rent tumor infiltrating the chest wall; one
patient with pulmonary metastasis and one
with a single lymph node metastasis.
H&E). Epithelial islands are irregularly distrib-
uted into an abundant collagenous and lamellar
stroma rich in plump spindle cells, which subtly
merge with epithelial cells (Fig. 3 H&E). Some-
times tubular structures appear to radiate from a
fibrosclerotic center similarly to a radial scar
(▶ Radial Scar). Within glands, varying degrees
of squamous differentiation are observed
(syringoid appearance), from focal not
keratinizing lining of glandular lumens to sizable
squamous pearls (Fig. 4 H&E). An attenuated
outer myoepithelial layer around glands and
cords can be seen (see below). Cytological atypia

Macroscopy

The macroscopic aspect of LGASCs can be

masked by the coexistence of other breast lesions
(see below); they tend to be firm, yellow-tan,
stellate or poorly circumscribed infiltrating
masses. The reported size varies from 0.5 to
8.0 cm (average about 2 cm). It must be Low-Grade Adenosquamous Carcinoma, Fig. 1 Low-
grade adenosquamous carcinoma. Ill-defined lesion
highlighted that both the macroscopic aspect (bottom) permeating the surrounding breast parenchyma
and the size of the LGASCs are quite different which contain an abundand lymphocytic infiltrate (top)
from the typical high-grade metaplastic breast (H&E)
carcinomas that usually are nodular masses, with
well circumscribed borders and a mean size of
3.9 cm. Three cases of LGASC reported in litera-
ture were bilateral (Senger et al. 2015).

Microscopy

At a low-power view LGASC shows infiltrative

borders with an intimate blend with adjacent
benign ducts and lobules; a brisk peripheral multi-
focal lymphocytic infiltration is typically present
(Fig. 1 H&E). At higher magnification the ep-
ithelial component consist of bland-looking
Low-Grade Adenosquamous Carcinoma, Fig. 2 Low-
glands and tubules with angulated edges, com-
grade adenosquamous carcinoma. Typical syringoid aspect
pressed cell clusters and cords often assuming with “tadpole” and “comma” shaped epithelial elements in
a “comma” or “tad pole” configuration (Fig. 2 a collagenized stroma (H&E)
Low-Grade Adenosquamous Carcinoma
Low-Grade Adenosquamous Carcinoma, Fig. 3 Low-
grade adenosquamous carcinoma. Fibrous stroma
containing numerous spindle cell elements disposed in a
lamellar pattern blending with epithelial component
(H&E)
Low-Grade Adenosquamous Carcinoma, Fig. 4 Low-
grade adenosquamous carcinoma. A solid focus of squa-
mous differentiation (H&E)
is mild with scant mitotic activity and absence of
necrosis; however, areas of transition from
LGASC to a high-grade metaplastic carcinoma
have been described. An in situ component may
be present, often with apocrine features. An
intriguing characteristic of LGASCs so far
described is the frequent association with other
breast lesions such as papillomas (▶ Intraductal
Papilloma), fibroadenomas (▶ Fibroadenoma),
various types of intraductal epithelial prolifera-
tions, in situ and invasive carcinomas, phyllodes
tumors (▶ Phyllodes Tumor) and fibrosclerosing
lesions. Not surprisingly, in these clinical
259
Low-Grade Adenosquamous Carcinoma, Fig. 5 Low-
grade adenosquamous carcinoma. Peripheral staining for
the myoepithelial marker p63 in the glandular elements and
in the compressed epithelial cords (H&E)
scenarios, LGASC may be an incidental finding
on histological examination of excisional biopsy
or mastectomy specimens.
Immunophenotype L
Immunohistochemically most of the LGASCs
are triple-negative (absence of Estrogen re-
ceptors, Progesterone receptors and HER2) with
a frequently associated positivity for cytokeratin
(CK) 5/6 and/or CK 14 and for epidermal growth
factor receptor (EGFR) which confirm a basal like
phenotype (Geyer et al. 2010).
Gland-like structures of LGASCs demonstrated
variable staining for both low and high molecular
weight cytokeratins (Kawaguchi and Shin 2012)
and for myoepithelial markers (p63, smooth muscle
myosin, smooth muscle actin, CD10, calponin)
confirming the presence of a peripheral
myoepithelial component, already visible in routine
staining (Fig. 5 p63 nuclear staining). The positiv-
ity of p63 in both myoepithelial and tumoral squa-
mous cells is expected; however, a higher intensity
of immunoreactivity can be observed in the former.
Variable degrees and distribution patterns
of myoepithelial markers are identifiable also
in stromal cells (Fig. 6 p63 nuclear staining)
which, moreover, can be focally positive for some
cytokeratins (Kawaguchi and Shin 2012; Geyer et al.
2010).
260
Low-Grade Adenosquamous Carcinoma, Fig. 6 Low-
grade adenosquamous carcinoma. Stromal spindle cells
showing focal positivity for p63
Molecular Features
Reports on molecular features of LGASC are scarce
and fragmentary, because of the rarity of this entity.
At present the most relevant data show complex
genetic and genomic profiles that vary from case to
case but with convincing evidence on molecular
similarities between epithelial and stromal cells,
suggesting that the latter originate from the former
through an epithelial-mesenchymal transition
mechanism (Geyer et al. 2010), as already shown
in other more aggressive metaplastic carcinomas.
Of some interest are also recent demonstrations of
genetic aberrations (in particular PI3K pathway
genes) shared by various sclerosing lesions
(▶ Radial Scar, ▶ Complex Sclerosing Lesion and
infiltrating epitheliosis (▶ Usual Ductal Hyperpla-
sia (UDH)) suggesting that these lesions may be
neoplastic rather than hyperplastic and that, all
together, are part of the spectrum of a single pathol-
ogy including also the LGASCs.
Differential Diagnosis
The distinction of a LGASC from other forms
of metaplastic carcinoma (▶ Invasive Metaplas-
tic Carcinoma) is an easy task due to its benign-
mimiking histology and absence of heterologous
elements. On the contrary differential diagnosis
with other lesions similarly constituted by
Low-Grade Adenosquamous Carcinoma
distorted epithelial-glandular islands immersed
in a desmoplastic stroma can be very difficult,
if not impossible. Entities falling within the mor-
phological spectrum of LGASC are
syringomatous tumor of the nipple
(▶ Syringomatous Tumor of the Nipple), scle-
rosing adenosis (▶ Sclerosing Adenosis), radial
scar/complex sclerosing lesions (▶ Radial Scar,
▶ Complex Sclerosing Lesion), infiltrating
epitheliosis (▶ Usual Ductal Hyperplasia
(UDH)), and tubular carcinoma (▶ Tubular
Carcinoma).
Histological appearance of syringomatous
tumor of the nipple is virtually indistin-
guishable from LGASC, the main difference
being its location: syringomatous tumor arises
in the nipple–areolar complex, whereas
LGAC occurs within breast parenchyma. There-
fore, if a LGASC involves the nipple diagnostic
difficulties become insurmountable. On the
other hand LGASC and syringomatous tumor
of the nipple are both locally aggressive lesions
with a propensity for local recurrence sharing
morphological and molecular features and prob-
ably they represent identical lesions arising in
different anatomical locations (Boecker
et al. 2014).
Benign fibrosclerosing lesions and the
histologically-related infiltrating epitheliosis of-
ten show an adenosquamous component and
therefore form a continuous morphological spec-
trum with LGASC, the latter typically being
more extensive and without lobular configuration.
Clinicopathological correlation and careful scru-
tiny of histologic features along with accurate
evaluation of immunohistochemical markers for
myoepithelial cells can assist in correct diagnosis.
The glandular structures of tubular carcinoma
are mostly angulated with open lumina and are
composed of single cell population (without
myoepithelial cells) opposed to LGASC and
syringomatous tumor, which have a variable
amount of squamous metaplasia and typical
“comma” or “tad pole” shapes.
In view of the abovementioned diagnostic
difficulties, it is strongly advisable to make a
definitive diagnosis only on complete excision
biopsies and not on limited material such as
Low-Grade Adenosquamous Carcinoma
needle aspirates, core biopsy specimens, or frozen
sections.
References and Further Reading
Boecker, W., Stenman, G., Loening, T., Andersson, M. K.,
Sinn, H. P., Barth, P., Oberhellmann, F.,
Bos, I., Berg, T., Marusic, Z., Samoilova, V., &
Buchwalow, I. (2014). Differentiation and histogenesis
of syringomatous tumour of the nipple and low-grade
adenosquamous carcinoma: Evidence for a common
origin. Histopathology, 65, 9–23.
Geyer, F. C., Lambros, M. B. K., Natrajan, R., Mehta, R.,
Mackay, A., Savage, K., Parry, S., Ashworth, A.,
261
Badve, S., & Reis-Filho, J. S. (2010). Genomic and
immunohistochemical analysis of adenosquamous car-
cinoma of the breast. Modern Pathology, 23, 951–960.
Kawaguchi, K., & Shin, S. J. (2012). Immuno-
histochemical staining characteristics of low-grade
adenosquamous carcinoma of the breast. American
Journal of Surgical Pathology, 36, 1009–1020.
Rosen, P. P., & Ernsberger, D. (1987). Low-grade
adenosquamous carcinoma: A variant of metaplastic
mammary carcinoma. American Journal of Surgical
Pathology, 11, 351–358.
Senger, J. L., Meiers, P., & Kanthan, R. (2015). Bilateral
synchronous low-grade adenosquamous carcinoma of
the breast: A case report with review of current litera-
ture. International Journal of Surgery Case Reports,
14, 53–57.
L
M
Male Breast Cancer
Valerie Speirs1, Matthew P. Humphries1 and
Abeer M. Shaaban2
1
Leeds Institute of Cancer and Pathology,
University of Leeds, Leeds, UK
2
Department of Cellular Pathology,
Queen Elizabeth Hospital Birmingham and
University of Birmingham, Birmingham, UK
Synonyms
MBC
Definition
Male breast cancer (MBC)
Clinical Features
• Incidence
Breast cancer in men is rare and accounts for
1% of all breast cancer diagnoses. In the UK,
some 350 men are diagnosed annually with
around 2470 in the USA. Data from cancer
registries in the UK and USA suggests that
the numbers of men receiving a breast cancer
diagnosis has been rising gradually since the
1970s.
© Springer Nature Switzerland AG 2020
A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
• Age
Typically over 60, although all ages can be
affected
• Sex
Breast cancer is found predominantly in
women, but it can also affect men. Breast can-
cer in men is around 100 times less common
than it is in women.
• Site
Breast tissue in men is typically situated
directly behind the nipple.
• Clinical presentation
A unilateral, firm, painless, or minimally tender
mass behind or adjacent to nipple or in axilla;
changes in appearance of the nipple, e.g., inver-
sion; and nipple discharge or bleeding. Because
breast cancer is perceived by the majority of
general public as a gender-specific condition,
men often postpone presenting to doctors with
symptoms, which can result in delays in diag-
nosis. The diagnostic pathway for MBC is sim-
ilar to that used in women where breast cancer is
suspected. While screening mammography is
not recommended, due to small amounts of
breast tissue in men, paradoxically this makes
palpation of a suspicious lesion easier. Diagno-
sis is based on physical examination and biopsy.
Sentinel lymph node biopsy is also used to
identify positive nodes (▶ Sentinel Node).
• Treatment
The absence of gender-specific trials for breast
cancer means that men are treated in exactly
264
the same way as women. Usually this is mas-
tectomy followed by chemotherapy and radio-
therapy. Some men opt for breast-conserving
surgery, if appropriate, because of reduced
morbidity and a better cosmetic outcome. As
most MBCs express estrogen receptor (ER),
they are suitable for treatment with endocrine
therapy, predominantly adjuvant tamoxifen.
Data from clinical trials such as ATAC, in
which the efficacies of aromatase inhibitors
(AIs) were compared to tamoxifen, have revo-
lutionized the treatment of ER positive breast
cancer in postmenopausal women, such that
AIs are now considered standard therapy.
Despite the fact that aromatase is expressed
in MBC, initial case series have shown nega-
tive or equivocal results meaning the efficacy
of aromatase inhibition in men has been
questioned. Because of the increase in testos-
terone seen after aromatase inhibition, this may
overcome the effect of AI blockade, by
saturating the enzyme pathway with substrate,
resulting in only a modest suppression of estro-
gen. Hence LHRH agonists are required to
reduce excessive substrate and maximize the
effect of aromatase inhibition. As a result, AIs
are generally contraindicated in MBC, unless
used with medical or surgical orchiectomy.
• Outcome
About 80 men will die of breast cancer in the
UK each year. In the USA, this is around 460.
Male Breast Cancer, Fig. 1 (a) A mastectomy specimen
with orientation sutures. It includes fibrofatty breast tissue
with an overlying nipple bearing ellipse of the skin. The
Male Breast Cancer
Survival rates for MBC are generally assumed
to be lower than female breast cancer, probably
as a result of presentation at a more advanced
stage than in women. However, in general, stud-
ies in which male and female breast cancer are
matched for key prognostic factors (size, grade,
and lymph node status) have refuted this, with
outcome almost identical between genders.
Macroscopy
Most specimens are mastectomies (Fig. 1a) with
either sentinel node biopsy or axillary node clear-
ance according to the presurgical nodal assess-
ment results. The macroscopic tumors are often
large, with frequent skin and nipple involvement
(Fig. 1b). Similar to the female type, the tumor
may appear circumscribed and infiltrative or show
cystic changes.
Microscopy
The main histological types and their frequency
in MBC are shown in Table 1. Of these, the
commonest type of MBC is invasive carcinoma
of no special type (NST) (▶ Invasive Carcinoma
NST) of grade 2 differentiation (Fig. 2). The
tumors comprise nests and trabeculae of malig-
nant cells within fibrous stroma. Invasive lobular
surgical margin is painted. (b) Slicing of the posterior
surface shows a well-defined, grayish-white hemorrhagic
tumor. The tumor is clear of surgical margins
Male Breast Cancer 265

Male Breast Cancer, Table 1 Main histological sub- reported from the EORTC10085, TBCRC, BIG,
types observed in MBC and their relative frequencies and NABCG International Male Breast Cancer
Histology % Frequency Program and other smaller studies from single
NST 85 centers. This is illustrated in Table 2. As with
Lobular 1–2 female breast cancer, ERa and PR are used to
Papillary 3–5 guide treatment and prognosis in MBC (▶ Hor-
Mucinous 1 mone Receptors in Breast Cancer). Other bio-
Medullary 0.5 markers that have been examined in MBC
Cribriform 0.5–1
using immunohistochemistry include AR,
Tubular 0.5
ERb1, ERb2, ERb5, Bcl-2, p53, E-cadherin,
Mixed 5
Ki67, survivin (both in the nucleus and cyto-
Data was obtained from several published articles, includ-
plasm), prolactin, and FOXA1. While these
ing the Veterans Affairs (VA) Central Cancer Registry and
Shaaban et al. (2012) biomarkers are not unique to MBC, some of
them, e.g., AR, is frequently expressed at
relativity high levels in men. Although AR is
currently not used for routine diagnostics
or management in MBC, its relative abundance
suggests that this could be used as a therapeutic
target for antiandrogen therapies. Examples
of ERa, PR, and AR expression in MBC are
shown in Fig. 3.
Although ERa expression is higher in
MBC than in female breast cancer (typically in
approximately 80% of MBCs vs. 60–70% of
female breast cancers), it has been proposed that
M
not all ERa-positive MBCs behave in the same
way as their female counterparts. This is founded
Male Breast Cancer, Fig. 2 (H&E) image of the most through observations of different grouping of hor-
frequent type of MBC, invasive carcinoma NST
mone receptor patterns when applying hierarchical
clustering. In female breast cancers, PR and ERa
carcinoma is extremely rare and so is lobular clustered together, while in MBC, ERa clustered
carcinoma in situ. Compared with female breast together with ERb and AR, with PR clustering
cancer, incidence of papillary carcinoma (both independently (Shaaban et al. 2012). Further clus-
intraductal and invasive) and mucinous ter analysis in MBC showed significant correlation
carcinoma is higher in the male breast (Shaaban of ERa, AR, and FOXA1 (Humphries et al. 2017).
et al. 2012). Ductal carcinoma in situ (DCIS; A number of cell cycle proteins have also been
▶ Ductal Carcinoma In Situ) is reported in examined in MBC. Enhanced proliferation seems
5–15% of cases. Reporting of MBC and cancer to be associated with poorer outcome in MBC,
datasets is the same as for female breast cancer. exemplified analysis of proliferation by mitotic
count, and the expression of cyclins -A, -B, and
D1 biomarkers.
Immunophenotype

A meta-analysis of 1986 cases, designed to iden- Molecular Features

tify common features of MBC, showed that
MBC is typically ERa- and PR-positive, with MBC is identical to female breast cancer
HER2 expression infrequent (Humphries et al. histologically; however data from molecular
2017). This is in line with preliminary results profiling studies using a variety of platforms is
266 Male Breast Cancer

Male Breast Cancer, Table 2 Overview of the clinico- group reported differential driver genes in MBC
pathological features of MBC in 16 published studies versus female breast cancer. Somatic genetic
examining a total of 1986 cases from 1996 to 2017
alterations typically seen in ERa-positive/HER2-
Feature Number (%) negative female breast cancers (the most common
Histology phenotype seen in MBC), e.g., PIK3CA and TP53
NST 1615 (84) mutations and 16q loss, were much less frequent in
Lobular 19 (1)
subtype-matched MBC, suggesting that MBC is
Other 239 (12)
driven by different somatic changes (Piscuoglio
N/A 60 (3)
et al. 2016). In a number of smaller studies,
Grade
gender-specific differentially expressed genes,
1 239 (13)
2 872 (48)
including those involved in translation, cell migra-
3 597 (33) tion/motility, immune response, membrane trans-
N/A 115 (6) port, apoptosis, and energy metabolism, have been
Node reported, adding weight to the hypothesis that male
+ 734 (42) and female breast cancers are biologically distinct.
742 (42) Promoter hypermethylation has been reported
N/A 275 (16) in MBC with methylation of a number of
ERa genes that are known to act as tumor suppressors.
+ 1584 (86) Accumulation of methylated genes and an overall
193 (10) high methylation pattern were correlated with a
N/A 74 (4) more aggressive phenotype and poorer survival.
PR Interestingly, RASSF1A, a well-characterized
+ 1321 (72) tumor suppressor gene, was significantly more
436 (24) frequently methylated in MBC than female breast
N/A 84 (5)
cancer, providing further evidence of likely bio-
HER2
logical differences between genders.
+ 160 (9)
Expression of microRNAs (miRs), small non-
1319 (77)
coding RNAs that alter gene expression at the
N/A 241 (14)
posttranscriptional level, has been examined in
Data adapted from Humphries et al. 2017, where details on
specific studies can be found MBC. Differential expression of several miRNAs
N/A not available has been reported between gynecomastia and
MBC and also between MBC and female breast
cancer. Despite these observational reports, the
starting to suggest there may be underlying role of miRs in MBC, and if this may contrast
gender-specific biological differences in their from female breast cancer, has not been studied
genomic landscapes, both genetically and fully.
epigenetically. Germline mutations of BRCA2 and, to a
As reported above, in general, the main histo- lesser extent, BRCA1 are associated with
logical subtype observed in MBC is invasive car- increased risk of men developing breast cancer
cinoma NST with the most common phenotype (approximately 5–10% and 1–5%, respectively).
ER- and/or PR-positive; HER2-negative, which A genome-wide association study of MBC
falls into the luminal A-like subgroup. However, identified a SNP in RAD51B which was associ-
one of the first gene profiling studies to compare ated with MBC susceptibility, but there is
male and female breast cancer showed two unique evidence that common variants associated
subgroups of MBC, termed luminal M1 and lumi- with female breast cancer may also impact
nal M2 (Johansson et al. 2012). These differed from MBC risk (Orr et al. 2012). More recent genotyping
the conventional molecular classifications observed of 1802 male carriers of BRCA1/2 mutations
in female breast cancer. Consequently, the same showed that weighted polygenic risk scores based
Male Breast Cancer
Male Breast Cancer, Fig. 3 Immunohistochemical examples of hormone receptors which are commonly expressed in
MBC. ERa (a), PR (b), and AR (c) are frequently expressed
on 88 female breast cancer susceptibility variants
were similarly associated with breast cancer risk in
men (Lecarpentier et al. 2017). A large ongoing
study into the causes of MBC has identified several
genetic variations associated with risk of develop-
ing the disease. These genetic variations appear to
have a different effect on risk between genders,
lending further support to the idea that the biology
of breast cancer is diverse in men and women.
Differential Diagnosis
The most important differentials are gynecomas-
tia, a benign enlargement of the male breast
(▶ Gynecomastia) and metastases to the breast,
such as metastatic prostatic carcinoma, mela-
noma, etc. Gynecomastia may present with florid
hyperplasia of the mammary ducts which can
mimic in situ carcinoma particularly on small
biopsy or in cytological preparations. Attention
267
M
to the architectural features of hyperplasia, admix-
ture of luminal and basaloid cells, and the absence
of significant atypia support a benign diagnosis.
Basal cytokeratins such as CK5 and CK14 show a
three-layered ductal epithelium in gynecomastia
(Kornegoor et al. 2012) and negative staining in
DCIS. Metastases to the breast should be identi-
fied by clinical correlation, unusual histological
features, and a suitable panel of immunohisto-
chemical biomarkers.
References and Further Reading
Humphries, M. P., Sundara Rajan, S., Honarpisheh, H.,
Cserni, G., Dent, J., Fulford, L., Jordan, L. B.,
Jones, J. L., Kanthan, R., Litwiniuk, M., et al. (2017).
Characterisation of male breast cancer: A descriptive
biomarker study from a large patient series. Scientific
Reports, 7, 45293.
Johansson, I., Nilsson, C., Berglund, P., Lauss, M.,
Ringner, M., Olsson, H., Luts, L., Sim, E.,
Thorstensson, S., Fjallskog, M. L., et al. (2012).
268
Gene expression profiling of primary male breast can-
cers reveals two unique subgroups and identifies
N-acetyltransferase-1 (NAT1) as a novel prognostic
biomarker. Breast Cancer Research, 14, R31.
Kornegoor, R., Verschuur-Maes, A. H., Buerger, H., & van
Diest, P. J. (2012). The 3-layered ductal epithelium in
gynecomastia. The American Journal of Surgical
Pathology, 36, 762–768.
Lecarpentier, J., Silvestri, V., Kuchenbaecker, K. B.,
Barrowdale, D., Dennis, J., McGuffog, L., Soucy, P.,
Leslie, G., Rizzolo, P., Navazio, A. S., et al. (2017).
Prediction of breast and prostate cancer risks in male
BRCA1 and BRCA2 mutation carriers using polygenic
risk scores. Journal of Clinical Oncology, 35,
2240–2250.
Orr, N., Lemnrau, A., Cooke, R., Fletcher, O., Tomczyk, K.,
Jones, M., Johnson, N., Lord, C. J., Mitsopoulos, C.,
Zvelebil, M., et al. (2012). Genome-wide association
study identifies a common variant in RAD51B associ-
ated with male breast cancer risk. Nature Genetics, 44,
1182–1184.
Piscuoglio, S., Ng, C. K., Murray, M. P., Guerini-Rocco, E.,
Martelotto, L. G., Geyer, F. C., Bidard, F. C., Berman, S.,
Fusco, N., Sakr, R. A., et al. (2016). The genomic
landscape of male breast cancers. Clinical Cancer
Research, 22, 4045–4056.
Shaaban, A. M., Ball, G. R., Brannan, R. A., Cserni, G.,
Di Benedetto, A., Dent, J., Fulford, L., Honarpisheh, H.,
Jordan, L., Jones, J. L., et al. (2012). A comparative
biomarker study of 514 matched cases of male and
female breast cancer reveals gender-specific biological
differences. Breast Cancer Research and Treatment,
133, 949–958.
Malignant
Adenomyoepithelioma
(M-AME)
Malcolm Hayes
Pathology Department, BC Cancer Agency,
University of British Columbia, Vancouver, BC,
Canada
Synonyms
Adenomyoepithelial carcinoma; Adenomyoe-
pithelioma with malignant transformation; Carci-
noma ex-adenomyoepithelioma; Carcinoma ex-
pleomorphic adenoma; Epithelial-myoepithelial
carcinoma
Malignant Adenomyoepithelioma (M-AME)
Definition
M-AME is a malignant neoplasm of the breast that
is arising within or intimately associated with a
clinically and/or histologically definable benign
adenomyoepithelioma or is a malignant neoplasm
showing concurrent epithelial and myoepithelial
differentiation. The entity of histologically benign
or borderline/atypical AME associated with
metastases (Nadelman et al. 2006) is not included
in this definition.
Classification of M-AME
– Epithelial-myoepithelial carcinoma (EMEC)
– AME containing in situ carcinoma
– AME associated with invasive carcinoma
(carcinoma ex-AME):
• Breast carcinoma of no special type (NST)
• Invasive lobular carcinoma
• Carcinoma of special types
Squamous or adenosquamous
Spindle cell
Carcinosarcoma
Metaplastic matrix producing
Myoepithelial carcinoma
Clinical Features
• Incidence
M-AME is a rare breast neoplasm confined to
individual case reports and small case series
(Ali and Hayes 2012). However, since the
malignant component often dominates within
the tumor and recognition of an associated
“benign” AME is a prerequisite for the diag-
nosis in most cases, it is likely that the entity is
under-recognized by pathologists. The EMEC
variant is often misclassified as a metaplastic
carcinoma.
• Age
M-AME is typically a neoplasm of postmeno-
pausal women aged > 60 years. In the series of
30 patients of M-AME at the British Columbia
Malignant Adenomyoepithelioma (M-AME)
Cancer Agency, the mean age is 70.6 years,
and the range is 42–96 years with only
2 patients aged <50 years.
• Sex
The reported cases in the literature have been
females, and no males are recorded in the
30 cases in our database. However, since
there are rare case reports of benign AME in
males, M-AME is most likely not confined to
females.
• Site
No specific site in the breast
• Treatment
Surgical excision of the primary tumor mass is
the mainstay of treatment. Since axillary lymph
node involvement is rare, axillary node dissec-
tion is contraindicated in the absence of
involved nodes on clinical or imaging studies,
but sentinel node biopsy is appropriate.
Regional radiation may be helpful and is used
empirically by most oncologists. The value of
standard chemotherapy is unknown with few
positive responses reported, but most cases are
treated as for triple negative breast cancer of
usual or metaplastic type. In the case of NST
carcinomas arising from AME, the manage-
ment should be appropriate to the breast bio-
marker status of the malignant component.
A recent case report describes the response of
M-AME to eribulin (Lee et al. 2015).
• Outcome
There is little data available on the outcome of
M-AME with invasive carcinoma due to the
rarity of the tumor, its occurrence in the older
age group where life span is already limited,
and poor follow-up in the small series of
cases reported to date. There is some
evidence that M-AME with components of
squamous or spindle cell metaplastic carci-
noma do better than those with components
of carcinosarcoma or metaplastic matrix-
producing carcinoma. In our records, 5 of
23 patients with M-AME and follow-up data
died of disease at 3, 24, 31, 36, and 54 months.
Three patients died of unknown cause at
36, 44, and 132 months. One patient is alive
with pulmonary and nodal metastases after
269
26 months, and two are alive and well after
two local recurrences. Eleven patients are alive
and one is dead with no evidence of disease
ranging from 6 to 130 months with a mean
follow-up of 50 months.
• Clinical Presentation
Most cases present as a palpable mass. Some
patients with M-AME report a long-standing
stable mass followed by a period of accelerated
growth. A few cases present on screening
mammography as mass lesions.
Macroscopy
M-AME with ductal carcinoma in situ
(DCIS) typically presents as a multilobu-
lated circumscribed mass similar to that of
benign AME.
The mass is often reported to be firm, rubbery,
and yellow-white in color. A few cases show
cystic change and necrosis. M-AME with an inva-
sive carcinoma presents as an irregular infiltrative
mass. The size ranges from 1.4 to 14 cm in
greatest dimension. Recognition of a pre-existing M
or associated low-grade or “benign” AME is key
to the diagnosis of carcinoma ex-AME. This
requires thorough sampling of the gross specimen
to include any focal mass lesions within the con-
fines of the main tumor. The precursor lesion is
typically nodular but may be papillary in nature.
Many cases of EMEC are also associated with a
low-grade benign AME.
Microscopy
Malignant AME of biphasic epithelial-
myoepithelial carcinoma (EMEC) type may
arise de novo without a precursor low-grade AME
(Petrozza et al. 2013), but some cases appear to
represent high-grade dual-lineage transformation
of a low-grade precursor lesion. The tumors are
typically large and have a mixture of partially
circumscribed nodules and diffuse areas of growth
with infiltrative borders. Glandular and papillary
structures exhibiting a disorganized architecture
270
Malignant Adenomyoepithelioma (M-AME), Fig. 1 (H&E) (a) EMEC showing lobulated architecture, (b, c)
disorganized ductal and myoepithelial elements, and (d) hyaline matrix material
are present, but the degree of cytological atypia
varies from case to case and in different areas of
the same tumor (Fig. 1). Often, in some foci, the
tumor retains a partially organized relationship
between the luminal cells lining the tubules and
papillary structures and the layers of underlying
malignant myoepithelial cells (MECs) (Fig. 2).
Recognition of these poorly organized dual-lineage
foci is key to differentiating this neoplasm from the
more common breast metaplastic carcinoma of car-
cinosarcoma or matrix-producing type (Yoon and
Chitale 2013). It is these areas that should be care-
fully scrutinized using immunohistochemistry in
order to confirm the dual lineage of the cells for
diagnostic purposes. The MEC component of
EMEC is typically plump spindle cells that encircle
the epithelial structures and extend as infiltrative
sheets and strands into the surrounding native
breast stroma (Fig. 3). Again, the morphology of
this component of the tumor is exceedingly vari-
able between different cases and even within the
same tumor. Areas with a bland spindle cell mor-
phology often associated with production of hya-
line collagenous matrix are seen. Elsewhere the
cells may exhibit marked cytological atypia,
numerous mitoses, matrix production, and
Malignant Adenomyoepithelioma (M-AME)
necrosis. Commonly, the malignant spindle cell
component of the tumor outgrows the epithelial
component in many areas of the tumor. Metastatic
EMEC may retain its dual phenotype in both nodal
and pulmonary metastases (Fig. 4).
It is likely that the entity of “borderline” or
“atypical” AME represents the precursor lesion
to this group of tumors. Borderline AME has the
morphological appearance of benign AME but
with superimposed cytological atypia and an
increased proliferative rate. Its non-infiltrative
growth pattern and generally benign clinical
behavior suggest that these “borderline” lesions
are better grouped with the benign AME category
for practical purposes. However, one has to be
aware that even so-called “benign” AME has the
potential to recur locally and even rarely metasta-
size (Nadelman et al. 2006).
The key to the diagnosis of carcinoma ex-AME
is the recognition of the underlying precursor low-
grade or benign AME within the background of the
carcinoma (Fig. 5). The precursor lesion can be
detected grossly or on low-power examination of
the tumor where it appears as a multilobulated
complex mass, sometimes with a papillary compo-
nent. High-power examination will reveal the
Malignant Adenomyoepithelioma (M-AME) 271

Malignant Adenomyoepithelioma (M-AME), Fig. 2 myoepithelial components; (Immunohistochemistry-IHC)

(H&E) (a) EMEC showing disorganized glands; (b, c) (d) CK 5/6 highlights the MEC component
cytological features of malignancy in both luminal and

Malignant Adenomyoepithelioma (M-AME), Fig. 3 (IHC) (a) CK18 and (b) estrogen receptors (ER) label the
epithelial component; (c) CD10 and (d) smooth muscle heavy chain myosin (SMM) label the MEC component

typical combination of luminal cells arranged in exceeding one cell thickness, and nests of cells
ducts and chords surrounded by numerous atypical that have larger nuclei than normal MECs often
MECs. The MEC component forms layers have abundant eosinophilic or clear cytoplasm
272 Malignant Adenomyoepithelioma (M-AME)

Malignant Adenomyoepithelioma (M-AME), Fig. 4 (H&E) (a) Metastases of EMEC to lymph node and (c) to lung
retaining dual lineage. (IHC) (b, d) p63 highlights MECs

Malignant Adenomyoepithelioma (M-AME), Fig. 5 (H&E) (a) Carcinoma ex-AME: low-grade AME component;
(IHC) (b) CK14, (c) p63, and (d) SMM
Malignant Adenomyoepithelioma (M-AME)
Malignant Adenomyoepithelioma (M-AME), Fig. 6 Carcinoma ex-AME. (H&E) (a) Malignant component – disor-
ganized ducts and (b); atypical spindle cells immunostained by (c) p63 and (d) CK14
and show mitotic activity. The cell shape of the
MECs varies from polygonal through to spindled
and often lies within an eosinophilic hyaline col-
lagenous or chondroid matrix. The luminal cells
may show squamous or sebaceous metaplasia.
The spectrum of pathological changes seen in
benign AME has been published in detail else-
where (Ali and Hayes 2012). Many cases of
AME, both benign and malignant, are initially mis-
classified as invasive NST carcinoma or invasive
metaplastic carcinoma especially on core biopsy.
Malignant transformation of the luminal cells may
result in the classical morphology of lobular carci-
noma in situ or low-grade cribriform DCIS with
rounded uniform nuclei evenly spaced and polar-
ized around secondary lumens (Warrier et al. 2013).
Transformation to high-grade DCIS can also occur
within an AME, a diagnosis that is based on the
cytological atypia, mitotic activity, and necrosis
and encompassing the morphological range of
DCIS encountered unassociated with AME.
AMEs harboring such in situ neoplastic prolifera-
tions are probably best regarded as “borderline” or
“atypical” AME rather than frankly malignant.
273
The morphology of the invasive carcinoma
M
ex-AME depends on the type of carcinoma that
evolves (see classification above). The most com-
mon variant is metaplastic carcinoma with spindle
cells and foci of squamous differentiation, which
varies from low-grade through to tumors that have
the morphology of high-grade carcinosarcoma
(Fig. 6). Sometimes the metaplastic carcinoma
produces malignant chondroid tissue or osteoid
and woven bone and may contain osteoclast-like
giant cells (Fig. 7). Rare cases resemble carci-
noma ex pleomorphic adenoma of salivary
gland, which may be considered an entity distinct
from malignant AME.
Ultrastructural Features
Electron microscopy may be helpful in confirming
myoepithelial differentiation within M-AME. The
myoepithelial cells exhibit the presence of both
tonofilaments and myofibrils in their cytoplasm.
Pinocytotic vesicles are also seen. A thick basal
lamina surrounds the cells, and hemidesmosomes
274
Malignant Adenomyoepithelioma (M-AME), Fig. 7 (H&E) (a) AME (b) transforming to EMEC and (c) metaplastic
chondroid and (d) osseous metaplasia in the MEC component
attach the MECs to adjacent cells and to the base-
ment membrane (Trojani et al. 1992).
Immunophenotype
The diagnosis of M-AME is often suspected
based on the morphology of the H&E stained
sections but is greatly supported by the use of
immunohistochemistry (Ali and Hayes 2012).
The aim is to delineate a dual population of
luminal cells and MECs within the lesion. In
theory, this is simpler than in practice because
the staining pattern of both the MECs and the
luminal cells in M-AME may be aberrant.
Classically, the luminal cells stain for low molec-
ular weight keratins such as CK18, CK7, and
CAM5.2, and the MEC component stains with
nuclear markers p63 and p40 and cytoplasmic
markers CD10 and S-100 protein, myogenic
markers (SMM, calponin, and actin), and high
molecular weight keratins CK 34-beta-E12,
CK5/6, and CK14. The expression of these
markers varies from case to case and in different
areas of the same tumor. It is frequent to
Malignant Adenomyoepithelioma (M-AME)
encounter positive staining of the luminal cell
component for high molecular weight keratins,
and occasionally CD10 and SMM, especially
when the cells show squamous metaplasia but
even when they resemble typical luminal epithe-
lial cells on morphology. Similarly, the MECs
can show staining for low molecular weight ker-
atins, but this is usually much weaker than that
seen in the luminal cell component of the lesion.
Often the MECs lose their expected
immunoprofile in an unpredictable pattern.
Thus, some MECs lose the myogenic markers
and other cytoplasmic markers but retain the
nuclear markers, but the reverse pattern also
occurs. The expression of the cytoplasmic
markers is unpredictable and variable. Therefore
a wide range of immunostains may be required in
order to investigate a particular case thoroughly
as sometimes only one of the many markers is
expressed. The immunostain for Ki-67 enables
assessment of the degree of proliferative activity
of M-AME (which typically has an index
of >15%) and indirectly reflects the malignant
potential of the neoplasm (Hungermann et al.
2005). With regard to breast biomarkers, stains
Malignant Adenomyoepithelioma (M-AME)
for ER and progesterone receptors are patchy
positive or completely negative in the luminal
cell compartment in most M-AMEs especially
those with a metaplastic component, but some
cases show strong diffuse staining. These stains
are negative in the myoepithelial or spindle cell
compartment of the neoplasm. Staining for
androgen receptor does not appear to have been
studied in these neoplasms. HER2 is typically
not overexpressed or amplified.
Molecular Features
A few cases of AME have been subject to genetic
and molecular analysis, and no clear pattern
has emerged. A p53 mutation has been identified
in several cases of M-AME (Angèle et al. 2004;
Han et al. 2006) and a balanced t(8;16)(p23;q21)
translocation in a benign AME (Gatalica et al.
2005). A case report of a M-AME associated
with GIST tumors, both exhibiting c-kit mutation
in a patient with NF-1, has also been reported
(Hegyi et al. 2009). Comparative genomic hybrid-
ization (CGH) analysis of benign AME showed
alterations comprising 13 gains and 5 losses
of chromosomal regions in 5 of 7 cases. In
M-AME 14 of 18 cases showed DNA copy num-
ber changes. Changes on chromosome 8 and 17p
were most frequent (Hungermann et al. 2005).
Differential Diagnosis
1. The differential diagnosis of M-AME
of EMEC type is from “benign” or “border-
line” AME (▶ Adenomyoepithelioma). The
“malignant” designation is based on the pres-
ence of marked cytological atypia, presence of
numerous mitoses and corresponding high
Ki-67 index (>15%), presence of necrosis,
and an infiltrative growth pattern.
2. Distinction between M-AME of carcinoma
ex-AME type and metaplastic carcinoma
(▶ Invasive Metaplastic Carcinoma) of the
breast (including poorly differentiated
myoepithelial-rich carcinoma) depends on the
demonstration of a low-grade (benign or
275
borderline) precursor AME intimately associ-
ated with the high-grade malignant epithelial
or myoepithelial component of the neoplasm.
This depends on the history suggesting a pre-
existing stable mass followed by a phase of
accelerated growth, a careful gross examina-
tion to search for such a precursor lesion,
and/or a thorough sampling of the tumor.
3. Distinction from malignant myoepithelioma
(▶ Myoepithelial Carcinoma of the Breast)
depends on the demonstration of both luminal
and MEC components in M-AME, whereas
luminal components are not seen in pure
malignant myoepithelioma.
References and Further Reading
Ali, R. H., & Hayes, M. M. (2012). Combined epithelial-
myoepithelial lesions of the breast. Surgical Pathology
Clinics, 5(3), 661–699.
Angèle, S., Jones, C., Reis Filho, J. S., Fulford, L. G.,
Treilleux, I., Lakhani, S. R., & Hall, J. (2004).
Expression of ATM, p53, and the MRE11-Rad50-
NBS1 complex in myoepithelial cells from benign
and malignant proliferations of the breast. Journal of M
Clinical Pathology, 57(11), 1179–1184.
Gatalica, Z., Velagaleti, G., Kuivaniemi, H., Tromp, G.,
Palazzo, J., Graves, K. M., Guigneaux, M., Wood, T.,
Sinha, M., & Luxon, B. (2005). Gene expression pro-
file of an adenomyoepithelioma of the breast with a
reciprocal translocation involving chromosomes 8 and
16. Cancer Genetics and Cytogenetics, 156(1), 14–22.
Han, B., Mori, I., Nakamura, M., Wang, X., Ozaki, T.,
Nakamura, Y., & Kakudo, K. (2006). Myoepithelial car-
cinoma arising in an adenomyoepithelioma of the breast:
Case report with immunohistochemical and mutational
analysis. Pathology International, 56(4), 211–216.
Hegyi, L., Thway, K., Newton, R., Osin, P., Nerurkar, A.,
Hayes, A. J., & Fisher, C. (2009). Malignant
myoepithelioma arising in adenomyoepithelioma of
the breast and coincident multiple gastrointestinal stro-
mal tumors in a patient with neurofibromatosis
type 1. Journal of Clinical Pathology, 62(7), 653–655.
Hungermann, D., Buerger, H., Oehlschlegel, C., Herbst, H.,
& Boecker, W. (2005). Adenomyoepithelial tumors and
myoepithelial carcinomas of the breast – A spectrum of
monophasic and biphasic tumors dominated by imma-
ture myoepithelial cells. BMC Cancer, 5, 92.
Lee, S., Oh, S. Y., Kim, S.-H., et al. (2015). Malignant
adenomyoepithelioma of the breast and responsive-
ness to eribulin. Journal of Breast Cancer, 18(4),
400–403.
Nadelman, C. M., Leslie, K. O., & Fishbein, M. C. (2006).
“Benign,” metastasizing adenomyoepithelioma of the
276
breast: A report of 2 cases. Archives of Pathology &
Laboratory Medicine, 130(9), 1349–1353.
Petrozza, V., Pasciuti, G., Pacchiarotti, A., et al. (2013).
Breast adenomyoepithelioma: A case report with
malignant proliferation of epithelial and
myoepithelial elements. World Journal of Surgical
Oncology, 11, 285.
Trojani, M., Guiu, M., Trouette, H., De Mascarel, I., &
Cocquet, M. (1992). Malignant adenomyo-
epithelioma of the breast. An immunohistochemical,
cytophotometric, and ultrastructural study of a case
with lung metastases. American Journal of Clinical
Pathology, 98(6), 598–602.
Warrier, S., Hwang, S., Ghaly, M., & Matthews, A. (2013).
Adenomyoepithelioma with ductal carcinoma in situ:
A case report and review of the literature. Case Reports
in Surgery, 2013, 521417.
Yoon, J. Y., & Chitale, D. (2013). Adenomyoepithelioma of
the breast: A brief diagnostic review. Archives
of Pathology & Laboratory Medicine, 137(5), 725–729.
Mammary Myofibroblastoma
Gaetano Magro and Lucia Salvatorelli
Department of Medical and Surgical Sciences and
Advanced Technologies, G.F. Ingrassia, Azienda
Ospedaliero-Universitaria “Policlinico-Vittorio
Emanuele,” Anatomic Pathology Section, School
of Medicine, University of Catania, Catania, Italy
Synonyms
Benign spindle cell tumor; Fibroma; Myogenic
stromal tumor
Definition
Myofibroblastoma (MFB) is a relatively rare benign
stromal tumor of the breast (Wargotz et al. 1987b;
Magro et al. 2001, 2012a; Magro 2016), which
belongs to the family of the “benign spindle cell
tumors of the mammary stroma” (Magro et al.
2001, 2002a). These tumors are closely related
lesions within a continuous morphological spec-
trum, variably composed of cells ranging from spin-
dly fibroblastic-like cells to plump myofibroblasts
(Magro et al. 2001, 2002a). As its name implies,
MFB is composed of cells which show
myofibroblastic differentiation at morphological,
Mammary Myofibroblastoma
immunohistochemical, and ultrastructural level
(Wargotz et al. 1987b; Magro et al. 2001, 2002a,
2016; Magro 2008). Other tumors, such as the
benign fibroblastic spindle cell tumor, the spindle
cell lipoma of the breast, and tumors with hybrid
features, have a fibroblastic profile, with cells
stained with vimentin and CD34 by means of immu-
nohistochemistry (Magro et al. 2001, 2002a).
Although MFB was originally described as a spindle
cell tumor, over time several morphological variants
have been recognized: fibrous/collagenized,
myxoid, epithelioid/deciduoid cell, lipomatous, and
palisaded/Schwannian-like variant (Magro et al.
2000a; Reis-Filho et al. 2001; Simsir et al. 2001;
Magro 2008; Laforga and Escandón 2017).
Clinical Features
• Incidence
MFB of the breast is an uncommon tumor, with
approximately 100 cases reported in the
English literature so far (Magro 2016). In the
last two decades, there has been an increased
incidence likely due to an increased mammo-
graphic screening (Magro 2008).
• Age
This tumor can occur at any age, including
infants and adolescents (Alam et al. 2002;
Soyer et al. 2012; Magro 2016), but is usually
diagnosed in older men and postmenopausal
women (Magro et al. 2012a; Magro 2016).
• Sex
Although most cases of MFB were originally
described in adult men, this tumor occurs with
equal frequency among males and females
(Magro et al. 2012a; Magro 2016). MFB has
no predilection for any particular race and it
usually occurs sporadically, with a few cases
diagnosed in association with gynecomastia
(Yoo et al. 1998; Reis-Filho et al. 2001). Only
rarely this tumor can be bilateral or multi-
centric (Hamele-Bena et al. 1996).
• Clinical Presentation
Clinically MFB presents as a unilateral, slow-
growing, painless, nontender nodule (Magro
2008, 2016). Imaging features are not specific
and MFB is usually confused with
fibroadenoma (Magro 2008, 2016).
Mammary Myofibroblastoma
• Radiographic Findings
Ultrasonography shows a well-circumscribed,
round to oval, homogeneous, slightly hypo-
echoic mass suggestive of fibroadenoma. Sim-
ilarly, mammography reveals a well-
circumscribed dense mass, devoid of calcifica-
tions. Magnetic resonance shows a well-
circumscribed nodular mass with homoge-
neous enhancement and internal septations.
• Treatment
Adequate treatment for MFB is local excision.
Clinical behavior is indolent with no local
recurrence after surgical treatment (Magro
2008, 2016).
Macroscopy
Grossly, MFB presents as a well-circumscribed
round to oval mass, ranging in size from a few
Mammary Myofibroblastoma, Fig. 1 Classic-type
myofibroblastoma. Tumor showing well-circumscribed
borders (a) (H&E), bland-looking spindle cells and
keloid-like collagen fibers (b) (H&E). Neoplastic cells,
277
millimeters to 13 cm, with a smooth, sometimes
lobulated, external surface (Magro 2008, 2016).
The cut surface usually shows a firm lesion,
white to grayish in color. Occasionally, tumor
may have whorled appearance similar to a uter-
ine leiomyoma. Myxoid changes or a
fatty component may be variably present in a
minority of cases. Necrosis and hemorrhage are
absent.
Microscopy
Classic-type MFB is a well-circumscribed but
nonencapsulated, bland-looking spindle cell
tumor which usually does not contain entrapped
mammary ducts/lobules (Fig. 1a; Table 1). Neo-
plastic cells have a myofibroblastic appearance,
with relatively abundant pale to slightly or deeply
arranged in short fascicles interrupted by keloid-like colla-
gen fibers (c) (H&E), are stained with desmin (d), CD34
(e), alpha-smooth muscle actin (f) and estrogen
receptors (g)
278
Mammary Myofibroblastoma, Table 1 Mammary
Myofibroblastoma: morphological, immunohistochemical
and cytogenetic features
Classic-type myofibroblastoma
Histological features
Margins: Well circumscribed; sometimes lobulated;
rarely focally infiltrative
Cells: Bland-looking spindle cells; a few oval to
epithelioid cells
Cytoplasm: Pale to deeply eosinophilic
Nuclei: Round to oval with one or two small nucleoli;
focal mild to moderate atypia; sometimes nuclear
grooves and/or pseudoinclusions
Growth pattern: Short, haphazardly intersecting
fascicles; focal storiform or neural-like patterns
Mitotic count: 0–2 mitoses  10 high power field
Stroma: Fibrous to focally myxoid; thick, keloid-like
collagen fibers among neoplastic cells
Vasculature: Small to medium-sized blood vessels;
often hyalinization and foamy macrophages in their walls
Additional intratumoral tissue components: Often
mature lipomatous and more rarely leiomyomatous,
cartilaginous, osseous tissues
Inflammatory component: Mast cells variably
interspersed among spindle cells
Immunohistochemistry
Positive markers: Vimentin, desmin, CD34 and
estrogen (ER), progesterone/androgen receptors
Variable expression: Alpha-smooth muscle actin,
calponin, CD10, bcl-2, CD99
Negative markers: Cytokeratins, EMA, S-100
protein, ALK-1, beta-catenin, STAT6
Cytogenetics
Cytogenetic analysis: Partial monosomy 13q; less
frequently partial monosomy 16q
FISH analysis: Loss of RB/13q14 and FOX01
(FKHR)/13q14 loci (70% of cases).
eosinophilic cytoplasm with distinct cell borders
and centrally located oval to round nuclei with
small nucleoli. Nuclear grooves or pseudo-
inclusions can be encountered. These cells are
closely arranged in short, haphazardly inter-
secting fascicles interrupted by brightly eosino-
philic keloid-like collagen fibers (Fig. 1b, c).
Rarely amianthoid-like collagen fibers, focal
storiform, and hemangiopericytoma-like and
nuclear palisading patterns can be seen. Mitoses
are rare (2 mitoses per 10 high-power fields).
Necrosis and atypical mitoses are absent. The
vasculature is mainly represented by small- to
Mammary Myofibroblastoma
medium-sized vessels, often with hyalinization
and foamy histiocytes in their walls. Scattered
mast cells can be usually found. Small islands of
adipose tissue and/or focal myxoid stromal
changes can be observed throughout the tumor.
In an otherwise classic-type MFB, the following
unusual morphological features can be encoun-
tered: focally infiltrative margins (Teng and You
2005), high cellularity (Gurzu and Jung 2012),
nuclear pleomorphism (moderate to high grade)
(Hamele-Bena et al. 1996; Lázaro-Santander et al.
1999), multinucleated floret-like cells (Gocht
et al. 1999; Magro et al. 1999), intracytoplasmic
and extracellular hyaline globules (Ozerdem et al.
2015), extensive myxo-edematous stromal
changes (Magro et al. 2014), blood vessels
containing fibrinoid material and foamy histio-
cytes in their walls (Magro et al. 2014), and
heterologous mesenchymal components
(mature lipomatous, leiomyomatous, cartilagi-
nous, osseous tissue) (Fukunaga et al. 1996;
Kobayashi et al. 1996; Fukunaga and Ushigome
1997; Thomas et al. 1997; Mnif et al. 2013).
Several morphological variants on the basic
common theme of the classic-type MFB have
been recognized in the last two decades
(Table 2). “Fibrous/collagenized MFB” is char-
acterized by a diffuse fibro-sclerotic stroma
which can obscure the neoplastic spindle cell
component (Fig. 2) (Simsir et al. 2001). “Myxoid
MFB” is a tumor composed entirely or predom-
inantly of myxoid extracellular matrix
containing both spindle- to stellate-shaped cells
and only a few keloid-like collagen fibers
(Magro et al. 2007a) (Fig. 3). Neoplastic cells
may show mild to moderate nuclear pleomor-
phism (Magro et al. 2007a) (Fig. 3b). The term
“epithelioid cell MFB” is referred to those
tumors composed predominantly (>50% of the
entire tumor) of medium-sized cells with epithe-
lioid morphology (Reis-Filho et al. 2001; Magro
2009, 2012; Magro et al. 2013a). These cells, set
in a variably fibrous to myxoid stroma, often
exhibiting mild to moderate nuclear pleomor-
phism, are arranged in various growth patterns,
including nests, solid sheets, micronodular,
pseudo-alveolar, or trabecular growth patterns
(Reis-Filho et al. 2001; Magro 2009; Magro
Mammary Myofibroblastoma
Mammary Myofibroblastoma, Table 2 Mammary
Myofibroblastoma: morphological variants
Morphological variants of myofibroblastoma
Fibrous/collagenized myofibroblastoma
Hypocellular tumor
Exclusive or predominant fibrous stroma
Blood vessels with degenerative changes: Fibrinoid
material and foamy histiocytes in their walls
Differential diagnosis: Reactive sclerotic nodule;
sclerotic area in fibrocystic changes
Myxoid myofibroblastoma
Hypocellular tumor
Exclusive or predominant myxoid stroma
Spindle- and stellate-shaped cells
Mild to moderate nuclear atypia
Isolated keloid-like collagen fibers within myxoid
stroma
Differential diagnosis: Myxoma; nodular fasciitis
(myxoid variant); low-grade sarcomas with myxoid
stromal changes (myxoid liposarcoma; low-grade
myxofibrosarcoma)
Epithelioid myofibroblastoma
Tumor with prominent (>50% of the entire tumor)
epithelioid cell component
Medium-sized, epithelioid mono- or bi-nucleated cells
with deeply eosinophilic cytoplasm;
Mild to moderate degree of nuclear pleomorphism
fibrous stroma with interspersed keloid-like collagen
fibers
Growth patterns: Single cells, single cell files, nests,
pseudo-alveolar, solid, trabecular, multinodular
Small islands of intratumoral adipocytes
Differential diagnosis: Invasive lobular carcinoma
Deciduoid myofibroblastoma
Tumor with deciduoid cell component (>50% of the
entire tumor)
Large-sized, mono-or multinucleated, deciduoid-like
cells with abundant cytoplasm; more rarely cells with
rhabdoid morphology
Moderate to severe nuclear pleomorphism
Fibrous stroma with interspersed keloid-like collagen
fibers
Growth patterns: Solid-sheets, nests
Differential diagnosis: Invasive pleomorphic lobular
carcinoma; apocrine carcinoma; high-grade metastatic
tumors
Lipomatous myofibroblastoma
Tumor with prominent (>50% of the entire tumor)
fatty component
Admixture of adipocytes and fibrous areas
Nonadipocytic component: Spindle to epithelioid cells
Growth patterns: Finger-like pseudoinfiltrative
(continued)
279
Mammary Myofibroblastoma, Table 2 (continued)
Morphological variants of myofibroblastoma
Keloid-like collagen fibers interspersed in the fibrous
areas
Mild to moderate nuclear atypia
Differential diagnosis: Desmoid-type fibromatosis;
low-grade (fibromatosis-like) spindle cell carcinoma
Palisaded/schwannoma-like myofibroblastoma
Tumor with prominent (>50% of the entire tumor)
nuclear palisading and formation of numerous Verocay-
like bodies
Minor component of classic-type myofibroblastoma
Differential diagnosis: Schwannoma
et al. 2013a) (Fig. 4). In some areas, they can be
arranged in single cells or single cell files,
resulting in a pseudo-infiltrative growth pattern,
closely reminiscent of invasive lobular carci-
noma (▶ Invasive Lobular Carcinoma) (Magro
2009). Keloid-like collagen fibers can encase
some cellular nests with formation of nerve-like
structures (Magro 2016). Rarely epithelioid cells
can adopt a deciduoid-like morphology with
more abundant eosinophilic to amphophilic
cytoplasm and large vesicular nuclei with prom-
M
inent nucleoli (Magro et al. 2008). Due to a close
resemblance to decidua, tumors exclusively/pre-
dominantly composed of such cells have been
labeled as “deciduoid cell MFBs” (Fig. 5)
(Magro et al. 2008). The term “lipomatous
MFB” has been coined for those tumors
containing a prominent (>50% of the entire
tumor) mature fatty component (Magro et al.
2000a). This variant of MFB resembles a fibro-
fatty tumor and is misdiagnosed as fibro-lipoma
or spindle cell lipoma (Magro et al. 2000a;
Magro et al. 2001). It consists of a prominent
mature fatty component in which there are dis-
persed nodular, or more frequently, irregularly
shaped fibrous areas with a finger-like pattern
similar to that seen in desmoid-type fibromatosis
(Magro et al. 2000a; Baxendine-Jones et al.
2001) (Fig. 6). In these fibrous areas, the typical
features of MFB, at least focally, can be recog-
nized: short, haphazardly intersecting fascicles
interrupted by keloid-like collagen fibers
(Fig. 6c). Mild to moderate nuclear pleomor-
phism is usually seen (Magro et al. 2000a).
280 Mammary Myofibroblastoma

Mammary Myofibroblastoma, Fig. 2 (H&E) Fibrous/ and histiocytes in their walls (a). Spindle cells, arranged in
collagenized myofibroblastoma. Low magnification show- distorted fascicles, are seen at higher magnification (b)
ing a fibrous lesion containing blood vessels with fibrin

Mammary Myofibroblastoma, Fig. 3 Myxoid myo- fibers (a) (H&E). Neoplastic cells show focal nuclear atypia
fibroblastoma. Tumor with extensive myxoid stroma (b) (H&E) and are stained with desmin (c)
containing spindle- to stellate-shaped cells and thick collagen
Mammary Myofibroblastoma
Mammary Myofibroblastoma, Fig. 4 (H&E) Epitheli-
oid myofibroblastoma. Tumor is composed predominantly of
epithelioid cells set in a fibrous stroma (a). Higher
“Palisaded/Schwannian-like MFB” is composed of
bland-looking spindle cells with a diffuse nuclear
palisading and formation of numerous Verocay-
like bodies (Magro et al. 2013b; Laforga and
Escandón 2017) (Fig. 7). Keloid-like collagen
fibers, a typical feature of classic-type MFB, are
seen. This tumor is closely reminiscent of
schwannoma and immunohistochemistry is helpful
for a correct diagnosis (absence of S100 protein
along with the expression of myogenic markers).
Immunophenotype
Classic-type MFB and all its morphological vari-
ants show a myofibroblastic profile. The neoplastic
cells are characteristically stained with desmin in
addition to vimentin and CD34 (Magro 2008,
2016). Alpha-smooth muscle actin is also
expressed, but with a more intralesional and
interlesional heterogeneous distribution and, in
281
magnification showing mono- or bi-nucleated cells with
mild to moderate nuclear atypia. Mitoses are absent (b)
M
some cases, can be absent. Accordingly, the major-
ity of mammary MFBs are desmin-positive
myofibroblastic tumors which usually express estro-
gen, progesterone, and androgen receptors (Magro
et al. 2000b, 2012a; Magro 2008, 2016). Calponin,
bcl-2 protein, CD99, and CD10 are also variably
expressed (Magro et al. 2007b; Magro 2016).
H-caldesmon expression can be focally observed
(Magro et al. 2003). Epithelial markers
(cytokeratins, EMA) and S100 protein are negative.
Molecular Features
Cytogenetic studies have showed that MFB is a
tumor with the loss of material from chromosome
13 and less frequently from chromosome
16 (Pauwels et al. 2000). FISH analyses, using
locus specific probes, reveal that about 70–80% of
mammary MFB exhibits the loss of the 13q14
region, which can be shown by the losses of
282
Mammary Myofibroblastoma, Fig. 5 Deciduoid
myofibroblastoma. Tumor is composed of closely packed
large-sized cells closely reminiscent of decidua (a) (H&E).
Higher magnification showing alarming features: large
RB/13q14 and/or FOX1(FKHR)/13q14 loci in
tumor cells (Magro et al. 2012b; Trépant et al.
2014). Interestingly similar results have been
reported in extra-mammary MFB (Maggiani
et al. 2006; Magro et al. 2012b). As spindle cell
lipoma and cellular angiofibroma share with MFB
the same chromosomal alterations (Maggiani
et al. 2007; Flucke et al. 2011), it has been
suggested a genetic link among these three tumors
(Flucke et al. 2011; Magro et al. 2012b).
Differential Diagnosis
The diagnosis of classic-type MFB is relatively
straightforward in surgical specimens if strict
morphological criteria are applied. MFB of the
breast should be suspected when dealing with a
pure spindle cell lesion with pushing borders,
composed of bland-looking spindle cells,
arranged in short, haphazardly intersecting fasci-
cles with interspersed keloid-like collagen fibers
(Magro 2008, 2016). High mitotic count (>3
Mammary Myofibroblastoma
mono- or multinucleated cells with abundant cytoplasm
and large nuclei with evident nucleoli (b) (H&E). Neoplas-
tic cells are diffusely stained with desmin (c)
mitoses  10 high power fields), atypical mitoses,
necrosis, and extensive infiltrative margins are not
features of MFB. The diagnosis is challenging on
core biopsy, but MFB can be suspected if tumor has
pushing borders (imaging information) and the
spindle cells are positive for desmin, CD34,
alpha-smooth muscle actin, estrogen/progesterone
receptors and negative for epithelial markers,
h-caldesmon, beta-catenin, S100 protein, and
STAT6. The differential diagnosis includes all the
bland-looking tumor or tumor-like spindle cell
lesions arising in the breast parenchyma, such as
the fascicular variant of pseudoangiomatous
stromal hyperplasia (▶ Pseudoangiomatous Stro-
mal Hyperplasia), reactive spindle cell nodule,
nodular fasciitis, inflammatory pseudotumor/
inflammatory myofibroblastic tumor (▶ Inflamma-
tory Myofibroblastic Tumor of the Breast),
leiomyoma, solitary fibrous tumor, desmoid-type
fibromatosis, low-grade (fibromatosis-like) spindle
cell carcinoma (▶ Invasive Metaplastic Carci-
noma), and low-grade myofibroblastic sarcoma
(Table 3). Among these lesions, the distinction
Mammary Myofibroblastoma
Mammary Myofibroblastoma, Fig. 6 Lipomatous
myofibroblastoma. Low-magnification showing a fibro-
fatty tumor with well-circumscribed borders (a) (H&E).
In some areas, there is a close admixture of fibrous areas
with adipose tissue, resulting in a pseudo-infiltrative
from inflammatory pseudotumor/inflammatory
myofibroblastic tumor, desmoid-type fibromatosis,
low-grade (fibromatosis-like) spindle cell carci-
noma, and low-grade myofibroblastic sarcoma is
crucial for their tendency to local recurrence. In
addition the latter two tumors are capable of distant
metastases.
Pseudoangiomatous stromal hyperplasia is
characterized by a proliferation of bland-looking
spindle cells set in a fibrous stroma with the for-
mation of anastomosing pseudovascular spaces
(Virk and Khan 2010). Focally this proliferation
can be more cellular (fascicular variant), adopting
a MFB-like appearance with obliteration of the
spaces (Magro and Bisceglia 2005). Although
pseudoangiomatous stromal hyperplasia may pre-
sent as a nodular mass (Lee et al. 2016), it is
usually an incidental histological finding (Virk
and Khan 2010). Unlike MFB, the proliferation
283
growth pattern (b) (H&E). Fibrous area exhibiting the
characteristic features of classic-type myofibroblastoma M
(c) (H&E). The spindle cells are diffusely stained
with CD34 (d)
involves both perilobular (more frequently) and
intralobular stroma, containing mammary ducts/
lobules (Magro and Bisceglia 2005; Virk and
Khan 2010; Lee et al. 2016). Reactive spindle
cell nodule is an exuberant myofibroblastic spin-
dle cell proliferation in response to a tissue
trauma. Accordingly, the clinical history of a pre-
vious biopsy or fine-needle aspiration (FNA) is
extremely helpful for making the correct diagno-
sis (Gobbi et al. 2000; Garijo et al. 2008; Sciallis
et al. 2012). The recognition of entrapped/
displaced epithelial mammary structures, hemo-
siderin (in the stroma or within macrophages),
lymphocytes, plasma cells, fat necrosis, and for-
eign body giant cell reaction, are all morphologi-
cal features which support the diagnosis (Gobbi
et al. 2000; Garijo et al. 2008; Sciallis et al. 2012).
Unlike MFB, nodular fasciitis has, at least focally,
irregular margins, a more abundant myxoid
284
Mammary Myofibroblastoma, Fig. 7 (H&E)
Palisaded/Schwannian-like myofibroblastoma. Low-
magnification showing a tumor with well-circumscribed
borders and numerous Verocay-like bodies. The overall
stroma and a tissue culture/granulation-like
appearance (Kang et al. 2015; Paliogiannis et al.
2016; Hayashi et al. 2017). Numerous mitoses
and entrapped ducts/lobules can be seen, espe-
cially at the periphery of the lesion. The cells of
nodular fasciitis are diffusely stained with alpha-
smooth muscle actin but are usually negative
for desmin and CD34 (Kang et al. 2015;
Paliogiannis et al. 2016; Hayashi et al. 2017).
Unlike MFB, inflammatory pseudotumor/inflam-
matory myofibroblastic tumor contains spindle
cells admixed with chronic inflammatory infiltrate
of plasma cells, lymphocytes, and less frequently
eosinophils and neutrophils. The spindle cells
show a variable expression of alpha-smooth mus-
cle actin, while desmin and CD34 are usually
negative or only focally positive (Vecchio et al.
2011; Zhou et al. 2013; Bosse et al. 2014). ALK-1
protein can be expressed in about 40–50% of
cases (Zhou et al. 2013; Bosse et al. 2014).
Apart from the more eosinophilic cytoplasm of
the cells and the more organized fascicular growth
pattern, leiomyoma can be distinguished from
MFB by demonstrating diffuse coexpression of
desmin, alpha-smooth muscle actin, and
Mammary Myofibroblastoma
picture is highly suggestive of schwannoma (a). High mag-
nification showing the cellular details (b). Neoplastic cells
are stained with desmin (inset)
h-caldesmon, while CD34 is lacking (Jones et al.
1994; Vecchio et al. 2013). As solitary fibrous
tumor and MFB share several morphological and
immunohistochemical features, some authors
have used interchangeably their names in the
past (Damiani et al. 1994; Magro et al. 2002a).
However, unlike MFB, SFT shows nuclear
expression of STAT6 (Magro et al. 2016) and is
usually desmin-negative. Desmoid type-
fibromatosis differs from MFB in that it is an
infiltrative lesion composed of spindle cells, usu-
ally aligned parallel to one another, separated by
fibrous stroma and arranged in long fascicles
(Wargotz et al. 1987a; Devouassoux-Shisheboran
et al. 2000; Magro et al. 2002b). In addition, the
cells are usually stained with beta-catenin (nuclear
staining) and alpha-smooth muscle actin, while
they are negative for desmin and CD34 (Magro
2016). Unlike MFB, low-grade (fibromatosis-
like) spindle cell carcinoma exhibits, at least
focally, infiltrative margins with projections into
adjacent mammary parenchyma (Wargotz et al.
1989; Gobbi et al. 1999; Sneige et al. 2001; Carter
et al. 2006; Dwyer and Clark 2015).
Immunostaining of neoplastic cells, at least
Mammary Myofibroblastoma
Mammary Myofibroblastoma, Table 3 Mammary Myofibroblastoma: differential diagnosis
Differential diagnosis of myofibroblastoma
Myofibroblastoma
PASH (fascicular variant)
Reactive spindle cell nodule
Nodular fasciitis
Inflammatory pseudotumor/
inflammatory myofibroblastic tumor
Leiomyoma
Solitary fibrous tumor
Desmoid-type fibromatosis
Low-grade (fibromatosis-like) spindle
cell carcinoma
285
Imaging features: Well-circumscribed nodule
Histology: Short, haphazardly intersecting fascicles interrupted by
keloid-like collagen fibers
Immunohistochemistry: Staining with desmin, CD34, estrogen, and
progesterone receptors; variable expression of alpha-smooth muscle
actin, bcl2, CD10, CD99; pancytokeratins, S100 protein, beta-catenin,
and STAT6 are negative
Imaging features: Not detectable; occasionally nodule with
circumscribed margins
Histology: Short fascicles of spindle cells set in a fibrous stroma
Immunohistochemistry: Staining with CD34; variable expression of
alpha-smooth muscle actin and desmin
Imaging features: Nodule with circumscribed margins, following
biopsy or FNAC
Histology: Short fascicles; focal storiform pattern; haemosiderin
deposition; foamy and hemosiderin-laden macrophages,
lymphocytes and plasma cells; fat necrosis and foreign body giant
cell reaction
Immunohistochemistry: Staining with alpha-smooth muscle actin;
CD34, desmin, beta-catenin and pancytokeratins are negative
Imaging features: Ill-defined margins, at least focally
Histology: Short, focally intersecting fascicles; foci of extravasated red
blood cells and lymphocytes; tissue culture-like appearance
Immunohistochemistry: Staining with alpha-smooth muscle actin;
CD34, desmin, beta-catenin and pancytokeratins are negative
Imaging features: Well-circumscribed nodule M
Histology: Spindle cell proliferation, often with swirling storiform
pattern, admixed with inflammatory cells (mainly lymphocytes and
plasmacells)
Immunohistochemistry: Variable staining with alpha-smooth muscle
actin, desmin, ALK-1 and pancytokeratins; CD34, beta-catenin and
STAT6 are negative
Imaging features: Well-circumscribed nodule
Histology: Deeply eosinophilic spindle cells with cigar-shaped nuclei,
arranged in intersecting fascicles
Immunohistochemistry: Staining with desmin, alpha-smooth muscle
actin and h-caldesmon; CD34, pancytokeratins, beta-catenin and STAT6
are negative
Imaging features: Well-circumscribed nodule
Histology: Short fibroblast-like spindle to round/ovoid cells, haphazardly
arranged; focal storiform pattern
Immunohistochemistry: Staining with CD34 and STAT6; desmin,
alpha-smooth muscle actin and pancytokeratins are negative
Imaging features: Ill-defined, often infiltrative margins
Histology: Long fascicles, focally intersecting
Immunohistochemistry: Staining with alpha-smooth muscle actin
and beta-catenin; CD34, desmin, pancytokeratins and STAT6 are
negative
Imaging features: Fairly defined margins
Histology: Proliferation of spindle cells with, at least focally, mild to
moderate nuclear atypia; scattered clusters of epithelioid to polygonal
(continued)
286 Mammary Myofibroblastoma

Mammary Myofibroblastoma, Table 3 (continued)

Differential diagnosis of myofibroblastoma
Low-grade myofibroblastic sarcoma
cells; occasionally small squamous-glandular structures and/or foci of in
situ or invasive carcinoma
Immunohistochemistry: Staining with pancytokeratins and p63;
variable expression of alpha-smooth muscle actin and desmin; CD34,
beta-catenin and STAT6 are negative
Imaging features: Fairly circumscribed nodule
Histology: Proliferation of spindle cells with fascicular arrangement; low
to focally moderate nuclear pleomorphism; occasionally severe nuclear
pleomorphism
Immunohistochemistry: Staining with alpha-smooth muscle actin;
desmin, pancytokeratins, beta-catenin, CD34 and STAT6 are negative

focally, with epithelial (cytokeratins) and
myoepithelial (p63) markers is mandatory for
making the diagnosis of spindle cell carcinoma.
Apart from the spindle cells, cytokeratins usually
highlight the neoplastic cells with epithelioid to
polygonal morphology, often arranged in small
cohesive clusters (Dwyer and Clark 2015). This
finding is an important diagnostic clue. Finally,
low-grade myofibroblastic sarcoma (low-grade
myofibrosarcoma) is a tumor with higher mitotic
activity (7 to 35 mitoses per10 high power fields)
and stained with alpha-smooth muscle actin,
while the expression of desmin and CD34 is
lacking (Taccagni et al. 1997; Gocht et al. 1999;
Lucin et al. 2003; Morgan et al. 2005).
Among the morphological variants of MFB,
lipomatous and epithelioid/deciduoid cell MFB
are unusual enough to deserve a separate differ-
ential diagnosis. Due to their alarming morphol-
ogy, they can represent potential diagnostic
pitfalls and confused with more aggressive
lesions, especially in core biopsies (Magro 2009;
Wahbah et al. 2011; Bakuła-Zalewska et al. 2012;
Alizadeh et al. 2015; Arafah et al. 2015). The
former is an uncommon variant, which shows a
close admixture of spindle cells with adipocytes,
resulting in a fibromatosis-like growth pattern.
However, lipomatous MFB has well-
circumscribed margins and the lipomatous com-
ponent is an integral part of the tumor and not
entrapped tissue due to infiltration of neoplastic
cells into adjacent breast parenchyma (Magro
et al. 2000a). Unlike desmoid-type fibromatosis,
it is stained with desmin, CD34, and estrogen/
progesterone receptors, while it is negative for
beta-catenin (Magro et al. 2000a). Epithelioid-
cell MFB may be misinterpreted as an invasive
lobular carcinoma (▶ Invasive Lobular Carci-
noma) as the neoplastic cells may adopt a single
cell and/or single-cell files growth patterns
(Magro 2009, 2012; Magro et al. 2013a). How-
ever, lobular carcinoma has infiltrative margins,
expresses epithelial markers (cytokeratins and
EMA), and is negative for myogenic markers
(desmin, alpha-smooth muscle actin). Patholo-
gists should also keep in mind that epithelioid
cells may occasionally exhibit a deciduoid-like
appearance, making more difficult the recognition
of a tumor as MFB (Magro et al. 2008). Deciduoid
cell MFB should be distinguished from malignant
tumors such as invasive pleomorphic lobular carci-
noma, apocrine carcinoma, metastatic pleomorphic
rhabdomyosarcoma, melanoma, or malignant
rhabdoid tumor (Magro et al. 2008). The well-
circumscribed margins, the absence or low mitotic
count (up 2 mitoses  10 HPF), the presence of
keloid-like collagen fibers, and the expression of
myogenic markers are all features supporting the
diagnosis of MFB (Magro et al. 2008).
Interestingly some cases of mammary MFB
may exhibit hybrid features with a lipomatous com-
ponent intermingling with epithelioid cells
(Wahbah et al. 2011; Alizadeh et al. 2015). These
are diagnostically challenging cases which are
often misdiagnosed as invasive lobular carcinomas
(▶ Invasive Lobular Carcinoma) in core biopsy due
to the apparent pseudo-infiltrative pattern of epithe-
lioid cells, singly dispersed or arranged in files,
Mammary Myofibroblastoma
admixed with the intratumoral fatty tissue. The
diagnosis of invasive lobular carcinoma will prompt
pathologists to perform immunohistochemical ana-
lyses for defining the tumor profile and the demon-
stration of estrogen/progesterone receptors,
typically observed in MFB, will further support
the mistaken diagnosis of carcinoma (Magro 2009;
Wahbah et al. 2011). Awareness of the lipomatous
and epithelioid/deciduoid cell MFB is crucial for
pathologists, who should always correlate morphol-
ogy with clinico-radiologic information. Immuno-
histochemistry, including myogenic and epithelial
markers, is mandatory in ambiguous cases.
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M
Microglandular Adenosis
Eliano Cascardi1,2, Caterina Marchiò2,3,4 and
Eugenio Maiorano1
1
Department of Emergency and Organ
Transplantation, Unit of Pathology, University
of Bari, Bari, Italy
2
Unit of Pathology, Candiolo Cancer Institute
FPO-IRCCS, Candiolo, Italy
3
Department of Medical Sciences,
University of Turin, Turin, Italy
4
Institut Curie, Paris, France
Definition
Microglandular adenosis (MGA) of the breast is
a glandular proliferation of uncertain malignant
potential, which mimics invasive carcinoma due
to haphazard infiltrative growth in breast stroma
and the lack of a myoepithelial cell layer. The
term atypical microglandular adenosis (AMGA)
290
is used when the glandular structures are more
crowded, with a back-to-back architecture and
higher variation in size and shape; epithelial pro-
liferation, as well as nuclear atypia and mitotic
activity, can be present.
Clinical Features
• Incidence
MGA is an exceedingly rare breast lesion.
• Age
It affects patients with an age range between
adolescence and senescence.
• Sex
All reported patients with microglandular
adenosis are female.
• Site
There is no predilection for a particular quad-
rant in the breast. MGA can be unifocal or
multifocal (Clement and Azzopardi 1983).
• Clinical Presentation
MGA usually is asymptomatic and may pre-
sent as a microscopic lesion or as a palpable
mass (Rosen 1983). It can be associated with
other benign breast lesions (cysts, sclerosing
adenosis, and fibroadenoma) (Clement and
Azzopardi 1983). A specific mammographic
pattern has not been described; nevertheless,
MGA can present on radiograms as an area
of increased density or show calcifications
only (Rosenblum et al. 1986).
AMGA and carcinoma arising in
microglandular adenosis (CaMGA) appear
mammographically as an infiltrative lesion
(Khalifeh et al. 2008).
• Treatment
Since MGA and AMGA may recur
if incompletely resected, excision with free
margins represents the standard treatment
when a diagnosis of MGA without evidence
of an invasive carcinoma is performed on
core needle biopsy (Khalifeh et al. 2008;
Salarieh and Sneige 2007). Close follow-up
is recommended, especially for AMGA
(Rosen 1983). Mastectomy and axillary dissec-
tion are recommended when carcinoma
in MGA is detected (James et al. 1993).
Microglandular Adenosis
• Outcome
Most case reports of MGA indicate an indolent
behavior (Tavassoli and Norris 1983) with an
excellent clinical outcome. However, carcino-
mas arising from or in conjunction with micro-
glandular adenosis have been reported in a
nonnegligible fraction of cases (up to 27%)
(Shui and Yang 2009). The prognosis of
CaMGA depends on the histologic type, grade,
and stage of the invasive component.
Macroscopy
On gross examination, microglandular adenosis
may be undetectable or appear as a poorly
circumscribed dense area (Lakhani et al. 2012).
Microscopy
Microscopically, MGA is a non-lobulocentric
proliferation of microglandular structures that
features an infiltrative growth pattern in adipose/
fibrotic mammary stroma, without a desmoplastic
reaction. At low magnification, the glands
appear round, regular, similar in size, with open
lumina (Fig. 1a) but they appear haphazardly
arranged. Eosinophilic, periodic acid-Schiff
(PAS)-positive, and diastase-resistant material
is frequently present in glandular lumina
(Lakhani et al. 2012), occasionally forming
calcium deposits. The tubules are covered by a
single epithelial cell layer and they lack
myoepithelial cells (Clement and Azzopardi
1983), even though they are surrounded by a
basement membrane. MGA cells are cuboidal
or flat, have clear to eosinophilic cytoplasm
without apical snouts; nuclei are cytologically
bland, mitotic figures are uncommon. On the
contrary, AMGA presents cytologic abnormalities
such as architectural complexity, irregular glands,
cellular expansion in lumina, prominent nucleoli,
rare mitoses, and focal apoptotic figures (Shin
et al. 2009).
A large number of breast malignancies, includ-
ing ductal and lobular carcinoma in situ (▶ Ductal
Carcinoma In Situ, ▶ Lobular In Situ Neoplasia),
Microglandular Adenosis
Microglandular Adenosis, Fig. 1 Representative pho-
tomicrographs of microglandular adenosis diagnosed
on core biopsy. (a) The microglandular proliferation
shows an infiltrative growth pattern and is haphazardly
distributed in the fibro-fatty mammary tissue (H&E). (b)
The cells lining the tubules show strong nuclear staining
adenomyoepithelioma (▶ Adenomyoepithelioma),
basal-like carcinoma, adenoid cystic carcinoma
(▶ Adenoid Cystic Carcinoma), matrix-producing
carcinoma, and spindle cell carcinoma (▶ Invasive
Metaplastic Carcinoma) can be seen in conjunction
with microglandular adenosis (Foschini and Eusebi
2018).
Cartilaginous or chondroid metaplasia also
has been reported in AMGA and CaMGA.
Immunophenotype
MGA and AMGA are characterized by a triple
negative phenotype, lacking expression for
estrogen receptor, progesterone receptor, and
291
M
for S100 protein. (c) Estrogen and progesterone receptors
are not expressed. (d) Absence of a myoepithelial cell layer
around the glandular structures, as shown by immunohis-
tochemistry with anti-p63 antibody (a normal lobule serves
as internal positive control)
HER2 (Fig. 1c). In addition, MGA/AMGA typically
show S100 protein expression (Fig. 1b), as well as
positivity for low-molecular-weight cytokeratin
markers (CAM 5.2, AE1 or CK8-18). Myoepithelial
markers are undetectable as a myoepithelial cell
layer is missing (Fig. 1d) (Tavassoli and Bratthauer
1993); however, collagen IVand laminin expression
confirms the presence of a basement membrane. The
proliferation index evaluated by Ki67 expression is
generally low.
Molecular Features
Genetic analyses by array-based comparative
genomic hybridization and next-generation
292
sequencing have shown that MGA and AMGA
associated with triple negative carcinomas share
clonal genetic alterations with invasive carcino-
mas, such as TP53 mutations (Guerini-Rocco
et al. 2016; Geyer et al. 2009, 2012; Shin et al.
2009). Of note, pure MGA/AMGA (i.e., with
no association with an infiltrative carcinoma) fea-
ture simpler genetic profiles and lack TP53 muta-
tions (Guerini-Rocco et al. 2016; Geyer et al.
2012). Taken together, these data suggest that
a subset of MGA/AMGA can be considered as
a clonal neoplastic lesion and a non-obligate pre-
cursor of high-grade, triple negative breast cancer,
underpinned by TP53 mutations.
It is interesting to note that MGA/AMGA
and acinic cell carcinomas (ACC) (▶ Acinic Cell
Carcinoma), a special histologic subtype of
triple negative breast cancer, share histologic and
immunophenotypic similarities. When analyzed at
the genetic level, no significant differences
in mutation burden and repertoire were detected
between MGA/AMGA/ACC analyzed (either indi-
vidually or as a whole group) and conventional
triple negative breast carcinomas (Geyer et al.
2017). These data support the existence of a “low-
grade breast neoplasia family,” which encompasses
triple negative lesions such as MGA, AMGA, and
ACC that, despite their low-grade morphology and
good outcome, recapitulate the complex genomic
landscape of common forms of triple negative
breast cancers (Geyer et al. 2017).
Differential Diagnosis
Numerous breast lesions may display a micro-
glandular pattern, such as sclerosing adenosis
(▶ Sclerosing Adenosis), adenomyoepithelial
adenosis (▶ Adenosis, Other Types), or tubular
carcinoma (▶ Tubular Carcinoma), and can be
misinterpreted as MGA (Foschini and Eusebi
2018). Contrary to MGA, sclerosing adenosis
shows a dense and hyalinized stroma that creates
distorted glandular structures. Of note, sclerosing
adenosis and adenomyoepithelial adenosis retain
a myoepithelial cell layer (Foschini and Eusebi
2018). Adenomyoepithelial adenosis also is
strongly immunoreactive for GCDFP-15. Unlike
Microglandular Adenosis
AMGA, the glandular distribution of tubular car-
cinoma is usually stellate, the glands are angular
and the stroma is frequently desmoplastic. Most
important, tubular carcinomas typically are estro-
gen receptor positive.
MGA and AMGA also share striking similarities
with acinic cell carcinomas (▶ Acinic Cell Carci-
noma), showing a microglandular growth pattern, a
triple negative phenotype, and S100 protein expres-
sion. Contrary to MGA/AMGA, acinic cell carcino-
mas may display a solid pattern with comedo-like
necrosis and intracytoplasmic zymogen-type gran-
ules, relevant mitotic activity and express high
levels of EMA and acinar differentiation markers
(lysozyme and amylase) (Lakhani et al. 2012).
References and Further Reading
Clement, P. B., & Azzopardi, J. G. (1983). Microglandular
adenosis of the breast – A lesion simulating tubular
carcinoma. Histopathology, 7, 169–180.
Foschini, M. P., & Eusebi, V. (2018). Microglandular
adenosis of the breast: A deceptive and still mysterious
benign lesion. Human Pathology, 82, 1–9.
Geyer, F. C., Kushner, Y. B., Lambros, M. B., Natrajan, R.,
Mackay, A., Tamber, N., . . . & Reis-Filho, J. S. (2009).
Microglandular adenosis or microglandular adenoma?
A molecular genetic analysis of a case associated with
atypia and invasive carcinoma. Histopathology, 55,
732–743.
Geyer, F. C., Lacroix-Triki, M., Colombo, P. E., Patani, N.,
Gauthier, A., Natrajan, R., . . . & Marchio, C. (2012).
Molecular evidence in support of the neoplastic and
precursor nature of microglandular adenosis.
Histopathology, 60, E115–E130.
Geyer, F. C., Berman, S. H., Marchiò, C., Burke, K. A.,
Guerini-Rocco, E., Piscuoglio, S., . . . & Schnitt, S. J.
(2017). Genetic analysis of microglandular adenosis and
acinic cell carcinomas of the breast provides evidence for
the existence of a low-grade triple-negative breast neo-
plasia family. Modern Pathology, 30, 69.
Guerini-Rocco, E., Piscuoglio, S., Ng, C. K., Geyer, F. C.,
De Filippo, M. R., Eberle, C. A., . . . & Yatabe, Y. (2016).
Microglandular adenosis associated with triple-negative
breast cancer is a neoplastic lesion of triple-negative
phenotype harbouring TP53 somatic mutations. The
Journal of Pathology, 238, 677–688.
James, B. A., Cranor, M. L., & Rosen, P. P. (1993).
Carcinoma of the breast arising in microglandular
adenosis. American Journal of Clinical Pathology,
100, 507–513.
Khalifeh, I. M., Albarracin, C., Diaz, L. K.,
Symmans, F. W., Edgerton, M. E., Hwang, R. F., &
Sneige, N. (2008). Clinical, histopathologic, and
Microinvasive Carcinoma of the Breast
immunohistochemical features of microglandular
adenosis and transition into in situ and invasive
carcinoma. The American Journal of Surgical
Pathology, 32, 544–552.
Lakhani, S. R., Ellis, I. O., Schnitt, S. J., Tan, P. H., &
van de Vijver, M. J. (2012). WHO classification of
tumors of the breast (pp. 106–107). World Health
Organization. Lyon, France. ISBN-10: 9283224337.
Rosen, P. P. (1983). Microglandular adenosis. A benign lesion
simulating invasive mammary carcinoma. The American
Journal of Surgical Pathology, 7, 137–144.
Rosenblum, M. K., Purrazzella, R., & Rosen, P. P. (1986).
Is microglandular adenosis a precancerous disease?
A study of carcinoma arising therein. The American
Journal of Surgical Pathology, 10, 237–245.
Salarieh, A., & Sneige, N. (2007). Breast carcinoma arising in
microglandular adenosis: A review of the literature.
Archives of Pathology & Laboratory Medicine, 131,
1397–1399.
Shin, S. J., Simpson, P. T., Da Silva, L., Jayanthan, J.,
Reid, L., Lakhani, S. R., & Rosen, P. P. (2009).
Molecular evidence for progression of microglandular
adenosis (MGA) to invasive carcinoma. The American
Journal of Surgical Pathology, 33, 496–504.
Shui, R., & Yang, W. (2009). Invasive breast carcinoma
arising in microglandular adenosis: A case report and
review of the literature. The Breast Journal, 15,
653–656.
Tavassoli, F. A., & Bratthauer, G. L. (1993).
Immunohistochemical profile and differential
diagnosis of microglandular adenosis. Modern Pathol-
ogy, 6, 318–322.
Tavassoli, F. A., & Norris, H. J. (1983). Microglandular
adenosis of the breast. A clinicopathologic study
of 11 cases with ultrastructural observations. The
American Journal of Surgical Pathology, 7, 731–737.
Microinvasive Carcinoma of
the Breast
Simonetta Bianchi and Vania Vezzosi
Division of Pathological Anatomy,
Department of Surgery and Translational
Medicine, University of Florence,
School of Human Health Sciences,
Florence, Italy
Synonyms
Microinvasive carcinoma, pT1mi, Invasive carci-
noma less than or equal to 1 mm in greatest
dimension
293
Definition
Microinvasive carcinoma (MIC) of the breast was
not clearly characterized until 1997 when the
Union for International Cancer Control (UICC)
first included pT1mic in the TNM classification
of breast carcinoma. It was defined as “invasive
mammary carcinoma with no focus exceeding
1 mm in greatest dimension.”
This definition has been carried through many
editions of the Cancer Staging Manual published
by American Joint Committee on Cancer (AJCC)
until the current edition (Amin et al. 2017) where
it is reported as “an invasive carcinoma with no
focus measured larger than 1 mm and classified
as pT1mi. MIC is reported as nearly always
encountered in a setting of ductal carcinoma in
situ (DCIS) (▶ Ductal Carcinoma In Situ)
(Fig. 1, (a) H&E. (b) Immunostaining for
smooth-muscle myosin heavy chain highlights
myoepithelial cells around the DCIS, while it is
absent in the invasive focus) or, infrequently,
lobular carcinoma in situ (LCIS) (▶ Lobular In
Situ Neoplasia) (Fig. 2, H&E), where small foci
of tumor cells invaded through the basement
M
membrane into the surrounding stroma, although
rare cases are encountered in the absence on non-
invasive disease” (Fig. 3, H&E) (Bianchi and
Vezzosi 2008).
The most recent World Health Organization
(WHO) Classification of Tumors of the Breast
(Pinder et al. 2012) defines MIC “as a lesion
characterized by one or more clearly separate
microscopic foci of infiltration of tumor cells
into the mammary stroma, each less than or
equal to 1 mm in size, and most commonly seen
in the background of high nuclear grade DCIS.”
This definition is very restrictive and tumors
fulfilling the criteria are consequently rare.
Historically, there has been wide variation in
the definition of MIC of the breast. The term
“microinvasion” was introduced in breast pathol-
ogy by Lagios in 1982 as synonymous of invasion
less than 1 mm. Although this term has been
reported for many years, it has not been applied
in a consistent, standardized manner. A variety
of different definitions have been used for MIC
such as:
294
Microinvasive Carcinoma of the Breast,
Fig. 1 Microinvasive carcinoma. (a) (H&E): A duct
with high grade ductal carcinoma in situ and an area
with irregular small tumor cell nests surrounded by a
Microinvasive Carcinoma of the Breast, Fig. 2
(H&E): Microinvasive lobular carcinoma associated
with LCIS
• DCIS with evidence of stromal invasion
• DCIS showing focal microinvasion below the
basement membrane in one or several individ-
ual ducts but not more than 10% of the surface
of the histological sections examined
• Breast cancer cells confined to the duct system
of the breast with only a microscopic focus of
malignant cells invading beyond the basement
membrane of the duct as determined by light
microscopy
• One or more microscopic foci of possible inva-
sion not >1 mm in greatest dimension
Microinvasive Carcinoma of the Breast
mononuclear cell infiltrate. (b) (Immunohistochemistry):
These irregular small tumor cell nests lack a surrounding
myoepithelial cell layer, consistent with stromal invasion
Microinvasive Carcinoma of the Breast, Fig. 3
(H&E): Microinvasive lobular carcinoma not associated
with ductal or lobular carcinoma in situ
• DCIS with limited microscopic stromal inva-
sion below the basement membrane but not
invading more than 10% of the surface of the
histological sections examined
• The maximal extent of invasion is not more
than 2 mm or comprising <10% of the tumor,
with 90% of DCIS
• A single focus of invasive carcinoma 2 mm
or up to three foci of invasion each not more
than 1 mm in greatest dimension
• A few single infiltrating tumor cells (from
1 to 15) or a few infiltrating tumor cell clusters,
defined as ductal carcinoma in situ with
Microinvasive Carcinoma of the Breast
microinvasion (DCIS-MI) type 1 and type 2,
respectively.
This lack of a uniform definition for MIC has
clearly contributed to the confusion regarding this
entity.
The fifth edition of the AJCC Cancer Staging
Manual published in 1997 recognizes a specific
T substage for MIC, defined as “the extension of
cancer cells beyond the basement membrane into
the adjacent tissues with no focus more than
0.1 cm in greatest dimension” and formally
reported it as pT1mic. The AJCC Cancer Staging
Manual further stated that “when there are multi-
ple foci of microinvasion, the size of only the
largest focus is used to classify the microinvasion
and that the size of the individual foci should not
be added together; the presence of multiple foci of
microinvasion should however be noted and/or
quantified, as it is with multiple larger invasive
carcinomas”.
Following the establishment of a National
Breast Screening Programme in the United
Kingdom, a Working Group of the Royal Col-
lege of Pathologists produced in 1990 a docu-
ment on Pathology Reporting in Breast Cancer
Screening where MIC was defined as “a tumor in
which the dominant lesion is noninvasive but in
which there are one or more foci of infiltration,
none of which measures more than 1 mm (about
2 high power fields) in maximum diameter.
Small invasive carcinomas without an in situ
component are classified as invasive.” In the
second edition of the Pathology Reporting in
Breast Cancer Screening published in 1995, it
is proposed that “only when unequivocal inva-
sion is seen outside the specialized lobular
stroma, namely into the non-specialized
interlobular stroma, should MIC be diagnosed.
If there is sufficient doubt about the presence of
invasion, the case should be classified as in situ
carcinoma.”
In the 2003 edition of WHO Classification of
Tumours of the Breast and Female Genital
Organs, in spite of the pT1mic category officially
being recognized by the fifth edition of the AJCC
Cancer Staging Manual, MIC was still considered
an evolving concept as there was no generally
295
accepted agreement particularly about the maxi-
mum diameter compatible with a diagnosis of
microinvasion.
In the fourth edition of the European Guide-
lines for Quality Assurance in Breast Cancer
Screening and Diagnosis published in 2006,
formed on the major basis of UK guidelines,
MIC was defined as a “tumor in which the dom-
inant lesion is in-situ carcinoma (usually exten-
sive high nuclear grade DCIS, rarely other types
of DCIS or LCIS) but in which there are one or
more, clearly separate, foci of infiltration of non-
specialized interlobular or interductal fibrous or
adipose tissue, none measuring more than 1 mm
(about 2 high power fields) in maximum diameter.
When there are multiple foci of MIC only the
size of the largest focus is used to classify the
microinvasion; the presence of multiple foci of
microinvasion should however be noted and/or
quantified.”
Not all authors accept the definition of MIC
that requires “clearly separate foci of infiltration
of nonspecialized interlobular stroma”: tumor
cells are, in fact, not known to leap or jump
or dissociate from the in situ component in order
M
to invade the stroma, in three dimension micro-
invasive tumor foci would be seen to grow
as solid cords extending from in situ area; further-
more the unequivocal influence of the plane
of section on the detection of continuity between
the in situ and invasive component render
the requirement “clearly separate foci” invalid;
moreover the “infiltration of nonspecialized
interlobular stroma” has been considered a
requirement untenable since vascular invasion
can occur even within the lobular stroma due to
the presence of vascular channels both within
the specialized lobular stroma and immediately
surrounding the basement membrane that invests
ductules.
Considering the difficulty to ascertain exten-
sion of malignant cells beyond the specialized
lobular stroma, the current WHO Classification
of Tumours of the Breast (Pinder et al. 2012)
reports that MIC is diagnosed when convincing
histological features are present, despite malig-
nant cells not being clearly beyond the specialized
lobular stroma.
296
Clinical Features
There are no specific clinical or radiologic fea-
tures associated with MIC.
In cases where MIC arises in association with in
situ lesions (prevalently high nuclear grade DCIS,
other types of DCIS and, more rarely, classic or
pleomorphic LCIS (▶ Lobular In Situ Neoplasia)
the clinical presentation is dictated by the in situ
carcinoma (mammographically detected micro-
calcifications, or less commonly a mass, asymme-
try, architectural distorsion).
• Incidence
Uncommon; the incidence rate of MIC ranges
from 0.7% to 2.4% (mean less than 1% of all
breast cancers).
• Age
MIC occurs throughout the age range of breast
carcinoma.
• Sex
Female patients, rarely in male patients.
• Site
No specific sites in breast.
• Treatment
The majority of patients, reported in literature
with MIC, were treated with mastectomy.
However, breast-conserving surgery has been
described as effective as mastectomy in several
reports. The presence of MIC probably has
little independent impact on the effectiveness
of local control in the breast. The characteris-
tics of in situ lesion that is associated with MIC
are crucial determinants for the type of surgical
treatment (mastectomy versus breast conserv-
ing therapy).
Although most clinicians have abandoned
the routine use of sentinel lymph node biopsy
(SLNB) in patients with in situ carcinoma
(DCIS and pleomorphic LCIS), many still
believe that there is a subset of patients with
in situ carcinoma at high risk for MIC and
subsequent axillary metastases who may ben-
efit from the SLNB. At present SLNB is a
common clinical practice in treatment of
patients with DCIS and MIC due to the possi-
bility of axillary lymph node metastases. How-
ever, most MICs with a positive SLN have
Microinvasive Carcinoma of the Breast
low-volume metastases and consequently a
low risk of additional metastases in axillary
lymph nodes, therefore complete axillary
lymph node dissection is not recommended.
A recent meta-analysis of nearly 1000
patients with MIC who underwent SLNB
showed that the SLN-positivity rate for macro-
metastasis was, even in the worst-case
scenario, acceptably low (5.6%); similar
low positivity rates were observed for micro-
metastases or ITC, concluding that the
indication for SLNB in patients with MIC
should be probably individualized. Conse-
quently, an accurate preoperative diagnosis
distinguishing MIC from frankly invasive car-
cinoma on percutaneous needle core biopsy
(NCB) or vacuum-assisted needle core biopsy
(VANCB) should be made because size of
invasive carcinoma could impact on surgical
decisions.
Only few studies have evaluated the role
of systemic adjuvant therapy in patients with
MIC. Further studies with prolonged follow-up
of large cohorts are necessary to assess the
significance of systemic treatment in MIC.
• Outcome
Considering the variety of definitions that have
been used to report MIC and that some lesions
categorized as MIC based on limited tissue
sampling could actually represent frankly inva-
sive carcinomas not submitted for histological
examination or not represented on the slides
because the cancer was deeper in the blocks,
robust data on the clinical behavior of MIC are
not available. Moreover the paucity and the
nonuniformity of the clinical outcome data
have led to uncertainty regarding the separa-
tion of MIC from in situ carcinomas and from
small invasive carcinomas.
The prevailing view is that MIC has an excel-
lent prognosis with a low risk of associated
axillary lymph node metastasis. The reported
incidence of axillary lymph node metastases in
patients given the diagnosis of MIC ranges from
0% to 28% (mean 9.4%) This wide range may
be explained by both the different histopatho-
logical criteria used to define MIC and the var-
iable degree of breast tissue sampling, but it also
Microinvasive Carcinoma of the Breast
depends on the different techniques utilized to
examine axillary lymph nodes (only H&E or
H&E plus immunohistochemistry (IHC) for
cytokeratins), especially after the introduc-
tion of SLNB. Moreover, the relatively high
frequency of axillary lymph node metastasis
reported is due to considering as positive also
lymph nodes with isolated tumor cells. It is
likely that when current AJCC definitions for
microinvasion and lymph node status are
used [“isolated tumor cells” have been
down-staged as pN0(i+)], the true frequency
of axillary lymph node involvement will be
quite low. Clinical outcome of MIC associ-
ated to in situ lesion is reported to be more
similar to in situ lesion than small invasive
carcinoma pT1a (>1 mm and less than or
equal to 5 mm.)
Data on clinical behavior of MIC not asso-
ciated to an in situ lesion are not available;
presumably, it will likely be more similar to
DCIS than small invasive carcinoma pT1a.
The number of microinvasive foci does not
have an impact on prognosis.
Macroscopy
MIC cannot, by definition, be identified on
gross pathologic examination, and it is typically
detected during microscopic examination of
breast specimens containing benign lesions or in
situ carcinoma.
Microscopy
The tumor focus/foci must usually invade into
the mammary stroma (specialized lobular,
interlobular or periductal stroma).
The cells deemed to be invasive must be dis-
tributed in a non-organoid pattern that does not
represent tangential sectioning of a duct or a lob-
ular structure involved by in situ carcinoma.
Tangentially sectioned foci of in situ carcinoma
that simulate microinvasion are within the special-
ized lobular and periductal stroma and usually
occur as compact groups of tumor cells that have
297
a smooth border surrounded by a circumferential
layer of myoepithelial cells and stroma or a thick-
ened basement membrane.
At sites of microinvasive focus, tumor cells are
distributed singly or as small groups having irreg-
ular shapes reminiscent of conventional invasive
carcinoma with no particular orientation (Hoda
2014).
When microinvasion occurs, especially in
cases associated with in situ lesions, it is likely
to be multifocal. It is therefore appropriate to
search carefully for additional small foci and to
confirm that the size of each focus does not exceed
1 mm in greatest dimension, the number of foci
and the range of their sizes, including the largest,
should be reported. The sum of the sizes should
not be used to determine pathological T factor.
When reporting the number of multiple foci is
difficult, it is recommended that an estimate of
the number be provided or, alternatively, a note
that the number of microinvasive foci is too
numerous to quantify but that no identified focus
is larger than 1 mm.
Absence of basement membrane components
(laminin and type IV collagen) around nests
M
of tumor cells and of myoepithelial cells are useful
to define invasion. However, immunohistochem-
istry (IHC) for laminin and type IV collagen is
reported to be technically problematic in formalin-
fixed paraffin-embedded tissue. Moreover, in situ
lesions may show variable basement membrane
loss and cells of invasive cancer can still synthe-
size some components of basement membrane
around invasive nests; therefore the use of
basement membrane markers for the detection of
stromal invasion is not formally recommended
and, when performed, should be interpreted with
caution.
IHC for myoepithelial markers is
recommended in cases of doubt about the
presence or absence of microinvasion, moreover
the use of IHC results in marked improvement of
the diagnostic consistency in identifying MIC
(Cserni et al. 2016). However, myoepithelial cell
markers vary in their sensitivity and specificity,
and the use of a panel (e.g., p63, calponin, smooth
muscle myosin heavy chain) is advised (Hilson
et al. 2009).
298
Smooth-muscle myosin heavy chain (SMM-HC)
and calponin are the most common antibodies used
to identify myoepithelial cells. SMM-HC is slightly
less sensitive than calponin. Actin antibodies (such
as 1A4 and HHF-35 clones) are the least specific
reacting also with myofibroblasts. Antibodies to
p63, a member of the p53 gene family, offer better
sensitivity and specificity for myoepithelial cells
than SSM-HC and calponin. However, p63 anti-
bodies have some limitations as well: (1) they occa-
sionally demonstrate an apparently discontinuous
myoepithelial layer around nests of in situ lesions
and (2) they react with a small but significant subset
of breast carcinomas, especially of basal phenotype
although this aberrant reactivity rarely causes diag-
nostic difficulties.
Detecting MIC can be difficult when there is a
marked periductal fibrosis or inflammation; in
these cases, IHC for cytokeratin may be of partic-
ular value in confirming the presence of separate
foci of neoplastic cells embedded in periductal
fibrosis or inflammation. MIC is typically associ-
ated with an inflammatory cell reaction, mainly of
lymphocytes.
The diagnosis of MIC still remains problem-
atic, even with the use of ancillary techniques.
If there is sufficient doubt about the presence of
microinvasion (i.e., in cases with marked fibrosis
or inflammation), the case should be classified as
in situ carcinoma with possible microinvasion.
Immunophenotype
There are only few studies reporting biomarkers
of MIC. Results of Estrogen (ER) and Progester-
one (PR) receptors, Ki-67 expression, and HER2
status are usually concordant between MIC and
the associated in situ lesion. If MIC is no longer
present on the slides recut for biomarkers, IHC
results of the associated in situ lesion should be
reported and used as a surrogate for the
immunophenotype of MIC.
HER2 positive status has been found signifi-
cantly higher (49%) in MIC compared with both
invasive carcinoma >1 mm (10–15%) and DCIS
(20%); although HER2 positivity in MIC is not
associated with nodal metastases or recurrence.
Microinvasive Carcinoma of the Breast
Molecular Features
Two possible explanations have been proposed
for higher rate of HER2 positivity reported in
MIC: first, that HER2-positive in situ
cancers are likely to be detected at mammographic
screening because they have large comedo micro-
calcifications; second, that due to its strong immu-
nogenicity, HER2 causes increased accumulation
of tumor-infiltrating lymphocytes (TILs) espe-
cially CD8+ cytotoxic T lymphocytes already
in the in situ stage and that a disruption of
myoepithelial cells and basement membrane
occurs during the stage of healing, so that cancer
cells are exposed in the stroma as cluster-like
invasion that leads to formation of MIC.
Most MIC are reported to develop from high
grade DCIS; however, MIC has been found to be
associated also with low- and intermediate grade
DCIS; on this basis, the presence of two different
progressive pathways, “low grade luminal” path-
way and “high grade HER2” pathway, has been
proposed based on genomic analysis (Morita
et al. 2016).
MIC is the first step in the development of
invasive carcinoma, and the lesion is positioned
between in situ and frankly invasive carcinoma.
Genetic analysis of in situ and invasive carcino-
mas has demonstrated that both entities display
remarkably similar genetic profiles when matched
by morphology and immunophenotype. However,
these molecular studies have failed to reveal spe-
cific genetic alterations in in situ cancers associ-
ated with an invasive component and hence
driving progression from the in situ to the invasive
stage. These results support the hypothesis that
the progression from in situ to invasive carcinoma
may not be necessarily determined by specific
genetic alterations or their consequences on gene
expression profile.
Differential Diagnosis
According to Fisher, MIC “represents one of, if
not the most, commonly overdiagnosed events in
the pathology of breast carcinoma.” Over-
diagnosing a MIC as a frankly invasive carcinoma
Microinvasive Carcinoma of the Breast
can be particularly harmful because it may lead to
overtreatment.
The differential diagnosis of MIC includes
pure in situ disease and, conversely, invasive
breast carcinoma measuring >1 mm; the size of
the focus should be carefully measured with an
ocular micrometer to exclude frankly invasive
breast carcinoma.
A variety of patterns in DCIS (▶ Ductal
Carcinoma In Situ) and, more rarely, in LCIS
(▶ Lobular In Situ Neoplasia) may be mis-
interpreted as stromal invasion (Schnitt and
Collins 2013). Lesions and artifacts commonly
mistaken for MIC include:
1. DCIS involving lobules (“lobular
cancerization”)
2. Chronic inflammatory reaction present in
association with, and obscuring, involved
ducts and acini
3. Branching of involved ducts
4. Distorsion or entrapment of involved ducts or
acini by fibrosis (sometime due to prior nee-
dling procedure)
5. Crush artifacts
6. Cautery effects
7. Artifactual displacement of DCIS or LCIS
cells into the surrounding stroma or adipose
tissue due to tissue manipulation or a prior
Microinvasive Carcinoma of the Breast, Fig. 4 Ductal
carcinoma in situ involving sclerosing adenosis.
(a) (H&E): Solid nests and glands composed
of neoplastic cells in a desmoplastic stroma raising
299
needling procedure. In cases with a history
of a prior needling procedure for preoperative
diagnosis (FNA, NCB or VANCB), the
diagnosis of MIC should be made with cau-
tion because artifactual disruption of the
epithelial-stromal junction of glandular struc-
tures involved by in situ carcinoma is not
infrequently encountered in subsequent exci-
sion biopsy or therapeutic specimen. Granu-
lation tissue, old or recent hemorrhage (iron-
laden macrophages, cholesterol crystals,
reactive fibrosis, hemosiderin deposition), tis-
sue tears, and a degenerative appearance of
the dislodged tumor cells can help in
distinguishing pseudo-invasion from true
invasion.
8. DCIS or LCIS involving benign complex scle-
rosing lesions such as radial scar (▶ Radial
Scar), sclerosing papilloma (▶ Intraductal
Papilloma), ductal adenoma (▶ Ductal Ade-
noma), and sclerosing adenosis (▶ Sclerosing
Adenosis) (Fig. 4, Ductal carcinoma in situ
involving sclerosing adenosis. (a) H&E.
(b) Calponin immunostain).
M
Additional H&E-stained sections may help to
define the nature of the process in problematic
cases. In many cases, IHC for myoepithelial
cells markers is of greater value for distinguishing
the suspicion of microinvasive carcinoma.
(b) (Immunohistochemistry): Calponin immunostain dem-
onstrates a myoepithelial cell layer around nests and glands
supporting the diagnosis of ductal carcinoma in situ
300
true MIC from its mimics (see “Microscopy”
section).
When there is doubt about the diagnosis of
MIC or the suspicious area is no longer seen on
any further sections or IHC, it is recommended
that the case should be diagnosed as in situ lesion
with no definite evidence of MIC.
As reported above, MIC can be not only over-
diagnosed but also underdiagnosed. MIC cannot
be reliably excluded unless all tissue is serially
sectioned, completely embedded, and submitted
for histological examination. This method is
now recommended in clinical guidelines
as well in breast screening programs.
However it is well-known that even with a
large number of paraffin blocks, only a part of
the tissue is examined microscopically, and
pathologists can never be absolutely certain that
MIC is really absent.
Serial sections supported by IHC usually
provide the best evidence of MIC. Care should
be taken to obtain IHC early in the evaluation
of suspected MIC, before the sample has been
sectioned excessively, first to confirm MIC and
second to exclude the possibility of larger
invasive foci.
References and Further Reading
Amin, M. B., Edge, S. B., Greene, F. L., et al. (Eds.).
(2017). AJCC cancer staging manual (8th ed.
pp. 589–628). New York: Springer.
Bianchi, S., & Vezzosi V. (2008). Microinvasive Carci-
noma of the Breast. Pathology and Oncology Research,
14, 105–111.
Cserni, G., Wells, C. A., Kaia, H., et al. (2016).
Consistency in recognizing microinvasion in breast
carcinomas is improved by immunohistochemistry for
myoepithelial markers. Virchows Archive, 468,
473–481.
Hilson, J. B., Schnitt, S. J., & Collins, L. C. (2009).
Phenotypic alterations in ductal carcinoma in situ-
associated myoepithelial cells: Biologic and diagnostic
implications. The American Journal Surgical Pathol-
ogy, 33, 227–232.
Hoda, S. A. (2014). Ductal carcinoma in situ.
In S. A. Hoda, E. Brogi, F. C. Koerner, & P. P. Rosen
(Eds.), Rosen’s breast pathology (4th ed., pp. 331–411).
Philadelphia: Lippincott Williams & Wilkins.
Morita, M., Yamaguchi, R., Tanaka, M., et al. (2016). Two
progressive pathways of microinvasive carcinoma:
Mucocele-like Lesion
Low-grade luminal pathway and high grade HER2
pathway based on high tumor-infiltrating lymphocytes.
Journal of Clinical Pathology, 69, 890–898.
Pinder, S. E., Ellis, I. O., Schnitt, S. J., et al. (2012).
Microinvasive carcinoma. In S. R. Lakhani, I. O.
Ellis, S. J. Schnitt, et al. (Eds.), WHO classification of
tumours of the breast (pp. 96–97). Lyon: International
Agency for Research on Cancer.
Schnitt, S. J., & Collins, L. C. (Eds.). (2013). Biopsy
interpretation of the breast (2nd ed.pp. 267–281).
Philadelphia: Lippincott Williams & Wilkins.
Mucocele-like Lesion
Janina Kulka
2nd Department of Pathology, Semmelweis
University, Budapest, Hungary
Synonyms
Mucocele-like tumor
Definition
Rosen, who first described these lesions in 1986,
gave the following definition: “mucin containing
cysts lined by flat or low cubical epithelium with
or without extravasated mucin” (Rosen 1986).
Clinical Features
• Incidence
Since the first description by Rosen in 1986,
single case reports or relatively small series
have been published. With the introduction of
screening programs, the incidence increased
due to the associated microcalcifications. The
incidence of MCLLs is very low, ranging from
0.25% (Jaffer et al. 2011) to <1% (102 MCLL
cases in a population of 13,412 women with
biopsy proven benign breast disease) (Meares
et al. 2016).
• Age
Since MCLLs are very often associated with
microcalcifications and are discovered mainly
Mucocele-like Lesion
on screening mammograms, the mean age
reported is 53–55 years.
• Sex
No MCLLs have been described in male
patients to date.
• Site
No specific site in the breast has been
described.
• Imaging
The majority of these lesions are nonpalpable,
detected on screening mammograms due to
associated indetermined, suspicious clustered,
coarse or pleomorphic microcalcifications
(Davies et al. 1995) (Fig. 1). Some MCLLs
present as a well-circumscribed mass. On ultra-
sound, cysts, cyst with calcification or a hypo-
echoic lesion may be present.
• Treatment
The appropriate treatment of MCLL is
debated. By definition, these lesions belong to
the B3 category of core biopsy diagnoses, and
earlier publications concluded that further sur-
gical excision is necessary. However, in recent
years, studies documented successful removal
of MCLLs by vacuum-assisted core biopsy
(VACB), a more conservative approach that
appears to be the appropriate treatment in
MCLLs without associated atypical epithelial
proliferation. In MCLLs associated with
Mucocele-like Lesion,
Fig. 1 Specimen
mammogram of a MCLL
detected in screening due to
the presence of coarse,
clustered
microcalcifications
301
atypical ductal hyperplasia (▶ Atypical Ductal
Hyperplasia) or DCIS (▶ Ductal Carcinoma In
Situ), even if VACB has been the diagnostic
method, further surgical excision seems the
right treatment.
• Outcome
According to the few large series (Jaffer et al.
2011; Meares et al. 2016; Dash et al. 2017), the
upgrade rate of MCLLs devoid of atypia diag-
nosed on VACB specimens is very low. Very
close radio-pathological correlation is necessary
and surgical excision can be avoided only if the
lesion had been removed entirely. In the Not-
tingham series (Rakha et al. 2013), 2/54 MCLL
without atypia on core biopsy were upgraded to
DCIS in the surgical excision specimen (4%
upgrade rate). However, altogether in published
series until 2013 among all MCLLs with atypi-
cal hyperplasia diagnosed on either 14G needle
biopsies or VACB the upgrade rate is 21%. In an
Australian series of 117 MCLLs, the upgrade
rate to DCIS – all low to intermediate grade –
was 5% (Dash et al. 2017).
The question of MCLL as a risk factor was
recently analyzed in one of the largest MCLL
M
series to date (Meares et al. 2016). Thirteen out
of 102 patients developed in situ or invasive
breast cancer during the follow-up period, the
median time to cancer was 11.8 years. It is
302
noteworthy that almost half of the cancers
developed in the contralateral breast. With
14.8 years median follow-up, it was found
that in women younger than 45, MCLL caused
only a nonsignificant increase in cancer risk
compared to the general population. In
women above that age, the cancer risk incre-
ment is low – equals that of proliferative breast
disease.
Macroscopy
Since MCLLs are usually less than 1 cm, non-
palpable lesions, description of their macroscopic
appearance is missing from most case reports and
is not emphasized either in larger case series. In
the original description by Rosen, the gross
appearances were described as follows: “irregular,
gelatinous, shiny area” or “ill-defined mucinous
mass,” or “multicystic colloid nodule.”
Microscopy
MCLLs of the breast are localized lesions, affect-
ing the terminal duct-lobular unit. The main fea-
ture is the dilatation and partial rupture of the
mucin filled- and cystically dilated ductules and
as a consequence, mucin leakage into the adjacent
stroma. (Fig. 2). MCLL has been described by
Mucocele-like Lesion,
Fig. 2 Subgross
appearance of a MCLL:
cystic, distended ductules in
a TDLU. Arrows point to
the extravasated mucin
Mucocele-like Lesion
numerous authors as part of the spectrum of
mucinous breast lesions, representing the first
step along the line leading to invasive mucinous
carcinoma through MCLL with atypia and mucin-
ous DCIS with mucocele-like features. MCLL
may have completely bland, flattened, cuboidal,
or low columnar epithelium, but some cases are
associated with papillary projections, epithelial
atypia, or frank DCIS (mucinous type, with crib-
riform, solid, papillary, or micropapillary archi-
tecture) and association with mucinous carcinoma
(▶ Invasive Mucinous Carcinoma) or no special
type invasive breast carcinoma (▶ Invasive Car-
cinoma NST) was also reported. MCLLs associ-
ated with DCIS (▶ Ductal Carcinoma In Situ)
may be extensive (Fig. 3, H&E: Low grade
DCIS associated with MCLL). The mucin filling
the ducts and extravasated in the stroma is PAS,
mucicarmin, and also Alcian blue positive at
pH 2.5, suggesting the presence of neutral to
acidic mucin in these lesions. An important clue
to the diagnosis is the lack of epithelial cell clus-
ters in the extravasated mucin pools. However, the
epithelial cells can detach from the cyst walls and
superficially may be reminiscent to the floating
epithelial cell clusters so characteristic in mucin-
ous carcinomas. It is of utmost importance that in
such cases the epithelial cell clusters be thor-
oughly analyzed: those in MCLLs are linear in
most of the cases, as they represent a cohesive
fragment of the lining epithelium of a mucin filled
Mucocele-like Lesion
Mucocele-like Lesion,
Fig. 3 H&E: Low-grade
DCIS associated
with MCLL
and/or ruptured cyst. In some cases, a complete
arborizing papillary structure may detach from the
cyst wall and be present in the extravasated
mucin. Lack of cellular atypia and presence of
myoepithelial cells are the key for the correct
diagnosis (Tan et al. 2008). A common feature
in MCLLs leading to their identification on
screening mammograms are (indeterminate – or
suspicious, coarse, and polymorphic) micro-
calcifications. Calcifications are common in the
mucin pools in MCLL (Fig. 4, H&E). In some
cases, a heavy stromal lymphoid cell infiltrate is
also present around the areas of extravasated
mucin (Fig. 5).
Immunophenotype
The epithelium in MCLL is two layered, as it is in
normal breast epithelium. Demonstration of the
presence of myoepitheial cells by p63, calponin,
smooth muscle actin, or other myoepithelial
markers may solve diagnostic dilemmas, if exist.
The MUC profile of MCLLs was investigated (Kim
et al. 2012) and compared to that of mucinous
carcinomas. MCLLs and mucinous carcinomas
type A showed similar MUC profile: MUC1
303
showed mainly luminal/apical or luminal/apical
and cytoplasmic expression. MUC2 was only
expressed in MCLLs associated with atypia or
DCIS and was positive in almost every mucinous
M
carcinoma studied.
Molecular Features
To date, no molecular studies have been
performed on MCLL series.
Differential Diagnosis
The most important differential diagnosis is
mucinous carcinoma (▶ Invasive Mucinous Car-
cinoma). In MCLL, in the extravasated mucin, no
epithelial cells are present as seen in cases of
mucinous carcinoma. However, in some cases of
MCLL, the epithelial lining of the cysts can be
detached, raising suspicion of mucinous carci-
noma. In such dubious cases, the correct diagnosis
may be assisted by the following features: in
MCLL, the epithelial cell clusters tend to be lin-
ear, and p63 immunohistochemistry shows the
presence of myopithelial cells. In contrast,
304
Mucocele-like Lesion,
Fig. 4 H&E: MCLL with
microcalcification
Mucocele-like Lesion,
Fig. 5 H&E: Foci of
lymphoid cell infiltrate in
the vicinity of acellular
mucin pools
mucinous carcinomas’ cell clusters are more
abundant and are formed by uniformly atypical
cells. When a MCLL is associated with atypia or
DCIS, the correct diagnosis requires even greater
caution.
The diagnostic dilemma is even more diffi-
cult in core biopsies, when only fragments of the
lesion can be evaluated. A helpful feature is the
presence of totally acellular mucin in cases of
MCLL and lack of atypia of the epithelial cells,
if present. Multiple levels may help to confirm
the lack of epithelium in the mucin pools. In
mucinous carcinoma the areas of extracellular
mucin often contain small vessels embedded in
thin fibrous bands, which is not a feature in
Mucocele-like Lesion
MCLLs. Cytology diagnosis of MCLL requires
great caution, since the presence of mucinous
material on the smears may lead to erroneous
conclusion. It is also important to keep in mind
that mucinous carcinomas occur mostly in older
women than do MCLLs. The difficulty is even
greater when MCLL is associated with atypia or
frank DCIS. In such cases, fragments of the
atypical epithelium may detach and float in the
extravasated mucin. The linear appearance of
these epithelial fragments may help not to over-
diagnose the case as mucinous carcinoma
(Fig. 3). Nevertheless, in some cases, it is
impossible to unequivocally differentiate a
MCLL from a mucinous carcinoma on core
Mucoepidermoid Carcinoma of the Breast 305

Mucocele-like Lesion, Table 1 Differential diagnosis of MCLL and mucinous carcinoma (Based on Torous et al. 2017)
Clinical presentation
Microscopy
Extracellular mucin
Epithelium
Immunohistochemistry
MCLL
Most often incidentally detected on
(screening) mammography due to
microcalcifications
Acellular; may contain detached linear
fragments of epithelium
Most often low cuboidal to columnar
without atypia, proliferative changes and
papillarization may be present; usual type-
or atypical ductal hyperplasia and DCIS
may be associated; myoepithelial cells are
present
Myoepithelial markers stain the
myoepithelial cells, but staining may be
absent in associated ADH or DCIS
Mucinous carcinoma
Usually presents as a mass (palpable or
radiologically detected)
Tumor cell clusters floating in the mucin;
evidence of neovascularization
Low to intermediate grade nuclear atypia of
the tumor cells that form small clusters in
the mucin pools; myoepithelial cells are not
seen
No myoepithelial cells can be identified

biopsy and these doubts have to be stated in the
report (Table 1).
Cystic hypersecretory breast lesions may
superficially resemble to MCLL at low power.
However, in cystic hypersecretory breast lesions
(hyperplasias and DCIS), the secretion that fills
the cystic spaces is deeply eosinophilic and
resembles thyroid colloid.
An extremely rare breast tumor, mucinous
cystadenocarcinoma may also possess extrava-
sated mucin pools, but myoepithelial cells are
not present, the epithelial cells are tall columnar
cells and contain intracellular mucin, both fea-
tures lacking in MCLL.
& Visscher, D. W. (2016). Mucocele-like lesions of the
breast: A cliniical outcome and histologic analysis of
102 cases. Human Pathology, 49, 33–38.
Rakha, E. A., Shaaban, A. M., Asma Haider, S., Jankins, J.,
Menon, S., Johnson, C., Yamaguchi, R., Murphy, A.,
Liston, J., Cornford, E., Hamilton, L., James, J., Ellis,
I. O., & Lee, A. H. S. (2013). Histopathology, 62,
894–898.
Rosen, P. P. (1986). Mucocele-like tumors of the
breast. American Journal of Surgical Pathology, 10, M
464–469.
Tan, P. H., Tse, G. M. K., & By, B. H. (2008). Mucinous
breast lesions: Diagnostic challenges. Journal of Clin-
ical Pathology, 6, 11–19.
Torous, V. F., Schnitt, S. J., & Collins, L. C. (2017). Benign
breast lesions that mimic malignancy. Pathology, 49,
181–196.

References and Further Reading

Mucoepidermoid Carcinoma
Dash, I., Dessauvagie, B., Hardie, M., Saunders, C., & of the Breast
Wilie, E. (2017). Mucocele-like lesions: Is surgical
excision still necessary. Clinical Radiology, 72, 992. Maria P. Foschini and Luca Morandi
e1–992.e6.
Davies, J. D., Kutt, E., Kulka, J., Farndon, J. R., & Webb,
Department of Biomedical and Neuromotor
A. J. (1995). Mucocoele-like lesions detected by the Sciences, University of Bologna, Unit of
mammographic presence of suspicious clustered Anatomic Pathology at Bellaria Hospital,
microcalcifications. The Breast, 5, 135–140. Bologna, Italy
Jaffer, S. J., Bleiweiss, I. J., & Nagi, C. S. (2011). Benign
mucocele-like lesions of the breast: Revisited. Modern
Pathology, 24, 683–687.
Kim, D., Jung, W.-H., & Koo, J. S. (2012). Expression Definition
of MUC1, MUC2, MUC5AC and MUC5B in
mucinous lesions of the breast. Pathobiology, 79,
144–153.
Mucoepidermoid carcinoma (MEC) of the breast
Meares, A. L., Frank, R. D., Degnim, A. C., Vierkant, is a tumor composed of mucous-secreting inter-
R. A., Frost, M. H., Hartmann, L. C., Winham, S. J., mediate and epidermoid cells. It can present a
306 Mucoepidermoid Carcinoma of the Breast

great variety of architectural patterns, ranging Macroscopy

from cystic to solid. Its features are similar to
MEC arising in the major and minor salivary Breast MEC presents as nodule, ranging from a
glands (Foschini et al. 2017; Foschini and Krausz few millimeters to 11 cm. Nodules can be solid or
2010). cystic.

Clinical Features Microscopy

• Incidence Histology is characterized by the presence of

Breast MEC is an extremely rare type of tumor. mucous-secreting intermediate and epidermoid
Its incidence is not exactly known, as only cells. Their features vary according to the tumor
single case or small series are reported grade (Di Tommaso et al. 2004; Foschini
(Basburg 2011; Foschini 2017). et al. 2017).
• Age
MEC affects mainly adult patients, aged from
29 to 80 years.
• Sex
At present breast MEC has been described in
female patients only.
• Site
MEC can arise in all breast quadrants. When it
affects the retro-areolar region, it can present
with nipple discharge.
• Treatment
Radical surgical resection is the treatment of
choice. Axillary lymph node dissection and
chemotherapy have been added in high-
grade MEC.
• Outcome Mucoepidermoid Carcinoma of the Breast,
Outcome mainly depends on MEC grading. Fig. 1 Low-grade MEC with predominant cystic component
MEC, according to breast or salivary gland (H&E)
grading systems, can be of low, intermediate,
or high grade. None of the patients with low or
intermediate grade tumors died of disease
(Basburg et al. 2011; Foschini and Krausz
2010; Foschini et al. 2017). One case only of
MEC low grade recurred as high grade, but the
patient, after receiving radical surgical exci-
sion, remained alive and well 156 months
after surgery (Tjalma et al. 2002).
On the contrary 5/11 patients affected by
high-grade MEC developed distant metastases
and died of the disease. All these cases had Mucoepidermoid Carcinoma of the Breast,
axillary metastases at presentation (Basburg Fig. 2 Low-grade MEC composed of different cell
types: basaloid cells (indicated by “B”) are located at the
et al. 2011). These features underline the
periphery of the neoplastic nests, while epidermoid cells
importance of correct grading and staging in (indicated by “E”) are located in the central part of the
this type of tumor. neoplastic nests (H&E)
Mucoepidermoid Carcinoma of the Breast
Low-grade MEC are characterized by mixture
of basaloid, intermediate, epidermoid, and
mucous-secreting cells arranged mainly in cystic
and solid nests (Figs. 1 and 2 H&E). Basaloid
cells are usually located at the periphery of the
neoplastic nodules, while the center of the nod-
ule is mainly composed of intermediate and epi-
dermoid cells (Fig. 3 H&E). True keratinization
is not a feature of MEC. Epidermoid and inter-
mediate cells have wide and granular eosino-
philic, less frequently clear cytoplasm that
can be enriched in mitochondria. Nuclei are
centrally located. Mucous cells usually line the
cystic areas (Fig. 3 H&E). Alcian Blue pH 2.5
and PAS after diastase digestion can evidence
the mucous-secreting cells. On rare occasions,
mucous-secreting cells have a signet ring
appearance (Fig. 4a and b H&E). In low-grade
MEC, atypia is mild, atypical mitotic
figures are extremely rare, and no necrosis is
Mucoepidermoid Carcinoma of the Breast,
Fig. 3 Low-grade MEC with cystic features; mucous-
secreting cells line the cystic component. Epidermoid
cells, devoid of true keratinization, are present (H&E)
Mucoepidermoid Carcinoma of the Breast, Fig. 4 (a and b) Low-grade (a) and intermediate-grade (b) MEC: single
mucous-secreting cells are indicated by arrows (H&E)
307
seen. In situ component having the same cell
population can be present, associated with inva-
sive MEC.
High-grade MEC share the same cell features
of low-grade MEC but show a higher degree of
cellular atypia and higher mitotic count; necrosis
can be encountered.
One case only of MEC of intermediate malig-
nancy grade was reported by Di Tommaso et al.
(2004). The same case showed solid architectural
pattern with prevalence of intermediate and epi-
dermoid cells and focal presence of mucous-
secreting cells.
Immunophenotype
Immunohistochemistry can be helpful in the
diagnosis of breast MEC, and each single cell
type has its peculiar immunohistochemical
pattern.
Basaloid, intermediate, and epidermoid cells
are mainly positive with high-molecular-weight
cytokeratins (CK) as CK 14 and with p63. These
same cells can be positive with anti-mitochondrial
M
antibody but to a lesser intensity than observed in
salivary gland counterpart.
On the contrary mucous-secreting cells are
positive with low-molecular-weight CK as CK7,
epithelial membrane antigen (EMA), and MUC 1,
MUC 5 AC, and MUC 6.
Estrogen, progesterone receptors, and HER2
are consistently negative in all the reported
cases.
308
Molecular Features
Salivary gland MEC is characterized by the
MECT-MAML2 translocation. Similarly, Camelo-
Piragua et al. (2009) found the 11q21 deletion at
the site of MAML2 gene.
Differential Diagnosis
Low-grade MEC diagnosis can be difficult when
clear cells or mitochondrion-rich cells are numer-
ous, raising the suspicion of clear cell carcinoma
or of oncocytic carcinoma (▶ Invasive Oncocytic
Carcinoma). The differential diagnosis is mainly
based on the detection of mucous-secreting cells
intermingled with the neoplastic population.
Diagnosis is more difficult in high-grade MEC.
Differential diagnosis should be carried out
mainly with carcinomas showing adenosquamous
features (▶ Low-Grade Adenosquamous Carci-
noma). These latter tumors usually show true
keratinization features that are usually lacking in
both low- and high-grade MEC.
References
Basbug, M., Akbulut, S., Arikanoglu, Z., Sogutcu, N.,
Firat, U., & Kucukoner, M. (2011). Mucoepidermoid
carcinoma in a breast affected by burn scars: Compre-
hensive literature review and case report. Breast Care
(Basel), 6, 293–297.
Camelo-Piragua, S. I., Habib, C., Kanumuri, P., Lago,
C. E., Mason, H. S., & Otis, C. N. (2009).
Mucoepidermoid carcinoma of the breast shares cyto-
genetic abnormality with mucoepidermoid carcinoma
of the salivary gland: A case report with molecular
analysis and review of the literature. Human Pathology,
40, 887–892.
Di Tommaso, L., Foschini, M. P., Ragazzini, T., Magrini,
E., Fornelli, A., Ellis, I. O., & Eusebi, V. (2004).
Mucoepidermoid carcinoma of the breast. Virchows
Archives, 444, 13–19.
Foschini, M. P., & Krausz, T. (2010). Salivary gland-type
tumors of the breast: A spectrum of benign and malig-
nant tumors including “triple negative carcinomas” of
low malignant potential. Seminar in Diagnostic Pathol-
ogy, 27, 77–90.
Foschini, M. P., Morandi, L., Asioli, S., Giove, G.,
Corradini, A. G., & Eusebi, V. (2017). The morpholog-
ical spectrum of salivary gland type tumours of the
breast. Pathology, 49, 215–227.
Myoepithelial Carcinoma of the Breast
Tjalma, W. A., Verslegers, I. O., De Loecker, P. A., & Van
Marck, E. A. (2002). Low and high grade
mucoepidermoid carcinomas of the breast. European
Journal of Gynaecological Oncology, 23, 423–425.
Myoepithelial Carcinoma of
the Breast
Horst Bürger
Institute of Pathology Paderborn/Höxter,
Paderborn, Germany
Synonyms
Malignant myoepithelioma; Metaplastic carci-
noma; Spindle cell carcinoma
Definition
A malignant lesion composed of myoepithelial
cells with increased mitotic activity and expres-
sion of myoepithelial markers, such as high
molecular weight cytokeratins, p63, smooth mus-
cle actin, and others.
Clinical Features
• Incidence
Myoepithelial carcinomas of the breast repre-
sent an extremely rare and poorly understood
entity of invasive breast cancer. The exact inci-
dence of these tumors is unknown, partially due
to the disputed definition. According to the
actual WHO classification, myoepithelial carci-
nomas are a subgroup of metaplastic carcinoma
(Reis-Filho et al. 2012). Under these assump-
tions, the incidence is probably significantly
lower than <1%.
• Age
Myoepithelial carcinomas have been seen in all
age groups from 25 to 81 years.
• Sex
Rare cases of myoepithelial carcinoma of the
breast have been described in women. The
incidence in male patients is not known.
Myoepithelial Carcinoma of the Breast 309

• Site
A predominant site within the breast has not
been described.
• Treatment
Recommendations concerning the treatment of
these lesions are differing. This is mainly due
to the unsharp definition of this tumor entity.
Since some regard atypical adenomyoe-
pithelioma as one end of a morphological spec-
trum and myoepithelial carcinoma as the other
end, the treatment of these former tumors sig-
nificantly differs from myoepithelial carci-
noma fulfilling the criteria of ▶ metaplastic
carcinoma. Myoepithelial Carcinoma of the Breast,
Fig. 1 Myoepithelial carcinoma of the breast (H&E)
Whereas atypical adenomyoepithelioma (200)
does not fulfil the criteria to justify a treatment
as invasive carcinoma, myoepithelial carcino-
mas are treated according to the respective supports the diagnosis of myoepithelial carci-
guidelines for metaplastic, hormone receptor- noma (Tan and Ellis 2013). Extensive sampling
negative cancers. of the tumor is required since in most cases an
• Outcome adenomyoepithelial component may give hints to
Reliable data concerning the outcome are rare. the myoepithelial differentiation of this tumor.
Limited follow-up data report an increased In-situ carcinoma can also be observed in a large
local recurrence rate and a rather low incidence subset of tumors, indicating the epithelial origin of
of regional lymph node metastasis. the malignant lesion.
M

Macroscopy
Immunophenotype
Myoepithelial carcinomas might present as round
The immunophenotype reflects the expression
to oval, well-demarcated nodules as well as
patterns observed in normal myoepithelial cells.
tumors with irregular borders and overt infiltrating
This includes the expression of keratins, mainly
growth pattern. Hemorrhage, cystic degenera-
high molecular weight cytokeratins (Ck5, 14, 17),
tions, and calcifications can be seen. In most
smooth muscle actin, vimentin, caldesmon,
cases, the tumors appear as white-grey tumors
calponin, S-100, CD10, GFAP, D2–40 (examples
with largely varying size (up to >20 cm diameter).
given in Fig. 2a–c) and the lack of expression of
estrogen receptor (ER), progesterone receptor (PR),
and negativity for HER2 (Schmitt et al. 2012).
Microscopy

Typically myoepithelial carcinoma presents as a Molecular Features

proliferation of spindle cells, sometimes
intermingled by epithelioid appearing cells
(Fig. 1). Typically, remnants of normal breast
parenchyma seem to be entrapped by the spindle
cells. In some cases, the spindle cells adjacent to
the normal breast remnants seem to originate from
normal myoepithelial cells. This finding strongly
Little is known about molecular features of “pure”
myoepithelial carcinomas. Since myoepithelial
carcinomas are nowadays regarded as a subgroup
of metaplastic carcinoma, more information on
the genetic status of these tumors are available
(Tavassoli and Eusebi 2009).
310
Myoepithelial Carcinoma of the Breast, Fig. 2 (a)
Myoepithelial carcinoma of the breast with focal positivity
for p63 (200). (b) Myoepithelial carcinoma of the breast
with focal expression of cytokeratin (200).
In general, these tumors reveal a high number
of genetic alterations, indicating a high genetic
instability. Major hallmarks, however, only seen
in rather small proportions are p53-alterations,
EGFR amplification, lack of HER2 expression,
and negativity for ER and PR.
However, one series described a lower rate of
genetic alterations per case compared to invasive
breast cancer no-special type. This discrepancy
seems to be a reflection of the controversial defi-
nitions of myoepithelial carcinoma.
Differential Diagnosis
The differential diagnosis of these tumors is,
despite a clear immunophenotype, complicated
and reflects the current discussion concerning the
Myoepithelial Carcinoma of the Breast
(c) Myoepithelial carcinoma of the breast with strong and
homogeneous positivity for D2–40 as a marker of
myoepithelial differentiation (200)
exact classification of these tumors (Weidner and
Dabbs 2012; Schnitt and Collins 2009; Fine and
Kurdek 2016).
Therefore, myoepithelial carcinomas should be
separated from all kind of spindle cell lesions of
the breast, mainly spindle cell carcinomas and all
forms of ▶ metaplastic carcinoma.
Since the morphological and immunohisto-
chemical differential diagnosis between these
tumors might be arbitrary, some authors regard
the distinction between these tumors rather as a
problem of semantics.
At the current state, it is not clear if this sub-
grouping is supported by other hallmarks, e.g.,
molecular findings. Other authors argue that due
to a very close morphological relationship
between myoepithelial carcinomas and
adenomyoepithelial tumors, these tumors might
Myoepithelial Carcinoma of the Breast
be seen as the extreme end of a morphological
continuum of tumors with a predominant
myoepithelial differentiation.
Malignant ▶ phyllodes tumor can be a differ-
ential diagnosis. However, the lack of epithelial
glands, expression of high molecular weight
cytokeratins, p63, and other markers of
myoepithelial differentiation allows a clear dis-
tinction from myoepithelial carcinomas in the
vast majority of the cases.
Fibromatosis, a spindle cell proliferation
rarely seen in the breast may also be considered.
Lack of p63 and high molecular weight
cytokeratin positivity in these lesions helps to
make distinction from myoepthelial carcinoma.
References and Further Reading
Fine, M. A., & Kurdek, L. A. (2016). An approach to the
diagnosis of spindle cell lesions of the breast. Histopa-
thology, 68, 33–44.
311
Reis-Filho, J. S., Lakhani, S. R., Gobbi, H., & Sneige,
N. (2012). Metaplastic carcinoma. In S. R. Lakhani,
I. O. Ellis, S. J. Schnitt, P. H. Tan, & M. J. van de Vijver
(Eds.), WHO classification of tumours of the breast
(pp. 119–124). IACR: Lyon.
Schmitt, F., Tan, P. H., Dabbs, D., & Jones, L. (2012).
Myoepithelial and epithelial–myoepithelial lesions.
In S. R. Lakhani, I. O. Ellis, S. J. Schnitt, P. H.
Tan, & M. J. van de Vijver (Eds.), WHO classifi-
cation of tumours of the breast (pp. 119–124).
IACR: Lyon.
Schnitt, S. J., & Collins, L. C. (2009). Spindle cell lesions.
In S. J. Schnitt (Ed.), Biopsy interpretation of the breast
(pp. 323–343). Philadelphia: Lippincott Williams &
Wilkins.
Tan, P. H., & Ellis, I. O. (2013). Myoepithelial and
epithelial–myoepithelial, mesenchymal and
fibroepithelial breast lesions: Updates from the WHO
Classification of Tumours of the Breast 2012. Journal
of Clinical Pathology, 66, 465–470.
Tavassoli, F. A., & Eusebi, V. (2009). Myoepithelial
lesions. In F. A. Tavassoli & V. Eusebi (Eds.), Tumors
of the mammary gland (pp. 249–262). Washington,
DC: Armed Forces Institute of Pathology.
Weidner, N., & Dabbs, J. D. (2012). Myoepithelial lesions
of the breast. In D. J. Dabbs (Ed.), Breast pathology
(pp. 307–323). Philadelphia: Saunders.
M
P
Paget Disease of the Nipple
Janina Kulka1 and Anna Sapino2,3
1
2nd Department of Pathology, Semmelweis
University, Budapest, Hungary
2
Unit of Pathology, Candiolo Cancer Institute
FPO-IRCCS, Candiolo, Italy
3
Department of Medical Sciences, University of
Turin, Turin, Italy
Synonyms
Mammary Paget disease; Paget disease of the
breast; Paget disease of the nipple and areola
Definition
Paget disease (PD) is characterized by the pres-
ence of malignant glandular epithelial cells (Paget
cells) within the squamous epithelium of the nip-
ple that may extend into the areola and adjacent
skin (Shousha et al. 2012).
Clinical Features
• Incidence
PD was first described by the British surgeon
Sir James Paget in 1874. It is a rare disease; its
exact incidence in unknown. It is estimated to
occur in 1–4% of all breast cancer patients. PD
© Springer Nature Switzerland AG 2020
A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
is associated with an underlying in situ or inva-
sive breast carcinoma in 82–94% of cases
(Wong et al. 2015). Wong et al. in their large
American patient cohort described statistically
significant decrease in the age-adjusted
incidence of the disease from 2000 to 2011,
mainly due to decreasing rates of PD with
underlying carcinoma (Wong et al. 2015). PD
without underlying malignant lesion is
considered pTis.
• Age
PD most commonly affects middle-aged
women, occurring between 50 and 60 years
of age, although it has been reported in young
patients in their late 20s.
• Sex
PD of the nipple almost exclusively affects
women. However, there have been rare cases
described in men (Adams and Kanthan 2016).
• Site
The nipple and adjacent areas are typical sites
of this lesion. However, rarely, in advanced
cases, PD may affect large areas of the
breast skin.
• Symptoms
The initial skin changes of PD often mimic
eczema or other inflammatory skin disease: a
crusted or scaly red or pale lesion involving the
nipple, with itching, burning sensations, sore-
ness, or pain. For this reason, the diagnosis is
often delayed up to 6 months or more. Most
women presenting with PD have an underlying
ductal carcinoma in situ (DCIS) (Fig. 1a) or
314
Paget Disease of the Nipple, Fig. 1 (a) Paget disease of
the nipple with underlying DCIS in large ducts (H&E).
(b) Paget cells in the epidermis forming nests (H&E).
(c) Massive intraepidermal spread of Paget cells is
invasive carcinoma, which may be palpable in
about half of the cases. Three different clinical
patterns have been described: (1) changes in the
nipple-areola complex with palpable mass,
(2) changes in the nipple-areola complex without
palpable mass, and (3) subclinical PD found
incidentally in the surgical pathology specimen
of either a breast mass or prophylactic mastec-
tomy (Sandoval-Leon et al. 2013).
• Treatment
Where no underlying malignant tumor is pre-
sent, and the disease is confined to the nipple
and areola, conservative surgery is
recommended with removal of the nipple and
areola along with a safe layer of the underlying
breast tissue. In case a breast cancer (in situ or
invasive) is found, the surgical or neoadjuvant
oncology treatment is tailored to their
characteristics.
• Outcome
The overall disease course depends upon the
nature and size of the underlying malignancy.
Paget Disease of the Nipple
highlighted by CK 7 positivity (CK7 IHC reaction). (d)
Paget cells are GATA3 positive (GATA3 IHC reaction). (e)
In this case, Paget cells are strongly HER2 positive (HER2
IHC reaction)
Macroscopy
In diagnostic excision specimens, an area of
superficial skin erosion may be identified or no
macroscopic lesion is present.
Microscopy
The cells of PD of the nipple are pleomorphic,
large, usually with nuclei showing irregular
nuclear contours, and prominent nucleoli. The
cytoplasm is eosinophilic or amphophilic, often
abundant and may contain mucin. Paget cells are
usually present singly or in small aggregates
(Fig. 1b); they rarely form glands (Shousha
2007; Barnes et al. 2007). The atypical cells
may be scattered within the whole thickness of
the epidermis. Rare reports of PD of the nipple
have been attributed to intraepidermal spread of
lobular carcinoma in situ (LCIS) (Sahoo
et al. 2002).
Paget Disease of the Nipple
Paget Disease of the Nipple, Fig. 2 Melanin pigment is
present in the cytoplasm of a Paget cell (H&E)
Pigmented variant of PD is an increasingly
well-recognized mimic of melanoma not only his-
tologically but clinically and dermatoscopically as
well. In this variant, the Paget cells have melanin
pigment in their cytoplasm (Fig. 2), and
melanophag cells are also present in the dermis.
In most such cases, immunohistochemical reac-
tions are necessary to the correct diagnosis. Ana-
plastic PD was first described in 1992 (Rayne and
Santa Cruz 1992) as a rare variant mimicking
Bowen’s disease. Full thickness atypia of the epi-
dermis and acantholysis (Fig. 3) are the main
features of this variant. Dyskeratotic cells are not
present, and rare atypical cells with
intracytoplasmic vacuoles can be found. Mucin
stains, and other usual immunohistochemical
markers of conventional PD (see below), may be
negative. In this first series of six cases, three
patients had underlying invasive carcinoma. Inva-
sive PD, i.e., invasion of the dermis by Paget
cells is extremely rare: only 15 patients have
been reported until 2014 (Lee et al. 2014). The
invasive foci show identical phenotype to the
intraepidermal lesion. Patterns of invasion are
either single-cell infiltration or small, solid cell
clusters or gland-forming tumor cell clusters.
Immunophenotype
Paget cells are almost invariably positive for
cytokeratin 7 (Fig. 1c), Cam 5.2 and EMA, usually
positive for CEA, GATA3 (Fig. 1d), often positive
for HER2 (Fig. 1e) and rarely for GCDFP-15.
Cytokeratin 7 negative PD have been described as
315
Paget Disease of the Nipple, Fig. 3 Acantholysis in a
case of PD (H&E)
a rare finding causing severe diagnostic dilemma
(Ozerdem et al. 2016). Paget cells are negative for
high molecular weight cytokeratins. S100
immunostaining may be positive in PD of the nip-
ple, but Paget cells are negative for other
melanocytic markers, e.g., HMB45, SOX10, and
Melan-A (Table 1). Other immunohistochemical
markers that have been described in more than
75% of PD cases are p16, androgen receptor,
CK8/18, CK19, MUC3, Claudins 3 and 4,
NY-BR1 (Sandoval-Leon et al. 2013). In a recent
study focusing on surrogate subtypes of PD of the
nipple-areola complex and the underlying breast
carcinoma, the authors showed that in PD the
HER2 subtype predominates (cca. two third of the
cases) followed by Luminal B HER2 positive sub- P
type. In the majority of the cases, PD and the under-
lying invasive carcinoma share immunophenotype;
however, discrepant cases are not uncommon (cca.
one quarter of the cases). The Ki67 labeling index is
above 20% (Wachter et al. 2019). Earlier studies
already showed that associated carcinomas are usu-
ally high grade, and Paget cells are estrogen and
progesterone receptor (ER/PR) negative in the vast
majority of cases (Meissner et al. 1990; Wolber et al.
1991; Anderson et al. 2003; Bianco and Vasef
2006).
Molecular Features
In a recent study using whole exome sequencing
technique, the most frequent recurrent mutations
occurred in the chromatin remodeling genes:
316 Paget Disease of the Nipple

Paget Disease of the Nipple, Table 1 Immunohistochemical characteristics of the main entities in the differential
diagnosis of Paget disease
Paget In situ squamous cell carcinoma/Bowen Malignant
disease Toker cells disease melanoma
Cytokeratin 7 + +
Cam 5.2 + +
EMA + +
CEA +
GATA3 + No reports
available
Cytokeratin +
5/6
p63 +
S100 + or + or +
Melan-A +
HMB45 +
SOX10 +
ER/PR Usually May be + or
HER2 Often +
Mucin May be + Not present Not present Not present
Major source: Jacobs, T.W. Clear Cells of Toker in the Nipple Epidermis, Case presentation, USCAP 2010 Annual
Meeting

KMT2C (MLL3, 39%) and ARID2 (22%), with
additional recurrent somatic mutations, such as
CDCC168 (34%), FSIP2 (29%), CASP8AP2
(29%), and BIRC6 (24%). Interestingly, in paired
mammary PD and underlying breast carcinoma
samples, in 3 cases out of 20, distinct gene muta-
tions were detected, suggesting independent
oncogenic events in the pathogenesis of these
lesions (Zhang et al. 2019). Mai et al. (2018)
described dysregulation of FOXA1 and the
nuclear receptor signaling pathway in both mam-
mary and extramammary PD.
Differential Diagnosis
Differential diagnosis of PD includes those
lesions characterized by so-called intraepidermal
“pagetoid spread” of atypical cells: pagetoid
Bowen’s disease, malignant melanoma, pagetoid
Spitz nevus, Merkel cell carcinoma, mycosis
fungoides, Langerhans histiocytosis, and ductal
eccrine carcinoma (Sandoval-Leon et al. 2013).
Paget cells are not to be mistaken with Toker cells
(▶ Toker Cells of the Nipple). In Bowen’s disease,
intracellular mucin, signet ring cells, and
glandular structures are absent. As opposed to
PD, high molecular weight cytokeratins are
expressed by the atypical cells. Paget cells may
take up melanin pigment released by epidermal
cells or melanocytes (referred to as pigmented PD
in the literature), mimicking malignant mela-
noma: both PD and melanoma in situ may show
an intraepidermal population of epithelioid cells
individually or arranged in small nests and the
presence of atypical epithelioid cells in the supra-
basal layer. Both lesions may show melanin pig-
ment not only within tumor cells’ cytoplasm but
also in dermal melanophages and within dendritic
melanocytes between tumor cells (Solinas et al.
2018). HER2 staining if positive is particularly
useful (especially in the differential diagnosis
with melanoma, pagetoid Spitz nevus, in situ
squamous cell carcinoma/pagetoid Bowen disease
and Toker cells (▶ Toker Cells of the Nipple),
which are all negative). The distinction between
LCIS involving the nipple skin in the form of PD
versus Toker cells may be difficult since both have
bland appearing cells. However, Toker cells are
E-cadherin positive as opposed to LCIS cells. The
neoplastic T cells in mycosis fungoides have large
convoluted (cerebriform) nuclei, pale cytoplasm,
Paget Disease of the Nipple
and show CD3 positivity. Similar to occasional
cases of PD, a clear halo is often seen around
single neoplastic cells. Furthermore, Pautrier
microabscesses may resemble glandular struc-
tures in PD. In various forms of histiocytoses,
the nuclei of the atypical cells are large, bean
shaped, and the cytoplasm stains pale. If in
doubt, CD1a, HLA-DR, and S100 immunohisto-
chemical positivity of the atypical histiocytes is
helpful (Lloyd and Flanagan 2000). Ductal
eccrine carcinoma arising in the nipple-areola
region may mimic PD both clinically and histo-
logically in a biopsy specimen (Park et al. 2001).
As opposed to PD, eccrine adnexal tumors are p63
positive. Merkel cell carcinomas may also have a
pagetoid intraepidermal component. The tumor
cells, however, are positive for neuroendocrine
immunohistochemical markers unlike Paget cells
(Stanoszek et al. 2017). Satellite invasive breast
carcinoma focus involving the areolar skin with
exulceration (pT4b) is a different entity and
should not be misinterpreted as PD.
References and Further Reading
Adams, S. J., & Kanthan, R. (2016). Paget’s disease of the
male breast in the 21st century: A systematic review.
The Breast, 29, 14–23.
Anderson, J. M., Ariga, R., Govil, H., Bloom, K. J.,
Francescatti, D., Reddy, V. B., et al. (2003). Assess-
ment of Her-2/Neu status by immunohistochemistry
and fluorescence in situ hybridization in mammary
Paget disease and underlying carcinoma. Applied
Immunohistochemistry and Molecular Morphology,
11, 120–124.
Barnes, P. J., Dumont, R. J., & Higgins, H. G. (2007).
Acinar pattern of mammary Paget’s disease: A case
report. The Breast Journal, 13, 520–526.
Bianco, M. K., & Vasef, M. A. (2006). HER-2 gene ampli-
fication in Paget disease of the nipple and extra-
mammary site: A chromogenic in situ hybridization
study. Diagnostic Molecular Pathology, 15, 131–135.
Jacobs, T. W. Clear cells of Toker in the Nipple Epidermis.
USCAP 2010 Annual Meeting, Specialty Conference,
Breast Pathology, Case 2. http://uscapknowledgehub.
org/newindex.htm?99th/specbreah2.htm
Lee, H. W., Kim, T. E., Cho, S. Y., Kim, S. W., Kil, W. H.,
Lee, J. E., Nam, S. J., & Cho, E. Y. (2014). Invasive
Paget disease of the breast: 20 years of experience at a
single institution. Human Pathology, 45, 2480–2487.
Lloyd, J., & Flanagan, A. M. (2000). Mammary and extra-
mammary Paget’s disease. Journal of Clinical Pathol-
ogy, 53, 742–749.
317
Mai, R., Zhou, S., Zhou, S., Zhong, W., Hong, L., Wang,
Y., Lu, S., Pan, J., Huang, Y., Su, M., Crawford, R.,
Zhou, Y., & Zhang, G. (2018). Transcriptome analyses
reveal FOXA1 dysregulation in mammary and extra-
mammary Paget’s disease. Human Pathology, 77,
152–158.
Meissner, K., Riviere, A., Haupt, G., & Loning, T. (1990).
Study of neu-protein expression in mammary Paget’s
disease with and without underlying breast carcinoma
and in extramammary Paget’s disease. American Jour-
nal of Pathology, 137, 1305–1309.
Ozerdem, U., McNiff, J. M., & Tavassoli, F. A. (2016).
Cytokeratin 7-negative mammary Paget’s disease:
A diagnostic pitfall. Pathology Research and Practice,
212, 279–281. https://doi.org/10.1016/j.prp.2016.01.004.
Epub 22 Jan 2016.
Park, B. W., Kim, S. I., Lee, K. S., & Yang, W. I. (2001).
Ductal eccrine carcinoma presenting as a Paget’s
disease-like lesion of the breast. The Breast Journal,
7, 358–362.
Rayne, S. C., & Santa Cruz, D. J. (1992). Anaplastic
Paget’s disease. American Journal of Surgical Pathol-
ogy, 16, 1085–1091.
Sahoo, S., Green, I., & Rosen, P. P. (2002). Bilateral Paget
disease of the nipple associated with lobular carcinoma
in situ. Archives of Pathology and Laboratory Medi-
cine, 126, 90–92.
Sanders, M. A. G. Paget disease. PathologyOutlines.com
website. http://www.pathologyoutlines.com/topic/breast
malignantpaget.html. Accessed 13 Jan 2019.
Sandoval-Leon, A. C., Drews-Elger, K., Gomez-
Fernandez, C. R., Yepes, M. M., & Lippman, M. E.
(2013). Paget’s disease of the nipple. Breast Cancer
Research and Treatment, 141, 1–12.
Shousha, S. (2007). Glandular Paget’s disease of the nip-
ple. Histopathology, 50, 812–814.
Shousha, S., Eusebi, V., & Lester, S. (2012). Paget disease P
of the nipple. In S. R. Lakhani, I. O. Ellis, S. J. Schnitt,
P. H. Tan, & M. J. van de Vijver (Eds.), WHO classifi-
cation of tumours of the breast (4th ed., pp. 152–153).
Lyon: IARC.
Solinas, A., Mahar, A., Cooper, W. A., Thompson, J. F.,
Spillane, A. J., & Scolyer, R. A. (2018). Pigmented
Paget’s disease of the nipple mistaken for melanoma
in situ: A diagnostic pitfall for the unwary. Pathology,
50, 364–367.
Stanoszek, L. M., Wang, G. Y., & Harms, P. W. (2017).
Archives of Pathology and Laboratory Medicine, 141,
1490–1502.
Wachter, D. L., Wachter, P. W., Fasching, P. A.,
Beckmann, M. W., Hack, C. C., Riener, M. O.,
Hartmann, A., & Strehl, J. D. (2019). Characterization
of molecular subtypes of Paget disease of the breast
using immunohistochemistry and in situ hybridiza-
tion. Archives of Pathology and Laboratory Medicine,
143, 206–211.
Wolber, R. A., Dupuis, B. A., & Wick, M. R. (1991).
Expression of c-erbB-2 oncoprotein in mammary and
extramammary Paget’s disease. American Journal of
Clinical Pathology, 96, 243–247.
318
Wong, S. M., Freedman, R. A., Stamell, E., Sagara, Y.,
Brock, J. E., Desantis, S. D., & Golshan, M. (2015).
Modern trends in the surgical management of Paget’s
disease. Annals of Surgical Oncology, 22, 3308–3316.
Zhang, G., Zhou, S., Zhong, W., Hong, L., Wang, Y., Lu,
S., Pan, J., Huang, Y., Su, M., Crawford, R., Zhou, Y.,
& Mai, R. (2019). Whole-exome sequencing reveals
frequent mutations in chromatin remodeling genes in
mammary and Extramammary Paget’s diseases. Jour-
nal of Investigative Dermatology, 139, 789–795.
Phyllodes Tumor
Mark O’Loughlin1 and Grace Callagy1,2
1
Discipline of Pathology, NUI Galway, Galway,
Ireland
2 Phyllodes tumors are uncommon, representing
NUI Galway Clinical Science Institute, Galway,
Ireland
Synonyms
Benign phyllodes tumor; Benign phylloides
tumor; Borderline phyllodes tumor; Borderline
phylloides tumor; Cystosarcoma phyllodes;
Cystosarcoma phylloides; Malignant phyllodes
tumor; Malignant phylloides tumor; Phyllodes
tumor; Phylloides tumor
Definition
Phyllodes tumors are true fibroepithelial neo-
plasms characterized by a biphasic growth pattern
which comprises an epithelial and a stromal com-
ponent and resembles an intracanalicular
fibroadenoma. The epithelial component is dou-
ble layered and arranged in clefts and is
surrounded by the hypercellular stromal compo-
nent. Together these give the appearance of leaf-
like structures. This appearance is the origin of the
name cystosarcoma phyllodes when they were
first described in 1838 by Müller (phyllos being
the Greek word for leaf, cysto- pertaining to the
cystic spaces identified, and sarcoma pertaining to
the sarcomatous stroma). The lesion was initially
described as benign, and it was not until 1931 that
Phyllodes Tumor
its malignant potential became known when a
metastatic case was reported by Lee and Pack.
Phyllodes tumors are classified as benign, border-
line, or malignant (Ellis et al. 2013).
Usage of the original term of cystosarcoma
phyllodes is discouraged given that the majority
of these neoplasms are benign. The preferred term
as recommended by the World Health Organiza-
tion in 1981 is phyllodes tumor, with the benign,
borderline, or malignant prefix used as appropri-
ate (Tan et al. 2016).
Clinical Features
• Incidence
approximately 1% of all breast neoplasms at
most (0.2–1%) and only 2.5% of fibroepithelial
breast lesions. The exact incidence of tumors
that fall into the benign, borderline, and malig-
nant categories is uncertain. This is because the
rates reported for each category vary consider-
ably between studies due to the use of different
classification systems and to the well-
recognized difficulty in distinguishing between
tumors in the different categories. It is esti-
mated that benign phyllodes tumors are likely
to account for at least 70%, malignant tumors
for 10–20%, and borderline tumors for the
remainder of all these cases (Ellis et al. 2013;
Tan et al. 2012, 2016).
Malignant phyllodes tumors are more com-
mon among Hispanic populations than other
ethnic groups, particularly those born in Cen-
tral and South America. Phyllodes tumors are
more common in nulliparous women (Tan
et al. 2012).
• Age
These tumors are more common in perimeno-
pausal and postmenopausal women. The aver-
age age at presentation is usually 40–50 years,
with the median age being 45 years. Phyllodes
tumors tend to develop a decade later than the
usual age for fibroadenomas and are relatively
rare below the age of 25. However, there have
been reports with ages ranging from younger
than 10 years to older than 70. In Asian
Phyllodes Tumor
populations, age at diagnosis is lower than for
other populations, approximately 25–30 years
(Tan et al. 2012).
• Sex
It predominantly affects women though there
have been a small number of cases described in
men, which is slightly more often found in
those with preexisting gynecomastia (Tan
et al. 2012).
• Site
These neoplasms affect breast tissue and rarely
involve the skin, though they can stretch the
skin if grown to a large size, giving a bluish
discoloration and dilated veins. This
stretching, nipple retraction, and potential
pain can all occur with both benign and malig-
nant phyllodes tumors. Ulceration onto the
skin surface is very rare and is far more likely
to be observed with malignant phyllodes than
with benign or borderline tumors, although
very large benign tumors can ulcerate the over-
lying skin. Phyllodes tumors are typically uni-
lateral, with multifocal or bilateral lesions
being regarded as rare (Ellis et al. 2013).
• Clinical Presentation
The presentation is classically a clinically pal-
pable mass in the breast parenchyma with an
average size of 4–5 cm. This lump is usually,
but not always, painless, well defined, and
mobile. It is not possible to distinguish a phyl-
lodes tumor from a fibroadenoma or other
benign breast lesion at clinical presentation,
although a phyllodes tumor is often rapidly
growing. Smaller tumors can present on rou-
tine mammography as well-defined lesions or
as hypoechoic masses with hyperechoic stria-
tions on ultrasound imaging (Ellis et al. 2013).
• Treatment
The currently accepted gold standard of treat-
ment for phyllodes tumors is surgical resection
with a margin of normal tissue. Unlike the case
for invasive carcinoma, there is no consensus
on what constitutes an adequate margin thick-
ness, especially for benign tumors. Most data
on margin status comes from retrospective
studies. Some advocate a margin of 1 cm
even for benign tumors, but robust evidence
for this is lacking. The data on recurrence from
319
retrospective reviews is contradictory with
some recording no relationship between mar-
gin width and recurrence rates, whereas others
found that recurrence increased with margins
<1 cm. Interpretation is compounded by the
fact that the rate of recurrence for
fibroadenomas, the main differential diagnosis
for a benign phyllodes tumor, is in the order of
15%. Moreover, not all benign phyllodes
tumors with a positive margin recur. In the
absence of definitive evidence, many would
consider the presence of tumor cells touching
ink or within 1 mm of the margin as a positive
margin. A benign phyllodes tumor with a pos-
itive margin can be managed conservatively;
however, most would advocate clear margins
for recurrent, borderline, and malignant phyl-
lodes tumors (Tan et al. 2016).
Mastectomy may be considered in some
cases depending on the size of the tumor and
the malignancy status. Axillary node sampling
is not recommended given the low rate of nodal
metastasis.
The role of adjuvant radiotherapy in the treat-
ment for malignant tumors is unclear. There are
some reports of reduced rates of local recurrence
but no effect on overall survival. There is no
evidence to support the use of cytotoxic or
targeted chemotherapy (Tan et al. 2016).
• Outcome P
Phyllodes tumors of all grades have the potential
for recurrence, although recurrence is rare when
the tumor is completely excised. Recurrence is
more common for malignant tumors (23–30%)
than for borderline (14–25%) or benign
(10–17%) tumors. In the vast majority of cases,
recurrence is local and usually occurs within
2–3 years of initial diagnosis. Recurrent disease
is typically of the same grade as the initial tumor,
though progression to a higher-, or rarely a
lower-, grade tumor can occur (Tan et al. 2012).
Metastatic rates vary from 1% to 22%, and
metastasis is associated with a poor prognosis
with death from disease most commonly ensu-
ing within 5–8 years after diagnosis. Virtually
all metastases occur following a diagnosis of
malignant phyllodes tumor. There are reports
of metastases occurring following a diagnosis
320
of borderline and, less commonly, benign phyl-
lodes tumor, but these are considered excep-
tionally rare occurrences. Metastatic sites
include the lungs, pleura, bone, and very rarely
the central nervous system. The metastases are
frequently composed of the sarcomatous stro-
mal component of the tumor without epithelial
elements. Spread to lymph nodes is rare, and
hence nodal sampling is not routinely
recommended in the management of phyllodes
tumors. In extremely rare cases, metabolic dis-
turbances caused by paraneoplastic syndrome
can occur whereby phyllodes tumors secrete
insulin-like growth factor II, causing severe
(or occasionally fatal) hypoglycemia (Ellis
et al. 2013; Tan et al. 2012).
• Factors Influencing Recurrence and
Behavior
Margin status is one of the most important
factors determining the risk for recurrence. In
many instances, recurrence is due to inade-
quate resection, and a further wide local exci-
sion can be curative. Conversely, positive
margins do not result in inevitable recurrence.
A review of factors associated with an
increased risk of adverse outcome identified
margin status as being the most important
with atypia, mitoses, stromal overgrowth also
being important, but the evidence for this is
weak. As yet, there are no validated prognostic
features to identify those patients who will
develop metastatic disease (Ellis et al. 2013).
Macroscopy
Tumor size is extremely variable with case reports
documenting cases from 1 cm in diameter up to
greater than 40 cm. The average size at diagnosis
is usually 4 cm or 5 cm with the size range most
commonly being between 2 and 10 cm. Mammo-
graphic screening has seen an increase in detec-
tion of smaller tumors that are between 2 and
3 cm. It is not possible to distinguish between
the different grades of phyllodes tumor by size
because there is significant overlap in the sizes of
benign, borderline, and malignant tumors. How-
ever, some reports suggest that larger tumors are
Phyllodes Tumor
more likely to be malignant. Phyllodes tumors in
general have a faster growth rate than
fibroadenomas (Ellis et al. 2013; Tan et al. 2012).
Phyllodes tumors are round to oval in shape,
with a well-circumscribed border and a firm tex-
ture. They vary between lobulated contours to hav-
ing a multinodular surface. Benign phyllodes
tumors can be grossly indistinguishable from
fibroadenomas. The cut surface shows a tan or
pink to gray-white whorled pattern that may have
a fleshy or mucoid consistency, though they are
more frequently firm. They typically have cleft
spaces, and larger tumors can have areas of cystic
degeneration, hemorrhage, or necrosis. These fea-
tures are more common in malignant compared to
benign phyllodes tumors. The borders of benign
tumors are usually well defined, whereas those of a
malignant phyllodes tumor may be grossly infiltra-
tive. Periductal stromal hyperplasia can occur adja-
cent to the phyllodes tumor and can make
assessment of the border difficult. In some
instances, a “pseudocapsule” composed of com-
pressed normal breast parenchyma can envelop
the tumor (Ellis et al. 2013).
Microscopy
Phyllodes tumors are derived from the specialized
lobular stroma of the breast, and the biphasic
growth pattern is the characteristic feature of this
tumor. Phyllodes tumors are composed of a dou-
ble layer of glandular epithelium with
myoepithelial and luminal epithelial cells that
line cleft-like spaces. The clefts create the appear-
ance of large leaflike structures in which the
stroma is cellular. The stroma is the dominant
component of the tumor; the epithelium appears
benign. Tumors are classified as benign, border-
line, or malignant based on the assessment of a
number of interrelated histological features, as
outlined in the WHO Classification of Tumors of
the Breast (Tan et al. 2012).
Benign Phyllodes Tumor
These lesions characteristically have pushing,
lobulated borders that are well circumscribed. In
benign phyllodes tumors, the biphasic growth
Phyllodes Tumor
patterns assume an exaggerated intracanalicular
appearance and give rise to the impression of
fronds or leaflike structures with clefts and
cystically dilated spaces (Fig. 1a H&E). The stro-
mal cellularity is at best regarded as mildly
increased and, in general, appears uniform
throughout the tumor (Fig. 1b H&E).
A commonly observed feature is in accentuation
of cellularity around ducts, but there is no stromal
overgrowth. The latter is defined so that low-
power views, achieved by the use a 4 objective
lens and a 10 eyepiece lens, only allow the
stroma to be visualized, in which epithelial ele-
ments are absent (Ellis et al. 2013).
In benign phyllodes tumors, the spindle cells in
the stroma will not display much, if any, pleomor-
phism. Mitotic figures are few, <5 per 10 high-
power fields (hpf). Necrosis is rare but can be seen
with edema and ulceration in benign tumors if they
reach a very large size. Stromal giant cells can
occasionally be seen and should not be interpreted
as an indicator of either a borderline or malignant
tumor. Adipose tissue can be seen within the
stroma, and if adipocytes are particularly promi-
nent, the term lipophyllodes tumor can be utilized.
This can also be seen in fibroadenomas and should
not be confused with malignant heterologous dif-
ferentiation in a malignant phyllodes tumor (Ellis
et al. 2013; Tan et al. 2016).
Phyllodes Tumor, Fig. 1 (H&E) (a) Architecture of a
benign phyllodes tumour. The characteristic leaf-like pro-
cesses are seen throughout a benign phyllodes tumor. (b)
High power image of benign phyllodes tumour (the same
case as in Figure 2) shows a minimal increase in cellularity,
321
In most centers, a preoperative diagnosis
of benign phyllodes tumors is made on a
needle core biopsy. This can be problematic
because of the small amount of tissue which may
not be representative of the larger tumor and
because the morphological features of phyllodes
tumor overlap with those of fibroadenomas and
other spindle cell lesions in the breast (see differ-
ential diagnosis) (Jara-Lazaro et al. 2010).
Malignant Phyllodes Tumor
The diagnosis of malignant phyllodes tumor is often
straightforward. These tumors have infiltrative bor-
ders and are characterized by a uniform and marked
increase in stromal cellularity, marked nuclear
atypia, numerous mitoses (>10 per 10 hpf), and
overgrowth of the stromal component (Fig. 2a, b
H&E). Stromal overgrowth can mean that the epi-
thelium is present focally and thorough sampling is
required to identify residual glandular elements.
Occasionally, the stromal growth is not as pro-
nounced as would be expected, and in this instance,
the finding of nuclear pleomorphism of stromal cells
and atypical mitoses is relied upon to correctly
characterize a lesion as malignant. The stroma
could be either monomorphic or pleomorphic
with appearances similar to that of a fibrosarcoma
and may have areas of malignant heterologous
differentiation such as liposarcomatous or
P
without pleomorphism, mitotic activity or stromal over-
growth. In this case, the overall cellularity is not increased
illustrating the fact that all of the classic features of a
tumour grade may not be present together
322
Phyllodes Tumor, Fig. 2 (H&E) (a) Stromal overgrowth
and increased cellularity in a malignant phyllodes tumor.
Note the absence of epithelial elements in this medium
power view. (b) Malignant phyllodes tumor shows hyper-
cellular stroma infiltrating normal breast tissue. (c and d)
chondrosarcomatous differentiation with possible
metaplastic cartilage or bone development
(Fig. 2c, d H&E). The latter can be present, albeit
rarely, without other features of malignancy and is
sufficient in itself for a diagnosis of malignant phyl-
lodes tumor. These elements must be distinguished
from benign adipose and chondroid differentiation
that can be seen in benign and borderline phyllodes
tumors. Foci of ductal carcinoma in situ, lobular
carcinoma in situ, or invasive carcinoma can be
seen in an otherwise typical phyllodes tumor, but
these are rare (Ellis et al. 2013; Tan et al. 2012).
Borderline Phyllodes Tumor
Borderline phyllodes tumors are those which fall
in between the benign and malignant categories.
These have highly variable morphologies but
Phyllodes Tumor
Heterologous elements present within a malignant phyl-
lodes tumor. Liposarcomatous differentiation is seen at low
power (c). Pleopmorphic lipoblasts are seen at high power
(d)
demonstrate a degree of stromal hypercellularity,
which is similar to or slightly more than in benign
phyllodes tumors, and have a pronounced
intracanalicular growth pattern when compared
to benign phyllodes tumors (Fig. 3a, b H&E).
Mitotic figures are only slightly higher than in
a benign phyllodes tumor, at 4–9 per 10 hpf. The
tumor borders are predominately pushing and
well circumscribed, but very focal infiltration
can be seen. These pushing margins with buds
projecting into surrounding stroma can be left
behind at surgical excision (Ellis et al. 2013; Tan
et al. 2012, 2016).
Grading of Phyllodes Tumors
Grading of phyllodes tumors is notoriously diffi-
cult. Various grading systems exist to differentiate
Phyllodes Tumor 323

Phyllodes Tumor, Fig. 3 (H&E) (a and b) Leaf-like overgrowth and no infiltrative margin. A high power view
architecture within a borderline phyllodes tumor (a). The of the same case shows an accentuation of stromal hyper-
mitotic activity was low in this case. There was no stromal cellularity in the subepithelial zone (b)

Phyllodes Tumor, Table 1 Histological features of fibroadenoma, benign, borderline, and malignant phyllodes tumor
Fibroadenoma Benign PT Borderline PT Malignant PT
Stromal Hypocellular but Mild, can be diffuse or Moderate Marked and
hypercellularity can be cellular heterogeneous diffuse
Cellular Absent Mild Moderate Marked
pleomorphism
Mitoses Absent or low (<2 Few (<5 per 10 hpf) Frequent (5–9 per Numerous (10
per 10 hpf) 10 hpf) per 10 hpf)
Borders Well defined Well circumscribed, Well defined, can be Infiltrative
pushing focally infiltrative
Stromal overgrowth None None None or present focally Usually present
Malignant None Absent Absent Can be present
heterologous
differentiation
P
Adapted from WHO Classification of Tumors of the Breast (Tan et al. 2012)

the different grades of tumor and combine the
assessment of the same features: tumor border,
stromal cellularity, stromal overgrowth, nuclear
pleomorphism, mitotic activity, and the presence
of heterologous elements. The WHO three-tier
system is the most widely used (Table 1) (Tan
et al. 2012).
Assessment and quantification of the histolog-
ical features are subjective, and the thresholds for
each parameter that assign a tumor in one grade
over another are unclear. For example, a benign
phyllodes tumor may show an increase in cellu-
larity with a focally infiltrative border but with
minimal mitotic activity and few leaflike struc-
tures. It is generally recommended that grading
should be based on the most florid area of
cellularity and architectural abnormality (Tan
et al. 2012).
As a general guide, it is recommended that
tumors are graded as malignant when all the fea-
tures of malignancy are present and as borderline
when only some are present. The presence of any
malignant heterologous elements implies a diag-
nosis of malignancy (Fig. 2c, d H&E) (Tan
et al. 2016).
Immunophenotype
The diagnosis of phyllodes tumor is made on
H&E staining; immunohistochemistry is not
required to make a diagnosis. Stromal cells
324
express CD34 and b-catenin, and their expression
is inversely related to tumor grade. Expression of
proliferation markers, e.g., Ki-67 as well as c-kit
(CD117), p53, p16, pRb, VEGF, CD10, and
EGFR, can be observed in the stromal cells with
increasing levels of expression from benign to
borderline to malignant phyllodes tumors.
Immunohistochemistry is required to distin-
guish phyllodes tumors from other entities.
CD34, p63, p40, and cytokeratins, e.g.,
MNF116, CK 5/6, 34be12, and AE1/3, are most
useful in the distinction between phyllodes tumor
and metaplastic spindle cell carcinoma. Tradition-
ally, CD34 was reportedly positive in the stromal
cells in all grades of phyllodes tumor and negative
in carcinomas, whereas p63, p40, and
cytokeratins were positive in carcinomas and neg-
ative in phyllodes tumors. Focal positivity for
cytokeratin can be observed in malignant phyl-
lodes tumor but not in lower-grade phyllodes
tumors. While benign and borderline phyllodes
tumors and fibroadenomas are negative for p63,
its isoform p40 and cytokeratin, malignant phyl-
lodes tumors can express p63, p40, and
cytokeratin in 57%, 29%, and 21% of cases,
respectively, and 43% of malignant phyllodes
tumors can be negative for CD34.
Molecular Features
Phyllodes tumors are considered to arise de novo.
There are very obvious morphological similarities
between fibroadenomas and phyllodes tumors,
but direct evidence supporting a precursor role
for fibroadenomas has been lacking. Recent
work, however, identified mutations in the medi-
ator complex subunit (MED) 12 gene, which is in
both fibroadenomas and phyllodes tumors,
supporting a common molecular link between
both lesions (Tan et al. 2016).
The biphasic appearance of a phyllodes tumor
is characterized by benign-appearing epithelium
and a dominant neoplastic stroma, particularly in a
periductal location. This feature is in keeping with
the hypothesis of an epithelial-stromal cross talk,
in which the epithelium induces stromal prolifer-
ation via the Wnt signalling pathway and
Phyllodes Tumor
upregulation of beta-catenin and cyclin D1
(among others), and the stroma promotes epithe-
lial proliferation via pathways such as IGF and
IGFR1. The epithelial-stromal feedback is dimin-
ished in malignant tumors where there is also
frequent loss of beta-catenin expression (Tan
et al. 2012).
Detailed genomic analysis has revealed chro-
mosomal changes in phyllodes tumors with the
aberrations being more frequent and more com-
plex in malignant and borderline phyllodes
tumors compared to benign tumors. Clonal
changes are detectable in both the epithelial and
stromal component of phyllodes tumors. Specific
genomic aberrations include gains in chromo-
some 1q, losses in chromosome 13, deletions of
chromosomal 9p, and MYC amplification (Tan
et al. 2012).
Differential Diagnosis
Benign Phyllodes Tumor
The main differential diagnosis for a benign phyl-
lodes tumor is a fibroadenoma (▶ Fibroadenoma).
It can often be very challenging because many of
the features relied upon are subject to
interobserver disagreement, and it is important
not to rely on and overinterpret the significance
of any single criterion to distinguish between
these two entities (Tan et al. 2016).
The distinction is particularly heightened for a
cellular fibroadenoma, a juvenile fibroadenoma,
and fibroadenomas occurring in children and ado-
lescents. Intracanalicular growth pattern and leaf-
like structures can be seen in both entities. In a
phyllodes tumor, the latter structures are generally
present throughout the tumor and are hyper-
cellular, whereas they are present only focally
and are often hyaline and hypocellular in a
fibroadenoma. If stromal fronds are not present
in a benign phyllodes tumor, then the long clefts
may also be a clue to the diagnosis of phyllodes
tumor (Fig. 4a H&E) (Tan et al. 2016).
It is recommended that fibroadenomas are
assessed for features of phyllodes tumors on first
viewing whenever there is an increase in stromal
cellularity. A more uniform increase in cellularity
Phyllodes Tumor
Phyllodes Tumor, Fig. 4 (H&E) (a) Benign phyllodes
tumor in which the features overlap with those of a cellular
fibroadenoma. In this low power view, leaf-like processes
are not seen; however, there are some cleft-like spaces. The
stromal cellularity and mitotic activity were increased and
some stromal fronds were seen elsewhere in the lesion.
This illustrates the heterogeneity that can be seen within a
benign phyllodes tumor and the diagnostic difficulty in
distinguishing benign phyllodes tumors from cellular
fibroadenomas. (b) Needle core biopsy of a fibroepithelial
favors a fibroadenoma. Mitotic activity may not
be particularly helpful in distinguishing between
these entities as it is low in both. Mitotic counts
above 2 per 10 hpf favor a phyllodes tumor how-
ever (Tan et al. 2012).
Caution is advised in diagnosing a benign
phyllodes tumor in children and adolescents
where increased stromal cellularity and high
mitotic activity (up to 7 mitoses per 10 hpf) can
be observed. In this situation, other features of
benign phyllodes tumor, e.g., leaflike architec-
ture, should also be seen to arrive at a diagnosis
of a phyllodes tumor (Tan et al. 2016).
The distinction between fibroadenoma and
benign phyllodes tumor can be especially chal-
lenging on a needle core biopsy. Increased stro-
mal cellularity has been found to be the most
helpful distinguishing feature on core biopsy.
The threshold cellularity that favors a phyllodes
tumor is unclear, and some have proposed that it
be present in over half of the core biopsy. The
presence of stroma without epithelial elements in
a 10 field, if seen, also favors a phyllodes
tumor. Fragmentation of the biopsy is another
clue to the diagnosis of a phyllodes tumor,
which is most likely due to the core being taken
325
lesion. This was classified as a fibroepithelial lesion with a
comment that a benign phyllodes tumor could not be
excluded. At low power, an obvious leaf-like architecture
is seen with only a minimal increase in stromal cellularity
and no mitotic activity. Fragmentation of the biopsy, as a
result of the needle passing through the fronds, is a clue to
the diagnosis of a benign phyllodes tumor. This lesion was
excised because it was large and a diagnosis of a benign
phyllodes tumor was made based on the features in the
excised tumor
through the frond (Fig. 4b H&E). Mitotic activ-
ity is often unhelpful on a core biopsy (Jara-
Lazaro et al. 2010).
In many cases, stating that the lesion is a
fibroepithelial lesion and that a phyllodes
tumor cannot be excluded is the best approach
with the most appropriate management
decided upon through multidisciplinary P
discussion. Clinical and radiological features
may aid in the decision with excision performed
if the lesion is growing to >3 cm in size (Jara-
Lazaro et al. 2010).
Pure stromal tumor is a rare entity in which a
spindle cell proliferation surrounds open ducts.
This entity lacks the architectural leaflike archi-
tecture of phyllodes tumor, but some reports sug-
gest that pure stromal tumor and phyllodes tumor
may be part of the same disease spectrum (Tan
et al. 2012).
Malignant Phyllodes Tumors
Malignant phyllodes tumors need to be distin-
guished from metaplastic carcinomas (▶ Inva-
sive Metaplastic Carcinoma) because the
management of both entities is different. Both
the malignant spindle cells and the heterologous
326
elements within a malignant phyllodes tumor
can lead to the tumor being confused with the
different morphological subtypes of a metaplas-
tic carcinoma (Tan et al. 2016).
The key feature in this distinction is the dem-
onstration of epithelial differentiation in the
spindle cells to support a diagnosis of carcinoma
and the demonstration of benign admixed epi-
thelium (i.e., biphasic growth) to support a diag-
nosis of malignant phyllodes tumor. In phyllodes
tumors, epithelium is both morphologically
benign and distinct from the stromal elements,
and thorough sampling may be required to iden-
tify it. Demonstration of convincing epithelial
differentiation within the stromal compartment
supports a diagnosis of carcinoma. Again, this
may require thorough sampling and the demon-
stration of cytokeratin positivity, bearing the
caveats outlined above in mind (see
immunophenotype). The presence of ductal car-
cinoma in situ adjacent to malignant spindle cells
also favors a metaplastic carcinoma (Ellis et al.
2013; Tan et al. 2016). In difficult cases, GATA3
and SOX10 can also be helpful. GATA3 is rarely
expressed in malignant phyllodes tumors and is
expressed in up to 50% of metaplastic carcino-
mas; SOX10 is negative in malignant phyllodes
tumors and is expressed in 40% of metaplastic
carcinomas. b-catenin is expressed in both
malignant phyllodes tumors and metaplastic car-
cinoma and is therefore unhelpful in
distinguishing these entities (Cimino-Mathews
et al. 2014).
Distinction between malignant phyllodes
tumor and the rare entity of pure stromal sarcoma
is made by the finding of the epithelial elements
of a phyllodes tumor. These can be very focal if
the stromal overgrowth is particularly pro-
nounced and thorough sampling is required.
However, the management of both is similar
(Tan et al. 2016).
References and Further Reading
Cimino-Mathews, A., Sharma, R., Illei, P. B., Vang, R., &
Argani, P. (2014). A subset of malignant phyllodes
tumors express p63 and p40: A diagnostic pitfall in
Pleomorphic Lobular Carcinoma
breast core needle biopsies. American Journal of Sur-
gical Pathology, 38, 1689–1696.
Ellis, I., Lee, A., Pinder, S., & Rakha, E. (2013). Tumors of
the breast. In C. Fletcher (Ed.), Diagnostic histopathol-
ogy of tumors (4th ed., pp. 1064–1065). Philadelpia:
Elsevier.
Jara-Lazaro, A. R., Akhilesh, M., Thike, A. A., Lui, P. C.-
W., Tse, G. M.-K., & Tan, P. H. (2010). Predictors of
phyllodes tumours on core biopsy specimens of
fibroepithelial neoplasms. Histopathology, 57, 220–232.
Tan, P. H., Tse, G., & Kee, A. (2012). Fibroepithelial
tumours. In S. Lakhani, I. Ellis, S. Schnitt, P. H. Tan,
& M. van de Vijver (Eds.), WHO classification of
tumours of the breast (4th ed., pp. 143–147). Geneva:
World Health Organisation.
Tan, B. Y., Acs, G., Apple, S. K., Badve, S., Bleiweiss, I. J.,
Brogi, E., . . . Tan, P. H. (2016). Phyllodes tumours of
the breast: A consensus review. Histopathology, 68,
5–21.
Pleomorphic Lobular
Carcinoma
Sofia Asioli1 and Chiara Baldovini2
1
Department of Biomedical and Neuromotor
Sciences (DIBINEM)-Surgical Pathology
Section, Alma Mater Studiorum – University of
Bologna, Bologna, Italy
2
Pathology Unit, Giannina Gaslini Institute,
Genoa, Italy
Definition
Pleomorphic lobular carcinoma (PLC) is currently
defined by the World Health Organization
(Lakhani et al. 2012) as a rare variant of invasive
lobular carcinoma (ILC), exhibiting marked
nuclear pleomorphism and cellular atypia. It may
be associated with pleomorphic lobular carcinoma
in situ (PLCIS), which refers to a lobular carci-
noma in situ (LCIS) with high-grade cytological
features. PLC was first documented by Martinez
and Azzopardi (1979) then subsequently reported
by Dixon (Dixon et al. 1982) and formally
described by Page and Anderson (1987). Further
characterization was provided in 1992 by Eusebi
(Eusebi et al. 1992) and Weidner (Weidner and
Semple 1992), who emphasized its aggressive
behavior and poor clinical outcome.
Pleomorphic Lobular Carcinoma
Clinical Features
• Incidence
The exact incidence of PLC is unknown
because of its rare occurrence and the lack of
large case studies addressing this issue. Based
on current literature, PLC represents approxi-
mately 10–15% of ILC, thus accounting for
less than 1% of all mammary gland carcinomas
(Al-Baimani et al. 2015).
• Age
PLC usually presents at older age than classic
ILC (ILC-C). It commonly affects postmeno-
pausal women aged between 60 and 80. How-
ever, it may also present earlier among patients
carrying BRCA2 mutations (Butler and Rosa
2013).
• Sex
In line with most variants of breast carcinoma,
PLC predominantly affects females. Only a
minority of cases have been reported among
males.
• Site
There is no specific preferential site. Similar to
ILC-C, PLC often arises bilaterally, showing
multifocal distribution.
• Treatment
Owing to the rarity of PLC, there is insuffi-
cient data to develop specific guidelines for
management. As for most breast cancers, sur-
gery remains the treatment of choice. Avail-
able data suggest that, compared with ILC-C,
PLC presents with larger tumors, increased
lymph node involvement, and higher inci-
dence of distant metastases. Although PLC
shares high rates of multifocality and multi-
centricity with ILC-C, it seems to require
mastectomy more often than ILC-C
(Al-Baimani et al. 2015). However, conserva-
tive surgery is favored for patients with local-
ized disease. Despite the lack of evidence
regarding the role of adjuvant therapy in
PLC, there is a tendency to administer adju-
vant chemotherapy, mainly based on PLC
adverse clinico-pathological characteristics.
Adjuvant endocrine therapy and trastuzumab
may be of value for patients displaying posi-
tivity for hormone receptors and human
327
epidermal growth factor receptor 2 (HER2),
respectively.
• Outcome
In the first descriptions PLC was referred to as
an aggressive variant of ILC. However, since
those studies were limited by small sample
size, other investigators attempted to better
define the prognosis of PLC based on larger
case series. As expected, several studies found
that PLC was associated with high-risk clini-
copathological features when compared with
ILC-C (larger tumor size, higher grade,
increased nodal involvement, and higher
expression of HER2). Jung found no differ-
ences in relapse-free survival (RFS) and dis-
ease specific survival (DSS) when comparing
PLC and invasive carcinoma no special type
(NST) (Jung et al. 2012). Another study indi-
cated that both disease free survival (DFS) and
overall survival (OS) were similar between
PLC and ILC-C, and that survival correlated
with well-established prognostic factors such
as tumor size, tumor stage, lymph node
involvement, and surgical treatment
(Narendra et al. 2015). Finally, Liu found that
PLC was initially associated with worse
progression-free survival (PFS) when com-
pared with ILC-C, but such a result
disappeared after adjustment for cancer stage.
There were no differences in OS (Liu et al. P
2017). Taken together, these findings suggest
that PLC may not be associated with increased
mortality as originally described.
Macroscopy/Imaging Findings
The gross appearance of PLC is usually described
as an irregular fibrotic area, without notable dif-
ferences from ILC-C. Neither can PLC be differ-
entiated from ILC-C based on imaging findings,
although it may present more aggressive features
(Jung et al. 2012). The reported higher detection
rate of PLC compared to ILC-C on mammogra-
phy might reflect such findings (Al-Baimani et al.
2015). Radiologically, most lesions consist of
spiculated masses or architectural distortions,
with or without calcifications. Magnetic
328 Pleomorphic Lobular Carcinoma

resonance imaging (MRI) has become increas- (WHO 2012). Sometimes, neoplastic cells may
ingly important in the detection of multifocal, also show singular intracytoplasmic vacuoles giv-
multicentric or contralateral disease, especially ing them the appearance of signet-ring cells. Polyg-
for patients diagnosed with lobular carcinoma onal cells with eosinophilic cytoplasm reminiscent
including PLC. of rhabdomyoblasts are also occasionally found
(Fig. 3 H&E). In contrast with ILC-C, PLC often
displays evidence of vascular invasion and high
Microscopy mitotic index. Owing to the marked degree of
nuclear pleomorphism, PLCs are more likely to
The original morphologic criteria are still applied to be scored as G2, G3 within the Nottingham grading
identify PLC. Although some investigators found system, depending on mitotic activity.
that nonclassical growth patterns were more fre-
quent in tumors with marked nuclear pleomor-
phism, in most studies PLC did not display
significant differences from ILC in terms
of architecture. Similar to ILC-C, PLC displays
poorly circumscribed lesions, characterized by dis-
sociated neoplastic cells, which may delineate
“targetoid” patterns around ducts and acini (Fig. 1
H&E). Alveolar, solid, and mixed patterns of
growth may be seen as well. In contrast to ILC-C,
PLC nuclei are larger – approximately four times
the size of a lymphocyte (Weidner et al. 1992) –
indented and often eccentrically placed. Prominent
and multiple nucleoli are generally present (Fig. 2
H&E). The cytoplasm is abundant, pale to eosino-
Pleomorphic Lobular Carcinoma, Fig. 2 The neoplas-
philic, but varying degrees of granular to vacuo- tic nuclei of PLC are larger, indented and often eccentri-
lated cells have been described. Indeed, according cally placed with prominent and multiple nucleoli (H&E)
with the last WHO classification, PLC may dem-
onstrate apocrine or histiocytoid differentiation

Pleomorphic Lobular Carcinoma, Fig. 1 The neoplas-

tic cells of PLC surround and invade the stroma around Pleomorphic Lobular Carcinoma, Fig. 3 Polygonal
residual ducts and acini in a concentric “targetoid” patterns neoplastic cells with eosinophilic cytoplasm reminiscent
similar to ILC (H&E) of rhabdomyoblasts are also occasionally found (H&E)
Pleomorphic Lobular Carcinoma
Immunophenotype
In contrast with invasive carcinoma NST, PLC
shares the loss of E-cadherin expression with
other subtypes of lobular carcinoma, estimated
to occur in 80–100% of cases (Al-Baimani
et al. 2015). Whereas, the expression of gross
cystic disease fluid protein 15 (GCDFP-15), asso-
ciated with apocrine differentiation, is signifi-
cantly higher in PLC than among ILC-C (Eusebi
et al. 1992).
Other immunohistochemical differences be-
tween PLC and ILC-C include the expression of
p53 tumor suppressor, which is rare in ILC-C and
high in PLC. Since the expression of p53 is asso-
ciated with an aggressive clinical course, this find-
ing could partly explain the biological behavior of
PLC. The higher proliferative index (as evaluated
with Ki67) in cases of PLC compared with ILC-C
further supports the clinical observation of its
aggressive nature.
Overexpression of HER2, which has been
documented in a wide range (40–80%) of PLC,
probably contributes to this aggressive pheno-
type. However, when considering only IHC 3+
cases, the positivity rate is much lower (13%)
(Butler and Rosa 2013).
There are conflicting data regarding the
expression of hormone receptors throughout
the literature: some investigators found a decreased
expression of both estrogen (ER) and progesterone
receptors (PR) in PLC, but this was not
confirmed in other series. Nevertheless, this
result could depend on methodological hetero-
geneity across studies. PLC also expresses andro-
gen receptor (AR). This finding is in line with
the occasional apocrine features and frequent
GCDFP-15 expression mentioned above.
Molecular Features
Molecular biology studies have shown an over-
lapping developmental pathway between PLC and
ILC, compared to NST carcinomas. Indeed, compar-
ative analysis of aCGH data showed that PLC and
ILC share some important molecular features (1q+,
11q , 16p+, and 16q ), thus indicating a possible
329
common origin. In addition, PLC may subsequently
acquire further alterations typical of high-grade NST
cancers (8q+, 17q24 q25+,13q , amplification of
8q24, 12q14, 17q12, 20q13), which may explain its
higher grade and more aggressive biology (Simpson
et al. 2008). In line with these findings, inactivation
of E-cadherin and p53 resulted in the development
of invasive mammary carcinomas with strong
resemblance with human PLC in mouse models
(Derksen et al. 2011).
The relationship between BRCA1 and BRCA2
status and PLC is still poorly understood.
Although BRCA1 loss of heterozygosity (LOH)
was found in approximately one third of PLC,
another study demonstrated a high rate (40%) of
BRCA2 mutations. Later studies corroborated
these data showing that BRCA2 mutation carriers
harbored significantly higher rates of PLC com-
pared to BRCA1 mutation carriers (Al-Baimani
et al. 2015).
Differential Diagnosis
High-grade NST carcinoma (▶ Invasive Carci-
noma NST) is often considered in the differential
diagnosis of PLC. High-grade NST carcinoma is
more likely to display solid patterns of growth
compared to PLC. Both tumors share marked
cellular pleomorphism, but the former may also P
display areas of spindled and squamoid differen-
tiation. In high-grade NST carcinoma necrosis is
extremely common as well as vascular invasion,
whereas these features are less frequent among
PLC cases. Intraductal carcinoma is present in
up to 70% of NST tumors. In most cases immu-
nohistochemistry allows a prompt differentiation,
with E-cadherin expression being preserved in
NST carcinomas and lost/reduced in PLC. In addi-
tion, ER, PR, and AR positivity favor a diagnosis
of PLC over NST cancer.
Both PLC and apocrine carcinoma (▶ Apo-
crine Carcinoma) possess similar cytological and
immunohistochemical features (GCDFP-15 and
AR positivity). However, they can be distin-
guished mainly based on architectural features
matched with E-cadherin immunostain. Indeed,
apocrine carcinoma usually retains the growth
330 Polymorphous Carcinoma

pattern typical of ductal carcinoma along with Derksen, P. W., Braumuller, T. M., et al. (2011). Mammary-
E-cadherin positivity. specific inactivation of E-cadherin and p53 impairs
functional gland development and leads to pleomorphic
invasive lobular carcinoma in mice. Disease Models &
Pleomorphic lobular carcinoma
Mechanisms, 4, 347–358.
Definition Dixon, J. M., Anderson, T. J., et al. (1982). Infiltrat-
– A rare variant of invasive lobular carcinoma (ILC), ing lobular carcinoma of the breast. Histopathology,
exhibiting marked nuclear pleomorphism 6, 149–161.
Age distribution Eusebi, V., Magalhaes, F., et al. (1992). Pleomorphic lob-
– Postmenopausal women aged between 60 and 80 ular carcinoma of the breast: An aggressive tumor
Clinical features showing apocrine differentiation. Human Pathology,
– Often arises bilaterally, showing multifocal 23, 655–662.
distribution Jung, S. P., Lee, S. K., et al. (2012). Invasive pleomorphic
Microscopic findings lobularcarcinoma of the breast: Clinicopathologic char-
– Dissociated neoplastic cells acteristics and prognosis compared with invasive duc-
– Nonspecific architectural pattern (classic, alveolar, tal carcinoma. Journal of Breast Cancer, 15, 313–319.
solid, mixed) Lakhani, S., Ellis, I., et al. (2012). WHO classification of
– Nuclei: Large, indented, lobulated, and eccentric Tumours of the breast (4th ed.). Lyon: IARC Press.
– Cytoplasm: Abundant, eosinophilic, granular, Liu, Y. L., Choi, C., et al. (2017). Invasive lobular breast
vacuolated (single or multiple vacuoles) carcinoma: Pleomorphic versus classical subtype, asso-
– Frequent vascular invasion and high mitotic activity ciations and prognosis. Clinical Breast Cancer,
– PLCIS 8209(16), 30558–30554.
Immunohistochemical findings Martinez, V., & Azzopardi, J. G. (1979). Invasive lobular
– E-cadherin: Negative carcinoma of the breast: Incidence and variants. Histo-
– Estrogen, progesterone, androgen receptors: pathology, 3, 467–488.
Frequently positive Narendra, S., Jenkins, S. M., et al. (2015). Clinical
– HER2: May be positive (2+/3+: 40–80%, 3+: 13%) outcome in pleomorphic lobular carcinoma: A case-
– P53: Frequently positive control study with comparison to classic invasive
– GCDFP-15: Frequently positive lobular carcinoma. Annals of Diagnostic Pathology,
19, 64–69.
Molecular findings
Page, D. L., & Anderson, T. J. (1987). Diagnostic his-
– Lobular histotype typical alterations: 1q+, 11q ,
topathology of the breast. Edinburgh: Churchill
16p+, and 16q
Livingstone.
– Ductal histotype typical alterations: Gains of HER2/
Simpson, P. T., Reis-Filho, J. S., et al. (2008). Molecular
neu, c-myc, p53 positivity, amplification of 8q24, 12q14,
profiling pleomorphic lobular carcinomas of the breast:
and 20q13
Evidence for a common molecular genetic pathway
– LOH BRCA2 40%
with classic lobular carcinomas. Journal of Pathology,
Differential diagnosis 215, 231–244.
– High-grade invasive carcinoma no special type Weidner, N., & Semple, J. P. (1992). Pleomorphic variant
(NST) of invasive lobular carcinoma of the breast. Human
– Apocrine carcinoma Pathology, 23, 1167–1171.
Prognosis and treatment
– Unfavorable prognostic factors
– Recent evidence of DFS and OS similar to ILC-C
– Mastectomy +/ adjuvant therapy (endocrine,
trastuzumab) Polymorphous Carcinoma

Sofia Asioli and Costantino Ricci

Department of Biomedical and Neuromotor
References and Further Reading Sciences (DIBINEM)-Surgical Pathology
Section, Alma Mater Studiorum – University of
Al-Baimani, K., Bazzarelli, A., et al. (2015). Invasive
pleomorphic lobular carcinoma of the breast: Patho- Bologna, Bologna, Italy
logic, clinical, and therapeutic considerations. Clinical
Breast Cancer, 15, 421–425.
Butler, D., & Rosa, M. (2013). Pleomorphic lobular carci-
Synonyms
noma of the breast: A morphologically and clinically
distinct variant of lobular carcinoma. Archives of
Pathology & Laboratory Medicine, 137, 1688–1692. Polymorphous low-grade adenocarcinoma
Polymorphous Carcinoma 331

Definition metastases can reach 50% of cases (Foschini

et al. 2017).
Polymorphous carcinoma is a very rare breast
carcinoma with epithelial cell differentiation
Macroscopy
showing morphological features similar to those
referred as polymorphous low-grade adenocarci-
Tumors are generally present as palpable and firm
noma in salivary glands.
nodules displaying indistinct borders. The size of
the lesion may be variable (range from 1.5 to
4 cm).
Clinical Features

• Incidence
Microscopy
Five cases of this special type of primary breast
carcinoma have been reported in literature with
Polymorphus carcinoma shows the same morpho-
morphological description.
logical features as that of minor salivary glands
• Age
counterpart.
Median age at presentation is 55 years, ranging
In particular, this neoplasm is non-encapsu-
from 37 to 74 years.
lated and is constituted of neoplastic cells show-
• Sex
ing a polymorphous structure that consists of
All the patients reported in literature are
central areas showing solid nests, surrounded at
female.
the periphery by alveolar and cribriform struc-
• Site
tures as well as trabeculae and “Indian file”
Breast without the prevalence of a specific
arranged cells. Combinations and transitions
mammary quadrant.
among all these patterns are frequent. The neo-
• Treatment
plastic cells are uniformly small, have round to
Wide excision with axillary lymph node dis-
ovoid nuclei with dispersed vesicular chromatin,
section is the choice of treatment of the cases
and have inconspicuous to small nucleoli.
reported in the literature, followed by radio-
Mitotic activity ranges from 10 to 12 per
therapy in two patients. Although no lymph
10 high-power fields; necrotic areas are not P
node metastases are found, polymorphous car-
seen. Altogether the histological grade,
cinoma seems to be an aggressive neoplasm
according to the Elston and Ellis grading system
and recommended treatment consists of wide
of breast cancer (Elston and Ellis 1991), is grade
excision with sentinel node biopsy and even-
2. Neither vascular nor perineural invasion has
tually axillary lymph node dissection.
been reported (Fig. 1).
• Outcome
Follow-up has been reported in three cases
(Asioli et al. 2006). In two out of these three
patients, the follow-up was very short. The Immunophenotype
other case had a very aggressive clinical course
with the patient developing liver metastases Estrogen and progesterone receptors, as well as
and dying of widespread disease 3 years after HER2, were consistently negative, so this entity is
the diagnosis. Therefore, it was suggested to considered as triple-negative breast carcinoma by
name the tumor in the breast as “polymorphous immunohistochemistry (Asioli et al. 2006). The
adenocarcinoma,” avoiding the term of “low neoplastic cells are faintly positive for cytokeratin
grade.” The same conclusion has led to rename 7, E-cadherin, and EGFR, and strongly stain for
the salivary gland counterpart as polymor- Bcl-2. On the contrary, EMA, cytokeratin
phous carcinoma, as at long-term follow-up 14, smooth muscle actin, and c-Kit are negative
the incidence of local recurrences and distant (Foschini et al. 2017; Reyes et al. 2013).
332
Polymorphous Carcinoma, Fig. 1 Polymorphous car-
cinoma shows different growth patterns including central
areas with solid nests (a; H&E, Original magnification
x40), alveolar and cribriform structures (b; H&E, Original
Molecular Features
No specific molecular alterations have been
reported on breast polymorphous carcinoma.
Differential Diagnosis
Differential diagnosis includes mainly invasive
lobular carcinoma ▶ Invasive Lobular Carci-
noma chapter and adenoid cystic carcinoma
▶ Adenoid Cystic Carcinoma. The fact that the
polymorphous carcinoma of the breast, as in
salivary glands, shows one type of cell only
and is devoid of smooth-muscle actin positive
Polymorphous Carcinoma
magnification x100), trabeculae (c; H&E, Original magni-
fication x200) and “Indian file” infiltration pattern (d;
H&E, Original magnification x40)
elements as well as c-kit renders these lesions
different from adenoid cystic carcinomas that,
on the contrary, show by definition two types of
cells and smooth muscle actin positive elements
(Foschini et al. 2017). An “Indian file” pattern of
infiltration of neoplastic cells in some peripheral
areas of polymorphous carcinoma can simulate
an invasive lobular carcinoma. The immunohis-
tochemical features help in the differential diag-
nosis. In polymorphous carcinoma, neoplastic
cells are E-cadherin positive and EMA, estro-
gen, and progesterone receptors negative, all
features different from those seen in invasive
lobular carcinoma (Asioli et al. 2006; Foschini
et al. 2017).
Pseudoangiomatous Stromal Hyperplasia
Polymorphous breast carcinoma – fact sheet
Definition
- Very rare breast carcinoma showing a triple-negative
profile and morphological features similar to those
referred to as polymorphous low-grade adenocarcinoma
in salivary glands
Age distribution
- Median age: 55 years (range 37–74 years)
Clinical features
- Palpable and firm nodules with indistinct borders
Microscopic findings
- Non-encapsulated lesion
- Polymorphous structure: central areas showing solid
nests, surrounded at the periphery by alveolar and
cribriform structures as well as trabeculae and Indian file
arranged cells
- Grade 2 carcinoma according to the Elston & Ellis
grading system
- Vascular and nerve invasions are uncommon
Immunohistochemical findings
- Estrogen and progesterone receptors, and HER2:
negative
- Cytokeratin 7, E-cadherin, EGFR, and Bcl-2: variably
positive
- EMA, cytokeratin 14, smooth muscle actin, and c-kit:
negative
Differential diagnosis
- Invasive lobular carcinoma
- Adenoid cystic carcinomas
Prognosis and treatment
- Wide excision with axillary lymph node dissection
- Not indolent clinical behavior
References
Asioli, S., Marucci, G., Ficarra, G., Stephens, M.,
Foschini, M. P., Ellis, I. O., & Eusebi, V. (2006).
Polymorphous adenocarcinoma of the breast. Report
of three cases. Virchows Archiv, 448, 29–34.
Elston, C. W., & Ellis, I. O. (1991). Pathological prognostic
factors in breast cancer. 1. The value of histological
grade in breast cancer: Experience from a large study
with long-term follow-up. Histopathology, 19,
403–410.
Foschini, M. P., Morandi, L., Asioli, S., Giove, G.,
Corradini, A. G., & Eusebi, V. (2017). The morpholog-
ical spectrum of salivary gland type tumours of the
breast. Pathology, 49, 215–227.
Reyes, C., Jorda, M., & Gomez-Fernández, C. (2013).
Salivary gland-like tumors of the breast express
basal-type immunohistochemical markers. Applied
Immunohistochemistry and Molecular Morphology,
21, 283–286.
333
Pseudoangiomatous Stromal
Hyperplasia
Janina Kulka1 and Anna Sapino2,3
1
2nd Department of Pathology, Semmelweis
University, Budapest, Hungary
2
Unit of Pathology, Candiolo Cancer Institute
FPO-IRCCS, Candiolo, Italy
3
Department of Medical Sciences, University of
Turin, Turin, Italy
Synonyms
Nodular myofibroblastic stromal hyperplasia of
the mammary gland (Leon et al. 2002).
Definition
Pseudoangiomatous hyperplasia of mammary
stroma (PASH) is a benign proliferation of keloid-
like fibrosis, containing slit-like pseudovascular
spaces lined by spindle shaped cells without mitotic
figures and atypia. (Ibrahim et al. 1989). PASH is
considered a breast-specific myofibroblastic prolif-
eration (Krings et al. 2017).
Clinical Features P
• Incidence
PASH of the breast was first described by
Vuitch et al. in 1986 (Vuitch et al. 1986). Its
incidence was later investigated in a series of
200 consecutive breast biopsies and surgical
specimens and was found to be an incidental
finding in breast biopsies in 23% of the cases
(Ibrahim et al. 1989). Incidental PASH can be
found in fibroadenomas, gynecomastia, nor-
mal breast tissue, hamartomas, and sclerosing
lobular hyperplasia. It has also been described
in surgical specimens of gigantomastia. Two
cases were described in immunosuppressed
patients (Seidman et al. 1993 and de Saint
Aubain Somerhausen et al. 1997). In a case
334
series of 24 mass forming PASH, it was found
that 40% of the female patients had family
history of breast cancer (Bowman et al. 2012).
• Age
PASH occurs in pre- or perimenopausal
patients and is often associated with fibrocystic
changes (Ibrahim et al. 1989). The mean age of
patients diagnosed with tumor forming
(nodular) PASH is 37 years (Powell et al.
1995). However, PASH was also described in
postmenopausal women: among them more
than half of those with tumor forming PASH
were receiving hormone replacement therapy
(Virk and Khan 2010). Rare cases of PASH
causing voluminous and rapidly growing
breast mass with severe breast asymmetry
occurring in adolescents have been described
(Pellini et al. 2018).
• Sex
PASH is mainly found in female breast tissue,
but it is also common in male gynecomastia:
according to one study, 23.8% of gynecomastia
cases harbored PASH (Milanezi et al. 1998).
Occurrence of PASH in the breast of a trans-
gender male patient has been described
(Bowman et al. 2012).
• Site
No specific site in the breast has been
described. PASH was reported in axillary
accessory breast tissue (Lee et al. 2005).
• Symptoms
PASH is found incidentally in most of the cases
without any clinical symptoms. Fewer cases or
case series are described in the literature with
PASH occurring as palpable mass. Raj et al.
reported 44% of PASH presenting as palpable
breast lesion (Raj et al. 2017). A rare manifes-
tation is diffuse massive process with asymme-
try of the breast (Shahi et al. 2015). PASH was
also described as a cause of gigantomastia
(Roy et al. 2015). In a published series of
seven cases, the lesions were identified on
mammograms as noncalcified masses measur-
ing 1.1–11 cm in largest diameter (Polger et al.
1996). Mammographic and ultrasound appear-
ance of nodular PASH is very similar to those
of fibroadenomas: on ultrasound, PASH often
Pseudoangiomatous Stromal Hyperplasia
appears as an oval, circumscribed, hypoechoic
mass. On magnetic resonance imaging, PASH
usually has progressive (Type 1) enhancement,
and high-signal slit-like spaces may be seen on
T2-weighted and short tau inversion recovery
(STIR) images (Raj et al. 2017). A case of
PASH (confirmed in a subsequent core biopsy)
was incidentally revealed due to focal
increased radiotracer uptake in the left breast
of a prostate cancer patient undergoing
Ga-labeled prostate-specific membrane anti-
gen ligand PET-CT (Malik et al. 2017).
• Treatment
The current recommendations are to excise
lesions more than 2 cm and conservative man-
agement and watchful waiting with smaller
lesions. Successful treatment of PASH with
Tamoxifen in a patient with PASH presenting
with breast enlargement, pain, and breast
masses was described (Pruthi et al. 2001).
• Outcome
Sporadic cases of recurrent PASH have been
described following incomplete excision. On
the other hand, spontaneous regression of
PASH is also documented in the literature.
Macroscopy
Only PASH forming a nodular lesion in the breast
can be seen macroscopically: the typical appear-
ance is a well-circumscribed firm or rubbery
tumor with a white-gray/tan cut surface (Powell
et al. 1995). The largest lesion described in the
literature measured 20 cm (Sasaki et al. 2008).
Microscopy
Microscopically, a spectrum of pathological stro-
mal changes can be seen ranging from anastomos-
ing slit-like spaces lined by flat, bland spindle
cells (Figs. 1 and 2) to more proliferative lesions
composed of bundles of plump spindle cells that
may obscure the underlying pseudoangiomatous
architecture in the most florid lesions (Powell
et al. 1995).
Pseudoangiomatous Stromal Hyperplasia
Pseudoangiomatous Stromal Hyperplasia, Fig. 1
(H&E) Detail of a breast hamartoma showing PASH
Pseudoangiomatous Stromal Hyperplasia, Fig. 2
(H&E) High magnification of PASH: slit-like spaces in
collagenous stroma lined by bland spindle cells
Nodular PASH (“tumorous” or “tumor forming”
PASH), as opposed to incidental PASH, is well
circumscribed microscopically and may be associ-
ated with florid ductal type epithelial hyperplasia.
Diffuse PASH is rare, less than 20 cases were
reported in the literature. It may be the cause of
rapidly developing gigantomastia during preg-
nancy (Krawczyk et al. 2016).
PASH with stromal giant cells is an extremely
rare variant, characterized by mostly multi-
nucleated myofibroblasts lining the slit-like
spaces (Comunoğlu et al. 2007). Two cases asso-
ciated with von Recklinghausen disease in males
were described and as a conclusion the authors
warn that PASH with stromal giant cells should be
recognized as a feature of gynecomastia in von
Recklinghausen’s disease (Damiani and Eusebi
2001).
Atypical PASH has also been described. Only
two formal case reports are available in the
335
English language literature. According to Rosen,
who mentioned two young girls’ cases with this
lesion in his famous Breast Pathology book, atyp-
ical PASH appears to be myofibroblastic sarcoma
(Rosen 2001). In the case published by Nassar
et al. (2010), atypical PASH occurred in the back-
ground of nodular PASH. The two lesions
described so far were rapidly growing breast
masses, showing atypia of the myofibroblasts lin-
ing the pseudovascular spaces, with mitotic activ-
ity (Noda et al. 2019).
Most probably as a coincidence, invasive
breast carcinoma rarely may be associated with
PASH (Ferreira et al. 2008).
Recavarren and co-workers described a similar
stromal change (Recavarren et al. 2009) called
PASH-like stroma seen intimately associated
with columnar cell change of the duct epithelium
(the acronym they used was CCPLS). They sug-
gest an epithelial-stromal interaction as the back-
ground of this finding, which differed from PASH
in terms of immunophenotype.
Immunophenotype
The spindle cells lining the slit-like spaces are
vimentin and CD34 positive but factor VIII and
CD31 are always negative. In more cellular fascic-
ular lesions, the stromal cells may be positive for P
desmin and smooth muscle actin. The immunohis-
tochemical features are consistent with
myofibroblastic histogenesis of PASH. Progester-
one receptor (PR) positivity in stromal cell nuclei is
usually more pronounced than estrogen receptor
(ER) positivity in these lesions. ER may be
completely negative in the spindle cells (Powell
et al. 1995). Because of the consistent finding
of PR positivity of the spindle cells lining the slit-
like spaces, it was suggested that hormonal factors
play a major role in the development of PASH.
Molecular Features
There are no literature data about the molecular
characteristics of PASH.
336
Differential Diagnosis
The most important differential diagnosis is well
differentiated angiosarcoma (▶ Angiosarcoma of
the Breast).
References and Further Reading
Bowman, E., Oprea, G., Okoli, J., Gundry, K., Rizzo, M.,
Gabram-Mendola, S., Manne, U., Smith,
G., Pambuccian, S., & Bumpers, H. L. (2012). Pseudo-
angiomatous stromal hyperplasia (PASH) of the breast:
A series of 24 patients. The Breast Journal, 18,
242–247.
Comunoğlu, N., Comunoğlu, C., Ilvan, S., Calay, Z., &
Müslümanoğlu, M. (2007). Mammary Pseudo-
angiomatous stromal hyperplasia composed of pre-
dominantly Giant cells: An unusual variant. The
Breast Journal, 13, 568–570.
Damiani, S., & Eusebi, V. (2001). Gynecomastia in type-1
neurofibromatosis with features of pseudoangiomatous
stromal hyperplasia with giant cells. Report of two
cases. Virchows Archiv, 438, 513–516.
de Saint Aubain Somerhausen, N., Larsimont, D., Cluydts, N.,
Heymans, O., & Verhest, A. (1997). Pseudo-
angiomatous hyperplasia of mammary stroma in an
HIV patient. General & Diagnostic Pathology, 143,
251–254.
Ferreira, M., Albarracin, C. T., & Resetkova, E. (2008).
Pseudoangiomatous stromal hyperplasia tumor:
A clinical, radiologic and pathologic study of
26 cases. Modern Pathology, 21, 201–207.
Ibrahim, R. E., Sciotto, C. G., & Weidner, N. (1989).
Pseudoangiomatous hyperplasia of mammary stroma.
Some observations regarding its clinicopathologic
spectrum. Cancer, 63, 1154–1160.
Krawczyk, N., Fehm, T., Ruckhäberle, E., Mohrmann, S.,

Riemer, J. Braunstein, S. Hoffmann, J. (2016) Bilateral
diffuse Pseudoangiomatous stromal hyperplasia
(PASH) causing Gigantomastia in a 33-year-old preg-
nant woman: Case report. Breast Care, 11, 356–358.
Krings, G., McIntire, P., & Shin, S. J. (2017).
Myofibroblastic, fibroblastic and myoid lesions of the
breast. Seminars in Diagnostic Pathology, 34,
427–437.
Lee, J. S., Oh, H. S., & Min, K. W. (2005). Mammary
pseudoangiomatous stromal hyperplasia presenting as
an axillary mass. The Breast, 14, 61–64.
Leon, M. E., Leon, M. A., Ahuja, J., & Garcia, F. U.
(2002). Nodular myofibroblastic stromal hyper-
plasia of the mammary gland as an accurate name
for pseudoangiomatous stromal hyperplasia of
the mammary gland. The Breast Journal, 8,
290–293.
Pseudoangiomatous Stromal Hyperplasia
Malik, D., Basher, R. K., Mittal, B. R., Jain, T. K., Bal, A.,
& Singh, S. K. (2017). 68Ga-PSMA expression in
Pseudoangiomatous stromal hyperplasia of the breast.
Clinical Nuclear Medicine, 42, 58–60.
Milanezi, M. F., Saggioro, F. P., Zanati, S. G., Bazan, R., &
Schmitt, F. C. (1998). Pseudoangiomatous hyperplasia
of mammary stroma associated with gynaecomastia.
Journal of Clinical Pathology, 51, 204–206.
Nassar, H., Elieff, M. L., Kronz, J. D., & Argani, P. (2010).
Pseudoangiomatous stromal hyperplasia (PASH) of the
breast with focal of morphologic malignancy: A case of
PASH with malignant transformation? International
Journal of Surgical Pathology, 18, 564–569.
Noda, Y., Nishimae, A., Sawai, Y., Inaji, H., & Yamasaki, M.
(2019). Atypical pseudoangiomatous stromal hyperpla-
sia showing rapid growth of the breast: Report of a case.
Pathology International. https://doi.org/10.1111/
pin.12786.
Pellini, D. F., Lorenzi, M., Gaudino, R., Accordini, B.,
Mirandola, S., Invento, A., & Pollini, P. D. (2018).
Pseudoangiomatous stromal hyperplasia (PASH) in
adolescence: A systematic review. World Journal of
Surgery and Surgical Research, 1, 1058.
Polger, M. R., Denison, C. M., Lester, S., & Meyer, J. E.
(1996). Pseudoangiomatous stromal hyperplasia:
Mammographic and sonographic appearances. Ameri-
can Journal of Roentgenology, 166, 349–352.
Powell, C. M., Cranor, M. L., & Rosen, P. P. (1995).
Pseudoangiomatous stromal hyperplasia (PASH):
A mammary stromal tumor with myofibroblastic dif-
ferentiation. American Journal of Surgical Pathology,
19, 270–277.
Pruthi, S., Reynolds, C., Johnson, R. E., & Gisvold, J. J.
(2001). Tamoxifen in the management of Pseudo-
angiomatous stromal hyperplasia. The Breast Journal,
7, 434–439.
Raj, S. D., Sahani, V. G., Adrada, B. E., Scoggins, M. E.,
Albarracin, C. T., Woodtichartpreecha, P., Posleman
Monetto, F. E., & Whitman, G. J. (2017). Pseudo-
angiomatous stromal hyperplasia of the breast: Multi-
modality review with pathologic correlation. Current
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Recavarren R. A., Chivukula M., Carter G., Dabbs D. J.
(2009). Columnar cell lesions and pseudoangiomatous
hyperplasia like stroma: is there an epithelial-stromal
interaction? International Journal of Clinical and
Experimental Pathology, 3, 87–97.
Rosen, P. P. (2001). Rosen’s breast pathology. Philadel-
phia: Lippincott Williams & Wilkins.
Roy, M., Lee, J., Aldekhayel, S., & Dionisopoulos, T.
(2015). Pseudoangiomatous stromal hyperplasia:
A rare cause of idiopathic Gigantomastia. Plastic and
Reconstructive Surgery. Global Open, 3, e501.
Sasaki, Y., Kamata, S., Saito, K., Nishikawa, Y., & Ogawa, J.
(2008). Pseudoangiomatous stromal hyperplasia (PASH)
of the mammary gland: Report of a case. Surgery Today,
38, 340–343.
Pseudoangiomatous Stromal Hyperplasia
Seidman, J. D., Borkowski, A., Aisner, S. C., & Sun,
C. C. (1993). Rapid growth of pseudoangiomatous
hyperplasia of mammary stroma in axillary
gynecomastia in an immunosuppressed patient.
Archives of Pathology and Laboratory Medicine,
117, 736–738.
Shahi, K. S., Bhandari, G., Gupta, R. K., & Sawai, M.
(2015). Pseudoangiomatous stromal hyperplasia:
337
A rare tumor of the breast. Journal of Cancer Research
and Therapy, 11, 1032.
Virk, R. K., & Khan, A. (2010). Pseudoangiomatous stro-
mal hyperplasia. An overview. Archives of Pathology
and Laboratory Medicine, 134, 1070–1074.
Vuitch, M. F., Rosen, P. P., & Erlandson, R. A. (1986).
Pseudoangiomatous hyperplasia of mammary stroma.
Human Pathology, 17, 185–191.
P
R
Radial Scar
Janina Kulka
2nd Department of Pathology, Semmelweis
University, Budapest, Hungary
Synonyms
Rosette-like lesion; Proliferation center;
Sclerosing adenosis with pseudo-infiltration;
Sclerosing papillary proliferation; Benign scle-
rosing ductal proliferation; Nonencapsulated
sclerosing lesion; Centre de proliferation
d’Aschoff; Fibroadenosis with fibroelastic core;
Lesioni focali sclero-elastotiche; Radial scleros-
ing lesion; Indurative mastopathy; Strahlige
Narben
Definition
The definition of radial scars was given by
Wellings as follows: a radial scar is a radially
symmetric tissue formation up to about 1 cm in
diameter; it is composed of a fibroelastic
core that often entraps small epithelial
tubules and is always surrounded by radiating
ducts and lobules showing variable degrees
of adenosis and epitheliosis (Wellings and
Alpers 1984).
© Springer Nature Switzerland AG 2020
A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
Clinical Features
• Incidence
The incidence of radial scars increased with the
introduction of mammographic screening, but
in the whole screened population it remains a
rare lesion. Assessing the incidence of radial
scars in the Welsh Breast Screening Pro-
gramme, 764 radial scars (0.05%) were
reported in a population of 1,285,716 women
attending breast screening between 1989 and
2007 (Osborn et al. 2011). In a study from the
Gustave Roussy Institute from 1985 (D’Amore
et al. 1985) studying surgical pathology mate-
rial of 6544 women operated for benign breast
lesions between 1976 and 1981, the authors
identified only 70 cases (1%) with radial
scars. Later, in a smaller cohort of 1396
patients with benign breast biopsies from the
Nurses’ Health Study, radial scars occurred in
7.1%. In their historical study describing sub-
gross findings in 300 whole human breasts,
Wellings and Alpers (1984) found much higher
incidence (14%) in 83 noncancerous breasts
that were collected during autopsies. An inter-
esting finding of this study was that the
12 breasts (12/83, 14%) had a total of 92 radial
scars indicating an average of 7.7 lesions per
breast. On the other hand, in the 107 cancer-
associated (ipsilateral or contralateral breast
cancer) breasts, they found 434 radial scars,
340
on average 15.5 per breast. Linell who
performed a study of 555 mastectomy speci-
mens found radial scars in 16%, but in the
group of breast cancer patients radial scars
were present in half of the specimens (Linell
1985). These findings led to suggest that radial
scars may be precancerous lesions.
• Age
In large studies, the age range of radial scars
varies between 25 and 89 years. The median of
this range is around the perimenopausal age
group.
• Sex
Radial scars are mainly found in female
breasts, but in occasional rare cases it may
occur in male breasts as well.
• Site
No specific site had been described as concerns
laterality or quadrant of the breast.
• Imaging
Many papers had been published describing
the imaging features of radial scars given that
the structure of these lesions may mimic small
stellate carcinoma on mammography. Tabar
and Dean (1983) have first described system-
atically the mammographic features that enable
the radiology diagnosis, as follows:
(i) depending on the view, the appearance of
the detected lesion is variable, (ii) in relation to
the long and thin spicules, the central opacity is
small, (iii) parallel to the spicules a very thin,
radiolucent line can be seen, (iv) the center of
the lesion is radiolucent, and (v) there is dis-
cordance between the mammographic finding
of a stellate lesion and the lack of a palpable
lesion by physical examination. Digital mam-
mography is more sensitive than analogue
mammography, and breast tomosynthesis
apparently discovers even more stellate lesions
than analogue or digital mammography, thus
seems to increase slightly the recall rate in
screening programs. In the Malmo Breast
Tomosynthesis Screening Trial, around 10%
of the false positive recalls were due to radial
scars. Ultrasound detects up to two-third of
radial scars, most commonly as a hypoechoic
area or mass. Parenchymal distortion without a
hypoechoic mass is present in about one-fifth
Radial Scar
of the cases diagnosed as radial scar. In almost
10% of the cases, the lesion is better visualized
by ultrasound than mammography. On MRI,
radial scars possess variable morphology and
their kinetic features are also not uniform.
Since they can demonstrate false positive
enhancement, ill-defined borders, and irregular
shape, not infrequently MRI findings mimic
invasive carcinoma.
• Treatment
Given that core biopsy diagnosis of radial scars
is coded as B3 according to present guidelines,
these lesions need further multidisciplinary
work-up. Until a few years ago, core biopsy
diagnosis of a radial scar was an absolute indi-
cation for surgical excision, and in large series
the upgrade rate for malignancy varied between
0% and 24%. More recently, with the wide-
spread use of vacuum-assisted core biopsy
(VACB), the indications for surgical excision
became more restricted. In the latest update of
the UK Breast Screening Quality Assurance
Guideline (2016 update), the management of
radial scars differs if the lesion was incidental
(not seen on mammography) or was identified
as a mammographic abnormality. For those
radial scars detected only histologically on
core biopsy performed for other radiologically
identified benign lesion, no further intervention
is needed. For those radial scars detected as
mammographic abnormality, at least 12 VACB
cores is recommended as a second intervention.
Radial scars completely removed by VACB
require surgical excision only if epithelial atypia
is associated to the lesion.
• Outcome
In one of the longest follow-up study of
32 patients with radial scar, only one patient
developed ipsilateral breast cancer 16 years
after the diagnosis of the radial scar
(Andersen and Gram 1984). The mean
follow-up period in this study was 19.5 years
(range 15–24 years). Many studies in the eight-
ies suggested an elevated cancer risk associ-
ated to radial scars; however, large recent
studies are less convincing especially
concerning radial scars devoid of atypical epi-
thelial proliferation and assessed on VACB.
Radial Scar
A meta-analysis showed a 1.33-fold increased
risk in pooled analysis of more than 2000 cases
and more than 20,000 controls, but this was not
statistically significant (Mengmeng et al.
2014). Epithelial proliferation associated to
radial scars slightly increases the risk to 1.6-
fold. This increase of relative risk is similar
to proliferative fibrocystic change (▶ Fibro-
cystic Breast Changes), usual type ductal
hyperplasia (▶ Usual Ductal Hyperplasia
Radial Scar, Fig. 1 Magnified mammographic appear-
ance of a radial scar. In this case microcalcifications were
associated. (By courtesy of Dr. Éva Ambrózay, MaMMa
Clinic Budapest)
Radial Scar, Fig. 2 H&E: (a) Distorted small ducts lacking any organoid arrangement in the central part of a small radial
scar. (b) Radial scar associated with flat epithelial atypia
341
(UDH)), sclerosing adenosis (▶ Sclerosing
Adenosis), and complex fibroadenoma
(▶ Fibroadenoma). The association of atypical
ductal (▶ Atypical Ductal Hyperplasia) - or
atypical lobular hyperplasia, in situ lobular
neoplasia (▶ Lobular In Situ Neoplasia), and
flat epithelial atypia (▶ Columnar Cell
Lesions) result in elevated relative cancer risk
similar to the relative risk of these low grade
atypical epithelial lesions measured outside of
the context of radial scars.
Macroscopy
Radial scars are either visible or not during gross
examination. By definition, these lesions are small,
less than 10 mm in maximum diameter. When
visible, a slightly firm, or rubbery, scar-like lesion
with irregular contour can be identified in the spec-
imen. On specimen mammography, identification
of the lesion may be easier since it may reveal the
characteristic stellate soft tissue density (Fig. 1).
Microscopy
Radial scars have a very characteristic micro-
scopic appearance that can be appreciated
already with very low magnification. They pos-
sess a central, focally elastotic “scar” from which
the epithelial structures showing various degree
of proliferative changes radiate toward the
R
342
periphery. Within the central scar, very often one
finds entrapped and distorted or ramifying small
ducts lacking any organoid arrangement
(Fig. 2a). The nuclei of the epithelial cells lying
the entrapped ducts are devoid of atypia and no
mitotic figures are present. Occasionally, the
central elastosis and the scar itself is so much
reminiscent to the contour of a totally obliterated
larger duct, for in the past periductal mastitis was
supposed as an etiologic factor for these lesions.
However, there are opponents to this theory who
believe that radial scars are per se proliferative
lesions of the breast.
The radiating projections contain epithelial
structures: ducts with various degree of dilatation
(Fig. 3), often with usual type ductal hyperplasia.
Sclerosing adenosis, small papillomas, adenosis,
and columnar cell change are also common fea-
tures. Apocrine changes may also be associated.
Radial Scar, Fig. 3 Subgross appearance of the periphery
of a radial scar (Mayer’s hematoxylin)
Radial Scar, Fig. 4 (a) p63 immunohistochemistry highlights the myoepithelial cells and (b) CK14 immunohistochem-
ical reaction shows the heterogeneous epithelial cell population in entrapped small ducts in the center of a radial scar
Radial Scar
In some lesions, lymphoid inflammatory infiltrate
is also found. Presence of small microcalcification
particles is not uncommon. Radial scars often
occur in the background of fibrocystic breast
parenchyma. The presence of atypical epithelial
proliferations (Fig. 2b), in situ carcinomas, or
invasive carcinomas in radial scars has been
described in larger lesions of older women
(Sloane and Mayers 1993). Association of inva-
sive carcinoma has not been described in lesions
that are smaller than 5 mm.
Immunophenotype
High molecular weight cytokeratins (cytokeratin
5/6, 14) and myoepithelial markers (p63, p40,
calponin, CD10, etc.) can help to identify the
benign nature of the epithelial proliferation asso-
ciated with a radial scar or may help to identify an
associated in situ or invasive cancer (Fig. 4).
Molecular Features
Very few molecular studies of radial scars have
been published to date. More than 20 years ago
Ruiz-Sauri compared radial scars and tubular car-
cinomas by image cytometry and flow cytometry
analysis (Ruiz-Saurí et al. 1995). The case num-
bers were small (17 radial scars and 6 small tubu-
lar carcinomas), and only image cytometry could
identify ploidy differences between the two types
of breast lesions: most radial scars were diploid, as
Radial Scar
opposed to only 50% of tubular carcinomas that
showed diploidy. However, using flow cytometry,
both radial scars and tubular carcinomas proved
diploid. In the early 2000s, stromal mRNA
expression pattern of radial scars and invasive
cancers was compared using small number of
cases and normal controls. Findings suggested
that expression of mRNAs encoding proteins
involved in the vascular stroma shows similarities
between radial scars and invasive breast cancers
(Jacobs et al. 2002). Chromosomal alterations
have also been described in radial scars, namely,
allelic imbalance of chromosome 16q and 8p.
This finding suggested that some areas of radial
scars are clonal and may be neoplastic (Iqbal et al.
2002). More recently a few studies using next
generation sequencing (NGS) detected PIK3CA
mutations in radial scars with higher frequency
compared to the 25–30% PIK3CA mutation fre-
quency detected in series of invasive breast carci-
nomas (Wilsher et al. 2017).
Differential Diagnosis
Radial scars may be misdiagnosed by the
unexperienced pathologist as invasive breast car-
cinoma NST (▶ Invasive Carcinoma NST) or
tubular carcinoma (▶ Tubular Carcinoma). It is
noteworthy to mention that the irregular, haphaz-
ardly arranged, compressed tubular structures in
radial scars are exclusively seen in the central
elastotic nidus. In invasive cancers, the neoplastic
tubules often invade the fat tissue which is not
a feature in radial scars. Furthermore, in the rela-
tively wide radiating arms, there are ducts and/or
lobules showing various degree of the
abovementioned proliferative epithelial changes.
As opposed to this, in small grade 1 carcinomas or
tubular carcinomas, the neoplastic tubules build
up the whole lesion and most of their stellate
peripheral projections are devoid of preexisting
ducts or lobules. In equivocal cases, immunohis-
tochemical markers for myoepithelial cells can
assist to exclude malignancy. In case of uncer-
tainty, high molecular weight cytokeratins are
useful to characterize the associated intraductal
proliferations.
343
The differential diagnosis may be more diffi-
cult in 14G needle core biopsies. However, in
close cooperation with the radiologist, the diag-
nosis of a radial scar can be made with confi-
dence even in such specimens. Tissue fragments
showing the central elastotic scar with entrapped
small ducts with normal two layered epithelial
lining (or usual type hyperplasia) are features
that help to identify RSs even in fragmented
specimens.
References and Further Reading
Andersen, J. A., & Gram, J. B. (1984). Radial scar in the
female breast. A long-term follow-up study of 32 cases.
Cancer, 53, 2557–2560.
D’Amore, E., Montes, E., Le, M. G., Lacombe, M. J.,
Bertin, F., Castaigne, D., & Contesso, G. (1985).
Aschoff’s center of proliferation. Experience of the
Gustave Roussy Institute. Annals of Pathology, 5,
173–182.
Hamperl, H. (1975). Strahlige Narben und obliterierende
Mastopathie. Virchows Archiv (Pathological Anatomy),
369, 55.
Iqbal, M., Shoker, B. S., Foster, C. S., Jarvis, C.,
Sibson, D. R., & Davies, M. P. (2002). Molecular and
genetic abnormalities in radial scar. Human Pathology,
33, 715–722.
Jacobs, T. W., Byrne, C., Colditz, G., Connolly, J. L.,
& Schnitt, S. J. (1999). Radial scars in benign
breast-biopsy specimens and the risk of breast can-
cer. New England Journal of Medicine, 340(6),
430.
Jacobs, T. W., Schnitt, S. J., Tan, X., & Brown, L. F. (2002).
Radial scars of the breast and breast carcinomas have
similar alterations in expression of factors involved in
vascular stroma formation. Human Pathology, 33, R
29–38.
Lång, K., Nergården, M., Andersson, I., Rosso, A., &
Zackrisson, S. (2016). False positives in breast cancer
screening with one-view breast tomosynthesis: An
analysis of findings leading to recall, work-up and
biopsy rates in the Malmö Breast Tomosynthesis
Screening Trial. European Radiology, 26(389),
9–3907.
Linell, F. (1985). Radial scars of the breast and their sig-
nificance for diagnosis and prognosis. Verhandlungen
der Deutschen Gesellschaft für Pathologie, 69,
108–118.
Mengmeng, L. V., Xingya, Z., Shanliang, Z., et al. (2014).
Radial scars and subsequent breast Cancer risk: A meta
analysis. PLoS One, 9, e102503.
NHS Breast Screening Programme Clinical guidance for
breast cancer screening assessment. (2016). NHSBSP
publication number 49, 4th ed.
344
Osborn, G., Wilton, F., Stevens, G., Vaughan-Williams, E.,
& Gower-Thomas, K. (2011). A review of needle core
biopsy diagnosed radial scars in the Welsh Breast
Screening Programme. Annals of Royal College of
Surgeons England, 93, 123–126.
Ruiz-Saurí, A., Almenar-Medina, S., Callaghan, R. C.,
Calderon, J., & Llombart-Bosch, A. (1995). Radial
scar versus tubular carcinoma of the breast.
A comparative study with quantitative techniques
(morphometry, image- and flow cytometry). Pathology
Research and Practice, 191, 547–554.
Sloane, J. P., & Mayers, M. M. (1993). Carcinoma and
atypical hyperplasia in radial scars and complex
Radial Scar
sclerosing lesions: Importance of lesion size and patient
age. Histopathology, 23, 225–231.
Tabar, L., & Dean, P. B. (1983). Teaching atlas of mammog-
raphy (pp. 95–96). Stuttgart: Georg Thieme Verlag.
Wellings, S. R., & Alpers, C. E. (1984). Subgross patho-
logic features and incidence of radial scars in the breast.
Human Pathology, 15, 475–479.
Wilsher, M. J., Owens, T. W., & Allcock, R. J. (2017).
Next generation sequencing of the nidus of early
(adenosquamous proliferation rich) radial sclerosing
lesions of the breast reveals evidence for a neoplastic
precursor lesion. Journal of Pathology: Clinical
Research, 3, 115–122.
S
Sclerosing Adenosis
Gyula Pekar
Division for Laboratory Medicine, Department of
Pathology, Lund University, Lund, Sweden
Synonyms
Sclerosing adenosis (SA)
Definition
SA is a lobulocentric proliferation of distorted
acini around a central duct with preservation of
myoepithelial cells, accompanied with varying
degrees of epithelial atrophy and stromal fibrosis.
Clinical Features
• Incidence
SA is often an incidental finding in breast tis-
sue removed for other reasons. In autopsy stud-
ies performed on patients with no history of
breast disease, the incidence of SA was in a
range of 7–20%. The lesion is present in
12–28% of breast biopsies without cancer and
in 5–7% of malignant biopsies.
• Age
Most patients are in their forties and fifties with
a peak in the 45–55 age group (34%), versus
© Springer Nature Switzerland AG 2020
A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
28.3% of older women and 21.6% of women
less than 45.
• Sex
SA is predominant in women and
more common in obese and in women using
hormone replacement therapy and with a
higher fibroglandular breast tissue density at
mammography (>25%). Because of increased
estrogen receptor (ER) expression observed
compared with normal glandular breast tissue,
it is assumed that hormone imbalance and
dysregulation of ER may play a role in devel-
opment of SA.
• Presentation
– Clinical appearance
Patients with a clinically palpable mass, termed
as nodular SA or adenosis tumor (▶ Adenosis,
Other Types), are generally younger, often in
their pre- or perimenopausal age. The lesion is
usually solitary, although multiple and bilateral
nodular SAwere reported. It may be ill-defined
and can be somewhat fixed within the breast
parenchyma.
– Mammography
The main features of SA are multiple, punc-
tuate microcalcifications (i.e., powdery, cot-
ton ball-like, “skipping stone-like”) (Fig. 1a).
Thick-section images demonstrate that the
radiologically detected microcalcifications
can have “onion ring” like psammomatous
appearance (Fig. 1b), and they are localized
within enlarged and distorted lobules
(Fig. 1c, d). Rarely mammographic
346
Sclerosing Adenosis, Fig. 1 SA associated with micro-
calcifications. Specimen mammography shows clusters of
cotton ball-like, powdery calcifications (a). Thick-section
images demonstrate that the radio dense phosphate calcifi-
cations can have “onion ring” like psammomatous-
calcifications may be amorphous and pleo-
morphic and in such cases indistinguishable
from non-comedo DCIS. SA is less com-
monly detected as a mass lesion, which is
generally circumscribed or lobulated and
may be associated with microcalcifications.
In rare cases, SA presents as an architectural
distortion.
– Ultrasound
Nodular SA often appears as a circum-
scribed, hypoechoic solid lesion. In cases
with asymmetrical density on mammogra-
phy, the typical ultrasound feature is focal
acoustic shadowing without a mass config-
uration. Mass-like lesions with irregular
contour in association with marked poste-
rior acoustic shadowing are also observed,
Sclerosing Adenosis
appearance (b), and localized within enlarged and distorted
lobules (c, d). The single black arrows on pictures d
represent the two expanded foci of SA comparing to an
intermingled normal lobule depicted with double black
arrows
and the distinction from infiltrating carci-
noma is impossible.
– Magnetic resonance imaging (MRI)
Typical SA lesions are indistinguishable
from breast parenchyma, but the enhance-
ment may increase moderately or rapidly
over time making it difficult to distinguish
nodular SA from malignant lesions.
• Treatment
Some evidence suggests that SA may regress
after the menopause. When SA is associated
with non-proliferative lesions as a part of fibro-
cystic change, further excision is not
recommended. If SA is diagnosed in a core nee-
dle biopsy (CNB), surgical excision of
the lesional area is recommended to rule out
carcinoma, particularly in cases associated with
Sclerosing Adenosis
radiographically suspicious calcifications, a
spiculated contour, or combined with radial scle-
rosing lesions, or atypical epithelial hyperplasia.
In the absence of the foregoing features, clinical
follow-up is recommended.
• Outcome
There is still disagreement as to whether SA is a
risk factor for subsequent breast carcinoma.
When only a small area of SA is present, there
may be no evidence that risk is elevated beyond
that of other non-proliferative lesions
(no increased breast cancer risk, 4% lifetime
risk) such as usual ductal hyperplasia. The com-
bination of SA with atypical ductal hyperplasia
(ADH) (▶ Atypical Ductal Hyperplasia) or atyp-
ical lobular hyperplasia (ALH) increases the risk
of cancer development (4.8–6.7). The associa-
tion with lobular neoplasia (▶ Lobular In Situ
Neoplasia) is found to occur almost three times
more commonly than would be expected by
chance. In addition, positive family history of
breast cancer (2.85 risk), patient age (2.24
risk in 45–55 years old group), and other risk
factors such as the degree of lobular involution
(2.67 risk in non-involutionary breast) and
higher Ki-67 expression in SA and/or adjacent
normal breast can increase the risk of subsequent
invasive carcinoma (Nassar et al. 2015).
Macroscopy
There are no distinctive gross appearances, the
breast tissue either appearing normal or showing
features of associated fibrocystic change. In cases
with nodular SA firm, lobulated but often ill-
defined rubbery mass can be seen varying in size
up to 5 cm. A nodular and whorled appearance
may be appreciated on the cut surface.
Microscopy
At low power three main forms of SA could
be observed: tiny foci in an otherwise normal breast
tissue, especially in perimenopausal women, larger
but still microscopic lesions as part of the spectrum
of fibrocystic change, and lesions that may form a
347
nodular mass. However the diagnostic clue is
swirling cluster of tubules or acini often around
central duct(s) with a whorled appearance
(Fig. 2a) usually referred to as lobulocentric in the
literature (Urban and Adair 1949). Further diagnos-
tic criteria of SA are its size which is approximately
twice the size of adjacent “normal” lobules, and at
least 50% of the acini of individual TDLU must be
involved by the sclerosing process (Jensen et al.
1989). However, the lobules can vary greatly in
size within the same breast; this criterion seems
difficult to be applied. The range of SA varies
from highly cellular lesions to sclerotic/hyalinized
areas, depending on the amount of epithelial and
myoepithelial cells (Fig. 2b p63 and Fig. 2d CK14
immunostaining of myoepithelial cells) and the
thickness of basement membranes (Fig. 2c). The
acini are distorted and elongated and predominance
of myoepithelial cells is common. Intraluminal
microcalcifications may be prominent justifying
the radiological abnormality. Both intraluminal
and stromal microcalcifications become progres-
sively more numerous with increasing sclerosis.
SA may be associated with (i) nonproliferative
changes (i.e., apocrine metaplasia, mild epithelial
hyperplasia) (8%); (ii) fibroadenoma, papilloma,
complex sclerosing lesions, columnar cell changes
(62.4%); and (iii) proliferative disease with atypia
(ADH and ALH equally distributed in 55.1%)
(Visscher et al. 2014). When SA is not limited to
a single lobule, the proliferating benign glands can
display a pseudo-infiltrative pattern. Spread to peri-
neural spaces is observed in 2–10% of the SA
cases, without impact on the biological behavior.
Rarely SA is involved by atypical epithelial pro- S
liferations. Atypical apocrine cells, so-called atyp-
ical apocrine adenosis, DCIS, or lobular carcinoma
in situ (LCIS) may be seen in SA (Fig. 3).
Immunophenotype
Due to its origin, SA maintains the immuno-
phenotype of normal lobules (i.e., CK7, CK 8/18,
p63, p40, smooth muscle actin, calponin, and high-
molecular weight cytokeratins (CK5/6, CK14)).
Using of more than one myoepithelial marker or
“cocktail” of markers can be helpful (Pavlakis et al.
348
Sclerosing Adenosis, Fig. 2 Histology of SA. Enlarged
lobule with dilated glands (a, H&E 20) and retained
myoepithelial cell layer which is highlighted with the p63
immunostain (b). Array of microtubular structures with
2006). Basement-membrane material is immunore-
active for collagen IV and laminin.
Molecular Features
A recent gene expression profile study revealed
overexpression of DLK2, EXOC6, KIT, RGS12,
and SORBS2 in SA at risk of cancer development
(Winham et al. 2017).
Differential Diagnosis
Normal Breast Versus SA
(1) Adenosis: lobules are enlarged; the number
of acini is increased. It occurs in normal
circumstances such as pregnancy (▶ Adenosis,
Other Types). (2) Lobules involution: involuting
lobules appear more eosinophilic than SA, being
dominated by luminal cells with plump blue nuclei.
Sclerosing Adenosis
partly obscured lumens on higher magnification (c, H&E
100) and the outer layer of myoepithelial cells being
positive with CK14 IHC (d)
Invasive Carcinoma
The features favoring SA against invasive carci-
noma are the following: lobulocentric architec-
ture, myoepithelial cells on hematoxylin and
eosin (HE) slides or by immunohistochemistry
(IHC), and dense rather than desmoplastic
stroma.
SA can mimic tubular carcinoma (TC)
(▶ Tubular Carcinoma). TC does not recapitu-
late the lobulocentric architecture and shows
haphazardly infiltrating growth pattern, edges
are irregular rather than circumscribed or lobu-
lated, and the tubules are more widely spaced. In
addition, TC shows angulated tubules with open
lumens and no myoepithelial cells. Invasive apo-
crine carcinoma (▶ Apocrine Carcinoma) can be
misdiagnosed in cases of atypical apocrine
adenosis. However, in atypical apocrine
adenosis, the organoid appearance is obvious
and specific IHC markers can demonstrate
myoepithelial cells.
Sclerosing Adenosis
Sclerosing Adenosis, Fig. 3 SA harboring LCIS. The
part of SA shows irregularly distributed acini expanded by
atypical cells of lobular type (a, H&E 80). E-cadherin
IHC shows that the cells of LCIS are completely lacking
Microglandular Adenosis (MGA)
MGA (▶ Microglandular Adenosis) is composed
of small round tubules scattered around normal
breast structures. Luminal spaces are opened with
round contours and eosinophilic secretions with-
out obvious stromal response. MGA can be dis-
tinguished from SA by lacking myoepithelial
cells, ER negativity, and S100 strong positivity
with IHC.
References and Further Reading
Jensen, R. A., Page, D. L., Dupont, W. D., & Rogers,
L. W. (1989). Invasive breast cancer risk in
women with sclerosing adenosis. Cancer, 64,
1977–1983.
Nassar, A., Hoskin, T. L., Stallings-Mann, M. L.,
Degnim, A. C., Radisky, D. C., Frost, M. H.,
Vierkant, R. A., Hartmann, L. C., & Visscher, D. W.
(2015). Ki-67 expression in sclerosing adenosis and
adjacent normal breast terminal ductal lobular units:
349
cytoplasmic membrane positivity and mixed with focally
remaining normal glandular cells with continuous and
intensive membrane staining (b). The myoepithelial cells
are intact as indicated by p63 IHC (c)
A nested case-control study from the Mayo Benign
Breast Disease Cohort. Breast Cancer Research and
Treatment, 151, 89–97.
Pavlakis, K., Zoubouli, C., Liakakos, T., Messini, I.,
Keramopoullos, A., Athanassiadou, S., Kafousi, M.,
& Stathopoulos, E. N. (2006). Myoepithelial cell cock-
tail (P63+SMA) for the evaluation of sclerosing breast
lesions. Breast, 15, 705–712.
Urban, J. A., & Adair, F. E. (1949). Sclerosing adenosis. S
Cancer, 2, 625–634.
Visscher, D. W., Nassar, A., Degnim, A. C., Frost, M. H.,
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350
Sebaceous Carcinoma of the
Breast
Zsuzsanna Varga and Linda Moskovszky
Institute of Pathology and Molecular Pathology,
University Hospital Zurich, Zurich, Switzerland
Synonyms
Carcinomas with sebaceous differentiation; Car-
cinomas with skin adnexal differentiation
Definition
Infiltrative carcinomas of the breast exhibiting
sebaceous cell differentiation in at least 50% of
the invasive tumor cells. In order to classify a
breast tumor as such, an extramammary tumor
especially carcinomas arising from the skin
adnexal structures must be excluded clinically or
immunohistochemically (Acosta et al. 2018; Maia
and Amendoeira 2018; Martin et al. 2017).
Clinical Features
• Incidence
This type of breast tumor is exceedingly rare,
accounting less than 1% of all breast carcino-
mas. Until now, 18 cases were reported in the
literature, most of them fulfilling the complete
criteria for a sebaceous breast carcinoma, and
some were described as invasive breast cancer
with sebaceous differentiation. Difficulties in
recognizing this entity requires precise knowl-
edge and recognition of the specialized addi-
tional cell type within the infiltrating tumor
cells (Acosta et al. 2018; Maia and
Amendoeira 2018; Sakai et al. 2018; Martin
et al. 2017; Yamamoto et al. 2017; Švajdler
et al. 2015; Wachter et al. 2014; Carlucci
et al. 2012; Müller et al. 2011; Murakami
et al. 2009; Hisaoka et al. 2006; Varga et al.
2000; Propeck et al. 2000; Tavassoli and
Sebaceous Carcinoma of the Breast
Norris 1986; van Bogaert and Maldague
1977).
• Age
Based on the available literature data, seba-
ceous breast carcinoma presents a wide range
of age, between 25 and 84 years at initial diag-
nosis with a mean age of 59.16 years, with
most patients being postmenopausal
(Murakami et al. 2009; Hisaoka et al. 2006;
Varga et al. 2000).
• Sex
Almost exclusively female patients were
reported in the literature so far. In one earlier
paper, a male patient with a large sebaceous
carcinoma in the breast area was described;
however this tumor as described in this paper
represents a skin adnexal tumor rather than a
primary breast carcinoma (Acosta et al. 2018;
Maia and Amendoeira 2018; Murakami et al.
2009; Hisaoka et al. 2006; Varga et al. 2000;
Ascari-Raccagni et al. 2011).
• Site
There is no site-specific predilection for this
tumor type. Both breasts are equally involved
(Acosta et al. 2018; Maia and Amendoeira
2018; Martin et al. 2017).
• Treatment
Depending on the pathological stage and grade
of the tumor under consideration of the pres-
ence or absence of the predictive markers as
estrogen and progesterone receptors and HER2
status, the current recommendation to surgery
and chemo- and radiotherapy is analogous to
breast cancer independently from the subtype
(Murakami et al. 2009; Hisaoka et al. 2006;
Varga et al. 2000).
• Outcome
Follow-up is available in most reported cases.
Based on this information and on the limited
number of cases, sebaceous breast carcinoma
tends to present with metastatic disease
(as skin, eyelid, and disseminated bone metas-
tases) in about a third of the cases (Maia and
Amendoeira 2018; Martin et al. 2017; Švajdler
et al. 2015; Carlucci et al. 2012; Müller et al.
2011; Varga et al. 2000). Death due to meta-
static disease has been described in four
Sebaceous Carcinoma of the Breast 351

patients. Seven of eighteen patients presented

with positive nodal status at initial diagnosis
(Maia and Amendoeira 2018; Švajdler et al.
2015; Müller et al. 2011; Murakami et al.
2009; Hisaoka et al. 2006). Tumor stage is
variable, and reported tumor sizes vary
between 12 and 120 mm (mean size
35.9 mm) (Acosta et al. 2018; Maia and
Amendoeira 2018; Sakai et al. 2018; Martin
et al. 2017; Yamamoto et al. 2017; Švajdler
et al. 2015; Wachter et al. 2014; Carlucci
et al. 2012; Müller et al. 2011; Murakami
et al. 2009; Hisaoka et al. 2006; Varga et al.
2000; Propeck et al. 2000; Tavassoli and Sebaceous Carcinoma of the Breast, Fig. 1 Low-
power appearance of a sebaceous carcinoma. The tumor
Norris 1986; van Bogaert and Maldague exhibits several large cells with pale cytoplasm with coarse
1977). and bubbly vacuolated tumor cells (H&E stain, low
magnification)

Macroscopy

Sebaceous carcinomas usually present with a pal-

pable mass in the breast, as noted above in a third
of the cases with nodular lesions within the met-
astatic site. It has been reported that sebaceous
carcinomas exhibit a yellowish whitish cut surface
and a multilobulated tumor contour with sharp
borders (Acosta et al. 2018; Maia and
Amendoeira 2018; Sakai et al. 2018; Martin
et al. 2017; Yamamoto et al. 2017; Švajdler et al.
2015; Wachter et al. 2014; Carlucci et al. 2012;
Müller et al. 2011; Murakami et al. 2009; Hisaoka
et al. 2006; Varga et al. 2000; Propeck et al. 2000;
Tavassoli and Norris 1986; van Bogaert and Sebaceous Carcinoma of the Breast, Fig. 2 High-
power appearance of a sebaceous carcinoma, large tumor
Maldague 1977). cells with pale, coarse, and bubbly vacuolated cytoplasm
(H&E stain, high magnification)
S
Microscopy (Figs. 1–3) (Acosta et al. 2018; Maia and
Amendoeira 2018). These cells may show vari-
Tumor with sebaceous differentiation often has a able stain with fat stains (as Sudan black or Oil
background of an infiltrating carcinoma NST, Red O) and usually remain negative at the PAS
which exhibits sharp borders toward the tumor stain. Intermingled among the sebaceous cells,
periphery. According to the 2012 WHO classifi- there are usually other cell components found
cation of breast tumors, it was defined that at least (as of spindle, squamous, or ovoid morphology).
50% of the whole tumor mass containing large A few studies conducted electron microscopy
tumor cells with coarse or bubbly vacuolated showing non-membrane-bound empty vacuoles
cytoplasm resembling sebaceous cells of the skin corresponding to lipid droplets of different sizes
appendage need to be present for this diagnosis (Sakai et al. 2018; Varga et al., 2000). Grading in
352
Sebaceous Carcinoma of the Breast, Fig. 3 High-
power appearance of a sebaceous carcinoma, large tumor
cells with pale, coarse, and bubbly vacuolated cytoplasm
(H&E stain, high magnification)
the reported cases is G2 or G3; until now there is
no case reported with well differentiated
(G1) morphology (Acosta et al. 2018; Maia and
Amendoeira 2018; Sakai et al. 2018; Martin et al.
2017; Yamamoto et al. 2017; Švajdler et al. 2015;
Wachter et al. 2014; Carlucci et al. 2012; Müller
et al. 2011; Murakami et al. 2009; Hisaoka et al.
2006; Varga et al. 2000; Propeck et al. 2000).
Immunophenotype
Most studies confirm that sebaceous cells are usu-
ally strongly positive for keratins, EMA, and
adipophilin. Recent case reports could addition-
ally show GATA 3 and AR positivity in the seba-
ceous cells. Three cases analyzed mismatch repair
proteins showing preserved epitopes without any
selective loss. Interestingly, GCDFP-15 and S100
are consequently negative in the sebaceous cells.
One case was shown to exhibit neuroendocrine
differentiation by synaptophysin positivity
(Hisaoka et al. 2006).
Predictive markers were tested in a large subset
of reported cases; most cases are hormone recep-
tor positive and HER2 negative, and three cases
were triple negative and two cases HER2 positive
(Acosta et al. 2018; Maia and Amendoeira 2018;
Sakai et al. 2018; Martin et al. 2017; Yamamoto
et al. 2017; Švajdler et al. 2015; Wachter et al.
Sebaceous Carcinoma of the Breast
2014; Carlucci et al. 2012; Müller et al. 2011;
Murakami et al. 2009; Hisaoka et al. 2006;
Varga et al. 2000; Propeck et al. 2000).
Molecular Features
No established molecular features are known cur-
rently. One reported case had a BRCA2 germ line
mutation; one additional case occurred within the
scope of the Muir-Torre syndrome, an autosomal
dominant inherited disease with variable pene-
trance and exhibiting at least one sebaceous gland
tumor and one additional malignancy (Acosta et al.
2018; Propeck et al. 2000) (Figs. 1, 2, and 3).
Differential Diagnosis
The main differential diagnosis encompasses a
primary skin adnexal tumor with sebaceous mor-
phology. The presence of in situ components
(DCIS, LN) in the tumor and the lack of connec-
tion to the skin of the breast are useful features,
which favor a primary sebaceous breast carci-
noma. Additionally, the use of immunohisto-
chemistry (especially a positive AR reaction and
the negativity for S100 and GCDFP-15 can sup-
port breast origin) (Table 1).
Further differential diagnosis is the different
types of breast cancers; especially the spectrum
of primary clear cell carcinomas needs to be
excluded. Apocrine breast carcinoma (▶ Apo-
crine Carcinoma), lipid-rich breast carcinoma,
and glycogen-rich breast carcinoma (▶ Glyco-
gen-Rich Clear Cell Carcinoma) are in the differ-
ential diagnosis. Morphology (large lipid
droplets, water-clear cytoplasm, or eosinophilic
cytoplasm) and positive special stains (granular
PAS stain and large fatty droplets with Sudan
Black and Oil Red O) favor another type of clear
cell breast carcinoma. Expansive growth in a lob-
ular pattern and the presence of a dual neoplastic
cell population of larger sebaceous cells and
smaller cells of different type are suggestive of a
sebaceous carcinoma (Acosta et al. 2018; Maia
and Amendoeira 2018; Murakami et al. 2009;
Hisaoka et al. 2006; Varga et al. 2000).
Sebaceous Carcinoma of the Breast, Table 1 Summary of reported cases
Tumor
Number Age size Nodal Histological ER/
Publication of cases (years) (in mm) status grade PR HER2 IHC positive IHC negative other Follow-up
Acosta 1 51 20 mm pNO 2 +/+ Neg AR BRCA2+ NA
(2018) MMRP
Maia 2(1) 65 70 mm pN1(1/2) NA Neg/ Neg AR Died 9 months after
(2018) neg MMRP initial diagnosis
Sebaceous Carcinoma of the Breast

GATA 3
Maia 2 71 37 mm pNO NA +/ Neg GATA3 AR 100 months uneventful
(2018) neg MMRP
Sakai 2018 1 74 23 mm NA G2 +/+ Neg AR Mammoglobin NA
GATA3
Adipophylin
Martin 1 59 NA NA G2 +/+ Neg EMA Eyelid metastasis
2017 CK7 2 years after initial
CAM2 diagnosis
Yamamoto 1 80 35 mm NA NA Neg/ Neg EMA AR NA
2017 neg BerEp4
Adipophylin
Svajdler 4(1) 65 16 mm pN1(1/1) G3 +/+ Neg EMA S100 27 months uneventful
2015
Svajdler (2) 61 17 mm pN1(2/5) G3 Neg/ Neg EMA Died after 28 months
2015 neg
Svajdler 3 66 30 mm pN1(1/10) G2 +/+ Neg GCDFP-15 70 months uneventful
2015 EMA
S100
Svajdler 4 25 NA NA G3 +/+ Neg EMA GCDFP-15 75 months uneventful
2015 S100
Wachter 1 53 12 mm pNO G3 +/+ Neg GATA3 NA
2014 MMRP
(continued)
353

S
 354

Sebaceous Carcinoma of the Breast, Table 1 (continued)

Tumor
Number Age size Nodal Histological ER/
Publication of cases (years) (in mm) status grade PR HER2 IHC positive IHC negative other Follow-up
Carlucci 1 84 120 NA NA Neg/ IHC EMA GCDFP-15 Metastases 10 years
2012 mm neg score S100 after initial diagnosis
3+ AR
Müller 1 61 NA pN3(18/19) G2 +/+ Neg EMA CEA Skin metastases 5 years
2011 Adipophylin after initial diagnosis
Muakami 1 50 24 mm pN1 NA Neg/ IHC AR GCDFP-15 NA
2009 neg score EMA S100
3+ Adipophylin
Hisaoka 1 63 20 mm pN1(1/9) NA +/+ Neg EMA GCDFP-15 NA
2006 Synaptophysin Vimentin
Lipid stains AR
P63
SMA
S100
Varga 2000 1 45 25 mm NA G2 +/+ Neg EMA + S100 Skin and disseminated
Vimentin bone métastases 8 years
CEA after initial diagnosis
Propeck 1 46 15 mm NA NA NA NA Muir- 6 months uneventful
1999 Torre
syndrome
Tawassoli 1 46 75 mm NA NA NA NA NA
1986
Van 3 NA NA NA NA NA NA NA
Bogaert
1977
Abbreviations: ER estrogen receptors, PR progesterone receptors, HER2 epidermal growth factor 2 receptors, AR androgen receptors, EMA epithelial membrane antigen, MMRP
mismatch repair protein, IHC immunohistochemistry, BRCA breast cancer, CEA carcinoembryonic antigen, GCDFP-15 gross cystic disease fluid protein 15, SMA smooth muscle
actin, NA not available
Sebaceous Carcinoma of the Breast
Sentinel Node
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& Pins, M. R. (2018). Sebaceous carcinoma of the
breast in a patient with a pathogenic BRCA2
(886delGT) mutation – focus on histopathologic and
immunohistochemical features. APMIS, 126, 353–356.
Ascari-Raccagni, A., Dondas, A., Padovani, F., Milandri,
C., Righini, M. G., & Trevisan, G. (2011). A case of
giant sebaceous carcinoma localized in the breast area
of a male patient. Indian Journal of Dermatology,
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Carlucci, M., Iacobellis, M., Colonna, F., Marseglia, M.,
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squamous and sebaceous differentiation in the primary
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24. Review.
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Hamada, T. (2006). Sebaceous carcinoma of the breast:
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metastasis masquerading as the great masquerader:
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Vogt, T., & Pfoehler, C. (2011). Metastatic breast car-
cinoma mimicking a sebaceous gland neoplasm: a case
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Hríbiková, Z., Kinkor, Z., Kazakov, D. V., Skálová,
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Polish Journal of Pathology, 66, 142–148. Review.
Tavassoli, F. A., & Norris, H. J. (1986). Mammary adenoid
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Pathology & Laboratory Medicine, 110, 1045–1053.
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Beckmann, M. W., & Hartmann, A. (2014). Sebaceous
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Reports, 3, 38.
Sentinel Node
Gábor Cserni
Bács-Kiskun County Teaching Hospital,
Kecskemét, Hungary
Department of Pathology, University of Szeged,
Szeged, Hungary
Synonyms
First echelon lymph node(s); Sentinel lymph
node(s)
Description
Nodal status (i.e., whether the regional lymph
nodes contain metastatic disease or not) is still
regarded as an important prognostic factor in
S
breast cancer and influences treatment decisions.
Lymph nodes are not identical, and those, which
are directly connected to the primary tumor site
by means of their afferent lymphatic vessels, are
the ones called sentinel nodes. The remaining
lymph nodes of the same regional nodal basin
are connected with each-other and/or the sentinel
node(s), but do not have direct connection with
the primary tumor site, and using a dichotomic
categorization, they are labeled as nonsentinel
nodes. The above definition implies that tumor
cells which spread from the primary tumor to the
356
regional lymph nodes as emboli via lymphatics
reach the sentinel node(s) (first echelon nodes)
first and nonsentinel nodes (second or further
echelon nodes) only after. This explains why the
sentinel nodes are the most likely site of nodal
metastasis, and also suggests that if they are not
involved by metastatic disease, the rest of the
lymph nodes can also be considered free of metas-
tases. Therefore the sentinel nodes “guard” the
regional nodal basin, what explains their name.
The kinetics of tumor cell migration from
the primary site to the sentinel nodes also apply
to tracer molecules which travel via lymphatics,
and first accumulate in the sentinel lymph nodes.
Vital dyes (such as patent blue, isosulfan blue, or
isocyanine green), 99-meta-technecium labeled
sulfur or albumin colloids, or super paramagnetic
iron oxide nanoparticles all use the same path,
i.e. the lymphatic vessels to reach and selectively
label the sentinel nodes. Depending on the tracers
used, the sentinel nodes can be selectively
removed after being detected by their color,
(probe-detected) radioactivity or magnetism.
Identification of the sentinel nodes with such
tracers is called lymphatic mapping, and their
removal sentinel (lymph) node biopsy or sentinel
lymphadenectomy.
Lymphatic mapping studies have revealed
that most sentinel nodes are located in the lower
axilla, but some can be located at higher levels of
the axilla or at extra-axillary sites like the sub-
clavicular or supraclavicular regions, the breast
itself (intramammary sentinel nodes), or along
the internal mammary artery (internal mammary
or parasternal sentinel nodes). The theoretical def-
inition of the sentinel node given at the beginning
of the present description can be complemented
with a second practical one: the sentinel nodes are
the ones that are identified as such during lym-
phatic mapping. Their number is highly variable,
but is generally 1–3. If the number of sentinel
nodes is consistently higher than this, one must
doubt about the adequacy of lymphatic mapping;
the American Joint Committee on Cancer has
adopted a rule of allowing the (sn) classifier in
the Tumor Node Metastasis (TNM) classification
only for breast cancers where the number of
sentinel nodes does not exceed 6. The pN0(sn),
Sentinel Node
pN1(sn), or pN2(sn) TNM categories denote path-
ological nodal stage categories established with
sentinel node biopsy.
Nodal staging of clinically node-negative
(cN0) early breast cancer patients with sentinel
node biopsy followed a stepwise evolution
reflected in the surgical consequences of finding
metastases in sentinel nodes. The concept of sen-
tinel nodes was validated in different clinical tri-
als, where lymphatic mapping was followed by
complete axillary lymph node dissection. These
studies proved that the sentinel nodes are really
more likely to harbor metastasis than nonsentinel
nodes. As sentinel nodes were often more thor-
oughly analyzed than the remaining of the lymph
nodes, a few validation studies have also sub-
jected nonsentinel nodes to the same scrutiny as
the sentinel nodes, and these studies also rein-
forced the theory that sentinel nodes are more
often involved by metastases (Turner et al. 1997;
Weaver et al. 2000). Following these initial vali-
dation studies and early learning periods (all com-
pleted with axillary nodal dissection), the scenario
of performing axillary lymph node dissection (as
a surgical treatment of the axilla) only in patients
with positive (i.e., metastatic) sentinel lymph
nodes became the rule. Patients with negative
sentinel nodes are spared from axillary clearance
and its potential morbidity (lymphedema, motor
dysfunction, sensory loss), although it must be
admitted that sentinel node biopsy can also have
complications, but less frequently and to a lesser
degree. This new era of axillary nodal staging has
also initiated a novel approach to teaching sentinel
node biopsy: supervision by surgeons already
trained in the procedure has become general
and no complete axillary dissection was mandated
any more to prove proficiency in removing the
proper lymph nodes. As the decision to clear the
axilla or not was dependent on the status of the
sentinel nodes, intraoperative assessment has
gained emphasis similarly to preoperative staging
by axillary ultrasound. Patients with negative axil-
lary palpation and axillary ultrasound findings
(cN0 patients) are offered lymphatic mapping
and sentinel node biopsy, whereas those with sus-
picious findings have ultrasound-guided sampling
(mostly fine needle aspiration, but sometimes core
Sentinel Node
needle biopsy) of the suspicious nodes or the most
suspicious one. The microscopic evidence of
nodal involvement excludes patients from lym-
phatic mapping, as the procedure is advocated
for cN0 patients. Later, a few studies explored
the idea that once nodal positivity was proven
by means of sentinel node biopsy, there was no
more need for axillary lymph node dissection in
the majority of patients. The American College
of Surgeons Oncology Group (ACOSOG) trial
Z-0011 concluded that patients with limited nodal
involvement (up to two metastatic lymph nodes
independently of the size of the metastasis) under-
going breast conserving surgery complemented
with whole breast irradiation needed no axillary
nodal dissection (Giuliano et al. 2017). The 6-year
results of the European Organization for Research
and Treatment of Cancer (EORTC) After Map-
ping of the Axilla: Radiotherapy Or Surgery?
(AMAROS) trial (Donker et al. 2014) and the
8-year results of the Hungarian National Institute
of Oncology Optimal Treatment of the Axilla:
Surgery Or Radiotherapy (OTOASOR) trial
(Sávolt et al. 2017) both concluded that axillary
irradiation was as effective as axillary lymph node
dissection in preventing regional recurrences in
patients with metastatic sentinel nodes. These
results have also led to a change in policy: at
present many patients with positive sentinel
nodes do not have an axillary lymph node dissec-
tion (Lyman et al. 2016). This change had obvi-
ously resulted in a decrease in intraoperative
examinations of the sentinel nodes, as the result
had no impact on subsequent surgery.
Another setting of applying sentinel node
biopsy as a staging procedure with lower morbidity
is its use after primary systemic (neoadjuvant)
treatment of locally advanced breast cancer. Neo-
adjuvant therapy is used for both clinically node-
negative and node-positive patients. In the second
set, it is widely accepted that sentinel node biopsy
should be offered only to patients who become
clinically node-negative after systemic treatment
(ycN0). The false-negative rate (the proportion
of cases without sentinel node involvement but
with metastasis in nonsentinel nodes) of sentinel
lymphadenectomy after neoadjuvant treatment of
initially cN0 patients has been found to be
357
comparable with that of sentinel
lymphadenectomy of cN0 patient not requiring
neoadjuvant treatment (Geng et al. 2016). It is
therefore common to perform sentinel node
biopsy after the completion of primary systemic
treatment, but the procedure has also been
performed before. For patients with initially
node-positive disease, the false-negative rates
have been found to be somewhat higher, but
with at least two sentinel nodes identified, and
adequate patient selection, post-neoadjuvant ther-
apy sentinel node biopsy has also been found
reliable enough (El Hage Chehade et al. 2016;
van Nijnatten et al. 2015).
Most surgeons remove only axillary sentinel
nodes and do not search for extra-axillary ones.
The latter, to be known about, require lympho-
scintigraphy, which visualizes them. Even if they
are evidenced by lymphoscintigraphy, internal
mammary sentinel nodes are rarely removed by
surgeons, despite the fact that reports indicate that
metastatic involvement of a parasternal sentinel
node may impact on the planning of radiotherapy
and the indication of systemic therapy. As a rule,
internal mammary sentinel nodes are smaller than
axillary ones, often less than 5 mm in size, and
commonly they are identified by gamma-probes
only on the basis of their radioactivity, and do not
label with dyes.
Pathological assessment of sentinel nodes
can be divided into two broad categories: the
intraoperative and the postoperative setting. As
concerns the intraoperative assessment, imprint
(or scrape) cytology, frozen section histology,
and molecular analysis of sentinel nodes have all S
been in use to assess metastatic involvement of the
sentinel nodes. Imprint cytology is based on the
exfoliation of tumor cells from the lymph node
freshly cut surface to the glass slides. This spon-
taneous detachment can be enhanced by scraping
the cut surface and smearing the cells on the
slides. Different stains have been described and
used (Figs. 1 and 2).
The advantages of intraoperative cytology
specimens include fast preparation, relatively
low costs, lack of tissue loss during the procedure,
and a microscopic verification of malignant cell
morphology. Its disadvantages include the
358
Sentinel Node, Fig. 1 Metastatic cells on imprint cytol-
ogy (H&E, original magnification  400)
Sentinel Node, Fig. 2 Metastatic cells on imprint cytol-
ogy (Giemsa, original magnification  400)
inability to measure the size of the metastasis, a
higher false negative rate (metastases detected
only after the histological examination of the sen-
tinel node), a few false positive reports, and the
need for training in cytopathology. The false neg-
ative rate can be diminished by increasing the
surface sampled (i.e., several cut surfaces). Fast
immunohistochemistry for the detection of epithe-
lial cells can also be combined with intraoperative
cytology; this increases the accuracy, the time
required for reporting, and the costs of the
examination.
Frozen sections have also often been used for
the intraoperative examination of sentinel lymph
nodes. They allow a better morphological evalua-
tion of metastases including the measurement of
Sentinel Node
size, and many pathologists are more familiar with
the method. However, frozen section morphology
is still suboptimal when compared to the gold
standard of formalin-fixed and paraffin-embedded
tissue histology. The tissues undergo artifacts,
which may prevent ideal interpretation of the
cells and structures seen. Some tissue is lost dur-
ing assessment. It also takes longer time to prepare
the sections. The costs are higher than those
of imprints. Frozen sections are also not perfect,
false negative cases do occur. The use of fast
immunohistochemistry and/or the investigation
of step sections improve the accuracy of the eval-
uation. Some centers have used the painstaking
approach to investigate the whole sentinel nodes
by frozen step sections to allow the most precise
intraoperative microscopic sampling, but most
have found the costs and workload of this
approach prohibitive. Meta-analyses have assessed
the accuracy of imprint cytology and frozen sec-
tion evaluation, and it is suggested that the latter
has a pooled sensitivity about 10% higher than the
former for detecting macrometastases (those
greater than 2 mm) intraoperatively. The choice
of which morphologic intraoperative method to
use depends on many factors, including personal
preference and experience of the pathologist in
charge (Cserni et al. 2003).
Molecular intraoperative examinations sub-
stantially differ from imprint cytology and frozen
section analysis, as they do not use microscopy
for detection. In contrast, they destroy the tissue
structures and cells to allow the extraction of
messenger ribonucleic acid (mRNA) of proteins
thought to represent metastatic tumor cells pro-
portionally to their amount. Different amplifica-
tion systems have been used, most often one step
nucleic acid amplification (OSNA) of cytokeratin
19 mRNA or reverse transcription polymerase
chain reaction (RT-PCR) of cytokeratin 19 and
mammaglobin mRNAs. These methods are more
sensitive than classical microscopic examinations,
but obviously are rather epithelium than metasta-
sis specific. Validation studies have been biased
by the fact that microscopic evaluation and molec-
ular analyses cannot be performed on the same
tissue parts, therefore different parts of the same
sentinel lymph nodes were investigated by the
Sentinel Node
different methods. It is accepted that different
parts of the sentinel nodes have different risks of
being involved by the metastatic process, i.e., the
areas at the junction of the tumor draining afferent
lymphatic vessels are involved at a much higher
frequency than areas away from this point. This is
why, the best comparisons were made when alter-
nating slices of the lymph nodes were subjected to
molecular and microscopic examinations. The
comparison of larger series suggests that molecu-
lar methods are substantially more sensitive in
detecting micrometastatic involvement of the sen-
tinel nodes than either frozen sections or imprint
cytology, but when it comes to macrometastases,
frozen sections are nearly as sensitive as molecu-
lar methods (Cserni 2012). To allow a nearly
complete assessment, many laboratories using a
molecular intraoperative assay use most if not all
nodal tissue to adequately sample the sentinel
nodes, and this leaves no tissue for a morpholog-
ical evaluation. A common recommendation pro-
poses to use at least one slice of tissue (generally
the central one) for histology and use only the
remaining parts of the sentinel node for the molec-
ular assay. Recommendations are in agreement
that intraoperative assessment of any type should
be restricted to cases where it has immediate
influence on the intervention to follow (Wells
et al. 2012).
The traditional evaluation of sentinel nodes,
which has been used as a gold standard for com-
parison with intraoperative examinations, is his-
topathological assessment. As the most likely
sites of nodal involvement, sentinel nodes have
been given more scrutiny: gross slicing, serial
sectioning at equidistant steps (including step sec-
tioning till the extinction of the tissue blocks), and
immunohistochemistry have been used, often in
combination. This approach led to detection of
metastatic nodal involvement at a higher rate
than the previous conventional approach of
assessing one hematoxylin and eosin stained
slide of each lymph node or of each slice of larger
lymph nodes divided into pieces. Increased detec-
tion was partly due to the fact that sentinel nodes
really harbor metastases more often than other
lymph nodes of the same nodal basin, but also
due to the use of more sensitive techniques of
359
detecting these metastases (Giuliano et al. 1995;
Cserni et al. 2003). As a consequence, the average
size of nodal tumor deposits became also smaller.
Micrometastases (earlier defined by an upper
inclusive size limit of 2 mm) were identified at
much higher rates than before the era of lymphatic
mapping. This led to a phenomenon called stage
migration: the same patients who were classified
as having node-negative disease after a conven-
tional nodal examination following axillary
lymph node dissection could be identified as
being node-positive by detecting tiny foci of met-
astatic disease in the better investigated sentinel
nodes that the conventional evaluation had no
chance to visualize. To limit stage migration, stag-
ing authorities have introduced a lower non-
inclusive limit of 0.2 mm (and later an additional
cell count limit of 200 for discohesive lobular
carcinoma cells) to the definition of micro-
metastasis and have considered anything smaller
than that as isolated tumors cells or clusters (ITC)
to be staged as part of the node-negative set of
patients (Figs. 3 and 4).
At the beginning, the definitions of isolated
tumor cells were not straight forward and uniform,
and this has limited the proper prognostic evalua-
tion of this subcategory, and its discrimination
from micrometastasis. At present, it seems that
neither isolated tumor cells or clusters nor micro-
metastases have major impact on breast cancer
S
Sentinel Node, Fig. 3 Isolated tumor cells of lobular
carcinoma detected by cytokeratin immunohistochemistry
(Cytokeratin AE1/AE3 immunohistochemistry, original
magnification  400)
360 Sentinel Node

patients and therefore should not initiate any epithelial can lead to erroneous interpretation in
therapeutic intervention on their own. This clari- any intraoperative test.
fication of the prognostic impact of low-volume Endosalpingiosis of axillary sentinel nodes has
tumor deposits in sentinel nodes discovered by also been reported. Epithelial cells or structures
enhanced pathological evaluation has resulted like glands may be lodged artifactually during
in recommendations proposing not to search for tissue processing into holes without tissue
micrometastases and smaller volume involvement, (cracks) on the sections (Fig. 7).
but to devise assessment protocols that identify Similarly, epithelial displacement by needling
virtually all macrometastases (Cserni 2012). procedures (e.g., core needle biopsy, wire locali-
It must be kept in mind that sentinel nodes zation of the primary tumor, or intratumoral injec-
(as any other lymph nodes) may harbor a number tion of the tracer) or massage used to help tracer
of other changes or diseases than metastasis from migration during lymphatic mapping can lead to
breast cancer. This has often been an argument the misdiagnosis of displaced epithelium as a real
against the use of all nodal tissue for molecular metastasis. Papillary lesions have been reported to
analysis. Capsular nevi are a relatively common be especially prone for misplacement: most
finding, and generally do not pose a major differ-
ential diagnostic problem. Often they do not show
melanin content (Fig. 5).
On occasions they may involve the trabeculae
and even the nodal parenchyma when the differ-
ential diagnostic concern may be greater. Being
completely different in nature, they can easily
be clarified by their positivity for melanocytic
markers of nevi and their negativity for epithelial
markers. Involvement by other neoplastic (com-
monly chronic lymphoid leukemia, less commonly
other lymphomas or metastatic melanoma, etc.)
or infectious diseases (e.g., cat scratch disease
or toxoplasmosis) can also be encountered. Epi-
thelial inclusions (often of mammary type) Sentinel Node, Fig. 5 Capsular nevus without
(Fig. 6) are not very common, but by being melanin content. (H&E, original magnification  400)

Sentinel Node, Fig. 6 Apocrine glandular inclusion

Sentinel Node, Fig. 4 Isolated tumor cell cluster in an axillary sentinel lymph node. Note the outer
detected by conventional staining (H&E, original myoepithelial and inner epithelial cell layers (H&E, origi-
magnification  400) nal magnification  400)
Sentinel Node
Sentinel Node, Fig. 7 Artifactually lodged liver tissue
(orientation marker of the tissue block) in a tissue crack
of the sentinel node (H&E, original magnification  100)
misplaced epithelial tissue reported to date was
related to papillary lesions. These may differ from
metastatic cells or fragments by location (in the
sinuses rather than the parenchyma of the sentinel
node), morphology, and/or immunophenotype;
and not uncommonly the primary site has also
features of misplaced epithelium (e.g., papillary
fronds in lymphatics in an area of traumatized
breast tissue showing wound healing, granulation,
hemosiderin, or frank hematoma). As displaced
epithelium never takes the form of a macro-
metastasis, misdiagnosing them as metastatic in
nature should imply no erroneous indication of
surgical or systemic treatment or radiotherapy.
Trials have been organized for identifying sub-
sets of breast cancer patients who might not
require sentinel node biopsy either.
References
Cserni, G. (2012). How much is enough? Pathologic eval-
uation of sentinel lymph nodes. Current Breast Cancer
Reports, 4, 89–95.
Cserni, G., Amendoeira, I., Apostolikas, N., Bellocq, J. P.,
Bianchi, S., Bussolati, G., Boecker, W., Borisch, B.,
Connolly, C. E., Decker, T., Dervan, P.,
Drijkoningen, M., Ellis, I. O., Elston, C. W.,
Eusebi, V., Faverly, D., Heikkila, P., Holland, R., Kerner,
H., Kulka, J., Jacquemier, J., Lacerda, M., Martinez-
Penuela, J., De Miguel, C., Peterse, J. L., Rank, F.,
Regitnig, P., Reiner, A., Sapino, A., Sigal-Zafrani, B.,
Tanous, A. M., Thorstenson, S., Zozaya, E., & Wells,
C. A. (2003). Pathological work-up of sentinel lymph
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nodes in breast cancer. Review of current data to be
considered for the formulation of guidelines. European
Journal of Cancer, 39, 1654–1667.
Donker, M., van Tienhoven, G., Straver, M. E., Meijnen, P.,
van de Velde, C. J., Mansel, R. E., Cataliotti, L.,
Westenberg, A. H., Klinkenbijl, J. H., Orzalesi, L.,
Bouma, W. H., van der Mijle, H. C., Nieuwenhuijzen,
G. A., Veltkamp, S. C., Slaets, L., Duez, N. J., de Graaf,
P. W., van Dalen, T., Marinelli, A., Rijna, H., Snoj, M.,
Bundred, N. J., Merkus, J. W., Belkacemi, Y., Petignat,
P., Schinagl, D. A., Coens, C., Messina, C. G.,
Bogaerts, J., & Rutgers, E. J. (2014). Radiotherapy
or surgery of the axilla after a positive sentinel node in
breast cancer (EORTC 10981-22023 AMAROS):
A randomised, multicentre, open-label, phase
3 non-inferiority trial. The Lancet Oncology, 15,
1303–1310.
El Hage Chehade, H., Headon, H., El Tokhy, O.,
Heeney, J., Kasem, A., & Mokbel, K. (2016). Is senti-
nel lymph node biopsy a viable alternative to complete
axillary dissection following neoadjuvant chemother-
apy in women with node-positive breast cancer at diag-
nosis? An updated meta-analysis involving 3,398
patients. American Journal of Surgery, 212, 969–981.
Geng, C., Chen, X., Pan, X., & Li, J. (2016). The feasibility
and accuracy of sentinel lymph node biopsy in initially
clinically node-negative breast cancer after neo-
adjuvant chemotherapy: A systematic review and
meta-analysis. PLoS One, 11, e0162605.
Giuliano, A. E., Dale, P. S., Turner, R. R., & Morton, D. L.
(1995). Improved axillary staging of breast cancer
with sentinel lymphadenectomy. Annals of Surgery, 222,
394–401.
Giuliano, A. E., Ballman, K. V., McCall, L., Beitsch, P. D.,
Brennan, M. B., Kelemen, P. R., Ollila, D. W.,
Hansen, N. M., Whitworth, P. W., Blumencranz, P. W.,
Leitch, A. M., Saha, S., Hunt, K. K., & Morrow, M.
(2017). Effect of axillary dissection vs no axillary dis-
section on 10-year overall survival among women with
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The ACOSOG Z0011 (Alliance) randomized clinical
trial. JAMA, 318, 918–926.
Lyman, G. H., Somerfield, M. R., Bosserman, L. D.,
Perkins, C. L., Weaver, D. L., & Giuliano, A. E. S
(2016). Sentinel lymph node biopsy for patients with
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& Mátrai, Z. (2017). Eight-year follow up result of the
OTOASOR trial: The optimal treatment of the axilla –
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node biopsy in early-stage breast cancer: A random-
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Giuliano, A. E. (1997). Histopathologic validation of
the sentinel lymph node hypothesis for breast carci-
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Nelemans, P. J., Beets-Tan, R. G., & Smidt, M. L.
(2015). The diagnostic performance of sentinel lymph
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European guidelines for quality assurance in breast can-
cer screening and diagnosis. Fourth edition, supplements
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Office for Official Publications of the European Union.
Solid Papillary Carcinoma
Elena Vissio2, Caterina Marchiò1,2,3 and Anna
Sapino1,2
1
Unit of Pathology, Candiolo Cancer Institute
FPO-IRCCS, Candiolo, Italy
2
Department of Medical Sciences, University of
Turin, Turin, Italy
3
Institut Curie, Paris, France
Synonyms
Solid Papillary Neuroendocrine Breast Carcinoma
Definition
Solid papillary carcinoma (SPC) is described in the
2012 WHO classification within the group of the
intraductal papillary lesions and is defined as a var-
iant of papillary carcinoma characterized by multiple
Solid Papillary Carcinoma
solid nodules of neoplastic cells arranged around
multiple fibrovascular spaces. Despite the lack of
the external myoepithelial layer, these lesions are
currently considered as noninvasive (Lakhani et al.
2012). However, cases of true invasive SPC exist.
Clinical Features
• Incidence
SPC is a rare entity, accounting for 1–2% of
breast carcinomas (BCs) (Otsuki et al. 2007).
• Age
It usually affects women in the seventh decade,
with a mean age of 73.2 years (Maluf and
Koerner 1995).
• Sex
It is more frequently observed in female
patients, but it has been sporadically described
in men (Nassar et al. 2006).
• Side
SPC is typically unifocal and localized in the
central region of the breast (Guo et al. 2016),
although a single case of bilateral synchronous
SPC has been reported in the literature
(Yoshimura et al. 2013).
• Clinical presentation
The clinical presentation does not differ from
the other BC histological types, being usually
diagnosed after the detection of a mammo-
graphic density or a palpable mass. In
20–25% of cases, a bloody nipple discharge
may occur (Lakhani et al. 2012).
• Treatment
Mastectomy or conservative surgery represents
the usual treatment for these tumors. However,
since the risk of recurrence is not related to the
surgical technique, mastectomy, as well as
lymph node excision, seems to represent an
overtreatment for small tumors with no signs
of invasion (Guo et al. 2016). There is no
agreement on the necessity of sentinel lymph
node biopsy for these patients. Regarding adju-
vant treatment, the benefit of radiation and
hormone therapy is still debated.
• Outcome
SPCs present an excellent prognosis. Lymph
node and distant metastasis are rare. Local
Solid Papillary Carcinoma
Solid Papillary Carcinoma, Fig. 1 (a) Solid
papillary carcinoma is characterized by a dense neoplastic
proliferation featuring well-defined borders (H&E);
recurrences have been reported, even if
uncommon, and death for SPC should be con-
sidered exceptional (Guo et al. 2016).
Recently, the 21-gene recurrence score
(RS) multigene assay was performed in
5 cases of SPC, and the RS resulted low in
3 cases and intermediate in the remaining
2 cases, confirming the good prognosis of this
histological type. The only woman who pre-
sented a local recurrence showed a RS of
25 (Turashvili et al. 2017).
When SPCs are associated to an invasive car-
cinoma, the outcome is related to the features
of the infiltrative component (Lakhani et al.
2012; Tan et al. 2016).
Macroscopy
At macroscopic examination, SPC usually
appears as a well-circumscribed lobulated mass,
characterized by a whitish-gray or yellowish-
brown color (Lakhani et al. 2012). The size may
be variable, with a reported average diameter of
2.5 cm (Guo et al. 2016).
Microscopy
At low magnification, SPC is characterized by
multiple cellular nodules. Although its borders
363
(b) calponin immunohistochemical reaction shows focal
lack of myoepithelial peripheral cell layer
appear well defined, the myoepithelial peripheral
layer is frequently absent at immunohistochemi-
cal analyses (Fig. 1a, b). To date, it is still debated
if SPC should be considered as a low-grade inva-
sive carcinoma or a variant of ductal carcinoma in
situ (▶ Ductal Carcinoma In Situ). Nonetheless,
because of their generally favorable clinical
course, the current WHO classification recom-
mends to consider SPCs as in situ lesions
(Lakhani et al. 2012). By contrast, irregular mar-
gins and multiple small nests arranged in a jigsaw
pattern represent typical features that suggest
invasive growth (Lakhani et al. 2012).
Inside the nodules, neoplastic cells are densely
organized. They may form typical peripheral
palisading around delicate fibrovascular struc-
tures (Fig. 2a). Cells usually present small dimen-
sions, hyperchromatic nuclei, granular S
cytoplasmic pattern, and occasionally spindle
cell features (Lakhani et al. 2012). They are gen-
erally low- or intermediate-grade lesions, with
low mitotic activity (Guo et al. 2016). SPC may
produce extracellular and/or intracellular mucin
(Wei 2016), and neuroendocrine differentiation
is reported in about half of cases (Fig. 2b)
(Otsuki et al. 2007).
SPCs may present foci of invasive carcinoma,
frequently characterized by neuroendocrine or
mucinous features (Nassar et al. 2006; Otsuki
et al. 2007), even if other histotypes have
been described. Invasive mucinous carcinomas
364
Solid Papillary Carcinoma, Fig. 2 (a) Densely
organized neoplastic cells form a peripheral palisading
layer around delicate fibrovascular structures (H&E).
associated with SPCs are usually classified as
type B, characterized by high cellularity, lower
mucin production, and neuroendocrine differenti-
ation (Nassar et al. 2006) (▶ Invasive Mucinous
Carcinoma).
Mixed cases, where SPC and encapsulated
papillary carcinoma (EPC) (▶ Encapsulated Pap-
illary Carcinoma) coexist, have been reported,
hypothesizing a common carcinogenetic process
for the two tumors (Cui and Wei 2015; Duprez
et al. 2012).
Immunophenotype
Similarly to other papillary tumors, SPC is com-
monly classified as Luminal A type, showing an
intensely positive expression of estrogen receptor
(ER) and progesterone receptor (PR), lack of
HER2 protein overexpression, and a low prolifer-
ation activity (Guo et al. 2016; Otsuki et al. 2007),
and a similar immunohistochemical pattern is fre-
quently reported also for the possibly associated
invasive component (Nassar et al. 2006).
Nonetheless, the PAM50 gene signature
applied on four cases of SPCs assigned them to
the Luminal B subtype (Piscuoglio et al. 2014).
Myoepithelial markers, like p63 and high
molecular weight cytokeratins (CK), may show
positive or negative result by immunohistochem-
ical staining (Ni and Tse 2016). Low molecular
Solid Papillary Carcinoma
(b) SPCs may show neuroendocrine differentiation
(immunohistochemical reaction with anti-synaptophysin
antibody)
weight CKs, such as CK8 and CK18, are fre-
quently positive (Lakhani et al. 2012).
Synaptophysin (Fig. 2b) and/or chromogranin,
considered typical neuroendocrine markers, is
expressed in more than 50% of cases (Guo et al.
2016; Lakhani et al. 2012; Otsuki et al. 2007).
Molecular Features
Copy number aberration patterns are similar
between papillary carcinomas (PCs) and ER+
invasive carcinomas of no special type of
similar grade (Duprez et al. 2012). However,
gene expression analysis showed a down-
regulation of genes related to cell migration, pro-
liferation, assembly, and organization in PCs,
whereas genes involved in cellular homeostasis
and angiogenesis were upregulated (Piscuoglio
et al. 2014).
Among the main types of PCs (SPC, EPC, and
invasive papillary carcinoma), no differences in
copy number aberrations were noted (Piscuoglio
et al. 2014). On the other hand, SPC, when com-
pared with EPC, presents a higher expression of
neuroendocrine-related genes (e.g., RET, ASCL1,
and DOK7), whereas EPC shows down-
regulation of genes involved in cell migration,
possibly explaining the histological differences
between these two entities (Piscuoglio
et al. 2014).
Syringomatous Tumor of the Nipple
Differential Diagnosis
Intraductal papilloma (▶ Intraductal Papilloma)
and florid usual ductal hyperplasia (▶ Usual Duc-
tal Hyperplasia (UDH)) may present similar fea-
tures with SPC, but they usually present no
mitoses and do not show neuroendocrine or
mucinous differentiation. Furthermore, in benign
lesions, CK5/6 is usually intensely positive; there-
fore, its evaluation may be helpful in challenging
cases (Lakhani et al. 2012; Rabban et al. 2006).
In case ER and/or PR expression are unusually
weak or absent, metastatic neuroendocrine tumors
to the breast should be taken into account, and the
clinical history of the patient should be accurately
reviewed in order to identify the primary malig-
nancy (Burt et al. 2016).
References and Further Reading
Burt, M., Madan, R., & Fan, F. (2016). Metastatic
gastrinoma in the breast mimicking primary solid pap-
illary carcinoma. Human Pathology, 56, 143–146.
Cui, X., & Wei, S. (2015). Composite encapsulated
papillary carcinoma and solid papillary carcinoma.
Pathology International, 65, 133–137.
Duprez, R., Wilkerson, P. M., Lacroix-Triki, M., Lambros,
M. B., MacKay, A., A’Hern, R., Gauthier, A., et al.
(2012). Immunophenotypic and genomic characteriza-
tion of papillary carcinomas of the breast. The Journal
of Pathology, 226, 427–441.
Guo, S., Wang, Y., Rohr, J., Fan, C., Li, Q., Li, X., &
Wang, Z. (2016). Solid papillary carcinoma of the
breast: A special entity needs to be distinguished from
conventional invasive carcinoma avoiding over-
treatment. The Breast, 26, 67–72.
Lakhani, S. R., Ellis, I. O., Schnitt, S. J., Tan, P. H.,
van de Vijver, M. J. (2012). WHO classification
of tumours of the breast. World Health Organization
classification of tumours. Lyon, IARC press. ISBN-10:
9283224337.
Maluf, H. M., & Koerner, F. C. (1995). Solid papillary
carcinoma of the breast. A form of intraductal carci-
noma with endocrine differentiation frequently associ-
ated with mucinous carcinoma. The American Journal
of Surgical Pathology, 19, 1237–1244.
Nassar, H., Qureshi, H., Adsay, N. V., Volkanadsay, N., &
Visscher, D. (2006). Clinicopathologic analysis of solid
papillary carcinoma of the breast and associated inva-
sive carcinomas. The American Journal of Surgical
Pathology, 30, 501–507.
Ni, Y. B., & Tse, G. M. (2016). Pathological criteria and
practical issues in papillary lesions of the breast –
A review. Histopathology, 68, 22–32.
365
Otsuki, Y., Yamada, M., Shimizu, S., Suwa, K.,
Yoshida, M., Tanioka, F., Ogawa, H., et al. (2007).
Solid-papillary carcinoma of the breast: Clinicopatho-
logical study of 20 cases. Pathology International, 57,
421–429.
Piscuoglio, S., Ng, C. K. Y., Martelotto, L. G., Eberle,
C. A., Cowell, C. F., Natrajan, R., Bidard, F. C., et al.
(2014). Integrative genomic and transcriptomic charac-
terization of papillary carcinomas of the breast. Molec-
ular Oncology, 8, 1588–1602.
Rabban, J. T., Koerner, F. C., & Lerwill, M. F. (2006). Solid
papillary ductal carcinoma in situ versus usual ductal
hyperplasia in the breast: A potentially difficult distinc-
tion resolved by cytokeratin 5/6. Human Pathology,
37, 787–793.
Tan, B. Y., Thike, A. A., Ellis, I. O., & Tan, P. H. (2016).
Clinicopathologic characteristics of solid papillary car-
cinoma of the breast. American Journal of Surgical
Pathology, 40, 1334–1342.
Turashvili, G., Brogi, E., Morrow, M., Hudis, C.,
Dickler, M., Norton, L., & Wen, H. Y. (2017). The
21-gene recurrence score in special histologic subtypes
of breast cancer with favorable prognosis. Breast
Cancer Research and Treatment, 165, 65–76.
Wei, S. (2016). Papillary lesions of the breast: An
update. Archives of Pathology & Laboratory Medicine,
140, 628–643.
Yoshimura, N., Murakami, S., Kaneko, M., Sakatani, A.,
Hirabayashi, N., & Takiyama, W. (2013). Synchronous
bilateral solid papillary carcinomas of the breast.
Case Reports in Surgery, 2013, 812129.
Syringomatous Tumor of the
Nipple
Zsuzsanna Varga and Linda Moskovszky
Institute of Pathology and Molecular Pathology,
University Hospital Zurich, Zurich, Switzerland
S
Synonyms
Infiltrating syringomatous adenoma of the nipple;
Syringomatous adenoma of the nipple
Definition
Syringomatous tumor of the nipple/areola region
(SAN) is a benign rare condition, which is typi-
cally observed in the dermal/subcutaneous region
of the nipple area and which exhibits sweat gland
366
differentiation (Ishikawa et al. 2015; Montgomery
et al. 2014; Boecker et al. 2014). These tumors
have no metastastic potential but can recur if
removed incompletely (Ishikawa et al. 2015;
Montgomery et al. 2014; Boecker et al. 2014).
Clinical Features
• Incidence
This type of nipple tumor is very rare, account-
ing less than 1% of all tumors arising in the
breast. Until now, 39 cases were reported in the
English literature, mostly in form of case
reports. Thirty seven patients were female,
and two were males (Ishikawa et al. 2015;
Montgomery et al. 2014; Oo and Xiao 2009;
Page et al. 2009; Jones et al. 1989; Carter and
Dyess 2004; Rosen 1983). The original
description of nipple syringomatous adenoma
was published by PP Rosen in 1983. Since this
description, this entity has been occasionally
addressed in reviews on diagnostic challenges
and immunohistochemical phenotypes as well
as reported in the above mentioned case report
series in different journals (Ishikawa et al.
2015; Montgomery et al. 2014; Boecker et al.
2014; Oo and Xiao 2009; Page et al. 2009;
Jones et al. 1989; Carter and Dyess 2004).
• Age
Patients are mostly peri-/postmenopausal at the
time of the diagnosis; however, one case was
described in a young prepubertal 11-year-old
girl occurring in a supernumerary nipple, and
one elderly patient of 87 years was reported
with this entity (Oo and Xiao 2009; Page
et al. 2009).
• Sex
Thirty-seven patients were female, and two
patients were males (Ishikawa et al. 2015;
Montgomery et al. 2014; Oo and Xiao 2009).
• Site
Both sides are equally affected and most
lesions are unifocal. Two papers reported
a syringomatous tumor arising in a supernu-
merary breast, each in one patient; two further
papers, each of them described one female
patient with bilateral syringomatous adenoma
Syringomatous Tumor of the Nipple
(Ishikawa et al. 2015; Montgomery et al. 2014;
Oo and Xiao 2009; Page et al. 2009).
• Treatment
Therapy is surgical excision with clear mar-
gins. If the tumor is close to the nipple and a
complete excision is therefore not possible, in
such cases, a thorough postoperative follow-up
with imaging is recommended (Ishikawa et al.
2015; Oo and Xiao 2009).
• Outcome
Prognosis is favorable in all cases; until now, no
metastastic lesions and no death due to tumor
progression were reported. However, local
tumor recurrence in a small subset of patients
in the literature was reported mainly due to
incomplete resection (Ishikawa et al. 2015;
Montgomery et al. 2014; Boecker et al. 2014;
Oo and Xiao 2009; Page et al. 2009; Jones et al.
1989; Carter and Dyess 2004).
Macroscopy
Syringomatous tumor usually presents as a solid
mass or ill-defined tumor in the dermis of the
nipple. Rarely the lesion is detected due to
mammographic calcifications in the surrounding
breast. Size of the lesion is variable, generally
between 5 mm and 50 mm in diameter, with an
average size of 17.7 mm in largest diameter
(Ishikawa et al. 2015; Montgomery et al. 2014;
Oo and Xiao 2009).
Microscopy
Syringomatous tumor of the nipple has an appar-
ent infiltrative growth in most cases arising in
a recognizable lobular growth pattern with nests
and branching cords of inconspicuous epithelial
cells situated in the dermis and in the subcutis of
the nipple or areola (Ishikawa et al. 2015) (Fig. 1).
The tumor cells typically show an infiltrative
growth between the stroma and the smooth mus-
cle cells of the dermis and subcutis (Fig. 2)
(Ishikawa et al. 2015; Montgomery et al. 2014).
Typically, there is no relationship between the
tumor and the overlying skin or the nipple
Syringomatous Tumor of the Nipple
Syringomatous Tumor of the Nipple, Fig. 1 Low
power appearance of a syringomatous tumor containing
infiltrative bland solid epithelial formations in the dermis
of the skin in the vicinity of thin epithelial cysts (H&E, low
magnification)
Syringomatous Tumor of the Nipple, Fig. 2 Low
power appearance of a syringomatous tumor containing
infiltrative bland solid epithelial formations in the dermis
of the skin surrounded by smooth muscle bundles (H&E,
low magnification)
epidermis and usually no ulceration is observed
(Ishikawa et al. 2015; Montgomery et al. 2014;
Oo and Xiao 2009; Rosen 1983). Tumor cells can
invade the perineural region and smooth muscles
and can surround small keratinous cysts extending
from the epidermis into the dermis (Fig. 3)
(Ishikawa et al. 2015; Montgomery et al. 2014;
Oo and Xiao 2009; Rosen 1983). The margin of
the lesion is not sharply defined due to infiltrative
growth and can be visualized more precisely
by immunohistochemical stains (Ishikawa et al.
2015; Montgomery et al. 2014; Boecker et al.
367
Syringomatous Tumor of the Nipple, Fig. 3 High
power appearance of a syringomatous tumor showing infil-
trative bland small epithelial formations surrounded by
smooth muscles and vessels of the dermal-subcutaneous
junction without any significant stromal desmoplasia
(H&E, high magnification)
2014). The epithelial structures are tubular and
solid, which are compressed or exhibit irregular
contours and show characteristic teardrop- or
comma-shaped formations. Usually there is
a deep infiltration into the severely fibrous under-
lying stroma (Ishikawa et al. 2015; Montgomery
et al. 2014; Oo and Xiao 2009; Rosen 1983).
Tumor cell nuclei are bland and lack any signifi-
cant atypia, the cytoplasm is rather pale or slightly
eosinophilic. Tumor cell formations consist
of a bilayered structure with an inner luminal
epithelial layer with cuboidal or flat cells, and an
outer layer of cells of similar appearance of pre-
sumably myoepithelial differentiation (Ishikawa
et al. 2015; Montgomery et al. 2014; Boecker
et al. 2014; Oo and Xiao 2009). Mitotic figures S
or necrosis are absent. The stroma around the
epithelial cells is fibrotic and can contain spindle-
shaped mesenchymal cells (Ishikawa et al. 2015;
Montgomery et al. 2014; Oo and Xiao 2009; Page
et al. 2009; Jones et al. 1989; Carter and Dyess
2004; Rosen 1983).
Immunophenotype
Luminal epithelial cells are uniformly positive for
high molecular weight cytokeratins as 34betaE12
and for basal cytokeratins as CK5/6 and in a large
368
subset with squamoid differentiation, also for p63.
The outer layer is consequently positive for
myoepithelial markers as p63 (Fig. 4), CK5/6
(Fig. 5), or smooth muscle myosin heavy chain
and also for high molecular weight cytokeratins as
34betaE12. Hormone receptors and HER2 are
Syringomatous Tumor of the Nipple, Fig. 4 P63
immunohistochemistry decorates consequently the outer
myoepithelial layer and in some glands also the inner
epithelial layer (p63 immunohistochemistry, clone 4A4,
low magnification)
Syringomatous Tumor of the Nipple,
Fig. 5 Cytokeratin 5/6 immunohistochemistry decorates
both the inner epithelial and the outer myoepithelial layer,
Syringomatous Tumor of the Nipple
negative in both components. Ki67 index is usually
very low (<5%) (Ishikawa et al. 2015; Montgomery
et al. 2014; Boecker et al. 2014).
Molecular Features
There are no molecular data available based on
current literature on syringomatous tumors of the
nipple. The triple negative intrinsic phenotype and
the low Ki-67 index seems to be the most charac-
teristic surrogate molecular marker (Ishikawa et al.
2015; Boecker et al. 2014; Oo and Xiao 2009).
Differential Diagnosis
The differential diagnosis includes low-grade
adenosquamous carcinoma, tubular carcinoma,
classical nipple adenoma and also inflamed cases
of epithelial hyperplasia, squamous metaplasia, or
highly differentiated invasive squamous carci-
noma (Ishikawa et al. 2015; Montgomery et al.
2014; Boecker et al. 2014; Oo and Xiao 2009).
note also the vicinity of the cystic protruding epidermal
structures (cytokeratin 5/6 immunohistochemistry, clone
D5/16B4, high magnification)
Syringomatous Tumor of the Nipple
The low-grade adenosquamous carcinoma
(▶ Low-Grade Adenosquamous Carcinoma) of
the breast shares overlapping histological
and immunohistochemical characteristics with a
syringomatous nipple tumor. Both lesions have
a bland cytological appearance and are mostly
triple negative and exhibit very similar expression
of basal cytokeratins and myoepithelial markers.
However, at difference from a syringomatous
adenoma a low-grade adenosquamous carcinoma
shows a clear deep infiltrative growth with
desmoplastic stromal reactions into the deeper
breast structures. A careful examination of the
whole histological and immunophenotypical con-
text is necessary to differentiate a syringomatous
tumor from low-grade adenosquamous carcinoma
(Ishikawa et al. 2015; Montgomery et al. 2014;
Boecker et al. 2014; Oo and Xiao 2009).
A tubular carcinoma (▶ Tubular Carcinoma)
can imitate the histological picture of
syringomatous adenoma especially if angular
and pointed structures are compressed due to
severe stromal sclerosis. Tubular carcinomas are
almost always hormone receptor positive and lack
myoepithelial cells, both morphologically and
immunohistochemically, which can help in the
differential diagnosis (Ishikawa et al. 2015;
Montgomery et al. 2014; Oo and Xiao 2009;
Page et al. 2009; Jones et al. 1989; Carter and
Dyess 2004; Rosen 1983).
Classical nipple adenoma also shares histolog-
ical features with syringomatous nipple tumors.
However, nipple adenomas usually exhibit
a marked epithelial intraductal hyperplasia (usual
ductal hyperplasia) and most of the cases
have a clear relationship with the overlying epi-
dermis with ulcerations (Ishikawa et al. 2015;
Montgomery et al. 2014; Oo and Xiao 2009).
Epithelial hyperplasia (▶ Usual Ductal Hyper-
plasia (UDH)) and squamous metaplasia occur
mostly in the area of acute or chronic inflammation
and do not show preferential growth around nerve
sheets or smooth muscle layers. Additionally, no
bilayered appearance can be identified on conven-
tional morphology at the hyperplastic/metaplastic
369
squamous epithelium (Ishikawa et al. 2015;
Montgomery et al. 2014; Oo and Xiao 2009).
Highly differentiated squamous carcinoma can
pose a diagnostic challenge if nuclear morphology
is completely bland. However, a desmoplastic
stromal reaction and a lack of lobular growth
are usually present in squamous cell carcinomas
(Ishikawa et al. 2015; Montgomery et al. 2014;
Oo and Xiao 2009).
References and Further Reading
Boecker, W., Stenman, G., Loening, T., Andersson, M. K.,
Sinn, H. P., Barth, P., Oberhellmann, F., Bos, I.,
Berg, T., Marusic, Z., Samoilova, V., & Buchwalow,
I. (2014). Differentiation and histogenesis of
syringomatous tumour of the nipple and low-grade
adenosquamous carcinoma: Evidence for a common
origin. Histopathology, 65, 9–23.
Carter, E., & Dyess, D. L. (2004). Infiltrating
syringomatous adenoma of the nipple: A case report
and 20-year retrospective review. The Breast Journal,
10, 443–447.
Ishikawa, S., Sako, H., Masuda, K., Tanaka, T.,
Akioka, K., Yamamoto, Y., Hosokawa, Y., &
Manabe, T. (2015). Syringomatous adenoma of the
nipple: A case report. Journal of Medical Case Reports,
13, 256.
Jones, M. W., Norris, H. J., & Snyder, R. C. (1989).
Infiltrating syringomatous adenoma of the nipple.
A clinical and pathological study of 11 cases.
The American Journal of Surgical Pathology, 13,
197–201.
Montgomery, N. D., Bianchi, G. D., Klauber-Demore, N.,
& Budwit, D. A. (2014). Bilateral syringomatous
adenomas of the nipple: Case report with immunohis-
tochemical characterization of a rare tumor mimicking
malignancy. American Journal of Clinical Pathology,
141, 727–731. S
Oo, K. Z., & Xiao, P. Q. (2009). Infiltrating syringomatous
adenoma of the nipple: Clinical presentation and
literature review. Archives of Pathology & Laboratory
Medicine, 133, 1487–1489.
Page, R. N., Dittrich, L., King, R., Boulos, F., &
Page, D. L. (2009). Syringomatous adenoma of the
nipple occurring within a supernumerary breast:
A case report. Journal of Cutaneous Pathology, 36,
1206–1209.
Rosen, P. P. (1983). Syringomatous adenoma of the nipple.
The American Journal of Surgical Pathology, 7,
739–745.
T
Tall Cell Variant of Papillary
Breast Carcinoma
Sofia Asioli and Francesca Ambrosi
Department of Biomedical and Neuromotor
Sciences (DIBINEM)-Surgical Pathology
Section, Alma Mater Studiorum – University of
Bologna, Bologna, Italy
Synonyms
Tall cell thyroid-like papillary carcinoma
Definition
Tall cell variant of papillary carcinoma is a unique
special type of primary breast neoplasm not
related to a thyroid gland neoplasm, showing
very frequently a triple-negative profile, but low
aggressive potential and a good prognosis.
Clinical Features
• Incidence
Thirty-seven cases of this special type of pri-
mary breast carcinoma have been reported in
the literature.
• Age
Median age at presentation is 61 years, ranging
from 45 to 85 years.
© Springer Nature Switzerland AG 2020
A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
• Sex
All patients reported in the literature are
females.
• Site
Breast without a prevalence of a specific mam-
mary quadrant.
• Treatment
Because of indolent clinical behavior, wide
excision is the best choice of treatment and
axillary dissection is generally avoided.
Although, some patients also received chemo-
and radiation therapy, these treatments might
not be appropriate.
• Outcome
Tall cell variant of papillary breast carcinoma
shows a consistent indolent clinical behavior.
In literature, of 30 cases with an available
follow-up, only 1 case developed bone metas-
tases 32 months after surgery (Cameselle-
Teijeiro et al. 2006). Another case of tall cell
variant of papillary breast carcinoma was
described in a patient presenting a metastasis
to an intramammary lymph node, but the nod-
ule had been clinically present for 10 years
before surgery; this patient was alive and free
of local or distant recurrence 10 years later
(Tosi et al. 2007). The last case with aggressive
behavior showed a local recurrence 5 years
after presentation and one axillary metastatic
lymph node out of 10. Both lesions were
surgically removed. This patient was alive
and free of disease 4 years later (Foschini
et al. 2017). The remaining 27 patients were
372 Tall Cell Variant of Papillary Breast Carcinoma

reported to be alive and free of disease with a

mean follow-up of 77 months after surgery.

Macroscopy

Tumors generally present either as palpable and

well-defined nodules or less frequently as screen-
detected nonpalpable lesions, thus the size of the
lesion may be variable (range 0.6–4.1 cm). On
mammography or ultrasound examination, tall cell
variant of papillary breast carcinomas are com-
monly interpreted as benign, due to their regular
margins. Tall Cell Variant of Papillary Breast Carcinoma,
Fig. 1 At low power, the present case of tall cell variant
of papillary carcinoma, shows a multilobar architecture;
margins are mostly pushing, with focal infiltrative area
Microscopy (H&E)

At low power, tall cell variant of papillary breast

carcinoma shows usually a multilobar architecture;
margins are mostly pushing, with focal infiltrative
areas. All the cases described in literature exhibit
striking common histological features and closely
mimic the features of the tall cell variant of papillary
thyroid carcinoma. In particular, neoplastic cells are
mainly arranged in papillary fronds, with a thin
fibrovascular core. Most of the papillae are closely
packed mimicking solid or trabecular structures that
appear as irregular nests of cohesive neoplastic cells
surrounded by loose to dense stroma rich in small
capillary-like vessels that, in a delicate-garland-like
fashion, envelopes all the epithelial structures. True Tall Cell Variant of Papillary Breast Carcinoma,
follicular-like structures may be seen (Figs. 1 and 2). Fig. 2 The present case of tall cell variant of papillary
These contain eosinophilic, amorphous material, carcinoma shows neoplastic cells arranged in follicular-like
structures that contain eosinophilic, amorphous material, very
very similar to thyroid colloid, including the
similar to colloid, including the scalloped periphery (H&E)
scalloped periphery (Fig. 3). A mixture of three
architectural patterns (papillary, solid, and follicular)
is generally present, one of which may be predom- of the cell height. Nuclear grooves and pseudo-
inant. Most of the cases show psammoma bodies as inclusions are frequently seen. Mitotic figures are
well as granular calcifications, both located within rare. The histological grade, according to Elston and
the colloid-like material or within the proliferating Ellis grading system of breast cancer (Elston and
epithelium. Neoplastic cells are columnar to cuboi- Ellis 1991), is grade 1. Vascular or perineural inva-
dal in shape and perpendicularly oriented toward the sion is usually absent. Clear-cut features of an in-situ
fibrovascular cores. The cytoplasm is frequently carcinoma have been reported in 7.7% of cases (Tosi
granular eosinophilic and occasionally homoge- et al. 2007). Foci of flat epithelial atypia at
neous and strongly eosinophilic. Pale, elongated the periphery have been observed in 15.4% of
nuclei are dislodged to the apical pole of neoplastic cases (Foschini et al. 2017). Metastatic deposits
cells or centrally located and occupy about one-third within lymph nodes, if present, exhibit identical
Tall Cell Variant of Papillary Breast Carcinoma
Tall Cell Variant of Papillary Breast Carcinoma,
Fig. 3 The neoplastic cells are columnar to cuboidal in
shape, with granular eosinophilic cytoplasm. The nucleus
occupies about 1/3 of the cell height and it is centrally
located, elongated and has clear chromatin. Nuclear
grooves and pseudoinclusions are present (H&E)
morphological and immunohistochemical features
with the primary neoplasm.
Immunophenotype
Estrogen and progesterone receptors are
completely missing or rarely (7.6% of cases)
expressed in less than 1% of the total neoplastic
proliferation and HER2 is negative, so that tall
cell variant of papillary breast carcinoma is
classified as triple-negative. Androgen receptor
is negative as well excluding an apocrine nature.
Ki67 proliferative index is low.
Cytokeratin 7 expression is strong and diffuse
within the neoplastic cells, while occasional
focal positivity for GCDFP-15, mammaglobin,
and GATA 3, which are “luminal” type markers,
may be observed. On the other hand, immunocy-
tochemical expression of “nonluminal/basal-like”
markers such as cytokeratin 14 and cytokeratin
5/6 has been reported in 8 cases (Eusebi et al.
2003; Tosi et al. 2007; Foschini et al. 2017).
Myoepithelial markers such as p63, calponin,
and smooth muscle actin are negative or mark
rare myoepithelial cells that surround occasional
neoplastic areas.
Collagen IVand laminin highlight the fibrovas-
cular cores present within the solid papillary nests
373
or a rim of basal lamina at the periphery of neo-
plastic epithelium. The intracytoplasmic granules,
mostly condensed at the basal pole of cells, are
strongly positive for mitochondrion antigen.
Immunohistochemical markers suggestive of
thyroid origin, that is, thyroglobulin and TTF1,
had been reported as consistently negative in
these tumors (Eusebi et al. 2003; Foschini
et al. 2017).
Molecular Feature
RET/PTC and BRAF genes alterations commonly
seen in papillary thyroid carcinomas have been
explored, with negative results (Cameselle-
Teijeiro et al. 2006; Eusebi et al. 2003; Hameed
et al. 2009). Mutations in isocitrate dehydroge-
nase 2 (IDH2) have been reported. In particular,
Chiang et al. (2016) detected hotspot mutations at
R172 IDH2 gene in 10 out of 13 cases of tall cell
variant of papillary breast carcinomas. Eight of
the 10 mutated cases displayed concomitant path-
ogenic mutations at PIK3CA or PIK3R1. In addi-
tion, the same authors, through functional studies,
demonstrated that IDH2 and PIK3CA hotspot
mutations were crucial in the neoplastic transfor-
mation of tall cell variant of papillary breast car-
cinoma and probably responsible of its peculiar
phenotype.
Differential Diagnosis
Lymph node metastases of papillary thyroid car-
cinoma have to be considered in the rare occa-
sion of metastatic tall cell papillary carcinoma of T
the breast. However, the site of metastases, the
absence of history of a primary thyroid carci-
noma, the immunohistochemical expression of
GCDFP-15, GATA3, and mammaglobin, and the
negativity of markers of thyroid origin as TTF1
and thyroglobulin and the absence of common
molecular alterations seen in papillary thyroid
carcinomas help distinguish between these two
entities. A possible differential diagnosis may
be required with the solid papillary variant of
breast carcinoma (▶ Solid Papillary Carcinoma).
374
The latter, at difference with the tall cell variant
of papillary breast carcinoma, is positive for
hormone receptor expression and frequently
exhibits neuroendocrine marker expression.
Tall cell variant of papillary breast carcinoma: fact
sheet
Definition
– Very rare type of primary breast neoplasm not related
to a thyroid gland neoplasm, showing very frequently a
triple-negative profile
Age distribution
– Median age: 61 years (range 45–85 years)
Clinical features
– Palpable and well-defined nodules with regular
margins
Microscopic findings
– Three architectural patterns: papillary, solid, and
follicular
– Neoplastic cells: columnar to cuboidal in shape, with
granular eosinophilic cytoplasm
– Presence of nuclear grooves, pseudoinclusions, and
psammoma bodies
– Mitosis is rare, and vascular invasion is uncommon
Immunohistochemical findings
– Estrogen, progesterone, androgen receptors, and
HER2: negative
– “Luminal” type markers (cytokeratin 7, GCDFP-15,
mammaglobin, and GATA 3): variably positive
– Myoepithelial markers (p63, calponin, and smooth
muscle actin): negative
– Thyroglobulin and TTF1: negative
Molecular findings
– Absence of alterations of RET/PTC and BRAF genes
– Mutations of IDH2 gene in 77% of cases tested
Differential diagnosis
– Solid papillary carcinoma of the breast
– Metastasis from papillary thyroid carcinomas
Prognosis and treatment
– Wide excision without aggressive treatment
strategies
– Indolent clinical behavior
References and Further Reading
Cameselle-Teijeiro, J., Abdulkader, I., Barreiro-
Morandeira, F., Ruiz-Ponte, C., Reyes-Santías, R.,
Chavez, E., Sobrinho-Simões, M. (2006). Breast
tumor resembling the tall cell variant of papillary thy-
roid carcinoma: A case report. International Journal of
Surgical Pathology, 14, 79–84.
Chiang, S., Weigelt, B., Wen, H. C., Pareja, F.,
Raghavendra, A., Martelotto, L. G., Burke, K. A.,
Basili, T., Li, A., Geyer, F. C., Piscuoglio, S., Ng, C.
Toker Cells of the Nipple
K. Y., Jungbluth, A. A., Balss, J., Pusch, S., Baker, G.
M., Cole, K. S., von Deimling, A., Batten, J. M.,
Marotti, J. D., Soh, H-C., McCalip, B. L., Serrano, J.,
Lim, R. S., Siziopikou, K. P., Lu, S., Liu, X., Hammour,
T., Brogi, E., Snuderl, M., Iafrate, A. J., Reis-Filho, J.
S., Schnitt, S. J. (2016). IDH2 mutations define a
unique subtype of breast cancer with altered nuclear
polarity. Cancer Research, 76, 1–12.
Elston, C. W., & Ellis, I. O. (1991). Pathological prognostic
factors in breast cancer. 1. The value of histological
grade in breast cancer: Experience from a large
study with long-term follow-up. Histopathology, 19,
403–410.
Eusebi, V., Damiani, S., Ellis, I. O., Azzopardi, J. G.,
Rosai, J. (2003). Breast tumor resembling the tall cell
variant of papillary thyroid carcinoma: Report of
5 cases. The American Journal of Surgical Pathology,
27, 1114–1118.
Foschini, M. P., Asioli, S., Foreid, S., Cserni, G., Ellis, I.
O., Eusebi, V., Rosai, J. (2017). Solid papillary breast
carcinomas resembling the tall cell variant of papillary
thyroid neoplasms: A unique invasive tumor with indo-
lent behavior. The American Journal of Surgical
Pathology, 41, 887–895.
Hameed, O., Perry, A., Banerjee, R., Zhu, X., Pfeifer, J. D.
(2009). Papillary carcinoma of the breast lacks evi-
dence of RET rearrangements despite morphological
similarities to papillary thyroid carcinoma. Modern
Pathology, 22, 1236–1242.
Tosi, A. L., Ragazzi, M., Asioli, S., Del Vecchio, M.,
Cavalieri, M., Eusebi, L. H. U., Foschini, M. P.
(2007). Breast tumor resembling the tall cell variant
of papillary thyroid carcinoma: Report of 4 cases with
evidence of malignant potential. International Journal
of Surgical Pathology, 15, 14–19.
Toker Cells of the Nipple
Luca Di Tommaso
Pathology Unit, Humanitas Clinical and Research
Center, Department of Biomedical Sciences,
Humanitas University, Milan, Rozzano, Italy
Synonyms
Clear cells of the nipple
Definition
Toker cells (TC) are clear elements that can be
seen in the lower layers of the epidermis of the
Toker Cells of the Nipple
Toker Cells of the Nipple, Fig. 1 (H&E) Toker cells
(TC) of the nipple. (a) Occasional clear cells are seen in the
lower layers of the epidermis of the nipple (arrows); (b) at
nipple as single elements and, more rarely, as
small glands (Toker 1970).
Hyperplastic TC lacks a definition. It has been
suggested to consider hyperplastic cases showing
(a) clusters of >7 TC (van der Putte et al. 1995), or
(b) 10–20 single cells and 3–10 glands
(Di Tommaso et al. 2008), or (c) clusters of >3
CK7+ cells (Nofech-Mozes and Hanna 2009).
From a practical point of view, normal TC disap-
pear after few recuts, while hyperplastic TC are
retained or even increased after several recuts.
Atypical TC are those exhibiting “cytologic
atypism of a degree insufficient for an un- equiv-
ocal diagnosis of cancerous change” (Toker
1970). This mild to moderate atypia shows up in
terms of irregular nuclear contour, increased
nuclear size, and small eosinophilic nucleoli.
Also, atypical TC are retained after several recuts
(Figs. 1, 2, 3, and 4).
A classification of normal, hyperplastic, and
atypical TC is proposed in Table 1.
375
higher magnification single elements and small glands are
characterized by bland cytological features
Clinical Features
• Incidence
Dr. Cyril Toker was the first to describe the
presence of clear cells in the nipple. Studying
H&E sections of 190 autopsies, he demon-
strated TC in 12% of the cases (Toker 1970).
This finding was later confirmed in a morpho-
logical study on 390 nipples from surgical spec-
imens (Di Tommaso et al. 2008). The use of T
CK7 immunostaining may help to recognize
TC. Thus, not surprisingly, CK7 reveals TC in
83% of autopsy cases (Lundquist et al. 1999)
and in 88% of surgical specimens (Nofech-
Mozes and Hanna 2009). The number of TC
cells disclosed by CK7 staining is about 10 per
low power field (10x) and mostly showing as
isolated elements. Finally, hyperplastic and
atypical TC have been reported, respectively,
in 8–27% and 3–12% of the series (Toker
1970; Di Tommaso et al. 2008).
376 Toker Cells of the Nipple

Toker Cells of the Nipple, Fig. 2 (H&E) Hyperplastic TC. (a) Numerous TC are easily seen at low magnification; (b)
while most of TC are still devoid of atypia, scattered prominent nucleoli and irregular nuclear profile can be observed

Toker Cells of the Nipple, Fig. 3 Atypical TC. (a) The TC show one or two prominent eosinophilic nucleoli
basal layer of this nipple is characterized by the presence of (H&E) (c) and demonstrate a faint, continuous
several TC, isolated and in small clusters (H&E); (b) most immunostaining for HER2

• Age and Sex were represented by eight males and ten

In his seminal paper, Toker described the pres- females with a mean age of 50 years (range,
ence of TC in the nipples of 18 patients. These 26–76 years). A similar distribution was
Toker Cells of the Nipple
Toker Cells of the Nipple, Fig. 4 Phenotypical features of TC. These hyperplastic TC show strong immunoreactivity to
estrogen receptors (a) and faint immunoreactivity to progesterone receptors (b)
confirmed by Lundquist in his autopsy series
(Lundquist et al. 1999). Subsequent studies
investigated the presence of TC in patients
undergoing mastectomy for breast cancer: epi-
demiological features of TC were confounded
by those of the underlining neoplastic disease.
Indeed, patients showing TC are significantly
younger if undergoing prophylactic mastec-
tomy for BRCA mutation rather than mastec-
tomy for breast cancer (Nofech-Mozes and
Hanna 2009).
• Site and Origin
TC have been reported not only in the nipple
but also in the areola, in the accessory nipple,
in the axilla, and in the vulva. Accordingly, it
has been suggested that TC represent (1) ele-
ments that migrated from mammary excretory
ducts into the epidermis of the nipple, or
(2) abortive mammary differentiation within
the basal layer of the epidermis, or (3) embry-
onic nests of cells related to eccrine and apo-
crine structures. A possible comprehensive
377
explanation on TC origin came from an embry-
ological study conducted on the anogenital
region of female and male fetus (van der
Putte 2011). This study demonstrated that
the primordial follicular cells involved in the
formation of apocrine and mammary-like
glands are displaced into the epidermis where
they proliferate and differentiate as
TC. Accordingly, it was speculated that TC of
the anogenital region may likely represent the
precursors of primary anogenital Paget disease. T
Similarly, TC of the nipple may represent the
precursors of primary Paget disease of the
nipple.
Microscopy
TC are cells larger than keratinocytes, round to
polygonal in shape, with faintly eosinophilic or
clear cytoplasm, oval nuclei, and small nucleoli.
Electron microscopy showed that the clear
378 Toker Cells of the Nipple

Toker Cells of the Nipple, Table 1 Proposed criteria for the classification of normal, hyperplastic, and atypical TC
Normal TC Hyperplastic TC Atypical TC
Isolated TC (n ) <10 10–20 Any; usually 10–20
Clusters of TC (n ) <3 3–10 Any; usually 3–10
TC after recuts Disappear Conserved/increased Conserved/increased
Cytological atypia Absent Absent Mild to moderate

Toker Cells of the Nipple, Table 2 Phenotypical features of Toker cells (TC) and Paget disease (PD) cells
ER (%) PgR (%) HER2/neu (%) p53 (%)
Normal TC 100 70 0 na
Hyperplastic TC 100 90 10 0
Atypical TC 100 100 80 0
PD (without coexisting carcinoma) 50–60 20 70–100 80
PD (with coexisting carcinoma) 10–40 0–20 80–100 10–60
Abbreviation: ER estrogen receptors, PgR progesterone receptors, na not available, DCIS ductal carcinoma in situ

cytoplasm is due to paucity of organelles and
filaments (Marucci et al. 2002). TC are seen
within the basal and/or spinous layers; they pre-
sent as single elements or as small glands. Hyper-
plastic TC retain cytological and architectural
features of normal TC. The distinctive diagnostic
feature is the increased number of single cells
and/or glands within the lower layers of the epi-
dermis, which makes these cases easily recogniz-
able at H&E as compared to normal TC even at
scanning magnification. Atypical TC are charac-
terized by nuclei with irregular contour and eosin-
ophilic nucleoli but with preserved nucleus/
cytoplasmic ratio. There are no signs of architec-
tural disorder, being most of the cell still localized
in the lower layers of the epidermis.
Immunophenotype
TC are consistently immunoreactive with CK7.
This marker, as well as EMA, can be used to
reveal TC or to disclose additional TC at the
periphery of those seen on H&E. Interestingly,
CK7 also highlights the dendritic profile
of rare TC. TC are p63 negative/ER positive/
PgR positive: a phenotype further reinforcing
the difference with keratinocytes and supporting
a mammary or mammary-like origin. Additional
markers tested in TC, mostly in the hyperplastic
and atypical groups, are p53 and HER2, due to
their role in the differential diagnosis with ▶ Paget
Disease (PD). Hyperplastic and atypical TC are
always p53 negative; a faint immunoreactivity for
HER2 is frequently seen in atypical TC and, more
rarely, in hyperplastic conditions.
Table 2 illustrates the immunohistochemical
profile of TC (normal, hyperplastic, and atypical)
as compared to PD (without or with a coexisting
carcinoma in the underlining breast parenchyma: for
a detailed explanation, see Differential Diagnosis).
Differential Diagnosis
As mentioned, the main differential diagnosis
of TC is PD of the nipple. In most of the cases,
PD represents an epidermotropic migration of
cancer cells from an underlying breast carci-
noma. However, the existence of PD with
extensive involvement of the epidermidis
lacking any carcinoma in the parenchyma or
that of PD in the areola in patient with con-
genital absence of the nipple does not support
the epidermotropic hypothesis. The few reports
about PD associated with TC hyperplasia in the
areola and that of PD indistinguishable from
TC hyperplasia in supernumerary nipple fur-
ther reinforce the hypothesis that rare
cases of PD may represent a malignant
transformation of TC, as suggested by Toker
himself (Toker 1970). This hypothesis was
Tubular Adenoma of the Breast
further strengthened by the observation that
intraepidermal cells of PD can be genetically
different from those of the underlying
carcinoma, thus possibly representing the
neoplastic transformation of TC (Morandi
et al. 2003).
PD usually presents with exudative crust, ery-
thema, pruritus, and/or bleeding of the nipple
while in normal, hyperplastic, and atypical TC,
the nipple is grossly unremarkable. PD cells have
abundant, weakly eosinophilic cytoplasm, pleo-
morphic nuclei, large eosinophilic nucleoli, and
overgrowth in any layer of the epidermis; none of
these features are observed in TC. Finally,
PD cells are mostly p53+ and HER2+ as opposite
to TC. However, from a practical point of view,
PD is in most of the cases a clinical condition,
while TC is always an occasional histopathologi-
cal finding.
References and Further Reading
Di Tommaso, L., Franchi, G., Destro, A., Broglia, F.,
Minuti, F., Rahal, D., & Roncalli, M. (2008). Toker
cells of the breast. Morphological and immunohisto-
chemical characterization of 40 cases. Human Pathol-
ogy, 39, 1295–1300.
Lundquist, K., Kohler, S., & Rouse, R. V. (1999).
Intraepidermal cytokeratin 7 expression is not restricted to
Paget cells but is also seen in Toker cells and Merkel cells.
American Journal of Surgical Pathology, 23, 212–219.
Marucci, G., Betts, C. M., Golouh, R., Peterse, J. L., Foschini,
M. P., & Eusebi, V. (2002). Toker cells are probably pre-
cursors of Paget cell carcinoma: a morphological and ultra-
structural description. Virchows Archiv, 441, 117–123.
Morandi, L., Pession, A., Marucci, G. L., Foschini, M. P.,
Pruneri, G., Viale, G., & Eusebi, V. (2003).
Intraepidermal cells of Paget’s carcinoma of the breast
can be genetically different from those of the underly-
ing carcinoma. Human Pathology, 34, 1321–1330.
Nofech-Mozes, S., & Hanna, W. (2009). Toker cells
revisited. The Breast Journal, 15, 394–398.
Toker, C. (1970). Clear cells of the nipple epidermis.
Cancer, 25, 601–610.
van der Putte, S. C. (2011). Clear cells of
Toker in the developing anogenital region of
male and female fetuses. American Journal of
Dermatopathology, 33, 811–818.
van der Putte, S. C., Toonstra, J., & Hennipman,
A. (1995). Mammary Paget’s disease confined to the
areola and associated with multifocal Toker cell
hyperplasia. American Journal of Dermatopathology,
17, 487–493.
379
Tubular Adenoma of the
Breast
Nicola Fusco and Chiara Corti
Division of Pathology, Fondazione IRCCS Ca’
Granda – Ospedale Maggiore Policlinico,
University of Milan, Milan, Italy
Synonyms
Pure adenoma of the breast; True adenoma of the
breast
Definition
Tubular adenoma of the breast is a rare benign
lesion that is characterized by a nodular prolifer-
ation of compact tubular structures lined by epi-
thelial and myoepithelial cells with no nuclear
atypia (Foschini et al. 2012). Since its first
description in 1968 as “pure adenoma of the
breast” (Persaud et al. 1968), only a few cases
have been described (O’Hara and Page 1985;
Maiorano and Albrizio 1995; Rovera et al.
2006; Düşünceli et al. 2012; Sengupta
et al. 2014).
Clinical Features
• Incidence
The introduction of mammography-based
breast cancer screening programs has
increased the detection of breast tubular ade- T
nomas. However, given the lack of large pop-
ulation studies focused on this benign
condition, its incidence is substantially
unknown. The prevalence of breast tubular
adenoma is reported to range from 0.1% to
2.8% of all benign breast lesions (Sengupta
et al. 2014; Foschini et al. 2012).
• Age
Tubular adenoma of the breast occurs mainly
during reproductive ages (Salemis et al. 2012).
It is rare before menarche and after menopause
380
(Foschini et al. 2012) and vanishingly rare in
elderly people (Nishimori et al. 2000; Rovera
et al. 2006). Pregnancy-associated tubular ade-
nomas can be observed and may show rapid
enlargement in tumor size (Nagata et al. 1998;
O’Hara and Page 1985; Salemis et al. 2012).
• Sex
Despite tubular adenoma has been described
only in females, the possible occurrence in
male individuals should not be excluded.
• Site
Akin to most benign breast lesions, tubular
adenomas arise within the terminal duct-
lobular unit (Foschini et al. 2012; Sciarra
et al. 2017). They preferentially involve the
upper and outer quadrants of the breasts
(Sengupta et al. 2014).
• Clinical Presentation
Breast tubular adenoma is usually asymptom-
atic and detected incidentally during screening
examinations (Rovera et al. 2006). When pre-
sent, the symptoms are nonspecific, being
related to the mass effect. They include a pal-
pable smooth, mobile, well-defined nodular
mass and breast tenderness in the area of the
lump (Salemis et al. 2012; Sengupta et al.
2014). These benign alterations cause no nip-
ple discharge or pain. Although the majority of
tubular adenomas grow slowly, they can also
present as a fast-growing nodule, particularly
Tubular Adenoma of the
Breast, Fig. 1 (a)
Mammography shows a
relatively dense, lobulated,
round lump. (b) Ultrasound:
uniform hypoechoic mass
with well-defined borders,
in the absence of a
consistent capsule –
arrowheads indicate the
lesion (Both images are
Courtesy of Dr. Luca
Despini; Fondazione
IRCCS Ca’
Granda – Ospedale
Maggiore Policlinico,
Milan, Italy)
Tubular Adenoma of the Breast
in pregnant and puerperal women (Salemis
et al. 2012).
The imaging features of breast tubular ade-
noma are nondiagnostic and consistent to
those of a benign breast lesion. At mammog-
raphy, it appears as a well-circumscribed
fibroadenoma-like nodule (Fig. 1a). Calcifica-
tions have been rarely observed, particularly
in elderly women (Soo et al. 2000; D’Orsi
et al. 2013). Ultrasonography reveals a well-
defined hypoechoic mass with a relatively
homogeneous internal texture, showing low-
to-mild posterior enhancement (Irshad et al.
2008) (Fig. 1b).
• Treatment
Given its benign clinicoradiological features
and low tendency to increase in size, clinical
observation usually suffices for the proper
management of these patients. However, in
high-risk individuals (e.g., elderly women and
young women with strong family history for
breast cancer), or in cases of fast-growing
lesions with significant mass effect, a diagnos-
tic core biopsy or surgical excision should be
performed (Salemis et al. 2012; Sengupta et al.
2014; Rovera et al. 2006; Calderaro et al.
2010).
• Outcome
Tubular adenoma of the breast has an indo-
lent clinical course (Foschini et al. 2012).
Tubular Adenoma of the Breast 381

After surgical excision with clear margins, Microscopy

no recurrences have been described. This
benign lesion is not associated with an
increased risk of breast cancer development.
However, rare cases of ductal carcinoma in
situ (DCIS) and/or invasive carcinoma of no
special type arising within tubular adenomas
have been reported (Hill and Miller 1954;
Case 1977; Domoto et al. 2002; Saimura
et al. 2015). These conditions are currently
considered “collision” tumors, given that
their clonal relationship has never been
demonstrated.
Macroscopy
Grossly, tubular adenomas are firm and well-
circumscribed nodules ranging from 1 to 8 cm
in greatest dimensions. Smaller lesions should be
classified within the fibrocystic changes contin-
uum (Shet and Rege 1998; Tavassoli 1999).
Notably, “giant” tubular adenomas (14 cm in
tumor size) have anecdotally been described
(Düşünceli et al. 2012). The cut surface is uni-
formly white-to-yellowish and shows macro-
scopic resemblance to that of fibroadenomas
and lactating adenomas, in the absence of a
fibrotic capsule (Rosen 2014; Tavassoli 1999;
Foschini et al. 2012). The overlying skin and
nipple usually show no alterations (Hertel et al.
1976; Nishimori et al. 2000).
Tubular adenomas of the breast are morphologi-
cally characterized by a lobulocentric prolifera-
tion of closely packed, small, round tubular
structures composed of epithelial (luminal) and
myoepithelial (basal) cells, showing no signs of
atypia (Fig. 2). Occasional larger tubules can give
rise to thin branches resembling those of benign
fibroepithelial lesions. The luminal epithelium is
characteristically cuboidal-to-columnar and is
rimmed by a well-preserved myoepithelial layer
composed of cells with clear-to-pale cytoplasm.
The epithelium may display vesicular nuclei with
visible, although not prominent, nucleoli that can
be potentially worrying when observed at high
magnification. Nuclear pleomorphism and archi-
tectural complexity are absent, while mitoses, if
present, are typical and unremarkable. Apocrine
and/or lactating features may be observed, partic-
ularly in young individuals. Lactational changes
can be present in pregnant or peripartum women
and pose diagnostic challenges, particularly on
small biopsy samples, given their close similarity
to those of lactational adenomas or normal breast
tissue during pregnancy. The stroma within the
tubules is typically inconspicuous but not absent,
although variable in proportion, with rare
myofibroblasts immersed in PAS-positive colla-
gen bundles separating the tubules. Although
tubular adenomas showing a prominent stromal
reaction, in which the tubules are arranged in an

Tubular Adenoma of the

Breast, Fig. 2 (H&E)
shows a pure epithelial
proliferation where T
densely-packed tubular
structures are lined by
epithelial and myoepithelial
cells with no nuclear atypia.
Inset: the nuclear
expression of ER at
immunohistochemistry is
diffuse and non-uniformly
intense, akin to the normal
breast tissue (Courtesy of
Dr. Gianluca Lopez,
University of Milan, Milan,
Italy)
382
intracanalicular growth pattern, have been rarely
reported, there is currently no biological evidence
for their classification in the nosology of breast
fibroepithelial lesions (Maiorano and Albrizio
1995). Akin to other benign conditions, a lympho-
cytic infiltrate of variable degree may be present.
The tubular clefts are often empty, although eosin-
ophilic proteinaceous material can be found
(Foschini et al. 2012). Various degrees of ische-
mic fibrosis can be observed (Tavassoli 1999), in
the absence of clear hemorrhage or necrosis
(Hertel et al. 1976).
Fine needle aspiration (FNA) cytology of
tubular adenomas is nonspecific and could lead
to overdiagnosis (Moross et al. 1983). The main
cytological findings include cells arranged in
small, three-dimensional clusters and tubular
structures. Cells have finely vacuolated cyto-
plasm, uniform nuclei with fine chromatin, and
inconspicuous nucleoli. Artefactual nuclear
atypia can be present (Calderaro et al. 2010;
Sengupta et al. 2014). Hence, a diagnosis of
tubular adenoma in FNA cytological specimens
is extremely challenging, not to say virtually
unachievable.
Immunophenotype
Since tubular adenoma of the breast is composed
of small ducts surrounded by a scarce stromal
tissue, its immunophenotype is consistent with
that of the normal breast tissue. The presence of
the basal cell layer can be demonstrated by the
immunoreactivity for myoepithelial markers, such
as p63, CK5/6, and S100 (Böcker et al. 1992; Yeh
and Mies 2008; Maiorano and Albrizio 1995).
Immunohistochemistry of the luminal (epithelial)
population includes strong positivity for CK7 and
E-cadherin and a nonhomogeneous low-to-mild
nuclear positivity for the estrogen receptor
(ER) (Fig. 2).
Molecular Features
There are no available data on the molecular fea-
tures of breast tubular adenoma.
Tubular Adenoma of the Breast
Differential Diagnosis
The diagnosis of breast tubular adenoma is
morphology-based and usually straightforward
when clinicoradiological correlations are present.
However, its close resemblance to other benign
conditions of the breast may pose diagnostic chal-
lenges. Its main differential diagnosis is with the
normal breast tissue and fibrocystic/apocrine
changes (Sciarra et al. 2017). In this respect,
detailed clinicoradiological information, particu-
larly in small biopsy samples, are warranted to
achieve the diagnosis of breast tubular adenoma
(Hertel et al. 1976).
The amount and cellularity of the stroma,
together with the tubular architecture of the
ducts, are key features in the differentiation of
tubular adenoma from fibroadenoma
(▶ Fibroadenoma) of the breast (Saimura et al.
2015; Irshad et al. 2008). From a molecular stand-
point, while the clonal and neoplastic origin of
breast tubular adenoma has not been demon-
strated, somatic mutations in exon 2 of the medi-
ator complex subunit 12 (MED12) have been
identified in 60% of breast fibroadenomas and
likely constitute their driving genetic event
(Piscuoglio et al. 2015). It is of note that lesions
showing either tubular adenoma and
fibroadenoma features have been described
(Komaki et al. 1992). In these cases, histology
revealed the presence of two discrete morpholog-
ical patterns in close proximity, suggesting a com-
bined tumor rather than a hybrid lesion.
Adnexal tumors of the breast comprise a spec-
trum of lesions that may have histological features
similar to those of tubular adenomas. Among
them, breast cylindroma is a non-encapsulated
but relatively well-demarcated lesion with irregu-
lar borders composed of nests and trabeculae of
cells arranged in a jigsaw puzzle pattern (Fusco
et al. 2016). Akin to tubular adenomas, these nests
and trabeculae are surrounded by thick eosino-
philic PAS-positive hyaline bands and are com-
posed of a dual cell population, epithelial and
myoepithelial, showing no nuclear atypia and
scarce mitoses. Within the nests, duct-like tubular
structures filled up with eosinophilic material can
be found. Despite the overlapping morphology of
Tubular Adenoma of the Breast
breast tubular adenoma and cylindroma, the latter
is consistently ER-negative and shows recurrent
splice-site somatic mutations in the tumor sup-
pressor cylindromatosis gene (CYLD).
The presence of luminal eosinophilic secre-
tions in the duct-like structures of tubular adeno-
mas has allowed some authors to speculate on its
possibly shared phylogenetic origin with lactating
adenoma (O’Hara and Page 1985). However,
based on their pathophysiology and morphology,
these two benign lesions should be considered
discrete conditions. Indeed, lactating adenomas
are hormone-related and tend to reflect lactational
alterations in hyperplastic and enlarged lobules
with variably complex architectural patterns. On
the contrary, tubular adenomas can occur
irrespectively of the obstetric history of the
patients and may show superimposed lactational
changes. Furthermore, the tubular structures of
breast tubular adenoma are characteristically
small and organized in a uniform architecture.
Differently from tubular adenomas, ductal ade-
nomas (▶ Ductal Adenoma) of the breast classi-
cally display glands that vary in size, sclerosing
stroma, and a fibrous capsule. Despite they tend to
be localized lesions, they are not completely
circumscribed nodules like tubular adenomas
(Saimura et al. 2015).
The absence of compression and distortion of
the ducts within the cellular stroma is a key mor-
phological feature that may help in the differenti-
ation of tubular adenoma with sclerosing adenosis
(▶ Sclerosing Adenosis) and microglandular
adenosis (▶ Microglandular Adenosis), a rare
proliferative lesion of the breast composed of
small glands in a hypocellular stroma (Guerini-
Rocco et al. 2016; Foschini et al. 2012). The latter,
however, is a non-lobulocentric proliferation of
ER-negative glands lacking the myoepithelial
cell layer, while tubular adenoma ducts are com-
posed of both epithelial and myoepithelial cells
and express ER.
References and Further Reading
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383
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C., Sapounas, K., Tsantilas, V., Sambaziotis, D., & enriched with small T1 breast cancers
Lagoudianakis, E. (2012). Tubular adenoma of the and in mammographic screening programs
breast: A rare presentation and review of the literature. (Anderson et al. 2004; Rakha et al. 2010).
Journal of Clinical Medicine Research, 4, 64–67.
• Age
Sengupta, S., Pal, S., Biswas, B. K., Phukan, J. P., Sinha,
A., & Sinha, R. (2014). Preoperative diagnosis of tubu- Approximately 60–70% of tubular carcinomas
lar adenoma of breast – 10 years of experience. The present as non-palpable, mammographically
Tubular Carcinoma
detected lesions and are more common in
women in their sixth or seventh decade who
are undergoing breast cancer screening.
• Sex
Female. Rare in male as for other forms
of breast cancer.
• Site
Anywhere in the breast but most frequent in the
upper outer quadrant like other types of breast
cancer. Multifocality has been reported in up to
20% of tubular carcinomas.
• Treatment
Local control and hormone therapy are the
main treatment options. Even when patients
have axillary metastases from tubular carci-
noma, the prognosis is very good, and the
axillary node dissection could be considered
unnecessary, and the use of systemic adjuvant
chemotherapy is typically not needed in pure
tubular carcinomas (Diab et al. 1999;
Papadatos et al. 2001; Fedko et al. 2010).
• Outcome
Tubular carcinoma has an exceptionally good
long-term prognosis (Diab et al. 1999;
Papadatos et al. 2001; Anderson et al. 2004;
Fedko et al. 2010; Rakha et al. 2010), and in
some series, the outcome is similar to age-
matched population without breast cancer
(Diab et al. 1999; Sullivan et al. 2005; Fedko
et al. 2010; Rakha et al. 2010). The risk of
local recurrence is so low that some centers
consider adjuvant radiotherapy unnecessary.
Ten-year disease-free and overall survival
rates after mastectomy or breast-conserving
surgery were reported to be 93.1–99.1% and
99–100%, respectively. Axillary node metasta-
ses occur infrequently (average 10%; range
0–22%) and rarely involve more than one or
two axillary lymph nodes.
Macroscopy
Tubular carcinoma presents as an ill-defined
gray to white, firm or hard mass with irregular
outlines measuring between 0.1 cm and 2 cm in
diameter; the majority are 1.5 cm or less. The
consistency is generally hard due to prominent
385
stromal desmoplasia. Foci of hemorrhage are usu-
ally attributable to a prior diagnostic needling
procedure. Necrosis is not a feature of tubular
carcinoma. Calcification is common in tubular
carcinoma and may be the presenting sign on
mammography.
Microscopy
The characteristic feature of tubular carcinoma
is the predominance of tubules composed of
a single layer of epithelial cells with open lumen
(Fig. 1). The tubules are arranged haphazardly;
are generally oval, rounded, and angulated in
shape; and lack peripheral myoepithelial cells.
The cells are small to moderate in size, regular
with little nuclear pleomorphism, inconspicuous
nucleoli, and scanty mitotic figures. Apical snouts
are seen in up to a third of cases but are not
pathognomonic. Multilayering of nuclei, marked
nuclear pleomorphism, and high mitotic activity
are contraindications for a diagnosis of tubular
carcinoma. The characteristic tubules of tubular
carcinoma comprise more than 90% of the tumor.
Adherence to the 90% rule is essential to correctly
identify tubular carcinoma which carries an excel-
lent prognosis. A tumor that shows features of
tubular carcinoma in 50–90% of the tumor and
another breast tumor type in the remainder of
the tumor, usually ▶ Invasive Carcinoma NST is
regarded as a tubular mixed carcinoma.
The stroma is typically cellular and
desmoplastic and commonly accompanying
the tubular structures. A consistent feature of
tubular carcinoma and one that is particularly
useful on needle core biopsy is the extension of T
tubules into surrounding fat.
Tubular carcinoma frequently coexists with
other low-nuclear-grade breast lesions including
▶ Columnar Cell Lesions, flat epithelial atypia,
▶ Atypical Ductal Hyperplasia, low-grade
▶ Ductal Carcinoma In Situ, and ▶ Lobular In
Situ Neoplasia. These lesions share morphologi-
cal, immunophenotypic, and molecular character-
istics and constitute the so-called low-nuclear-
grade neoplasia family. An association with
▶ Radial Scar has also been proposed.
386
Tubular Carcinoma, Fig. 1 (H&E) A case of tubular
carcinoma showing haphazardly arranged tubules lacking
myoepithelial cells and with characteristically open lumina
Immunophenotype
Tubular carcinoma is a special type of low-grade
invasive breast carcinoma that typically displays
a luminal A phenotype with high expression
of hormone receptors, luminal cytokeratins, and
E-cadherin. Tubular carcinoma does not
express basal cytokeratins, lacks HER2 gene
amplification, and is usually negative for
epidermal growth factor receptor, p-cadherin
and p53.
Molecular Features
Tubular carcinoma has a low frequency of genetic
alterations with the most frequent genetic alter-
ations seen at chromosomes 16q (loss) (78–86%),
Tubular Carcinoma
(shown in Fig. 1c) and desmoplastic stroma. Tubular car-
cinoma is associated with columnar cell change, flat epi-
thelial atypia, and low-grade DCIS (Figs. 1a and b )
followed by 1q (gain) (50–62%), and they usually
occur concomitantly. Other alterations include
16p gain and loss of 8p, 3p (FHIT gene locus),
and 11q (ATM gene locus). Global gene expres-
sion profiling studies have demonstrated that
tubular carcinoma belongs to the “luminal A”
molecular class of breast cancer.
Differential Diagnosis
Tubular carcinoma should be differentiated
from ▶ Sclerosing Adenosis,▶ Complex Scleros-
ing Lesion, and ▶ Microglandular Adenosis.
Tubular carcinoma should also be differentiated
from grade 1 NST carcinomas that have worse
prognosis compared to tubular carcinoma by the
90% rule of tubule formation. Sclerosing adenosis
Tubular Carcinoma 387

is characterized by the lobular architecture and the carcinoma. Cancer Epidemiology, Biomarkers &
compression and distortion of glandular struc- Prevention, 13, 1128–1135.
Diab, S. G., Clark, G. M., Osborne, C. K., Libby, A.,
tures. Myoepithelial cells are always present. Allred, D. C., & Elledge, R. M. (1999). Tumor
Complex sclerosing lesions/radial scars have cen- characteristics and clinical outcome of tubular and
tral fibrosis and elastosis containing a few small, mucinous breast carcinomas. Journal of Clinical
often distorted, tubular structures around which Oncology, 17, 1442–1448.
Fedko, M. G., Scow, J. S., Shah, S. S., Reynolds, C.,
myoepithelial cells are present. The peripheral Degnim, A. C., Jakub, J. W., & Boughey, J. C.
glandular structures in a radial scar show varying (2010). Pure tubular carcinoma and axillary nodal
degrees of dilatation and ductal epithelial hyper- metastases. Annals of Surgical Oncology, 17(Suppl 3),
plasia. Microglandular adenosis that typically 338–342.
Papadatos, G., Rangan, A. M., Psarianos, T., Ung, O.,
shows haphazard, diffuse, infiltrative pattern Taylor, R., & Boyages, J. (2001). Probability of axil-
with tubules lacking peripheral myoepithelial lary node involvement in patients with tubular carci-
cells shows more rounded and regular tubules noma of the breast. British Journal of Surgery, 88,
that often contain colloid-like secretory material. 860–864.
Rakha, E. A., Lee, A. H., Evans, A. J., Menon, S.,
Microglandular adenosis also lacks desmoplastic Assad, N. Y., Hodi, Z., Macmillan, D.,
stroma characteristic of tubular carcinoma. Blamey, R. W., & Ellis, I. O. (2010). Tubular carcinoma
of the breast: Further evidence to support its excellent
prognosis. Journal of Clinical Oncology, 28, 99–104.
Sullivan, T., Raad, R. A., Goldberg, S., Assaad, S. I.,
References and Further Reading Gadd, M., Smith, B. L., Powell, S. N., Taghian, A. G.
(2005). Tubular carcinoma of the
Anderson, W. F., Chu, K. C., Chang, S., Sherman, M. E. breast: A retrospective analysis and review of the
(2004). Comparison of age-specific incidence rate literature. Breast Cancer Research and Treatment, 93,
patterns for different histopathologic types of breast 199–205.

T
U
Usual Ductal
Hyperplasia (UDH)
Anna Sapino1,2, Davide Balmativola1, Maria
Giulia Disanto1 and Caterina Marchiò1,2,3
1
Unit of Pathology, Candiolo Cancer Institute
FPO IRCCS, Candiolo, Italy
2
Department of Medical Sciences, University of
Turin, Turin, Italy
3
Institut Curie, Paris, France
Synonyms
Epithelial ductal hyperplasia; Epitheliosis; Florid
ductal hyperplasia; Hyperplasia of usual type;
Intraductal hyperplasia; Papillomatosis
Definition
Benign proliferative lesion within terminal ductal
lobular units that typically shows lumen filled by
cells arranged in a streaming-like fashion and
peripheral slit-like spaces. Rarely usual ductal
hyperplasia (UDH) may show an infiltrative pat-
tern of growth.
Clinical Features
Impalpable lesion. No specific clinical features are
described being a microscopic finding.
© Springer Nature Switzerland AG 2020
A. Sapino, J. Kulka (eds.), Breast Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-319-62539-3
• Incidence
UDH is a common finding in fibrocystic
changes of the breast and may be seen in
papillomas.
• Age
All ages may be affected. Infiltrative
epitheliosis is more frequent in postmeno-
pausal age (range 54–80 years).
• Sex
It usually occurs in female breast, but it can be
rarely observed in male breast.
• Site
No specific site is identified; this lesion
can occur anywhere within the breast
parenchyma.
• Imaging
Specific radiological patterns are not described
for UDH. Infiltrative epitheliosis may rarely
mimic invasive tumor at mammography.
• Treatment
UDH does not require treatment. Infiltrative
epitheliosis if discovered on preoperative core
biopsy specimens should be excised to exclude
an invasive carcinoma.
• Outcome
Relative risk of breast cancer for UDH is low
(1.5- to 2-fold).
Macroscopy
UDH is discovered at microscopy, the gross fea-
ture is not specific.
390
Microscopy
UDH may affect multiple terminal ductal structures,
which appear irregularly distended by a heteroge-
neous cell population that occupies the lumen. Cells
are arranged in a streaming-like fashion and form
secondary abortive lumen with nuclei parallel to
lumen long axis and slit-like spaces or cleft at the
periphery (Fig. 1, H&E). Cells have indistinct
border and different shape, nuclei are mainly oval
and normochromatic and may present pale
intranuclear inclusions; nucleoli are small or indis-
tinct. Cells lining peripheral clefts may show apical
snouts (Fig. 2, H&E). Foci of infiltrative epitheliosis
are generally small and discovered within complex
sclerosing lesions, papillomas and usual epitheliosis
is frequently present all around.
Eusebi and Millis (2010) described the histologic
features of infiltrative epitheliosis, which is similar
to that described in complex sclerosing lesions
(▶ Complex Sclerosing Lesion): (1) bulk of the
lesion composed of florid UDH, with frequent
focal squamoid appearance; (2) scleroelastotic
Usual Ductal Hyperplasia (UDH), Fig. 1 Duct
distended by UDH (H&E)
Usual Ductal Hyperplasia (UDH)
stromal changes seen throughout the lesion, adja-
cent to epithelial foci, rather than confined to a
central scleroelastotic nidus as in radial scars
(RS) (▶ Radial Scar), and (3) frequent presence of
a desmoplastic stromal reaction and keloid-like
fibrous bands (Fig. 3, H&E). The involved ducts
often have jagged or irregular edges and
the proliferating epithelium often appears to “flow-
out” into adjacent stroma (Eberle et al. 2016).
Immunophenotype
UDH shows a heterogeneous ER and PR
staining limited to about 10–15% of cells, with
scattered positivity in few contiguous
areas. HER2 is negative. Ki67 positive cells
are rare. High molecular weight cytokeratins
(34betaE12, CK14, CK5/6) are expressed in a
mosaic-like fashion (Otterbach et al. 2000;
Martinez et al. 2016) (Fig. 4, CK14). Alpha-
smooth muscle actin and p63 and p40
stain myoepithelial cells at the periphery of
the lesion. Infiltrating epitheliosis may show rare
or no p63/p40-positive myoepithelial cells and ER
may be completely absent (Eberle et al. 2016)
(Fig. 5a, ER) or both ER and p63/p40 may be
heterogeneously expressed (Fig. 5b, p63).
Molecular Features
Activating PIK3CA mutations have been
documented in UDH (Ang et al. 2014).
PIK3CA hotspot mutations, and/or PIK3R1
somatic mutations, have been found in all
infiltrating epitheliosis (Eberle et al. 2016).
Differential Diagnosis
UDH should be differentiated from atypical duc-
tal hyperplasia (ADH) (▶ Atypical Ductal
Hyperplasia). ADH have features that may over-
lap with those of low-grade ductal carcinoma in
situ (▶ Ductal Carcinoma In Situ): homogenous
cell population that produces cribriform spaces,
shows homogeneous expression of ER, and is
negative for basal cell markers. Loss of
Usual Ductal Hyperplasia (UDH) 391

Usual Ductal
Hyperplasia (UDH),
Fig. 2 UDH showing
typical peripheral slit-like
spaces lined by luminal
cells with occasional apical
snouts. (High
magnification, H&E)

Usual Ductal
Hyperplasia (UDH),
Fig. 3 Florid UDH and
infiltrating epitheliosis
within keloid like stroma.
(H&E)

Usual Ductal
Hyperplasia (UDH),
Fig. 4 Mosaic like CK14
immunostaining of cells
in UDH

U
392
Usual Ductal Hyperplasia (UDH), Fig. 5 (a) ER immunostaining is almost negative in a field of infiltrating UDH.
(b) p63 highlights myoepithelial cells
heterozygosity on chromosomes 16q and 17p is
reported in ADH at high frequency and is rare in
epitheliosis.
UDH involving papilloma (▶ Intraductal Pap-
illoma) should be differentiated from solid papil-
lary ductal in situ carcinoma (▶ Solid Papillary
Carcinoma) (Rabban et al. 2006). Basal
cytokeratin 5/6 and 14, expressed in a mosaic-
like fashion in UDH, are negative in the luminal
neoplastic proliferation of solid papillary ductal in
situ carcinoma.
The overall appearance of infiltrating epitheliosis
may simulate invasive carcinoma (▶ Invasive
Carcinoma NST), in particular ▶ low grade
adenosquamous carcinoma both morphologically
and immunophenotypically.
References and Further Reading
Ang, D. C., Warrick, A. L., Shilling, A., Beadling, C.,
Corless, C. L., & Troxell, M. L. (2014). Frequent
This encyclopedia includes no entries for V, W, X, Y and Z.
Usual Ductal Hyperplasia (UDH)
phosphatidylinositol-3-kinase mutations in prolifera-
tive breast lesions. Modern Pathology, 27, 740–750.
Eberle, C. A., Piscuoglio, S., Rakha, E. A., Ng, C. K.,
Geyer, F. C., Edelweiss, M., Sakr, R. A., Weigelt, B.,
Reis-Filho, J. S., & Ellis, I. O. (2016). Infiltrating
epitheliosis of the breast: Characterization of histolog-
ical features, immunophenotype and genomic profile.
Histopathology, 68, 1030–1039.
Eusebi, V., & Millis, R. R. (2010). Epitheliosis, infiltrating
epitheliosis, and radial scar. Seminar in Diagnotic
Pathology, 27, 5–12.
Martinez, A. P., Cohen, C., Hanley, K. Z., & Li, X. B. (2016).
Estrogen receptor and cytokeratin 5 are reliable markers to
separate usual ductal hyperplasia from atypical ductal
hyperplasia and low-grade ductal carcinoma in situ.
Archive of Pathology and Laboratory Medicine, 140,
686–689.
Otterbach, F., Bankfalvi, A., Bergner, S., Decker, T.,
Krech, R., & Boecker, W. (2000). Cytokeratin 5/6
immunohistochemistry assists the differential diagno-
sis of atypical proliferations of the breast. Histopathol-
ogy, 37, 232–240.
Rabban, J. T., Koerner, F. C., & Lerwill, M. F. (2006). Solid
papillary ductal carcinoma in situ versus usual ductal
hyperplasia in the breast: A potentially difficult distinc-
tion resolved by cytokeratin 5/6. Human Pathology, 37,
787–793.