Buku Biopsi Interpretation

BIOPSY INTERPRETATION SERIES
BIOPSY INTERPRETATION OF
THE BREAST
2nd Edition
Series Editor: Jonathan I. Epstein, M.D.
Biopsy Interpretation of the Gastrointestinal Tract Mucosa: Neoplastic,

2/e (Vol. 2)
Elizabeth A. Montgomery and Lysandra Voltaggio, 2012
Biopsy Interpretation of the Upper Aerodigestive Tract and Ear, 2/e
Edward B. Stelow and Stacey E. Mills, 2012
Biopsy Interpretation of the Breast, 2/e
Stuart J. Schnitt and Laura C. Collins, 2013
Biopsy Interpretation of the Lung
Saul Suster and Cesar A. Moran, 2013
Biopsy Interpretation of the Gastrointestinal Tract Mucosa:
Non-Neoplastic, 2/e (Vol. 1)
Elizabeth A. Montgomery and Lysandra Voltaggio, 2011
Biopsy Interpretation of the Central Nervous System
Matthew J. Schniederjan, Daniel J. Brat, 2011
Biopsy Interpretation of the Bladder, 2/e
Jonathan I. Epstein, Mahul B. Amin, and Victor E. Reuter, 2010
Biopsy Interpretation of Soft Tissue Tumors
Cyril Fisher, Elizabeth A. Montgomery, and Khin Thway, 2010
Biopsy Interpretation of the Thyroid
Scott L. Boerner and Sylvia L. Asa, 2009
Biopsy Interpretation of the Skin
A. Neil Crowson, Cynthia M. Magro, and Martin C. Mihm, 2009
Biopsy Interpretation: The Frozen Section
Jerome B. Taxy, Aliya N. Husain, and Anthony G. Montag, 2009
Biopsy Interpretation of the Uterine Cervix and Corpus
Anais Malpica, Michael T. Deavers and Elizabeth D. Euscher, 2009
Biopsy Interpretation of the Liver, 2/e
Stephen A. Geller and Lydia M. Petrovic, 2009
Biopsy Interpretation of the Prostate, 4/e
Jonathan I. Epstein and George Netto, 2007
Biopsy Interpretation
of the BREAST
2nd Edition
Stuart J. Schnitt, MD
Professor of Pathology,
Harvard Medical School,
Boston, Massachusetts
and
Director, Division of Anatomic Pathology,
Beth Israel Deaconess Medical Center,
Laura C. Collins, MD
Associate Professor of Pathology,
Harvard Medical School,
and
Associate Director,
Division of Anatomic Pathology,
Beth Israel Deaconess Medical Center,
Senior Executive Editor: Jonathan W. Pine, Jr.
Product Director: Julia Seto
Vendor Manager: Alicia Jackson
Senior Manufacturing Manager: Benjamin Rivera
Creative Director: Doug Smock
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Library of Congress Cataloging-in-Publication Data
Schnitt, Stuart J.
Biopsy interpretation of the breast / Stuart J. Schnitt,
Laura C. Collins.—2nd ed.
p. cm.—(Biopsy interpretation series)
ISBN 978-1-4511-1301-3
1. Breast—Biopsy. 2. Breast—Diseases—Cytodiagnosis.
3. Breast—Cancer—Cytodiagnosis. I. Collins, Laura C. II. Title.
RG493.5.B56S34 2012
618.190758—dc23
2012028718
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10 9 8 7 6 5 4 3 2 1
Preface to the First Edition
In recent years, the tools of molecular biology have provided new insights
into the genetic alterations and molecular pathways involved in breast
tumorigenesis as well as new information regarding breast cancer prog-
nostic and predictive factors and classification. While these advances will
likely have a major impact on the practice of breast pathology in the near
future, careful examination of routine histologic sections, supplemented
by the judicious use of immunostains, remains at this time the cornerstone
for the diagnosis of breast lesions.
There are currently several comprehensive textbooks of breast pathol-
ogy available and this book is not intended to be a substitute for them.
Rather, the purpose of this book is to serve as a concise, practical bench-
side guide to the diagnostic surgical pathology of breast diseases.
Wherever feasible, lesions are grouped together according to their
histologic patterns in order to simulate the manner in which pathologists
encounter them as they examine slides on a daily basis. It is our belief that
grouping lesions in this manner facilitates the discussion and illustration
of key diagnostic and differential diagnostic points helpful in distinguish-
ing among lesions with similar patterns. Thus, unlike most traditional text-
books of breast pathology, the approach taken here is based upon pattern
recognition and the emphasis is on differential diagnosis.
We recognize that for some breast lesions there are no universally
agreed upon diagnostic criteria. In such instances, we have attempted to
highlight the areas of uncertainty but also present the approach to these
lesions that we use in our own practice.
The clinical significance and impact on patient management of the
various diagnoses are discussed and key clinical and management issues
are highlighted. In addition, problems and pitfalls that are unique to core
needle biopsy specimens are emphasized, where appropriate.
Although the genetics and molecular biology of breast lesions are not
discussed in detail, some recent genetic and molecular observations that
have already had a direct impact on routine breast pathology practice and
on our understanding of breast tumorigenesis are discussed.
The more than 550 high-quality color photomicrographs in this book
are supplemented by over 300 additional images available electronically.
In addition, almost 60 tables are used to highlight key diagnostic features
and important points in differential diagnosis. The reference list in each
chapter is not meant to be exhaustive; citations are limited to selected
references for each lesion under consideration.
We hope that practicing pathologists and pathologists-in-training
will find Biopsy Interpretation of the Breast to be a valuable resource as
they examine breast biopsies in the course of daily sign-out.
v
Preface to the Second Edition
There have been important advances in our understanding of the molecu-

lar biology and genetics of breast cancer and other breast lesions since
the publication of the first edition of this book. However, histopathology
remains the basis for the diagnosis of all breast lesions. Thus, the major
goal of this book is unchanged from that of the first edition: to serve as a
concise and practical bench-side guide to breast pathology for practicing
pathologists and pathology trainees.
The text in this edition builds upon the foundation of the first edition
and has been updated to present the most current views on terminology
and diagnostic criteria. In particular, the most recent (fourth edition)
World Health Organization nomenclature and diagnostic criteria are
emphasized throughout the book and areas of continued controversy and
unresolved issues are highlighted. The uses and limitations of adjunctive
immunostains to solve diagnostic problems are discussed where appro-
priate. Although advances in molecular biology and genetics will clearly
transform the practice of breast pathology, only those that we consider the
most clinically relevant at this time are discussed.
This edition features over 100 new high-quality color photomicro-
graphs. As in the first edition, almost 60 tables highlight key diagnostic
features and differential diagnostic considerations.
We hope that the second edition of Biopsy Interpretation of the
Breast will serve as a practical and up-to-date resource for practicing
pathologists and pathology trainees during their examination of breast
specimens.
vii
Acknowledgments
We are fortunate to have trained and worked at an institution that has pro-
vided us with extraordinary opportunities as well as the chance to benefit
from the wisdom and guidance of a number of exceptional pathologists
who have been our teachers, colleagues, and mentors. Drs. Donald A.
Antonioli, Richard B. Cohen, James L. Connolly, Harvey Goldman, and
Seymour Rosen in particular have had a profound influence in shaping
our careers and our approach to the practice of pathology. Our current
department chair, Dr. Jeffrey Saffitz, has provided us with unconditional
support and encouragement. We are also grateful for the opportunity to
work with excellent pathology residents and fellows who ask thought-
provoking questions for which we do not always have answers.
We would like to acknowledge and thank the pathologists and clini-
cians who have sent us interesting and challenging cases and the many
patients whose materials we have had the opportunity to review. Without
them, this book would not have been possible.
ix
Contents
Preface to the First Edition...........................................................................v

Preface to the Second Edition.................................................................... vii
Acknowledgments........................................................................................ix
1 Normal Anatomy and Histology�� 1

2 Reactive, Inflammatory, and Nonproliferative Lesions.................... 25
3 Intraductal Proliferative Lesions: Usual Ductal Hyperplasia,
Atypical Ductal Hyperplasia, and Ductal Carcinoma In Situ.............. 58
4 Columnar Cell Lesions and Flat Epithelial Atypia............................ 107
5 Lobular Carcinoma In Situ and Atypical Lobular Hyperplasia.......... 136
6 Fibroepithelial Lesions..................................................................... 171
7 Adenosis and Sclerosing Lesions.................................................... 202
8 Papillary Lesions.............................................................................. 228
9 Microinvasive Carcinoma................................................................ 267
10 Invasive Breast Cancer.................................................................... 282
11 Spindle Cell Lesions......................................................................... 363
12 Vascular Lesions.............................................................................. 387
13 Other Mesenchymal Lesions........................................................... 408
14 Miscellaneous Rare Lesions............................................................. 419
15 Nipple Disorders.............................................................................. 429
16 Male Breast Lesions......................................................................... 451
17 Breast Lesions in Children and Adolescents................................... 462
18 Axillary Lymph Nodes...................................................................... 471
19 Treatment Effects........................................................................... 493
20 Specimen Processing, Evaluation, and Reporting......................... 507
Index......................................................................................................... 527
xi
1
Normal Anatomy
and Histology
Gross Anatomy
The breast lies on the anterior chest wall over the pectoralis major muscle
and typically extends from the second to the sixth rib in the vertical axis
and from the sternal edge to the mid-axillary line in the horizontal axis.
Breast tissue also projects into the axilla as the tail of Spence. The breast
extends laterally over the serratus anterior muscle and inferiorly over the
external oblique muscle and the superior rectus sheath. Bundles of dense
fibrous connective tissue, the suspensory ligaments of Cooper, extend
from the skin to the pectoral fascia and provide support to the breast. The
only boundary of the breast that is anatomically well-defined is the deep
surface where it abuts the pectoral fascia. However, despite this macro-
scopic demarcation, microscopic foci of glandular tissue may extend into
and even through the pectoral fascia (Fig. 1.1, e-Fig. 1.1). The clinical
importance of this observation is that even a total mastectomy does not
result in the removal of all glandular breast tissue.
The principal arterial supply to the breast is provided by the inter-
nal mammary and lateral thoracic arteries. Branches of the thoraco
acromial, intercostal, subscapular, and thoracodorsal arteries make
minor contributions to the mammary blood supply.1 Venous drainage of
the breast, as in other locations, shows considerable individual varia-
tion but largely follows the arterial system. The most important drainage
basin for lymphatic flow from the breast is the axilla, and the axillary
lymph nodes receive >90% of the lymph drained. A small portion of
lymph drains via the internal thoracic and posterior intercostal lymph
atics into the internal mammary and posterior intercostal lymph nodes,
respectively.
1
2 –––––– BIOPSY INTERPRETATION OF THE BREAST
FIGURE 1.1 Chest wall biopsy from a patient who had previously undergone mastectomy.
Breast lobules are present in association with pectoral muscle fibers.
Histology
The adult female breast consists of a series of branching ducts and duct-
ules that terminate in the acini (also called terminal ductules). The acini
are grouped together to form the lobules. The arrangement of these
structures has been likened to a flowering tree (Fig. 1.2, e-Fig. 1.2).2 The
lobules represent the flowers, draining into ductules and ducts (twigs and
branches) which, in turn, drain into the collecting ducts (trunk) that open
onto the surface of the nipple. At the nipple, the ducts are expanded to
form lactiferous sinuses. The sinuses terminate in cone-shaped ampullae
just below the surface of the nipple.
The mammary ducts and lobules are embedded within a stroma
composed of varying amounts of fibrous tissue and adipose tissue. The
stroma comprises the major portion of the non-lactating adult breast, and
the relative proportions of fibrous tissue and adipose tissue vary with age
and among individuals (Fig. 1.3, e-Fig. 1.3).
The ductal–lobular system of the breast is arranged in the form
of segments or lobes. Although these segments can be readily appreci-
ated by injecting the ductal system with dyes or radiologic contrast agents
(Fig. 1.4), they are anatomically poorly defined, and no obvious boundaries
can be appreciated between these segments during surgery, upon gross
inspection of mastectomy specimens, or on histologic examination. In
addition, the segments show considerable individual variation with regard
to their distribution,3 and the ramifications of individual segments may
overlap. The segmental nature of some neoplastic processes in the breast,
Normal Anatomy and Histology ——— 3
FIGURE 1.2 Microanatomy of normal adult female breast tissue showing extralobular
ducts (ELD), terminal ducts (TD), and lobules (L), the latter composed of groups of small
glandular structures, the acini.
particularly ductal carcinoma in situ, is now widely appreciated. This rec-

ognition, in conjunction with observations in developmental anatomy and
morphology, has led to the development of the “sick lobe” hypothesis of
breast cancer.4,5 This theory postulates that early breast carcinoma (ductal
carcinoma in situ) is a lobar disease, often isolated to a single ductal system
(or lobe). Thus, surgical resection of the involved segment is an important
therapeutic goal. Unfortunately, because it is not possible for the surgeon
to define the boundaries of the involved segment intraoperatively, perform-
ing a “segmentectomy” to remove the entirety of a diseased segment is at
this time more of a theoretical concept than a practically attainable goal.
The number of segments in the breast and their relationship to each
other has long been a matter of debate. Most textbooks indicate that there
are 15 to 20 ductal orifices on the nipple’s surface and suggest that this
corresponds to the number of ductal systems, segments, or lobes in the
breast.6-9 However, the relationship between the number of nipple duct
orifices, nipple ducts, and breast segments remains unclear. One study
indicated that there are more orifices on the surface of the nipple than
there are nipple ducts or breast segments. The proposed explanations for
this are: 1) that some orifices on the nipple surface represent openings of
sebaceous glands or other non-ductal structures that do not contribute
to the ductal–lobular anatomy of the breast and 2) that some lactiferous
ducts bifurcate immediately prior to entering the nipple.6 In contrast, a
more recent study that included three-dimensional reconstruction found
that the number of orifices on the surface of the nipple is fewer than the
B
FIGURE 1.3 The stroma is the predominant component of the nonlactating breast and
consists of varying amounts of collagen and adipose tissue. A: Low-power view of breast
with dense, fibrotic stroma. B: Low-power view of breast with predominantly fatty stroma.
number of nipple ducts because multiple ducts may join to share a com-
mon orifice.10 Further, a number of mammary duct injection studies have
suggested that there are far fewer (only between 5 and 10) discrete breast
ductal systems or segments than there are ducts in the nipple or orifices
on the nipple surface.
FIGURE 1.4 Ductogram (galactogram), performed by injecting contrast material into an

orifice of a lactiferous duct at the nipple, which demonstrates the complex ramifications
of a single mammary ductal system (also known as a segment or lobe).
The issue of anastomoses between ductal systems is also unresolved.

One study indicated that while ductal systems may lie in close proximity
to one another and even intertwine within a particular quadrant, they do
not interconnect.6 However, anastomoses between ductal systems have
been reported by others.11
The cellular lining throughout the ductal–lobular system is bilayered.
It consists of an inner (luminal) epithelial cell layer and an outer (basal)
myoepithelial cell layer. The importance of this double cell layer cannot be
overemphasized, because it is one of the main guides used to distinguish
benign from malignant lesions.12 The luminal epithelial cells of the resting
breast ducts and lobules are cuboidal to columnar in shape and typically have
pale eosinophilic cytoplasm and relatively uniform oval nuclei. These epithe-
lial cells express a variety of low-molecular-weight cytokeratins, including
cytokeratins 7, 8, 18, and 19. The outer or myoepithelial cell layer, although
always present, is variably distinctive (Fig. 1.5, e-Fig. 1.4). Myoepithelial
cells range in appearance from barely discernible, flattened cells with com-
pressed nuclei to prominent epithelioid cells with abundant clear cytoplasm
(Fig. 1.6, e-Fig. 1.5). In some cases, the myoepithelial cells have a myoid
appearance featuring a spindle cell shape and dense, eosinophilic cytoplasm,
B
FIGURE 1.5 The mammary ductal–lobular system is lined by a dual-cell population, an
inner epithelial cell layer, and an outer layer of myoepithelial cells. A: High-power view
of a lobule. The myoepithelial cells surrounding the acinar epithelial cells are variably
conspicuous. B: High-power view of an extralobular duct showing distinct epithelial and
myoepithelial cell layers.
FIGURE 1.6 Myoepithelial cells can vary in their histologic appearance. Myoepithelial cells
in this lobule show prominent cytoplasmic clearing.
reminiscent of smooth muscle cells (Fig. 1.7, e-Fig. 1.6). Even when incon-
spicuous on hematoxylin and eosin–stained sections, myoepithelial cells can
be readily demonstrated using immunohistochemical stains for a variety of
markers including S-100 protein, actin, calponin, smooth muscle myosin
heavy chain, p63, and CD10 (Fig. 1.8). However, these markers vary in
both sensitivity and specificity for myoepithelium. Myoepithelial cells also
FIGURE 1.7 In this lobule, the myoepithelial cells show myoid features.
B
FIGURE 1.8 Extralobular duct (A) and lobule (B) immunostained for p63. The myoepithelial
cells show strong nuclear reactivity, whereas the epithelial cell nuclei are negative.
express high-molecular-weight cytokeratins 5/6, 14, and 17 (Fig. 1.9), but

the expression of cytokeratin 14 is restricted to the myoepithelial cells of the
large ducts and terminal ducts; expression is not seen in myoepithelial cells
of the intralobular ductules and acini.13
A third cell type dispersed irregularly throughout the ductal–lobular
system expresses high-molecular-weight cytokeratins 5 and 14 in the
FIGURE 1.9 Immunostain for the basal cytokeratin CK5/6 highlighting the myoepithelial
cells around ductules and acini.
absence of expression of markers of differentiated luminal epithelial cells

(such as low-molecular-weight cytokeratins) or myoepithelial cells (such
as smooth muscle actin). These cells have been postulated to represent
progenitor cells capable of differentiating into both luminal epithelial cells
and myoepithelial cells.14 The relationship of these putative “progenitor”
cells to mammary stem cells is at this time an unresolved issue.14,15
However, it is now clear that cells with the characteristic features of stem
cells (i.e., self-renewal and the ability to differentiate down different cell
lineages to form all of the cell types found in the mature tissue) do exist
in the breast. Mammary stem cells appear to be important in both breast
development16 and mammary carcinogenesis.15,17,18 Immunophenotypic
features that have been associated with the mammary stem cell popula-
tion include lack of expression of estrogen receptor (ER) and progester-
one receptor (PR), high expression of CD44, low or absent expression of
CD24, and expression of aldehyde dehydrogenase (ALDH1),18,19 although
the most accurate combination of markers to reliably identify mammary
stem cells is unresolved at this time.
A basal lamina consisting of type IV collagen and laminin surrounds
the mammary ducts, ductules, and acini.20,21 This basal lamina is present
outside of the myoepithelial cell layer and serves to demarcate the breast
ductal–lobular system from the surrounding stroma (Fig. 1.10). Beyond
the basal lamina, the extralobular ducts exhibit a zone of fibroblasts and
capillaries. Elastic tissue is normally present in variable amounts around
ducts and is generally more prominent in older than in younger women.
Elastic fibers are not typically seen around the terminal ducts or acini.
FIGURE 1.10 Immunostain for type IV collagen highlights the basal lamina around the
acini of a lobule.
The lobule, together with its terminal duct, has been called the
terminal duct lobular unit (TDLU). This represents the structural and
functional unit of the breast. During lactation, epithelial cells in both the
terminal duct and lobule undergo secretory changes. Thus, the terminal
ducts are responsible for both secretion and transport of the secretions
to the extralobular portion of the ductal system. Subgross studies have
shown that most lesions originally termed ductal (e.g., cysts, ductal epi-
thelial hyperplasia, and ductal carcinoma in situ) actually arise from the
TDLU, which “unfolds” with coalescence of the acini to produce larger
structures resembling ducts. The majority of pathologic changes in the
breast, including in situ and invasive carcinomas, are generally considered
to arise from the TDLU.2,22 Indeed, the only common lesion thought to
arise from the large or medium-sized duct rather than from the TDLU is
the solitary intraductal papilloma.
The normal lobule consists of a variable number of blind-ending
terminal ductules, also called acini, each with its typical double cell
layer. The lobular acini are invested by a loose, fibrovascular intralobular
stroma, with varying numbers of lymphocytes, plasma cells, macrophages,
and mast cells. This specialized intralobular stroma is sharply demarcated
from the surrounding denser, more highly collagenized, paucicellular
interlobular stroma and stromal adipose tissue (Fig. 1.11, e-Fig. 1.7).
One feature of note that is sometimes encountered in the interlobular
stroma is the presence of multinucleated giant cells.23 Their significance is
unknown, and although they may present a disturbing appearance, they
should not be mistaken for malignant cells (Fig. 1.12, e-Fig. 1.8).
B
FIGURE 1.11 Intralobular and interlobular stroma. A: Low-power view of several lobules
that are invested by loose, intralobular stroma. The interlobular stroma is composed
primarily of dense collagen with admixed adipose tissue. B: Higher power view contrasts
loose intralobular stroma with more collagenized interlobular stroma.
The size of mammary lobules and number of acini per lobule are
extremely variable. Russo et al.24-26 have described four lobule types. Type 1
lobules are the most rudimentary and are most prevalent in prepubertal
and nulliparous women. These lobules are comprised primarily of ducts
with sprouting alveolar buds. Type 1 lobules gradually evolve to more
B
FIGURE 1.12 Multinucleated stromal giant cells. A: Low-power view showing multinucleated
giant cells scattered in the stroma. B: High-power view illustrates cytologic detail. These cells
have a mesenchymal phenotype. Despite their worrisome histologic appearance, they have
no known clinical significance.
mature structures (type 2 and type 3 lobules) through the development of

additional alveolar buds. The number of alveolar buds per lobule increases
from approximately 11 in type 1 lobules to 47 and 80 in type 2 and 3 lobules,
respectively. In the parous, premenopausal woman, type 3 lobules are most
prevalent. Type 4 lobules are those seen during pregnancy and lactation.
Of interest, Russo et al.26 have reported that type 1 lobules predominate in

the breasts of women with breast cancer, regardless of pregnancy history.
They have also provided experimental evidence suggesting that type 1 and
2 lobules are more susceptible to malignant transformation than are type
3 lobules upon exposure to chemical carcinogens.27 However, more recent
data indicate that women with predominantly type 1 lobules or lobules
that have undergone involution have a reduced risk of subsequent breast
cancer compared with women with predominantly type 3 lobules or those
that have not undergone involution.28,29 It should be noted though that
type 1, 2, and 3 lobules commonly coexist in the same breast and that
the value of distinguishing among them in clinical practice remains to
be defined.
The lobules exhibit morphologic changes during the menstrual cycle,
and these are seen in both the epithelial and stromal components. These
changes are summarized in Table 1.1.30 Although the changes that occur
during the menstrual cycle are variable among lobules in the same breast,
even among immediately adjacent lobules, a dominant morphologic pat-
tern is typically present in each phase. However, these menstrual cycle–
related changes are subtle when compared with the dramatic alterations
seen during pregnancy and lactation and when compared with the men-
strual cycle–related changes seen in the endometrium.
Occasionally, the TDLU epithelial cells show prominent clear cell
change in the cytoplasm. This may be seen in both premenopausal and
postmenopausal women and appears to be unrelated to pregnancy or
exogenous hormone use (Fig. 1.13, e-Fig. 1.9).31
ERα expression can be demonstrated in the nuclei of both ductal and
lobular epithelial cells, with a higher proportion in lobules than in ducts.
However, even in the lobules, only a small proportion of the cells show
ERα immunoreactivity. Most often, ERα-positive cells in the lobules are
distributed singly, admixed with and surrounded by ERα-negative cells
(Fig. 1.14, e-Fig. 1.10).32 Furthermore, there is considerable heterogene-
ity in staining for ERα among lobules in the same breast. Of interest, in
breast tissue from premenopausal women, there is generally an inverse
relationship between expression of ERα and markers of cell prolifera-
tion. Specifically, most ERα-positive cells do not show expression of the
proliferation-related antigen Ki67, and Ki67-positive cells are typically
ERα-negative. The proportion of ERα-positive cells gradually increases
with age, but remains relatively stable after menopause. The incidence of
lobules showing contiguous patches of ERα-positive cells also increases
with age and with involutional changes.32 In addition, the proportion of
ERα-positive proliferating cells increases with age.33 In premenopausal
women, ERα expression varies with the phase of the menstrual cycle and
is higher in the follicular phase than in the luteal phase.34 Myoepithelial
cells do not show ERα immunoreactivity.
Recent studies have indicated that a second form of ER, ERβ, is also
expressed in normal breast tissue. Expression of ERβ has been observed
TABLE 1.1 Histologic Changes in Lobules during the Menstrual Cycle
Menstrual
Cycle Phase Epithelium Acinar Lumens Intralobular Stroma
Early Cells: Single cell type evident (small, polygonal cells with pale eosinophilic Largely closed and Dense, cellular, with
follicular cytoplasm); myoepithelial cells inconspicuous inapparent plump fibroblasts
Orientation: Poor; Secretion: None; Mitoses/apoptosis: Rare
Late follicular Cells: Three cell types, including luminal basophilic cells, intermediate pale Well-defined Less cellular and
cells (as seen in early follicular phase), and myoepithelial cells with clear more collagenized
cytoplasm than in early luteal
Orientation: Radial around lumen; Secretion: None; Mitoses/apoptosis: Rare phase
Early luteal Cells: Three cell types, including luminal basophilic cells with minimal apical Open and enlarged Loose
snouting, intermediate pale cells, and myoepithelial cells with prominent compared with
cytoplasmic vacuolization and ballooning follicular phase,
Orientation: Radial around lumen; Secretion: Slight; Mitoses/apoptosis: Rare with slight
secretion
Late luteal Cells: Three cell types, including luminal basophilic cells with prominent Open, with secretion Loose, edematous,
apical snouting, intermediate pale cells, and myoepithelial cells with congested blood
prominent cytoplasmic vacuolization vessels
Orientation: Radial around lumen; Secretion: Active apocrine secretion from
luminal cells
Mitoses/apoptosis: Frequent (peak of mitotic activity)
Menstrual Cells: Two cell types, including luminal basophilic cells with scant cytoplasm Distended with Dense, cellular
and less apical snouting than in late luteal phase and myoepithelial cells secretion
with extensive cytoplasmic vacuolization
Orientation: Radial around lumen; Secretion: Resorbing
Mitoses/apoptosis: Rare
Adapted from McCarty KS, Nath M. Breast. In: Sternberg SS, ed. Histology for Pathologists. Philadelphia, PA: Lippincott-Raven; 1997;71-82.
FIGURE 1.13 Lobule with clear cell change in epithelial cells.
not only in epithelial cells of ducts and lobules but also in myoepithelial
cells, endothelial cells, and stromal cells.35,36 The expression of this form
of ER does not seem to vary with the phase of the menstrual cycle. It has
been speculated that the relative levels of ERβ and ERα may be important
in determining the risk of breast cancer development and that higher
FIGURE 1.14 Immunostain for estrogen receptor alpha in normal lobule. A minority of
epithelial cells show nuclear staining.
levels of ERβ relative to ERα are protective against neoplastic progression

in the breast.35 However, additional studies are needed to more clearly
elucidate the role of ERβ in normal breast physiology and in breast cancer
pathogenesis.
The expression of PR has not been as extensively studied in normal
breast tissue as has ER. PR, like ERα, is expressed in the nuclei of duc-
tal and lobular epithelium. However, in contrast to ERα expression, PR
expression does not seem to vary with the phase of the menstrual cycle.34
The nipple-areolar complex is a circular area of skin that exhibits
increased pigmentation and contains numerous sensory nerve endings.
The nipple is placed centrally and is elevated above the surrounding
areola. The tip of the nipple contains 15 to 20 orifices. However, as dis-
cussed earlier, the number of such openings may not correlate directly
with the number of breast segments. In the non-lactating breast, these
duct openings typically possess keratin plugs. The areola surface exhibits
numerous small, rounded elevations, the tubercles of Montgomery.
Both the nipple and areola are covered by keratinizing, strati-
fied squamous epithelium and this extends for a short distance into the
terminal portions of the lactiferous ducts. The epidermis of the nipple-
areolar complex may contain occasional clear cells that are cytologi-
cally benign and that must not be confused with Paget cells.37,38 Some of
these cells represent clear keratinocytes, whereas others are thought to
be derived from epidermally located mammary ductal epithelium (Toker
cells) (Fig. 1.15).37
FIGURE 1.15 Toker cells in nipple epidermis. These cells should not be mistaken for the
cells of Paget disease.
FIGURE 1.16 Cross section through the nipple. The irregular, pleated, or serrated
contour of the nipple duct is evident.
The proximal ramifications of the mammary ductal system that are

present in the dermis of the nipple typically have a pleated or serrated
contour (Fig. 1.16, e-Fig. 1.11). These ducts are surrounded by a stroma
rich in circular and longitudinal smooth muscle bundles, collagen, and
elastic fibers (Fig. 1.17). Occasionally, lobules may be seen in the nipple.
FIGURE 1.17 High-power view of nipple dermis/stroma demonstrating prominent

bundles of smooth muscle fibers.
FIGURE 1.18 Montgomery areolar tubercle. These tubercles are units composed of a
lactiferous duct and associated sebaceous gland.
Simple mammary ducts are also present throughout the dermis of the
areola, even at its periphery, and these may extend to within <1 mm of the
basal layer of the epidermis.39
Although the nipple-areolar complex lacks pilosebaceous units and
hairs except at the periphery of the areola, the dermis contains numerous
sebaceous glands. Some of these glands open directly onto the surface of
the nipple and areola, whereas others drain into a lactiferous duct or share
a common ostium with a lactiferous duct. The tubercles of Montgomery
represent a unit consisting of a sebaceous apparatus and an associated
lactiferous duct (Fig. 1.18, e-Fig. 1.12). During pregnancy, these tubercles
become increasingly prominent. Apocrine sweat glands may also be seen
in the dermis of the nipple and areola.
Another finding that may occasionally be encountered within the
breast parenchyma is the presence of intramammary lymph nodes. These
lymph nodes may be identified as an incidental finding in breast tissue
removed because of another abnormality or they may be seen as densities
on mammograms.
Pregnancy and Lactation

During pregnancy, there is a dramatic increase in the number of lobules
as well as in the number of acinar units within each lobule secondary to
epithelial cell proliferation and lobuloalveolar differentiation. This lobular
development and expansion occurs at the expense of both the intralobular
and interlobular stroma. By the second and third trimesters, the acinar
units begin to appear monolayered and the myoepithelial cells in the acini
are difficult to discern due to the increase in size and volume of the epi-
thelial cells. The cytoplasm of the epithelial cells becomes vacuolated and
secretion accumulates in the greatly expanded lobules. After parturition,
the lactating breast is characterized by distension of the lobular acini by
abundant secretory material and prominent cytoplasmic vacuolization of
the epithelial cells. Many of the epithelial cells have a bulbous or hobnail
appearance and protrude into the acinar lumina (Fig. 1.19, e-Fig. 1.13).
Myoepithelial cells remain attenuated and inconspicuous. The florid
changes seen in pregnancy and lactation can be alarming to the inex-
perienced observer; areas of infarction, which occasionally occur in the
pregnant breast, may compound the problem.
When lactation ceases, the lobules involute and return to their
normal resting appearance. Involution usually proceeds unevenly and
takes several months. Involuting lobules are irregular in contour and are
frequently infiltrated by lymphocytes and plasma cells. Occasionally, an
isolated lobule showing secretory changes may be seen in the breasts of
women who are not pregnant or who have never been pregnant. Such
pregnancy-like changes can be associated with mammographic micro-
calcifications and on occasion may show cytologic atypia.40 In some
cases, pregnancy-like change merges with areas of cystic hypersecretory
hyperplasia.40
Menopause
During the postmenopausal period, with the reduction of estrogen and
progesterone levels, there is involution and atrophy of the mammary
TDLUs, with reduction in the size and complexity of the acini, and there
is loss of the specialized intralobular stroma.30,41 Ducts may become vari-
ably ectatic. The postmenopausal breast is characterized by a marked
reduction in glandular tissue and collagenous stroma, often with a con-
comitant increase in stromal adipose tissue. The end stage of menopausal
involution is typified by remnants of the TDLUs, typically composed of
ducts with atrophic acini, surrounded by hyalinized connective tissue
or embedded within adipose tissue with little or no surrounding stroma
(Fig. 1.20, e-Fig. 1.14).
Molecular Markers
A number of studies have shown that histologically normal TDLUs can
exhibit an abnormal genotype, characterized by loss of heterozygosity42
or allelic imbalance43,44 at various chromosomal loci, or show altered
gene expression signatures.45 At this time, however, the significance of
these genetic and molecular alterations in histologically normal breast tis-
sue remains to be determined.46-49
B
FIGURE 1.19 Lactating breast tissue. A: The lobules are enlarged and contain numerous
acini. B: High-power view illustrates prominent epithelial cell enlargement, cytoplasmic
vacuolization, and protrusion of cells into the acinar lumen. Some of the cells have a
hobnail appearance. Myoepithelial cells are inconspicuous.
B
FIGURE 1.20 Postmenopausal breast tissue. A: This sample consists primarily of fibrotic
stroma with a few atrophic acini. B: In this specimen, a few residual, atrophic lobular acini
are evident in a fatty stroma.
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2
Reactive, Inflammatory, and
Nonproliferative Lesions
Some reactive, inflammatory, and nonproliferative lesions of the breast

present problems clinically but are treated without resorting to a biopsy.
In others, a biopsy is required to make the correct diagnosis and to
distinguish the process from malignancy. In this chapter, reactive and
inflammatory conditions that are most likely to be encountered in breast
biopsies are discussed first, followed by brief considerations of other
conditions in these categories. Finally, several common nonproliferative
lesions are considered.
Biopsy Site Changes

Changes related to a prior biopsy are the most common reactive lesions
encountered in the breast. The details of the changes observed are related
to a variety of factors including the type of procedure performed (needle
vs. open surgical biopsy) and the time interval between the original pro-
cedure and removal of the subsequent specimen. Post-biopsy changes in
the breast that are similar to those encountered elsewhere include recent
and organizing hemorrhage, fat necrosis, acute and chronic inflamma-
tion, foreign body giant cell reaction, granulation tissue, and scarring
(Fig. 2.1, e-Fig. 2.1).
Reactive spindle cell nodules (RSCNs) similar in appearance to the
postoperative spindle cell nodules reported in the genitourinary tract and
thyroid may also occur in the breast.1 These are most commonly seen
following needle biopsy trauma to lesions with a prominent fibrous stro-
mal component such as papillary lesions and complex sclerosing lesions.
RSCNs are composed of intersecting fascicles of plump spindle cells
with admixed blood vessels, collagen fibers, and a mixed inflammatory
infiltrate including lymphocytes, plasma cells, and macrophages, some of
25
FIGURE 2.1 Biopsy site changes include organizing hemorrhage (A), fat necrosis and
foreign body giant cell reaction (B), and scarring (C).
Reactive, Inflammatory, and Nonproliferative Lesions ——— 27
which are hemosiderin-laden. The spindle cells show mild to moderate

pleomorphism, rare mitotic figures, and an immunophenotype consistent
with myofibroblasts. While distinguishing RSCNs from other spindle cell
lesions of the breast may be challenging, a history of a previous needling
procedure and the presence of other changes associated with biopsy sites
such as hemosiderin and foamy histiocytes favor a diagnosis of RSCN.
Squamous metaplasia may be seen in duct and lobular epithelium in
the vicinity of a prior biopsy site, and in some cases, the metaplastic epitheli-
um completely replaces the native glandular epithelium (Fig. 2.2, e-Fig. 2.2).
B
FIGURE 2.2 Squamous metaplasia of terminal duct lobular unit epithelium in the vicinity
of a biopsy site at low (A) and high (B) power. Most of the glandular epithelial cells have
been replaced by epithelial cells with squamous features.
FIGURE 2.3 Papillary lesion with infarction. The patient had previously undergone a
core-needle biopsy that showed fragments of benign intraductal papilloma. At excision,
the lesion was completely infarcted, precluding further categorization.
Partial or total infarction of lesions, especially papillary lesions

and fibroepithelial lesions, may occur following sampling by fine-needle
aspiration or core-needle biopsy (CNB), and this can confound the inter-
pretation of subsequent excision specimens (Fig. 2.3, e-Fig. 2.3). Total
infarction can preclude the definitive categorization of a lesion as benign,
atypical, or malignant.
There are a number of additional alterations seen following a CNB.
Marking devices are typically placed in the breast following the CNB
procedure so that the location of the biopsy site can be identified on
subsequent radiologic examination. One type is composed of pellets
of a resorbable copolymer of polylactic acid/polyglycolic acid (similar
to Vicryl suture material); within one of the pellets is a stainless steel
marker. The copolymer pellets, which dissolve during tissue processing,
are initially associated with a fibrotic rim, with sparse lymphocytes and
eosinophils, around empty spaces. Later biopsies show a histiocytic and
foreign body–type giant cell reaction around the empty spaces and infiltra-
tion of the spaces by fibrinous material. Another type consists of a plug of
bovine collagen that contains a titanium clip. The collagen plugs appear
as broad bands of eosinophilic, acellular material. There is an accom-
panying inflammatory infiltrate composed of lymphocytes, plasma cells,
e osinophils, and occasionally neutrophils, initially at the periphery of the

plug but later within the plug, admixed with the collagen fibers. Foreign
body–type giant cells are uncommon (Fig. 2.4, e-Fig. 2.4). With time, the
plug is infiltrated by granulation tissue and there is deposition of native
B
FIGURE 2.4 Collagen plug marking device at the site of a prior core-needle biopsy.
A: Note bundles of acellular collagen fibers and inflammatory infiltrate. B: At higher power,
the inflammatory infiltrate can be seen to be composed of primarily mononuclear cells.
Foreign body–type giant cells are conspicuously absent.
FIGURE 2.5 Squamous epithelial-lined cyst at the site of a prior core-needle biopsy.
collagen.2 A third type of marking device is composed of a biodegradable

hydrogel polymer containing a metal marker. After placement in the
breast, the device expands by hydration. Subsequent degradation of the
polymer material results in cystically dilated spaces surrounded by histio-
cytes. On low-power examination, these areas can thereby be mistaken
for dilated ducts and this can create difficulty in identifying the area as a
biopsy site.3
Occasionally, squamous epithelial-lined cysts may be present at the
CNB site (Fig. 2.5, e-Fig. 2.5). These may result from displacement of the
epidermis or epithelium from cutaneous appendages into the biopsy site
or from squamous metaplasia of duct epithelium.4
The CNB procedure (and fine-needle aspiration biopsy procedures)
may also result in lesion disruption and the displacement of epithelium
into the stroma and/or vascular spaces.5-8 The likelihood of finding
epithelial displacement appears to be inversely related to the length of
time between the CNB and subsequent surgical excision. Epithelial dis-
placement into the stroma is particularly common following a CNB of
papillary lesions9 but may also be seen following biopsy of other benign
lesions and ductal carcinoma in situ (DCIS). Epithelial displacement
into axillary lymph nodes may also occur (see Chapter 18).
The finding of displaced epithelial cells in the stroma may result in
the erroneous diagnosis of invasive carcinoma in patients with benign
lesions or DCIS (Figs. 2.6 and 2.7, e-Fig. 2.6) or in the erroneous
B
FIGURE 2.6 Displaced epithelium following core-needle biopsy of ductal carcinoma in
situ (DCIS). A: Low-power view demonstrating DCIS in upper half of field and core-needle
biopsy tract in the center. B: The biopsy tract contains fragments of malignant
epithelial cells.
diagnosis of lymphovascular invasion. In some cases, particularly fol-

lowing biopsy of papillary lesions, the stroma may contain numerous
nests of epithelium that show varying degrees of degenerative changes
and, not infrequently, squamoid features (Fig. 2.8, e-Fig. 2.7). When
epithelial fragments or clusters are confined to the organizing hemor-
rhage, granulation tissue, or scar of the needle biopsy site, a diagnosis of
epithelial displacement should be favored. A diagnosis of invasive carci-
noma should be considered only if epithelial cell nests are present in the
B
FIGURE 2.7 Displaced epithelium following core-needle biopsy of papillary ductal
carcinoma in situ (DCIS). A: The space containing papillary DCIS has been disrupted by the
needling procedure. There is fragmentation of the lesion and associated hemorrhage.
B: Irregular nests of neoplastic epithelium have been displaced into the stroma.
stroma clearly away from the biopsy site and/or have features character-
istic of a recognized type of invasive cancer. This is particularly important
in the absence of a prior diagnosis of invasive carcinoma. Immunostains
for myoepithelial markers are of value in distinguishing between dis-
placed epithelium and invasive carcinoma only if they demonstrate the
B
FIGURE 2.8 Displaced epithelium following core-needle biopsy of a benign intraductal
papilloma. A: Note the papilloma (right) and adjacent biopsy site reaction (left). The
biopsy site contains numerous small nests of epithelial cells. B: At high magnification, the
epithelial cells have enlarged hyperchromatic nuclei and squamoid features. These nests
were confined to the area of the biopsy site. C: Immunostain for cytokeratin highlights
the numerous epithelial cell nests in the biopsy site.
C
FIGURE 2.8 (Continued)
presence of myoepithelial cells around the epithelial nests, a feature indi-

cating a benign lesion. However, in many instances, particularly in cases
of DCIS and in papillary lesions, the epithelial cells alone are displaced
into the stroma; therefore, absence of myoepithelial cells cannot be used
as evidence of an invasive process (Fig. 2.9).
FIGURE 2.9 Immunostain for p63 shows no myoepithelial cells in association with these
displaced epithelial cells (same case as in Fig. 2.8). The lack of myoepithelial cells in this
setting cannot be used as evidence of invasive carcinoma.
FIGURE 2.10 Displaced epithelial cells in vascular spaces. The patient had a prior
core-needle biopsy that showed ductal carcinoma in situ (DCIS). On excision, there was
residual DCIS, but no invasive carcinoma was identified. However, epithelial cells were
seen in a few small vascular spaces in the biopsy site, presumably representing displaced
DCIS cells.
Epithelial displacement into lymphovascular spaces can be even

more problematic (Fig. 2.10). In patients with invasive carcinoma, it may
not be possible to distinguish artifactual displacement of epithelial cells
from bona fide lymphovascular invasion. In the absence of documented
invasive carcinoma, the interpretation of epithelial cells in vascular spaces
as lymphovascular invasion by carcinoma should be made with extreme
caution, particularly if the involved lymphovascular spaces are confined
to the area of the needle biopsy site.
Fat Necrosis
Fat necrosis most commonly occurs following physical injury to the breast
(e.g., surgery, needling procedures, radiation, and trauma), but in approxi-
mately half of the cases, no history of injury can be elicited. The impor-
tance of fat necrosis lies in the fact that it may closely simulate carcinoma
both clinically and on mammographic examination.
The macroscopic appearance of fat necrosis depends on its age. In
early lesions, there is hemorrhage and indurated fat. With time, a firm
mass is formed. The cut surface of the lesion at this stage has a varie-
gated, yellow-gray appearance with focal hemorrhage. Cavitation may
subsequently occur as a result of liquefactive necrosis. The lesion may
eventually be converted to a dense, fibrous scar or may remain a cystic
FIGURE 2.11 Fat necrosis with cystic spaces and foamy histiocytes.
cavity with calcification of its walls. The term membranous fat necrosis
has been used to describe these cyst-like lesions.10
Upon microscopic examination, early lesions show cystic spaces
surrounded by lipid-laden histiocytes and foreign body–type giant cells
with foamy cytoplasm (Fig. 2.11, e-Fig. 2.8). A variable, acute inflam-
matory cell infiltrate may be present, and there may be focal hemor-
rhage. With time, there is fibroblastic proliferation and deposition of
collagen. Scattered, chronic inflammatory cells are usually present,
and focal hemosiderin deposition may be observed. Even in older
lesions, foamy histiocytes and foreign body–type giant cells are usually
discernible.
Reactions to Foreign Material

Foreign body–type granulomatous inflammation has been described fol-
lowing injection of a variety of substances, including paraffin and silicone,
into the breast. Clinically, these lesions generally appear as firm nodules
that may be tender.
A variety of tissue reactions have been reported in association with
mammary implants.11 One of these is the formation of a fibrous capsule in
the surrounding tissue. In 10% to 40% of patients, there is contracture of
this capsule that results in breast tightness or firmness and deformation of
the implant, necessitating either capsulotomy or removal of the implant
and the surrounding capsule. Histological examination of the capsular tis-

sue shows varying degrees of fibrosis, chronic inflammation, fat necrosis,
granulation tissue, fibrin deposition, histiocytes, and foreign body giant
cells. Additionally, in the case of silicone gel implants, silicone (and where
it has been used as part of the implant shell, polyurethane) may be present
within the capsule. Silicone gel leakage may be seen even in the absence
of implant rupture and characteristically produces oval, cystic spaces that
appear empty or contain amorphous, pale material, which is not birefrin-
gent with polarized light (Fig. 2.12, e-Fig. 2.9).12 Silicone can diffuse to a
variety of sites around the body, and silicone lymphadenopathy has been
reported in axillary lymph nodes (see Chapter 18); hematogenous dissemi
nation can also occur. Implant-associated lymphomas have also been
described (see Chapter 14).
Some capsules surrounding breast implants develop a cellular lin-
ing that histologically, immunohistochemically, and ultrastructurally
resembles either normal synovium or synovium with papillary hyperpla-
sia (proliferative synovitis) and has physiological properties similar
to those of synovium (Fig. 2.13, e-Fig. 2.10).11 This change has been
variably described as “pseudoepithelialization,” “synovial metaplasia,”
and “capsular synovial hyperplasia.” The factors associated with develop-
ment of synovial metaplasia in this setting are not known, but this may
be a consequence of mechanical forces (e.g., micromotion and friction)
between the implant and the surrounding tissue.
FIGURE 2.12 Breast implant capsule. This fibrous capsule shows cystic spaces containing
pale material consistent with silicone. Vacuolated histiocytes and foreign body–type giant
cells are also present.
B
FIGURE 2.13 Breast implant capsules with synovial metaplasia. A: This fibrous capsule is
lined by a cellular layer with an appearance identical to that of synovium. B: The lining of
this implant capsule resembles proliferative synovitis.
Mammary Duct Ectasia (Periductal Mastitis)

Mammary duct ectasia occurs primarily in perimenopausal and post-
menopausal women and is characterized by varying amounts of periduc-
tal inflammation, periductal fibrosis, and duct dilatation.13 Patients may
present with pain, nipple discharge, nipple retraction, and/or a mass.
The clinical findings may mimic those of carcinoma. Mammography may
demonstrate a ductal pattern of calcification that simulates the pattern of
mammographic calcifications seen in association with DCIS.
It is not uncommon to find variable degrees of dilatation or ectasia
of extralobular ducts in breast tissue obtained at autopsy and in surgi-
cally excised material; this has been observed in 30% to 40% of women
older than 50 years (Fig. 2.14). Clinically evident mammary duct ectasia,
however, occurs much less frequently,14 and simply observing ectatic ducts
in breast tissue sections is insufficient for a diagnosis of mammary duct
ectasia.
In the early stages, the lesion is confined to the large subareolar ducts,
but later an entire mammary segment may be involved. Cut section of the
gross specimen often reveals dilated, thick-walled ducts that contain pasty,
yellow-brown secretions, which is an appearance that may be mistaken
for DCIS with comedo necrosis. The intervening stroma may be fibrotic.
A wide spectrum of histologic changes are observed in this condi-
tion. Some cases are characterized by inspissation of lipid-rich material
within ducts, with evidence of duct leakage or rupture and prominent
FIGURE 2.14 Breast tissue with ectatic duct. Ectatic ducts are commonly observed in
breast tissue. However, this should not be mistaken for the disorder known as mammary
duct ectasia.
periductal inflammation. Plasma cells may be a prominent component

of the periductal inflammatory infiltrate. Foamy histiocytes are typically
present within the inspissated intraductal secretions and may infiltrate the
wall and the epithelium of involved ducts (Figs. 2.15 and 2.16, e-Fig. 2.11).
In some cases, histiocytes containing lipofuscin pigment (“ochrocytes”)
B
FIGURE 2.15 Duct ectasia. A: Low-power view showing ducts with inspissated secretions
and periductal inflammation. B: At higher power, foamy histiocytes are evident within the
intraductal secretions.
FIGURE 2.16 Duct ectasia. Numerous foamy histiocytes are present in the duct lumen
and within the duct epithelium. There is a periductal chronic inflammatory infiltrate
composed of lymphocytes and plasma cells.
are present. Less frequently, the periductal inflammatory infiltrate may be

granulomatous or xanthogranulomatous (Fig. 2.17). Occasionally, there is
an acute inflammatory component, and this can result in abscess or fistula
formation.
In other cases, periductal fibrosis predominates (Fig. 2.18, e-Fig. 2.12).
This is often accompanied by ectasia of the ducts and/or obliteration of
duct lumens. The obliterated lumens may be surrounded by a ring of
epithelial-lined tubular structures, which is sometimes referred to as “the
garland pattern,” or one or two epithelial-lined spaces may be seen to one
side of an obliterated duct (Fig. 2.19, e-Fig. 2.13).
Duct ectasia may be difficult to distinguish from cysts in cases in
which there is prominent ductal dilatation with little or no inflammatory
component. However, duct ectasia is a disorder of the extralobular ducts,
whereas cysts arise in the terminal duct lobular units. If necessary, elastic
tissue stains can be used to help make this distinction, because ducts
contain elastic tissue in their walls, whereas cysts do not. The key histo-
logic features of duct ectasia are summarized in Table 2.1.
The pathogenesis of this condition has not been fully established.
It has been postulated that periductal inflammation leads to periductal
fibrosis, which subsequently results in ductal dilatation.14 However, it has
B
FIGURE 2.17 Duct ectasia. A: Low-power view demonstrating inspissated intraluminal
secretions, calcifications and histiocytes, and periductal fibrosis and chronic inflamma-
tion, including poorly formed granulomas (arrow). B: High-power view of periductal poorly
formed granuloma.
FIGURE 2.18 Duct ectasia, later stage, characterized by ectatic ducts, prominent periductal
fibrosis, and scant inflammation.
FIGURE 2.19 Duct ectasia. In this duct, the lumen is obliterated by fibrous tissue. The
obliterated lumen is surrounded by a "garland" of epithelial-lined spaces.
TABLE 2.1 Key Histologic Features of Mammary Duct Ectasia
• Inspissation of lipid-rich secretions within duct lumens

• Periductal inflammation, often with prominent plasma cell component
• Foamy histiocytes within luminal secretions and within the wall and
epithelium of involved ducts
• Evidence of duct rupture may be seen
• Periductal fibrosis; obliteration of duct lumens
• Dilatation of ducts
also been suggested that periductal mastitis and duct ectasia represent
two separate entities, based on differences between women with these
two disorders with regard to age, clinical history, and smoking history.15
In particular, smoking has been reported to be associated with periductal
inflammation but not with duct dilatation.
Lymphocytic mastopathy/Diabetic mastopathy

This condition, which primarily affects young to middle-aged women,
is most commonly seen in association with type 1 (insulin-dependent)
diabetes, but similar histologic changes have been described in associa-
tion with other autoimmune diseases, such as Hashimoto thyroiditis, in
patients with various types of autoantibodies in their serum, in patients
without diabetes or other autoimmune diseases, and in men.16-18
Patients present with palpable or mammographically detected breast
masses that may be multiple and bilateral. Histological examination shows
a characteristic constellation of features.18 These include dense, keloid-like
fibrosis; periductal, perilobular, and perivascular lymphocytic infiltrates
(primarily composed of B-lymphocytes); and epithelioid myofibroblasts
in the stroma (Fig. 2.20, e-Fig. 2.14). The appearance of these latter cells
may be alarming and, particularly when numerous, may lead to an errone-
ous diagnosis of an invasive carcinoma or a granular cell tumor.19 The key
histologic features of lymphocytic mastopathy/diabetic mastopathy are
summarized in Table 2.2.
Although the pathogenesis of this condition is unknown, it may rep-
resent an autoimmune reaction. Recurrences have been reported in up to
one-third of patients.18
B
FIGURE 2.20 Lymphocytic mastopathy/diabetic mastopathy. A: This breast biopsy
shows stromal fibrosis, periductal and perivascular lymphocytic infiltrates, and epithelioid
myofibroblasts in the stroma. B: High-power view of epithelioid myofibroblasts.
TABLE 2.2 Key Histologic Features of Lymphocytic Mastopathy/

Diabetic Mastopathy
• Keloidal fibrosis
• Periductal, perilobular, and perivascular lymphocytic infiltrates
• Epithelioid myofibroblasts in stroma
Granulomatous Lesions
As noted earlier, granulomatous inflammation may be seen in duct ectasia
(Fig. 2.17) or as a reaction to foreign material. Some infections, including
those due to mycobacteria, fungi, and parasites, are typically associated
with granulomatous inflammation, but are rare in Western countries. The
histologic appearance of the granulomas in these disorders resembles
that seen in other sites (Fig. 2.21). Mastitis characterized by granulomas,
neutrophils, and cystic spaces has also been described in association with
Corynebacterium infection.20 In addition, non-necrotizing, sarcoid-type
granulomas may be seen in the stroma of some breast carcinomas.21
Sarcoidosis
Involvement of the breast by sarcoidosis is rare, but when present may
clinically simulate a neoplasm.22 Histologically, the lesions consist
FIGURE 2.21 Tuberculous mastitis. The breast stroma shows granulomatous

inflammation with caseous necrosis. Acid-fast bacilli were demonstrated in this lesion.
FIGURE 2.22 Sarcoidosis involving the breast, characterized by nonnecrotizing

granulomatous inflammation.
of nonnecrotizing granulomas, with varying numbers of giant cells

in the interlobular and intralobular stroma (Fig. 2.22, e-Fig. 2.15).
As in other organs, sarcoidosis is a diagnosis of exclusion, and other
causes of granulomatous inflammation, such as infections and reac-
tions to foreign materials, must be ruled out. Sarcoidosis must also be
distinguished from idiopathic granulomatous mastitis (see the subse-
quent text).
Idiopathic Granulomatous Mastitis/Lobular Granulomatous
Mastitis
The cause of this uncommon lesion is obscure.23-25 It usually presents as a
mass, nearly always in young parous women, and is often related to recent
pregnancy. Clinically, the lesion can simulate carcinoma. Bilateral disease
sometimes occurs. Idiopathic granulomatous mastitis is characterized his-
tologically by primarily lobulocentric granulomas that often contain neu-
trophils (Fig. 2.23). The neutrophils may be numerous enough to create
microabscesses. Foci of necrosis may be present within the granulomas,
but true caseous necrosis is not seen.
Although the lobulocentricity of the granulomas and the presence
of neutrophils should raise the possibility of idiopathic granulomatous
mastitis, other causes of granulomatous inflammation (such as infections,
sarcoidosis, and reaction to foreign materials) should always be excluded.
B
FIGURE 2.23 Idiopathic granulomatous mastitis/lobular granulomatous mastitis. This lesion
is characterized by lobulocentric granulomas (A), which often contain neutrophils (B).
There is some evidence to suggest that patients with this condition

respond favorably to corticosteroid therapy.
The key histologic features of granulomatous lesions of the breast are
TABLE 2.3 Key Histologic Features Distinguishing Granulomatous

Lesions of the Breast
Granulomatous Lesion Key Features
Mycobacterial, fungal, Granulomas resemble those seen in

parasitic infections comparable infections in other sites; may
be necrotizing or non-necrotizing
Sarcoidosis Non-necrotizing granulomas in interlobular
and intralobular stroma
Idiopathic granulomatous Lobulocentric granulomas; often contain
mastitis neutrophils
Mammary duct ectasia Periductal granulomas; may have
xanthogranulomatous features
Reaction to foreign Foreign body–type granulomas; foreign
materials body–type giant cells; foreign material
IgG4-related Sclerosing Mastitis

This recently described lesion is part of a growing family of IgG4-related
sclerosing diseases26 and is characterized by discrete, painless breast
masses that may be unilateral or bilateral. The masses consist of dense,
diffuse, or nodular lymphoplasmacytic infiltrates with lymphoid follicles
and a large component of IgG4-positive plasma cells along with stromal
sclerosis and lobular atrophy (Fig. 2.24). Patients may also have elevated
A
FIGURE 2.24 IgG4-related sclerosing mastitis. A: Low-power view demonstrating stromal
sclerosis and a primarily diffuse chronic inflammatory cell infiltrate including lymphoid
follicles. B: High-power view of inflammatory infiltrate demonstrating numerous plas-
ma cells. C: Immunostain for IgG4 demonstrates numerous IgG4-positive plasma cells
(photomicrographs courtesy of Dr. John K.C. Chan).
C
serum levels of IgG4 as well as similar lesions in other organs. The clinical
course appears to be benign.27
Eosinophilic Mastitis
Eosinophilic mastitis presents as a palpable breast mass and has been
reported in association with peripheral eosinophilia, hypereosinophilic
syndrome, Churg-Strauss syndrome, and allergic conditions.28,29
Histologically, there is extensive eosinophilic infiltration around ducts
and lobules. Lymphocytes and plasma cells may be admixed. The duct and
B
FIGURE 2.25 Eosinophilic mastitis. A: Stromal inflammatory infiltrate composed of
numerous eosinophils, as well as lymphocytes and plasma cells. B: Higher power view
demonstrating eosinophils in stroma as well as within the epithelium of a small duct.
lobular epithelium in the areas of inflammatory infiltration may exhibit

reactive changes (Fig. 2.25). These rare lesions may recur following exci-
sion if the underlying disorder is not appropriately managed.
Miscellaneous reactive and inflammatory lesions

Galactocele
This uncommon lesion occurs following abrupt suppression of lactation
and is characterized by a cystic, milk-filled cavity beneath the areola.
On histologic examination, this lesion consists of dilated, anastomosing,
epithelial-lined channels. The luminal epithelium may show secretory

activity. Leakage of the cyst contents into the surrounding tissue may lead
to a lipogranulomatous reaction.30 In some instances, a focal collection of
foamy histiocytes containing milk may be seen, even in the absence of a
classic galactocele.31
Juvenile (Virginal) Hypertrophy
Juvenile hypertrophy is characterized by rapid and distressing enlarge-
ment of one or, more frequently, both breasts, which is often asymmetri-
cal. Histologic examination shows features strikingly similar to those of
gynecomastia. This is discussed in more detail in Chapter 17.
Gestational Macromastia
Massive enlargement of the breast associated with pregnancy is less com-
mon than juvenile hypertrophy.32 This condition commences early in preg-
nancy, with rapid and massive bilateral breast enlargement. The breasts are
erythematous, edematous, and painful; ulceration of the overlying skin may
occur. This condition typically regresses after parturition, but involution
may not be complete and recurrence is usual in subsequent pregnancies.
Mondor Disease
Mondor disease, or phlebitis of the thoracoepigastric vein, is an uncom-
mon condition predominantly affecting women in the fourth, fifth, and
sixth decades.33 Patients typically present with a tender, linear, cord-like
subcutaneous mass. Histologic examination shows phlebitis and periphle-
bitis associated with varying degrees of thrombosis.
Other Reactive and Inflammatory Lesions
Acute mastitis, sometimes with the formation of breast abscesses, is most
often seen in association with lactation. Biopsy specimens from patients
with this condition are uncommon since it is usually managed effectively
by non-surgical means. Breast infarction is rare and has been associated
with the use of warfarin therapy. Other systemic diseases, such as various
forms of vasculitis, connective tissue diseases, and amyloidosis, may also
involve the breast, as can diseases of the skin and subcutaneous tissues.
Dirofilarial infection can result in a clinically or radiologically detected
mass.34 Other reactive spindle cell lesions of the breast, such as nodular
fasciitis, are discussed in Chapter 11.
Nonproliferative Lesions
The most common nonproliferative lesions in the breast are cysts and
metaplastic changes. In general, nonproliferative lesions do not confer
an increase in the risk of developing breast cancer, although some stud-
ies have suggested that gross cysts are associated with a slight increase in
breast cancer risk.35
Cysts
Cysts are fluid-filled round to ovoid structures that vary in size from
microscopic to grossly evident. They are derived from the terminal duct
lobular units and arise through dilatation and ultimately unfolding and
coalescence of lobular acini. “Gross cysts,” as defined by Haagensen, are
those that are large enough to produce palpable masses. The lining of cysts
usually consists of two layers: an inner (luminal) epithelial layer and an
outer myoepithelial layer. In some cysts, the epithelium is markedly atten-
uated or absent (Fig. 2.26); in others, the lining epithelium shows apocrine
metaplasia, as described subsequently (Fig. 2.27, e-Fig. 2.16). Cysts may
contain calcifications of varying types including milk of calcium, calcium
phosphate/apatite, or calcium oxalate.
Cysts do not usually cause major diagnostic problems on histologic
examination. However, several issues merit particular comment. First,
cysts may be confused with duct ectasia. The presence of elastic tissue can
be demonstrated around ectatic ducts but not cysts, as discussed earlier.
Second, several neoplastic lesions may be mistaken for cysts at scanning
magnification, particularly flat epithelial atypia and cystic hypersecretory
carcinoma (discussed in Chapters 4 and 3, respectively). Finally, CNB
sampling of cysts may yield only portions of the cyst wall. These are char-
acterized by areas of fibrosis with or without adjacent epithelium. Such
areas are typically present at the edge of core biopsy samples and may be
readily overlooked (Fig. 2.28).
FIGURE 2.26 Cyst. This cyst is lined by an attenuated epithelial layer.

FIGURE 2.27 Cysts. In these cysts, the epithelial lining shows apocrine metaplasia.
FIGURE 2.28 Core-needle biopsy showing portion of cyst wall composed of fibrous
connective tissue and epithelium along the edge of the tissue fragment.
Metaplastic Change
The most common metaplastic change in the breast is apocrine meta-
plasia, which is characterized by enlarged epithelial cells with abundant
granular, eosinophilic cytoplasm that may show apical luminal blebbing
or snouting. Supranuclear vacuoles or eosinophilic granules may be pres-
ent. The nuclei are round, are of variable size, and generally have vesicu-
lar chromatin with prominent nucleoli (Fig. 2.29). Apocrine metaplastic
epithelium may be present in a single layer or in multiple layers and may
sometimes have a papillary configuration (papillary apocrine change)
(Fig. 2.30). The cytologic features of apocrine epithelium can be worri-
some. After the apocrine nature of the cells has been recognized, however,
care should be exercised in the interpretation of such cytologic features.
Immunophenotypically, apocrine metaplastic cells are estrogen receptor
negative, bcl-2 negative, and androgen receptor positive and generally
express gross cystic disease fluid protein. Of note, ducts and cysts lined
by benign epithelium with apocrine metaplasia may show a reduction or
complete loss of the surrounding myoepithelial layer.36
Squamous metaplasia of breast epithelium is uncommon and is
far less frequent than apocrine metaplasia. As noted earlier, it may be
seen not only in duct and lobular epithelium in the vicinity of a prior
biopsy site, such as in Fig. 2.2, but also in a variety of lesions including
cysts, usual ductal hyperplasia, intraductal papillomas, benign phyllodes
tumors, fibroadenomas, and gynecomastia.
FIGURE 2.29 Apocrine metaplasia. The epithelial cells show abundant eosinophilic
cytoplasm with apical snouting and supranuclear eosinophilic granules. The nuclei are
round and have variably prominent nucleoli.
FIGURE 2.30 Papillary apocrine change. Epithelial cells with apocrine metaplasia are
present in a papillary configuration.
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2000;113(2):288-294.
2. Guarda LA, Tran TA. The pathology of breast biopsy site marking devices. Am J Surg
Pathol. 2005;29(6):814-819.
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in surgical breast specimens following stereotaxic core biopsy. Am J Clin Pathol.
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duct ectasia. Br J Surg. 1983;70(10):601-603.
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16. Schwartz IS, Strauchen JA. Lymphocytic mastopathy. An autoimmune disease of the
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lymphocytic lobulitis of the breast—evidence for an autoimmune pathogenesis.
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mastitis—a source of confusion with invasive carcinoma. Mod Pathol. 1994;7(1):49-54.
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an underappreciated pattern strongly associated with gram-positive bacilli. Am J Clin
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in breast cancer. An analysis of 5 cases with immunohistochemical investigations.
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Pathol Lab Med. 1984;108(8):673-675.
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3
Intraductal Proliferative
Lesions: Usual Ductal
Hyperplasia, Atypical Ductal
Hyperplasia, and Ductal
Carcinoma in Situ
Intraductal proliferative lesions are a diverse group of epithelial prolifera-

tions confined to the mammary ductal–lobular system.1 They are divided
into three major categories based on their architectural and cytologic fea-
tures: usual ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH),
and ductal carcinoma in situ (DCIS). While the term intraductal is com-
monly used to describe these lesions, they most often arise in and are
frequently confined to the terminal duct lobular units, although they may
also involve extralobular ducts. The clinical importance of these lesions is
that they are associated with an increased risk of breast cancer, albeit of
differing magnitudes.
Usual Ductal Hyperplasia

Also known as hyperplasia of the usual type, UDH is a benign epithelial
proliferation characterized by a tendency for the proliferating epithelial
cells to bridge across and often fill and distend the involved spaces. Mild
forms show epithelial proliferation two to four cell layers thick, but these
do not appear to be associated with the same increase in breast cancer risk
seen with the more florid examples of UDH.
The proliferation in UDH may have a solid, fenestrated, or micro-
papillary architecture. If lumens are present within the proliferation, they
are irregular and variable in size and shape, often slit-like, and frequently
58
INTRADUCTAL PROLIFERATIVE LESIONS ——— 59
arranged around the periphery. When epithelial bridges are present, they
appear stretched or twisted and commonly show central attenuation.
Micropapillary projections, if present, are typically tuft-like or elongated
and tapering, resembling the pattern of hyperplasia seen in gynecomastia.
The cells comprising UDH are cytologically benign; vary in size, shape,
and orientation; are arranged in a haphazard pattern; and have poorly
defined borders that may result in a syncytial appearance. The cells do
not polarize around lumens within the proliferation. In some instances,
there is prominent streaming or swirling of the cells. The nuclei vary in
size, shape, and contour and may show overlapping. Nuclear grooves
and intranuclear cytoplasmic inclusions may be evident. These archi-
tectural and cytologic features of UDH are illustrated in Figs. 3.1–3.9
and e-Figs. 3.1–3.8. Multiple cell types (including metaplastic cells with
apocrine or, less often, squamous features) may be present (Figs. 3.10
and 3.11, e-Figs. 3.9 and 3.10). Foamy histiocytes (Fig. 3.12), as well as
calcifications (Fig. 3.13), may be seen in association with the proliferating
epithelial cells. Rarely, foci of necrosis are present (Fig. 3.14, e-Fig. 3.11).
Alterations in the surrounding stroma, such as fibroblastic proliferation,
elastosis, and mononuclear cell infiltrates, are uncommon. The key fea-
tures of UDH are summarized in Table 3.1.
FIGURE 3.1 Usual ductal hyperplasia. There is a solid proliferation of cells filling the
space. The cells and nuclei vary in size, shape, and orientation.
B
FIGURE 3.2 Usual ductal hyperplasia. A: The few fenestrations present in this mostly solid
proliferation are slit-like and irregular in shape and present primarily toward the periphery.
B: Higher power view illustrates heterogeneity in cell size, shape, and placement, as well
as poorly defined cell borders.
B
FIGURE 3.3 Usual ductal hyperplasia. A: Fenestrations in this proliferation vary in size
and shape. B: Higher power view demonstrates haphazard arrangement of cells, with no
regular orientation around the fenestrations.
FIGURE 3.4 Usual ductal hyperplasia. Solid proliferation of cells with poorly defined cell
borders and peripheral fenestrations.
FIGURE 3.5 Usual ductal hyperplasia. The cellular bridges that traverse the lumen appear
stretched and thinned. Nuclei in these bridges are compressed, stretched, and oriented in
the same direction as the bridges.
FIGURE 3.6 Usual ductal hyperplasia. The bridge traversing the lumen shows extreme
attenuation.
FIGURE 3.7 Usual ductal hyperplasia with micropapillary (gynecomastoid) features.

Micropapillary fronds, many of which taper toward their tips, project into the lumen. This
appearance is similar to that seen in gynecomastia.
B
FIGURE 3.8 Usual ductal hyperplasia. A: Prominent cellular swirling is seen in the center
of this proliferation. B: Higher power view illustrates cellular swirls with overlapping
nuclei.
FIGURE 3.9 Usual ductal hyperplasia with several intranuclear cytoplasmic inclusions
(arrows).
FIGURE 3.10 Usual ductal hyperplasia with foci of apocrine metaplasia.

FIGURE 3.11 Usual ductal hyperplasia with apocrine metaplasia (upper left) and
squamous metaplasia (lower right).
FIGURE 3.12 Usual ductal hyperplasia with foamy histiocytes.

FIGURE 3.13 Usual ductal hyperplasia with calcification.
Immunophenotype and Genetics

The cells comprising UDH show variable expression of estrogen receptor
(ER) (Fig. 3.15) as well as a low proliferation rate.2 A mosaic pattern of
expression of high-molecular-weight cytokeratins (CKs) as demonstrated
with antibodies to CK5/6 is a characteristic feature (Fig. 3.16, e-Fig. 3.12).3
FIGURE 3.14 Usual ductal hyperplasia (UDH) with necrosis. This cellular proliferation
with features characteristic of UDH also exhibits foci of necrosis. Although uncommon,
the presence of necrosis does not preclude a diagnosis of UDH if the architectural and
cytologic features of the proliferation support that diagnosis.
TABLE 3.1 Key Features of Usual Ductal Hyperplasia
Cytologic features
• Heterogeneous cell population
• Variation in cell size, shape, and orientation
• Cell borders poorly defined
• Variation in size, shape, and placement of nuclei, with areas of nuclear
overlapping and intranuclear cytoplasmic inclusions
Architectural features
• Solid, fenestrated, or micropapillary
• Lumens irregular, variable in size and shape, often slit-like and displaced to
periphery without polarization of surrounding cells
• Bridges stretched or twisted with central attenuation
The use of immunostain cocktails composed of antibodies to both low-

molecular-weight (luminal) and high-molecular-weight (basal) CKs fur-
ther highlights the heterogeneity of the cell population in UDH (Fig. 3.17).
While a subset of UDH lesions show chromosomal losses and gains,
most studies have found no consistent genetic alterations in these lesions.
Moreover, UDH lesions share few genetic abnormalities with ADH,
DCIS, or invasive breast cancer. This has led to the view that most UDH
lesions do not represent direct cancer precursors, but rather are markers
of a generalized increase in breast cancer risk.4,5
FIGURE 3.15 Usual ductal hyperplasia immunostained for estrogen receptor (ER). There
is heterogeneity of nuclear ER expression in the cells comprising this lesion. Some cells
are strongly positive, others are more weakly positive, and others are negative.
B
FIGURE 3.16 Usual ductal hyperplasia (UDH). A: H&E-stained section. B: Immunostain for
CK5/6 illustrates the mosaic pattern of staining characteristic of UDH.
Clinical Course and Prognosis

UDH is associated with a 1.5- to 2-fold increase in the risk of breast
cancer, and the subsequent cancer may occur in either breast.6,7 This
risk is slightly higher among women with UDH who have a positive
FIGURE 3.17 Usual ductal hyperplasia immunostained with a cocktail of antibodies to

low-molecular-weight (luminal) cytokeratins CK7/18 (red cytoplasmic staining), high-
molecular-weight (basal) cytokeratins CK5/14 (brown cytoplasmic staining), and p63
(brown nuclear staining). The proliferation is composed of a mixture of cells with luminal
and basal phenotypes. p63-positive myoepithelial cells are confined to the periphery of
the involved space.
family history of breast cancer in a first-degree relative.8,9 There are at

present no prognostic factors or biomarkers that permit the identifica-
tion of patients with UDH who are more likely to develop invasive
breast cancer.
Atypical Ductal Hyperplasia

ADH is an epithelial proliferation confined to the mammary ductal–
lobular system and is composed, at least in part, by a neoplastic cell
population similar to that seen in low-grade DCIS. This population
is characterized by relatively small, monomorphic cells with generally
rounded nuclei that are evenly spaced and have well-defined borders.
The cells may grow in arcades, rigid bridges or bars of uniform thick-
ness, micropapillae that are typically broader at the tips than at the base
(club-shaped), solid patterns, or fenestrated (cribriform) patterns in
which the cells show polarization around extracellular lumens within
the proliferation. The involved spaces may also contain a population
of cells more characteristic of UDH or residual normal epithelium
(Figs. 3.18–3.23, e-Figs. 3.13–3.19).
FIGURE 3.18 Atypical ductal hyperplasia. A portion of this space (left) contains a
proliferation of monotonous cells with uniform, round, evenly spaced nuclei reminiscent
of those seen in low-grade ductal carcinoma in situ. The cellular proliferation in the
remainder of the space has features more characteristic of usual ductal hyperplasia.
FIGURE 3.19 Atypical ductal hyperplasia (ADH). The proliferation on the left side of this
space has features of low-grade ductal carcinoma in situ, characterized by a uniform cell
population and punched-out spaces. However, the attenuated cellular bridges on the
right are characteristic of those seen in usual ductal hyperplasia. Therefore, a diagnosis of
ADH is appropriate.
B
FIGURE 3.20 Atypical ductal hyperplasia. A: The uniform, atypical cell population
involves only a portion of the space. B: High-power view of the atypical cell population
demonstrating relatively evenly placed cells with uniform nuclei that focally polarize
around extracellular lumina.
FIGURE 3.21 Atypical ductal hyperplasia with calcification.
A diagnosis of ADH should only be applied to lesions in which the

diagnosis of low-grade DCIS is seriously considered but in which the fea-
tures are not sufficiently developed for a definite diagnosis of DCIS. The
extent of the atypical proliferation is the critical feature that distinguishes
ADH from low-grade DCIS. Unfortunately, when spaces are completely
involved, there is at present no universally accepted size or extent cutoff
for this distinction. Page et al.6 originally proposed that all features of
low-grade DCIS be present in at least two separate spaces before a diag-
nosis of DCIS is rendered and that anything less be categorized as ADH.
Tavassoli and Norris7 subsequently proposed that lesions with all of the
architectural and cytologic features of low-grade DCIS that are <2 mm in
size be given the diagnosis of ADH and that larger lesions be categorized
as low-grade DCIS (Fig. 3.24). The 2011 WHO Working Group concluded
that it was not possible to recommend one of these approaches over the
other and many experts, in fact, use combinations of both in their clini-
cal practice. It should be noted that quantitative thresholds are meant to
be practical guidelines that are useful in preventing the categorization of
very small, low-grade lesions as DCIS and, in turn, in avoiding overtreat-
ment of patients with minimal or equivocal lesions.8 The Working Group
further recommended that a conservative approach be used particularly in
core-needle biopsy specimens in which the differential diagnosis includes
ADH and low-grade DCIS of limited extent. Categorization of such lesions
as either ADH or as “atypical intraductal proliferative lesion” should be
sufficient to prompt a surgical excision. Definitive categorization of such
lesions should be based on evaluation of the subsequent surgical excision
B
FIGURE 3.22 Atypical ductal hyperplasia with micropapillary features. A: Low-power view
demonstrates a few club-shaped micropapillae protruding into the duct lumen. Only
a portion of the space is involved. B: High-power view illustrates uniformity of the cell
population within the micropapillae.
specimen. If no further lesion is found on the subsequent excision, the

patient should be managed similarly to patients with ADH.
In our practice, we prefer to fall short of a diagnosis of overt DCIS
for small (<2 mm) lesions with borderline features in order to avoid
overdiagnosis (Figs. 3.24 and 3.25). In such cases, we render a diagnosis of
C
FIGURE 3.23 Atypical ductal hyperplasia. A: This duct contains a few bulbous
micropapillations and a rigid arcade. High-power views of micropapillae (B) and cellular
arcade (C) illustrate a monotonous cell population. The nuclei in the arcade are relatively
round and evenly spaced.
B
FIGURE 3.24 Atypical ductal hyperplasia vs. low-grade ductal carcinoma in situ (DCIS)
seen at scanning magnification (A) and at high power (B). This lesion consists of a cribri-
form epithelial proliferation composed of a uniform population of cells with small, mono-
morphic nuclei. It is limited to two spaces and is less than 2 mm in size. Therefore, it
could be categorized as either low-grade DCIS using the original Page criteria6 or atypical
ductal hyperplasia using the Tavassoli and Norris criteria7. In current practice, most
pathologists would fall short of categorizing a low-grade lesion of such limited extent
as DCIS.
B
FIGURE 3.25 Severely atypical intraductal proliferation in a terminal duct lobular unit at
low (A) and medium power (B). The qualitative features of this lesion approach those of
low-grade ductal carcinoma in situ, but the lesion is limited in extent (see text).
“severely atypical intraductal proliferation bordering on low-grade DCIS.”

If a lesion of this type is present at or near a margin of an excisional
biopsy, we recommend a re-excision to exclude the possibility of DCIS.
Rendering this diagnosis on a core-needle biopsy sample will prompt
excision without labeling the patient as having DCIS in the event that no
worse lesion is found on excision.
TABLE 3.2 Key Features of Atypical Ductal Hyperplasia
Cytologic features
• Atypical cell population similar to that of low-grade ductal carcinoma in situ
(small, uniform cells with generally rounded nuclei that are evenly spaced
and have well-defined borders)
• In association with atypical cell population: rigid bridges and arcades of
uniform thickness, micropapillations with bulbous tips, cribriform pattern
with polarization of cells around lumens, solid pattern
Size/extent
• Partial involvement of multiple spaces; complete involvement of less than
two spaces or ≤2 mm in extent (see text)
It should be emphasized that size or extent criteria apply only to the

distinction of ADH from low-grade DCIS; intermediate- or high-grade
DCIS should be diagnosed as DCIS, even if present in a single space or
less than 2 mm in size.
The key features of ADH are summarized in Table 3.2.
The cells comprising ADH typically show strong and uniform expression
of ER and have a low proliferative rate.9 These cells lack expression of
high-molecular-weight CKs by CK5/6 immunostaining (Fig. 3.26).10
FIGURE 3.26 Atypical ductal hyperplasia, CK5/6 immunostain. The neoplastic cells
comprising this proliferation are CK5/6 negative (surrounding myoepithelial cells show
staining for CK5/6).
Genetic studies have identified several recurrent alterations includ-

ing losses at 16q and 17p and gains at 1q4,5; these genetic abnormalities
are similar to those seen in low-grade DCIS, implying a precursor–product
relationship (see the subsequent text).

ADH is associated with a threefold to fivefold increase in the risk of
subsequent breast cancer. These cancers occur with approximately equal
frequency in both breasts.11,12 Earlier studies suggested that a family his-
tory of breast cancer more than doubles the risk among women with
ADH,13 but more recent studies have not found a substantial additive
effect of family history on the level of breast cancer risk in women with
ADH.14,15 Patients with ADH are most often managed by close follow-up.
Tamoxifen and aromatase inhibitors may also be used to reduce the risk
of developing breast cancer.16 At present, there are no prognostic factors
or biomarkers that can identify which patients with ADH are more likely
to develop invasive breast cancer.
The finding of ADH on a core-needle biopsy is considered by most
to be an indication for surgical excision. Even when larger gauge needles
and vacuum-assisted devices are used, up to 15% of patients with ADH
on a core-needle biopsy will be found to have a “worse” lesion on exci-
sion (most often DCIS, but sometimes invasive cancer).17 A number of
investigators have attempted to identify patients with ADH on core-needle
biopsy who can safely be spared an excision, but at this time such a subset
has not been reproducibly defined.18-21
Ductal Carcinoma in Situ

The term DCIS encompasses a heterogeneous group of lesions that differ
in their clinical presentation, histologic features, biomarker profile, genet-
ic abnormalities, and biologic potential. They have in common the pres-
ence of neoplastic epithelial cells confined to the mammary ductal–lobular
system, without extension beyond the basement membrane. DCIS may
involve ducts and/or identifiable lobules. In most cases, DCIS involves
the breast in a unicentric, segmental distribution; true multicentric disease
is uncommon.22
Clinical Presentation
In current clinical practice, DCIS most often presents as mammographic
microcalcifications. However, up to 30% of DCIS lesions may present
with other mammographic findings, such as a soft tissue density with or
without microcalcifications or an area of architectural distortion.23 Less
commonly, DCIS presents as a palpable mass, a pathologic nipple dis-
charge, Paget disease of the nipple, or an incidental microscopic finding
in breast tissue removed because of another abnormality.
Gross Pathology
Most DCIS lesions detected because of the identification of mam-
mographic microcalcifications present no macroscopic abnormalities.
Palpable DCIS as well as some mammographically detected DCIS may
appear as a firm, tan tumor mass, with cords of pasty material exuding
from the cut surface of the specimen or readily expressed from involved
ducts by specimen palpation or compression.
Histopathology
classification. There is currently no universally accepted classification
system for DCIS.24,25 Traditionally, DCIS was classified based primarily on
the architectural features or growth pattern of the lesions and five major
types were recognized: comedo, cribriform, micropapillary, papillary, and
solid (Fig. 3.27, e-Fig. 3.20). More recently proposed classification systems
stratify DCIS into three grades, primarily on the basis of nuclear grade
and/or necrosis (Fig. 3.28, e-Fig. 3.21).26
B
FIGURE 3.27 Architectural patterns of ductal carcinoma in situ: comedo (A), cribriform
(B), micropapillary (C), papillary (D), and solid (E).
E
C
FIGURE 3.28 Nuclear grading of ductal carcinoma in situ: low-grade nuclei (A),
intermediate-grade nuclei (B), and high-grade nuclei (C).
In 1997, a consensus conference was convened in an attempt to

reach agreement on the classification of DCIS.27 Although the panel did
not endorse any one system of classification, there was agreement that
certain features be routinely documented in pathology reports of DCIS
lesions. These include nuclear grade (low, intermediate, or high), the pres-
ence of necrosis (comedo or punctate), cell polarization, and architectural
pattern(s). In our clinical practice, we primarily classify DCIS based on
the nuclear grade, but also comment on the architectural patterns and the
presence of comedo necrosis, and we report other features in accord with
the recommendations of the College of American Pathologists.28,29
low-grade dcis. Low-grade DCIS is characterized by a proliferation of small
cells with well-defined cell membranes that exhibit uniform size, shape, and
placement. The nuclei are small, with relatively homogeneous chromatin
distribution and inconspicuous nucleoli. The cells show a subtle increase
in the nuclear–cytoplasmic ratio. Mitotic figures are rare (Fig. 3.28A). The
growth pattern may be cribriform, micropapillary, solid, or, less frequently,
papillary or the cells may grow in arcades and bridges (Fig. 3.29, e-Fig. 3.22).
The cribriform pattern features extracellular lumens within the proliferation.
These are typically round and rigid with a punched-out appearance. The
neoplastic cells show polarization around these lumens (Figs. 3.27B and
3.29A). In the micropapillary pattern, tufts of proliferating cells project into
the lumen of the ductal–lobular spaces but lack the fibrovascular cores char-
acteristic of true papillary lesions. The micropapillae frequently have a club-
shaped appearance, and the cells within the micropapillae have a uniform
A
FIGURE 3.29 Low-grade ductal carcinoma in situ with cribriform (A) and micropapillary
(B) patterns. In both cases, the nuclei are small and uniform in appearance.
B
appearance and an even distribution (Figs. 3.27C and 3.29B). In the solid
growth pattern, involved ductal–lobular spaces are filled with solid sheets of
cohesive cells that frequently show small, incompletely formed microacini
or rosette-like areas, with polarization of the surrounding cells (Fig. 3.30).
Cellular polarization may also be evident at the periphery of the involved
FIGURE 3.30 Low-grade ductal carcinoma in situ, solid pattern. Numerous microacini or
rosette-like structures are present and are characterized by polarization of cells around
small lumens.
FIGURE 3.31 Low-grade ductal carcinoma in situ with comedo necrosis.
spaces. Arcades and bridges are typically of uniform thickness and have rigid
contours, and the cells within these structures are evenly spaced. Necrosis is
usually not present in low-grade DCIS, but may be observed in some cases
and may even be of the central, comedo type (Fig. 3.31). Calcifications
are common and, when present, are usually rounded and laminated
(psammomatous) and deposited within intraluminal secretions (Fig. 3.32,
e-Fig. 3.23). These calcifications may be detected by mammography and
FIGURE 3.32 Psammomatous calcification in low-grade ductal carcinoma in situ.

TABLE 3.3 Key Features of Low-Grade Ductal Carcinoma In Situ
Cytologic features
• Monotonous, uniform, rounded cell population
• Subtle increase in nuclear–cytoplasmic ratio
• Equidistant or highly organized nuclear distribution
• Rounded nuclei with inconspicuous nucleoli
• Hyperchromasia may or may not be present
• Cribriform, micropapillary, or solid patterns most frequent
• Bridges and arcades, when present, of uniform thickness
• Cells polarize around extracellular lumens
• Comedo necrosis rare
their mammographic appearance overlaps with that of benign lesions.22 The

key features of low-grade DCIS are summarized in Table 3.3.
high-grade dcis. High-grade DCIS is composed of cells with large, pleo-
morphic nuclei that have vesicular or coarse chromatin and prominent
nucleoli. Occasionally, the nuclear pleomorphism is striking. Mitoses are
frequent and may be atypical (Fig. 3.28C). Central, comedo-type necrosis
is often present, but is not required for the diagnosis of high-grade DCIS
(Figs. 3.27A and 3.33, e-Fig. 3.24). Necrosis may be so extensive that only
FIGURE 3.33 High-grade ductal carcinoma in situ, comedo pattern. This case demon-
strates a solid proliferation of large cells with pleomorphic nuclei at the periphery of the
space. There is central necrosis.
FIGURE 3.34 High-grade ductal carcinoma in situ, clinging pattern. This space exhibits a
large area of central necrosis surrounded by a single layer of highly atypical cells.
one layer or a few cell layers are present at the periphery of the involved
space, producing a “clinging” pattern (Fig. 3.34). The malignant cells occa-
sionally produce a solid sheet, filling the duct lumen without central necrosis
(Fig. 3.35). Alternatively, the cells may grow in true cribriform or micropap-
illary patterns but without prominent cell polarization (Fig. 3.36). More
often, however, pseudocribriform or pseudomicropapillary patterns result
from varying degrees of cellular dropout, as a consequence of apoptosis or
FIGURE 3.35 High-grade ductal carcinoma in situ, solid pattern.

FIGURE 3.36 High-grade ductal carcinoma in situ, micropapillary pattern. Nuclear

pleomorphism is prominent (compare with Fig. 3.25B).
necrosis. Calcifications are often found within the central necrotic material,
are amorphous, and usually produce a linear, branching, or casting pattern
on mammography (Fig. 3.37).22 Fibroblastic proliferation with collagen
deposition (desmoplasia), chronic inflammation, and vascular proliferation
(angiogenesis) is often seen in the stroma surrounding the involved spaces
FIGURE 3.37 High-grade ductal carcinoma in situ with amorphous calcification in

necrotic debris.
FIGURE 3.38 High-grade ductal carcinoma in situ with prominent desmoplasia and
chronic inflammation in the surrounding stroma.
(Fig. 3.38, e-Fig. 3.25). The desmoplasia may be so prominent that it results
in a palpable abnormality in the breast. Involvement of identifiable lobules
is frequent (Fig. 3.39, e-Fig. 3.26). Paget disease of the nipple is almost
invariably associated with high-grade DCIS (see Chapter 15).
intermediate-grade dcis. A diagnosis of intermediate-grade DCIS is war-
ranted when the cells comprising the lesion do not fulfill the cytologic
criteria for either low-grade or high-grade DCIS as described earlier. The
cells of intermediate-grade DCIS show mild to moderate variability in
FIGURE 3.39 High-grade ductal carcinoma in situ involving acini of a lobule.

FIGURE 3.40 Intermediate-grade ductal carcinoma in situ (DCIS), cribriform pattern. The
nuclei show mild variability in size and shape. Cell polarization around lumens is present,
but not as well-developed as in low-grade DCIS.
nuclear size, shape, and placement. There may be chromatin clumping

and nucleoli are variably conspicuous (Fig. 3.28B). The growth pattern
may be solid, cribriform, micropapillary, or papillary or the cells may
form arcades and bridges. Cell polarization around extracellular lumens
and within micropapillae is not as well-developed as in low-grade DCIS
(Fig. 3.40, e-Fig. 3.27A). Necrosis may be present and may, in some cases,
be comedo in type (Fig. 3.41, e-Fig. 3.27B). Calcifications, when present,
FIGURE 3.41 Intermediate-grade ductal carcinoma in situ with necrosis and calcifications.
may be laminated or amorphous.20 Some types of intermediate-grade

DCIS grow in patterns mimicking those seen in UDH, with irregular cel-
lular placement and cellular streaming (Fig. 3.42).
special types of dcis. Several types of DCIS have distinctive features and
cannot be categorized by nuclear grade alone.
B
FIGURE 3.42 Intermediate-grade ductal carcinoma in situ (DCIS). A: The cells show a
haphazard pattern, simulating that seen in usual ductal hyperplasia. An area of central
necrosis is present. B: At high power, the cells show a moderate degree of nuclear atypia
characteristic of intermediate-grade DCIS.
Apocrine DCIS
Apocrine DCIS is characterized by cells that have abundant, eosino-
philic cytoplasm.30 The growth pattern may be solid, cribriform, or
micropapillary, and necrosis may be present (either punctate or comedo).
Calcifications may be seen in involved spaces. The nuclei may be of low,
intermediate, or high grade and commonly have one or more prominent
nucleoli (Fig. 3.43, e-Fig. 3.28).
B
FIGURE 3.43 Apocrine ductal carcinoma in situ. A: Low-power view illustrates ducts
filled with and distended by a solid epithelial proliferation. Necrosis is present in some of
the spaces. B: The cells have abundant eosinophilic cytoplasm and nuclei with moderate
pleomorphism and prominent nucleoli.
A diagnosis of high-grade apocrine DCIS is usually straightforward

because these lesions are characterized by marked cytologic atypia and,
frequently, comedo necrosis. At the other end of the spectrum, it may be
difficult to distinguish low-grade apocrine DCIS from atypical apocrine
hyperplasia or even from apocrine metaplasia because the nuclei of these
lesions share similar characteristics, such as a round shape and single
prominent nucleoli. In our view, an apocrine intraductal proliferative
lesion in which the cells have nuclei showing minimal deviation from
those of benign apocrine cells should only be categorized as DCIS in the
presence of fully developed architectural features of one or more of the
recognized patterns of DCIS. Some authors have suggested that size crite-
ria should be used to help make this distinction,30 but as for non-apocrine
intraductal proliferations, there is no agreement with regard to size cutoff
that should be used for this purpose.
Apocrine DCIS can extend into lobules and into areas of sclerosing
adenosis, which may produce a pattern that simulates invasive carcinoma.
Immunostains for myoepithelial cells may be a valuable aid in making this
distinction. It may be difficult or impossible to distinguish apocrine DCIS
involving sclerosing adenosis from atypical apocrine adenosis, particularly
when cytologic atypia is mild or modest.
Cystic Hypersecretory DCIS
This is an uncommon pattern of DCIS characterized macroscopically
by cysts filled with viscid material.31,32 Microscopic examination reveals
multiple cyst-like structures containing homogeneous eosinophilic material
that resembles thyroid colloid. Some of the cyst-like structures are lined by
histologically benign, flat, or columnar epithelium. In others, the lining
epithelium shows various degrees of hyperplasia and foci of DCIS with a
micropapillary or cribriform pattern (Fig. 3.44). The lining cells may show
evidence of secretory activity, with features reminiscent of the lactating
breast. Stains for mucin show focal positivity within the epithelial cells,
with the majority of the cyst contents being negative. This lesion can be
easily overlooked and should be borne in mind when examining appar-
ently benign cysts. Occasionally, the lining of the cysts shows epithelial
hyperplasia without fully developed DCIS. Such lesions are termed cystic
hypersecretory hyperplasia. Some examples of cystic hypersecretory hyper-
plasia and DCIS arise in a background of pregnancy-like changes.33,34
Other Unusual Types
The cells comprising DCIS may, on occasion, show squamous (Fig. 3.45,
e-Fig. 3.29), clear cell (Fig. 3.46), signet ring cell, mucinous (Fig. 3.47), or
spindle cell features. The cells of some DCIS show histologic and immu-
nohistochemical evidence of endocrine differentiation, but the so-called
endocrine DCIS appears to be the same lesion described by others as solid
papillary DCIS (see Chapter 8).35 Even less commonly, DCIS may exhibit
small cell or adenoid cystic differentiation (Fig. 3.48, e-Fig. 3.30).
B
FIGURE 3.44 Cystic hypersecretory ductal carcinoma in situ. A: Scanning magnification
demonstrates cysts containing eosinophilic, colloid-like material. B: The spaces are lined by
a monotonous population of epithelial cells forming tufts and abortive micropapillations.
Biomarkers and Genetics

Low-grade DCIS lesions typically show diffuse and strong expression
of ER and progesterone receptor (PR) (Fig. 3.49, e-Fig. 3.31), have a
low proliferative rate, and do not show HER2 protein overexpression
or gene amplification. In contrast, high-grade DCIS lesions may be ER
FIGURE 3.45 Ductal carcinoma in situ with squamous features. This intraductal
proliferation is composed of a pure population of variably atypical squamous epithelial
cells, some of which are glycogenated.
FIGURE 3.46 Ductal carcinoma in situ (DCIS) with clear cell features. In this intermediate-
grade DCIS, the cells show prominent cytoplasmic clearing.
FIGURE 3.47 Ductal carcinoma in situ with mucinous features. Abundant extracellular
mucin is evident in the duct lumen.
FIGURE 3.48 Ductal carcinoma in situ with adenoid cystic differentiation. Amorphous
eosinophilic material and mucoid material is present around and between the
neoplastic cells.
FIGURE 3.49 Estrogen receptor immunostain in low-grade ductal carcinoma in situ

showing strong nuclear staining of the neoplastic cells.
and PR positive or negative, have a high proliferative rate, and frequently

show HER2 protein overexpression and gene amplification (Fig. 3.50,
e-Fig. 3.32). The accumulation of p53 protein and p53 gene mutations are
commonly seen in high-grade DCIS. Intermediate-grade DCIS lesions, as
might be expected, are more heterogeneous with regard to expression of
FIGURE 3.50 HER2 immunostain in high-grade ductal carcinoma in situ. The neoplastic
cells show intense membrane staining, indicating HER2 protein overexpression.
these biomarkers.4,5,9,24,36 The cells comprising low-grade, intermediate-

grade, and most high-grade DCIS lack expression of high-molecular-
weight CKs by CK5/6 immunostaining; however, a small proportion of
high-grade DCIS contains CK5/6-positive cells.10,37
Currently, the only biomarker used clinically in DCIS is ER status.
Tamoxifen has been shown to significantly reduce the risk of local recur-
rence in patients with ER-positive DCIS.38 Therefore, determination of the
ER status of DCIS should be a routine part of the pathologic evaluation
of these lesions.
Recent molecular studies have provided evidence that low-grade
DCIS and high-grade DCIS are genetically distinct disorders. Low-grade
lesions are characterized by chromosomal losses at 16q and 17p and gains
at 1q, whereas high-grade lesions show losses at 11q, 14q, 8p, and 13q and
gains at 17q, 8q, and 5p, among other alterations.4,5,39 In addition, all of
the major molecular subtypes of invasive breast cancer identified in gene
expression profiling studies (i.e., luminal A, luminal B, HER2, and basal-
like) have been identified in DCIS, primarily using surrogate biomarkers
(ER, PR, HER2, CK5/6, and EGFR). However, the frequency with which
these subtypes are observed among cases of DCIS differs from their fre-
quency among invasive breast cancers.40

DCIS is a non-obligate precursor to invasive breast cancer, but its natural
history is poorly understood. Invasive carcinoma has been reported in 14%
to 60% of women with low-grade DCIS who have had no more than a diag-
nostic biopsy. The risk of subsequent invasive breast cancer among women
with high-grade DCIS is even less well known because most patients with
this lesion have had some form of therapeutic intervention.24,36
Treatment of DCIS is aimed at complete eradication of the lesion to
prevent local recurrence, particularly to prevent the development of an
invasive carcinoma. Treatment options include mastectomy and breast-
conserving therapy (i.e., excision and radiation therapy or excision alone)
with or without tamoxifen. Although mastectomy achieves cure rates
approaching 100%, this represents overtreatment for many patients, espe-
cially those with small, mammographically detected lesions. In current
clinical practice, mastectomy is generally reserved for those with extensive
disease, and most patients with more limited DCIS are managed with
breast-conserving therapy. The use of radiation therapy following exci-
sion reduces the risk of the local recurrence rate by approximately 50%,
and tamoxifen further reduces the risk of local recurrence among patients
treated with excision and radiation therapy.41 However, some patients
with DCIS are likely to be adequately treated with excision alone, and the
identification of such a subset of patients is an area of active research.42-44
Patients with DCIS who undergo breast-conserving treatment are at
risk for recurrence in the breast. Approximately half of the recurrences
are DCIS and half are invasive carcinomas. Factors most often reported
TABLE 3.4 Features Associated with Local Recurrence Following

Breast-Conserving Treatment for Ductal Carcinoma In Situ
• Young age (<45 years)

• High nuclear grade
• Comedo necrosis
• Larger lesion size
• Involved margins of excision
to be associated with local recurrence are listed in Table 3.4. The status of
the margins of excision is arguably the most important of these factors. It
has been suggested that patient age, grade of DCIS, size of the lesion, and
width of the margins can be combined into a prognostic index to predict
the likelihood of local recurrence after breast-conserving therapy and to
select among the various treatment options (the University of Southern
California-Van Nuys Prognostic Index, USC-VNPI).45 Although all of the
factors included in the USC-VNPI are important considerations in the
selection of the appropriate treatment options for patients with DCIS,
their relative importance and the interactions among them are not well
understood.46 Most recently, a nomogram incorporating 10 clinical and
pathologic features has been developed to stratify risk among patients
with DCIS,47 but its role in clinical practice requires validation.
The identification of biomarkers that might be helpful in determin-
ing which patients with DCIS are at high and low risk of progression to
invasive breast cancer is an area of active investigation,48 but at the present
time no markers singly or in combination are sufficiently validated for rou-
tine clinical use. Recently, a commercially available reverse transcription
polymerase chain reaction–based assay has been introduced to help stratify
the risk of local recurrence and subsequent invasive cancer in patients with
DCIS, but the clinical utility of this assay remains to be determined.49
Although there should theoretically be no risk of lymph node
involvement or metastatic disease among patients with DCIS, a small
proportion of women given the diagnosis of DCIS develop axillary nodal
or distant metastases due to the presence of invasive carcinoma that was
not sampled or not recognized. Approximately 10% to 15% of women
with DCIS have tumor cells demonstrable in sentinel lymph nodes when
evaluated by CK immunostains.43,50,51 The results of two recent clinical tri-
als, however, suggest that the presence of these small tumor cell deposits
in sentinel lymph nodes is of no clinical significance.52,53
Differential Diagnosis
Although the diagnoses of UDH, ADH, and DCIS can usually be made
employing the criteria enumerated earlier, there are a few problematic
areas that deserve particular comment.
UDH versus ADH: In problematic cases, the features most useful

in the distinction between UDH and ADH are the presence in ADH of a
monomorphic population of cells similar to those seen in low-grade DCIS
and the presence of regular, round, punched-out spaces with surrounding
cellular polarization, or rigid bridges and arcades of uniform thickness con-
taining a monotonous and evenly placed cell population. In lesions with
equivocal features, a diagnosis of UDH should be favored. Immunostaining
for CK5/6 and ER may be of value in difficult cases. The presence of a
distinct population of cells that are negative for CK5/6 and show strong
expression of ER supports a diagnosis of ADH, whereas a mosaic pattern
of CK5/6 expression and variable ER expression favors UDH.2,10
UDH versus DCIS: The distinction of UDH from low-grade DCIS
and from high-grade DCIS is straightforward in most cases. The pres-
ence of necrosis should always raise concern for DCIS. However, if the
intraductal proliferation otherwise has the characteristic cytologic and
architectural features of UDH, necrosis does not preclude that diagnosis.
A more common problem is the distinction of UDH from intermediate-
grade DCIS. This problem may arise because some intermediate-grade
DCIS exhibits cytologic and/or architectural features that overlap with
UDH (particularly, irregular cell placement and cellular streaming). The
use of CK5/6 and ER immunostaining may be very helpful in making
this distinction because UDH exhibits a mosaic pattern of expression and
shows variable expression of ER, whereas in intermediate-grade DCIS, the
cells are uniformly CK5/6 negative and are generally diffusely ER posi-
tive. Although some high-grade DCIS lesions are CK5/6 positive, nuclear
atypia and pleomorphism in these lesions should serve to distinguish them
from UDH.10,37
ADH versus DCIS: The distinction between ADH and limited exam-
ples of low-grade DCIS is arguably the most controversial area in the evalu-
ation of intraductal proliferative lesions. There are no qualitative features,
singly or in combination, that permit the reliable distinction of these lesions
from each other, even with the use of standardized histologic criteria.
Moreover, there are no biomarkers that are of value in this distinction. As
indicated earlier, the key feature used to distinguish between these lesions
is the size or extent of the atypical cell population criteria, but there is no
uniform agreement on the size that should be used for this purpose.8,10-12
These difficulties have led some to question the wisdom of attempting to
distinguish between ADH and small, low-grade DCIS. However, there are
well-documented, clinically important differences between ADH and fully
developed low-grade DCIS that are taken into consideration in formulating
management recommendations (Table 3.5). Therefore, an effort should be
made to distinguish ADH from DCIS whenever possible.
DCIS versus Other Intraductal Proliferative Lesions: Collagenous
spherulosis may be mistaken for cribriform pattern DCIS.54 In problematic
cases, immunostains for myoepithelial cells are of value in highlighting the
myoepithelial cells around the spherules, which contrasts with the pres-
ence of polarized epithelial cells that are present around the lumens in
TABLE 3.5 Clinically Important Differences between Atypical Ductal

Hyperplasia (ADH) and Low-Grade Ductal Carcinoma In Situ (DCIS)
ADH Low-Grade DCIS
Magnitude of breast cancer risk Lower (3–5×) Higher (8–10×)

Laterality of breast cancer risk Either breast Ipsilateral breast
(same site)
Management Surveillance and/ Complete local
or tamoxifen eradication
cribriform pattern DCIS. The presence of lobular carcinoma in situ (LCIS)

in collagenous spherulosis may create particular difficulties in the distinc-
tion from DCIS because of the monomorphism imparted by the presence
of LCIS cells.55 In such cases, immunostains for E-cadherin and p120
catenin in addition to stains for myoepithelial markers may be helpful in
making this distinction (see Chapter 5).56
Gynecomastoid hyperplasia may be mistaken for micropapillary
pattern DCIS because both lesions are characterized by the formation of
micropapillae. However, the micropapillae of gynecomastoid hyperpla-
sia typically have a tapered configuration and heterogeneity of cell and
nuclear placement within the micropapillary structures. In contrast, the
micropapillations of DCIS are most often club shaped and have uniform
distribution of cells and nuclei within the micropapillae.
DCIS versus LCIS: In most cases, the distinction between DCIS
and LCIS is straightforward, but some cases create diagnostic problems
because (a) DCIS and LCIS show overlap in their patterns of involvement
of the ductal–lobular system (i.e., LCIS can involve ducts and DCIS can
involve recognizable lobules); (b) some DCIS lesions have features that
overlap with those of LCIS (e.g., small cells with monomorphic nuclei,
intracytoplasmic vacuoles, and solid growth pattern); and (c) some LCIS
lesions have features that overlap with those of DCIS (e.g., nuclear pleo-
morphism, comedo necrosis, apocrine features, and pseudocribriform
pattern). Furthermore, the diagnoses of DCIS and LCIS are not mutually
exclusive; these two lesions may coexist in the same breast, in the same
terminal duct lobular unit, and even in the same space (Fig. 3.51). Poor
cellular cohesion and the presence of intracytoplasmic vacuoles favor a
diagnosis of LCIS, whereas cohesive growth, lack of intracytoplasmic
vacuoles, polarization of cells at the periphery of the involved spaces, and
microacinar formation favor a diagnosis of DCIS. In problematic cases,
immunostaining for E-cadherin and p120 catenin may be of value: LCIS
is typically E-cadherin negative and shows cytoplasmic expression of
p120 catenin, whereas the cells of DCIS usually show strong membrane
staining for E-cadherin and p120.37,56 This is discussed in more detail in
Chapter 5.
FIGURE 3.51 Ductal carcinoma in situ and lobular carcinoma in situ involving the same
spaces.
DCIS versus Invasive Carcinoma: Several types of invasive carci-

noma exhibit patterns that simulate those of DCIS, particularly invasive
cribriform carcinoma and adenoid cystic carcinoma. In addition, some
invasive cancers invade the stroma in circumscribed or rounded nests
that simulate DCIS. Conversely, involvement by DCIS of lobules and,
particularly, of sclerosing lesions may produce patterns that simulate
invasive carcinoma. Immunostains for myoepithelial markers are of great
value in such cases; the presence of a peripheral myoepithelial cell layer
around nests of neoplastic cells supports a diagnosis of DCIS, whereas the
absence of peripheral myoepithelial cells supports a diagnosis of invasive
carcinoma.3,57-59
DCIS versus Lymphovascular Invasion: Invasive carcinoma cells
within lymphovascular spaces may form circumscribed nests that fill
the spaces and produce patterns that simulate DCIS. The presence of
comedo necrosis in the cell nests further compounds the diagnostic dif-
ficulty. Although the identification of endothelial cells lining the spaces
is of value in making the distinction between lymphovascular invasion
and DCIS, these may be difficult to appreciate. In our experience, the
two features that are the most helpful in recognizing the nests as lympho-
vascular invasion rather than as DCIS are the presence of uninvolved,
benign ducts within the area of concern and, at low-power examination,
the distribution of the cell nests in a pattern characteristic of the distribu-
tion of lymphovascular spaces (i.e., in a periductal location and in asso-
ciation with other vascular structures). Immunostains for the endothelial
marker D2-40 should be used with caution in this setting, since D2-40 is
expressed by myoepithelial cells as well as by lymphatic endothelial cells.
This could, therefore, result in the erroneous interpretation of DCIS as
intralymphatic carcinoma.60
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4
Columnar Cell Lesions and
Flat Epithelial Atypia
Lesions characterized by the presence of columnar epithelial cells lining

the terminal duct lobular units (TDLUs) of the breast have long been
recognized by pathologists and have been described under a wide variety
of names.1-4 These lesions are of current interest because they are being
encountered increasingly in breast biopsies performed due to the presence
of mammographic microcalcifications.
Classification and Histologic Features

The classification of these lesions has varied among different authors. We
currently categorize them as columnar cell change, columnar cell hyper-
plasia, or flat epithelial atypia (FEA).2
Columnar cell change is characterized by enlarged TDLUs with
variably dilated acini that often have an irregular contour (Fig. 4.1,
e-Fig. 4.1). The acini are lined by one or two layers of columnar epithe-
lial cells with uniform, ovoid to elongated nuclei oriented in a regular
fashion perpendicular to the basement membrane, with evenly dispersed
chromatin and without conspicuous nucleoli (Fig. 4.2, e-Figs. 4.2–4.6).
Mitotic figures are rarely encountered. Apical cytoplasmic blebs or snouts
are often present at the luminal surface of the epithelial cells but are not
usually prominent or exaggerated. Flocculent secretions may be present in
the lumina of the involved acini. In addition, luminal calcifications may
be present.
Columnar cell hyperplasia similarly features enlarged TDLUs
with variably dilated acini, which are often irregular in contour. These
acini are lined by columnar cells that have cytologic features similar
to those seen in columnar cell change but that, in addition, show cel-
lular stratification of more than two cell layers. Again, the nuclei are
ovoid to elongated and, for the most part, oriented perpendicular to the
107
FIGURE 4.1 Columnar cell change. Low-power view illustrating a terminal duct lobular unit
with variably dilated acini. The acini have irregular contours and some contain secretions.
FIGURE 4.2 Columnar cell change. High-power view demonstrates the columnar cell
nature of the epithelium lining this acinus. Many of the cells have apical cytoplasmic blebs
or snouts. The nuclei are slender, ovoid, and oriented in a regular fashion perpendicular
to the basement membrane, imparting a “picket-fence”-like appearance.
basement membrane. Crowding or overlapping of the nuclei in these

proliferative foci may give the appearance of nuclear hyperchromasia.
The proliferating columnar cells may form small mounds, tufts, or abor-
tive micropapillations (Fig. 4.3, e-Figs. 4.7–4.11). Exaggerated apical
Columnar Cell Lesions and Flat Epithelial Atypia ——— 109
B
FIGURE 4.3 Columnar cell hyperplasia. A: Scanning magnification demonstrates an
enlarged terminal duct lobular unit with variably dilated acini, many of which have irregu-
lar contours. Flocculent luminal secretions and luminal calcifications are evident in many
of these spaces. B: Medium-power view demonstrates stratified columnar cells, many
with prominent apical snouts. C: At high power, the columnar cells show stratification
with foci of cellular tufting. The nuclei generally maintain their ovoid shape as well as their
regular orientation perpendicular to the basement membrane. Crowding and overlapping
of nuclei impart the appearance of nuclear hyperchromasia.
C
cytoplasmic snouts and abundant flocculent intraluminal secretions are

often present, and some of the cells comprising such lesions may have a
hobnail appearance (Fig. 4.4). These lesions frequently show intralumi-
nal calcifications, which in some instances may have the configuration
of psammoma bodies.
Lesions that we now categorize as columnar cell change and colum-
nar cell hyperplasia have been previously described under a variety of
other names, including atypical lobules type A, columnar alteration of
lobules, columnar metaplasia, blunt duct adenosis, enlarged lobular units
with columnar alteration, hyperplastic unfolded lobules, hyperplastic
enlarged lobular units, and columnar alteration with prominent apical
snouts and secretions without atypia.5
FEA consists of enlarged TDLUs in which the native epithelial cells
are replaced by one to several layers of cuboidal to columnar epithelial
cells that show cytologic atypia of the low-grade or monomorphic type.6
The acini of the involved TDLUs are variably dilated and often have round
contours. The cytologic atypia of FEA is characterized by the presence of
relatively monomorphic, round to ovoid nuclei that resemble those seen
in the cells comprising low-grade ductal carcinoma in situ (DCIS). These
nuclei are not regularly oriented perpendicular to the basement membrane
and show an increase in the nuclear/cytoplasmic ratio (Figs. 4.5 and 4.6,
e-Figs. 4.12–4.15). As a result of this increased nuclear/cytoplasmic ratio, the
involved TDLUs typically have a more basophilic appearance at scanning
FIGURE 4.4 In this example of columnar cell hyperplasia, there is only mild cellular
proliferation, but many of the cells have a hobnail appearance.
A
FIGURE 4.5 Flat epithelial atypia (FEA). A: At scanning magnification, the dilated acini
in this enlarged terminal duct lobular unit are evident. Secretions and calcifications are
present within the acinar lumina. The acini generally have a more rounded configuration
than that of columnar cell change and columnar cell hyperplasia. B: Medium-power view
illustrating lining cells with prominent apical cytoplasmic snouts. The nuclei are round
to ovoid and relatively uniform in appearance. C: This high-magnification view illustrates
the low-grade, monomorphic-type cytologic atypia that characterizes most examples
of FEA.
C
magnification than normal TDLUs. Cellular and nuclear stratification are

seen in some cases. The nuclear chromatin may be evenly dispersed or
slightly marginated and nucleoli are variably prominent. Mitotic figures
may be seen, but are uncommon. In some cases, apical cytoplasmic snouts
or blebs may be prominent or exaggerated, and the cells cytologically may
resemble those comprising the tubules of tubular carcinoma. In a minority
of cases of FEA, the nuclei retain a more oval shape as well as an orientation
B
FIGURE 4.6 Flat epithelial atypia. A: This medium-power illustration demonstrates dilated
acini with relatively round contours. Flocculent luminal secretions are evident, as are
prominent apical cytoplasmic snouts. B: High-power view illustrating one to several layers
of epithelial cells with monomorphic-type cytologic atypia.
perpendicular to the basement membrane (Fig. 4.7). However, in contrast

to the relatively slender, bland nuclei of columnar cell change and colum-
nar cell hyperplasia, the chromatin in these nuclei may show clumping and
margination, nucleoli are variably prominent, and the nuclear/cytoplasmic
ratio of the cells is markedly increased.
B
FIGURE 4.7 Flat epithelial atypia. A: Low-power view demonstrating basophilia of
involved acini, the result of the cells having an increased nuclear/cytoplasmic ratio.
B: In this case, the nuclei of the columnar cells maintain an ovoid shape. These cells are
distinguished from those of columnar cell change and columnar cell hyperplasia by the
presence of marked nuclear stratification, a higher nuclear/cytoplasmic ratio, and irregular
nuclear chromatin with variably prominent nucleoli.
The epithelial cells in FEA lesions may form small mounds, tufts, or
short, abortive micropapillations. However, complex architectural patterns
such as well-developed, club-shaped micropapillations, rigid cellular bridges,
bars and arcades, or sieve-like fenestrations are not present nor is there
evidence of cellular polarization within the micropapillations and bars or
around the fenestrations. Thus, it should be apparent that flat is a relative

term and simply denotes the absence of the complex architectural patterns
described previously. These lesions also frequently show intraluminal cal-
cifications, which in some instances may have the configuration of psam-
moma bodies (Fig. 4.8). However, the mammographic appearance of the
calcifications associated with FEA is non-specific.7 A variable lymphocytic
infiltrate may be present in the stroma surrounding spaces involved by FEA
(Fig. 4.9). Lesions currently included within the category of FEA have pre-
viously been described by a wide assortment of other names, most notably
“clinging carcinoma” of the monomorphic type (Table 4.1).8-10
FIGURE 4.8 Calcifications in flat epithelial atypia are most often irregular and granular (A),
but may be psammomatous (B).
FIGURE 4.9 Flat epithelial atypia. A prominent lymphocytic infiltrate is evident in

intralobular stroma of the involved terminal duct lobular units.
Columnar cell change, columnar cell hyperplasia, and FEA may

coexist in the same breast and even within the same TDLU. Therefore,
these diagnoses should not be considered mutually exclusive. The histo-
logic features of these lesions are summarized in Table 4.2. An algorithmic
approach to the diagnosis of columnar cell lesions and FEA is presented
in Figure 4.10.
TABLE 4.1 Other Names Used to Describe Lesions within the Category
of Flat Epithelial Atypiaa
Atypical columnar cell lesions (1)

Atypical cystic duct (11)
Atypical cystic lobules (12)
Atypical lobules type A (13)
Clinging carcinoma (monomorphic type) (14, 15)
Columnar alteration with prominent apical snouts and secretions with atypia (16)
Columnar cell change with atypia (5)
Columnar cell hyperplasia with atypia (5)
Ductal intraepithelial neoplasia of the flat monomorphic type (17)
Hypersecretory hyperplasia with atypia (18)
Pretubular hyperplasia (19)
Small ectatic ducts lined by atypical ductal cells with apocrine snouts (20)
The names are listed in alphabetical order.

a
TABLE 4.2 Histologic Features of Columnar Cell Change, Columnar

Cell Hyperplasia, and Flat Epithelial Atypia
Columnar Cell Columnar Cell Flat Epithelial

Change Hyperplasia Atypia
Topography Enlarged TDLUs Enlarged TDLUs Enlarged TDLUs

with variably with variably with variably
dilated acini; dilated acini; dilated acini;
acini tend to acini tend to acini tend to have
be irregular in be irregular in round contours;
contour contour involved TDLUs
often more
basophilic than
normal TDLUs
Architecture One to two layers Cellular stratification, One to several
of columnar with more than layers of cuboidal
cells two cell layers to columnar
of columnar epithelial
cells, sometimes cells; complex
forming tufts or architectural
mounds; complex patterns not
architectural present
patterns not
present
Cytology Columnar cells Columnar cells with Cuboidal to
with uniform uniform ovoid to columnar
ovoid to elongated nuclei; cells with
elongated nucleoli absent monomorphic-
nuclei; or inconspicuous; type cytologic
nucleoli hobnail cells may atypia; cells may
absent or be present resemble those of
inconspicuous tubular carcinoma
Apical snouts Often present; Often present; may Often present; may
usually not be exaggerated be exaggerated
prominent or
exaggerated
Intraluminal May be present; May be present and May be present and
secretions usually not prominent prominent
prominent
Calcifications May be present Often present; Often present;
may be may be
psammomatous psammomatous
TDLU, terminal duct lobular unit.

Modified from Schnitt SJ, Vincent-Salomon A. Columnar cell lesions of the breast. Adv
Anat Pathol. 2003;10(3):113-124.
Columnar Cell Lesion
Cellular Stratification
No Yes
Simple Complex
Cytologic Atypia* (arcades, bridges, micropapillae)
No Yes Cytologic Atypia*

Atypical
Columnar Flat No Yes Ductal
Cell Change Epithelial Hyperplasia
Atypia or
DCIS
Columnar Flat (depending on details of
combined architectural and
Cell Epithelial cytologic features)
Hyperplasia Atypia
*monomorphic type atypia
FIGURE 4.10 Algorithmic approach to the diagnosis of columnar cell lesions and flat
epithelial atypia. DCIS=ductal carcinoma in situ.

The cells comprising columnar cell change, columnar cell hyperpla-
sia, and FEA exhibit expression of low-molecular-weight cytokeratins
(CKs), such as CK8, 18, and 19 (Fig. 4.11).9,10,21,22 In contrast, most if not
all of these cells lack expression of high-molecular-weight cytokeratins
(HMW-CKs) as defined by antibody 34βE12 and antibodies to CK5 or
CK5/6 (Fig. 4.12, e-Fig. 4.16).10,21-23 The practical implication of the
FIGURE 4.11 Flat epithelial atypia immunostained for low-molecular-weight cytokeratins

using antibody CAM 5.2 demonstrating intense cytoplasmic staining of the epithelial cells.
B
FIGURE 4.12 Cytokeratin (CK)5/6 immunostains of columnar cell change (A) and flat
epithelial atypia (B). The epithelial cells comprising these lesions lack expression of CK5/6.
Surrounding myoepithelial cells are variably CK5/6 positive.
latter observation is that absence of HMW-CK expression cannot be

used as an objective marker of atypia in columnar cell lesions.23-25
Columnar cell lesions and FEA typically exhibit intense and diffuse
nuclear expression of estrogen receptor (Fig. 4.13, e-Fig. 4.17).22,12,26-30
and progesterone receptor21,22,30 in the majority of the cells. These cells
B
FIGURE 4.13 Estrogen receptor expression in columnar cell change (A) and flat epithelial
atypia (B). Intense, diffuse nuclear expression of estrogen receptor is a characteristic of
these lesions.
also show strong cytoplasmic expression of bcl-2 (Fig. 4.14).26 The cells
comprising columnar cell lesions and FEA have a low proliferative rate
as determined by Ki-67 staining (Fig. 4.15).26 However, these cells appear
to have a higher proliferation rate and less apoptosis than the cells lining
normal TDLUs.30
FIGURE 4.14 Cytoplasmic expression of bcl-2 in flat epithelial atypia.
Recent genetic studies have indicated that FEA is a clonal lesion that
shares genetic alterations with low-grade DCIS and tubular carcinoma,
such as losses at chromosome 16q. These findings have been cited as evi-
dence that FEA represents a precursor of these lesions.22,17,31-34 Of note,
some examples of columnar cell change and columnar cell hyperplasia have
also been found to exhibit chromosomal losses and gains at various loci.22,35
FIGURE 4.15 Ki-67 immunostain of flat epithelial atypia showing rare positive cells.

FEA commonly coexists with well-developed examples of atypical duc-
tal hyperplasia (ADH) (Fig. 4.16, e-Figs. 4.18–4.20), low-grade DCIS
(Fig. 4.17, e-Fig. 4.21), and tubular carcinoma (Fig. 4.18, e-Fig. 4.22),
and the cells comprising the FEA share cytologic and immunophenotypic
B
FIGURE 4.16 Flat epithelial atypia (FEA) and atypical ductal hyperplasia (ADH). A: The
spaces are mostly lined by a flat layer of epithelium characteristic of FEA. However, two
spaces show a few rigid arcades with fenestrations. The architectural complexity in these
areas, although limited, is still sufficient for a diagnosis of ADH. B: High-power view
showing that the arcades are composed of cells cytologically identical to those comprising
the areas of FEA. C: The spaces at the bottom of this field show FEA. The space in the
center of the field shows a focal cribriform proliferation. Again, the cells in this prolifera-
tion are cytologically identical to those of the FEA, but the complex architecture in this
space merits a diagnosis of ADH. D: Some of the spaces in this terminal duct lobular unit
show the characteristic features of FEA. One space shows a rigid bridge and cellular tufts
composed of cells cytologically identical to those comprising the FEA. However, because
of the more complex architecture in this space, a diagnosis of ADH is warranted.
D
f eatures with the cells comprising these other lesions.8-10,36 A number of

authors have also noted an association between columnar cell lesions/
FEA and lobular neoplasia (lobular carcinoma in situ and atypical lobu-
lar hyperplasia [ALH]) (Fig. 4.19, e-Fig. 4.23)31,19,37-40 as well as the triad
of FEA, tubular carcinoma, and lobular carcinoma in situ (Fig. 4.20,
e-Fig. 4.24).31,37,41 Based on the foregoing observations in conjunction
with recent genetic data, it is reasonable to conclude that at least some
columnar cell lesions, particularly FEA, are neoplastic proliferations
that may well represent either a precursor to or the earliest morpho-
logic manifestation of low-grade DCIS as well as a precursor to invasive
B
FIGURE 4.17 Flat epithelial atypia (FEA) and low-grade ductal carcinoma in situ (DCIS).
A: Some of the spaces in this illustration demonstrate the features characteristic of FEA
(bottom half of field). In other spaces, similar cells form solid and cribriform patterns
characteristic of low-grade DCIS. B: Higher power view demonstrates the similarity of the
cytologic features of the cells comprising the FEA and the DCIS.
FIGURE 4.18 Flat epithelial atypia (FEA, lower left) and tubular carcinoma. Note the
cytologic similarities between the cells comprising the FEA and those comprising the
tubules of the tubular carcinoma.
A
FIGURE 4.19 A: Columnar cell change (left) and lobular carcinoma in situ (right) in
adjacent terminal duct lobular units. B: Flat epithelial atypia (right) and lobular carcinoma
in situ (left) in adjacent terminal duct lobular units. C: Flat epithelial atypia and lobular
carcinoma in situ involving a single space.
C
FIGURE 4.20 The triad of flat epithelial atypia, tubular carcinoma, and lobular carcinoma
in situ.
carcinoma, particularly tubular carcinoma.32,33 Although this is of great

interest from a biological point of view, the clinical implications of these
observations can only be determined from follow-up studies.
Follow-up studies of patients with columnar cell lesions suggest
that they are associated with a mild (˜1.5-fold) increase in breast cancer
risk.38-40,42,43 However, this increased risk is not clearly independent of the
risk associated with concomitant proliferative lesions such as usual ductal
hyperplasia (UDH).
The few follow-up studies of patients with FEA, all of which are
retrospective, have demonstrated an extremely low rate of recurrence
and progression to invasive breast cancer, even among those who had
no more than a diagnostic biopsy (Table 4.3).8,14,44,45 These results suggest
that despite the morphologic, immunophenotypic, and genetic similarities
between the cells of FEA and those of fully developed examples of low-
grade DCIS and tubular carcinoma, the risk of progression of FEA to inva-
sive cancer appears to be extremely low when present as an isolated lesion.
In fact, based on the available data, the breast cancer risk associated with
these lesions appears to be substantially lower than that associated with
established forms of atypical hyperplasia (ADH and ALH). As a result,
the 2011 WHO Working Group concluded that despite the presence of
“atypia” in the name, FEA should not be regarded as equivalent to ADH
or ALH with regard to cancer risk assessment or patient management.6
Additional clinical follow-up studies are needed to better understand the
magnitude of the breast cancer risk associated with these lesions.
FIGURE 4.20 The triad of flat epithelial atypia, tubular carcinoma, and lobular carcinoma
in situ.
carcinoma, particularly tubular carcinoma.32,33 Although this is of great

interest from a biological point of view, the clinical implications of these
observations can only be determined from follow-up studies.
Follow-up studies of patients with columnar cell lesions suggest
that they are associated with a mild (˜1.5-fold) increase in breast cancer
risk.38-40,42,43 However, this increased risk is not clearly independent of the
risk associated with concomitant proliferative lesions such as usual ductal
hyperplasia (UDH).
The few follow-up studies of patients with FEA, all of which are
retrospective, have demonstrated an extremely low rate of recurrence
and progression to invasive breast cancer, even among those who had
no more than a diagnostic biopsy (Table 4.3).8,14,44,45 These results suggest
that despite the morphologic, immunophenotypic, and genetic similarities
between the cells of FEA and those of fully developed examples of low-
grade DCIS and tubular carcinoma, the risk of progression of FEA to inva-
sive cancer appears to be extremely low when present as an isolated lesion.
In fact, based on the available data, the breast cancer risk associated with
these lesions appears to be substantially lower than that associated with
established forms of atypical hyperplasia (ADH and ALH). As a result,
the 2011 WHO Working Group concluded that despite the presence of
“atypia” in the name, FEA should not be regarded as equivalent to ADH
or ALH with regard to cancer risk assessment or patient management.6
Additional clinical follow-up studies are needed to better understand the
magnitude of the breast cancer risk associated with these lesions.
TABLE 4.3 Outcome of Patients Diagnosed with Flat Epithelial Atypiaa
Eusebi et al. EORTC 10853 de Mascarel et al.

(14) (44) (45)
Number of patients 25 59 115
Type of study Retrospective Prospective, Retrospective

review of randomized review of cases
breast biopsies clinical trial originally
originally considered
considered “clinging
benign carcinoma of the
monomorphic
type”
Treatment Diagnostic Excision alone • Surgical biopsy
biopsy; no or excision alone (n = 70)
attempt at and • Surgical biopsy
excision radiation and radiation
therapyb therapy (n = 45)
Follow-up 19.2 y (mean) 5.4 y (median) 13.3 y (median)
Number (%) with 1 (4%) c
0 3 (2.6%)
local recurrence
Number with 0 0 3 (2.6%)d
subsequent
invasive breast
cancer
a
In these studies, the term “clinging carcinoma” of the monomorphic type was used to
describe the lesions evaluated; these lesions would currently be categorized as “flat epithelial
atypia.”
b
Number of patients in each treatment arm with pure “clinging carcinoma” arm not
provided.
c
The “local recurrence” in this case consisted of a “clinging carcinoma” lesion histologically
identical to the original lesion; it is, therefore, not possible to determine whether this simply
reflected persistence of the original lesion due to inadequate excision or if this represents a
true local recurrence.
d
All were invasive ductal carcinomas that developed in the ipsilateral breast 1, 7, and 12
years later (two following surgical biopsy alone; one following surgical biopsy and radiation
therapy).
Columnar cell change, columnar cell hyperplasia, and FEA are all
characterized by TDLUs with enlarged, dilated acini containing vari-
able amounts of secretory material. Therefore, all of these lesions may
be mistaken for microcysts on scanning magnification (Figs. 4.5–4.7
and 4.9). Examination of the dilated acini at a higher power will reveal
the columnar nature of the lining epithelial cells, distinguishing these

lesions from microcysts that are typically lined by attenuated, cuboi-
dal, or apocrine epithelium. In addition, higher power examination
will reveal the monomorphic-type cytologic atypia that characterizes
FEA and that represents the cardinal feature that distinguishes this
lesion from both columnar cell change/hyperplasia and microcysts.17
The features useful in making the distinction of columnar cell change,
columnar cell hyperplasia, and FEA from each other are provided in
Table 4.2. In our view, however, it is more important to distinguish both
columnar cell change and columnar cell hyperplasia from FEA than it
is to distinguish columnar cell change and columnar cell hyperplasia
from each other.
Columnar cell change, columnar cell hyperplasia, and FEA must also
be distinguished from benign apocrine lesions, such as apocrine metapla-
sia and apocrine hyperplasia. Although the cells comprising columnar
cell lesions, FEA, and apocrine lesions may all feature apical cytoplasmic
snouts, the cells of apocrine lesions possess more abundant, granular,
eosinophilic cytoplasm than those of these other lesions. In addition, the
nuclei of apocrine lesions tend to be round and have a single prominent
nucleolus. Furthermore, whereas hobnail-type cells and highly exagger-
ated apical snouting are seen in some columnar cell lesions and FEA,
they are not seen in apocrine lesions. Finally, in contrast to the cells of
columnar cell lesions and FEA, which typically show strong expression
of estrogen receptor and bcl-2, apocrine epithelial cells characteristically
lack expression of both of these proteins.26
When columnar cell lesions become more proliferative, the differen-
tial diagnostic considerations include UDH, ADH, and DCIS. Columnar
cell hyperplasia may have areas that begin to mound up into broad-
based tufts, raising the differential diagnosis with UDH. Although the
pronounced columnar nature of the cells and the pencillate nuclei favor
columnar cell hyperplasia over UDH, making this distinction is of no
diagnostic importance.
Some lesions composed of columnar cells show more complex archi-
tectural patterns, such as well-developed micropapillations, rigid cellular
bridges, bars and arcades, or punched-out fenestrations, with at least some
evidence of cellular polarization within the micropapillations and bars
or around the fenestrations. It has been suggested that such lesions be
categorized as columnar cell hyperplasia with moderate or severe atypia46
or as columnar cell hyperplasia with architectural atypia or with architec-
tural and cytologic atypia.22 However, we believe that it is most prudent to
categorize columnar cell lesions that show both cytologic atypia and com-
plex architectural patterns as either ADH or DCIS, depending upon the
severity and extent of the cytologic and architectural features.47 Columnar
cell lesions with cytologic atypia in which the features do not possess the
combined cytologic and architectural criteria for ADH and DCIS are best
classified as FEA.1
FIGURE 4.21 High-grade ductal carcinoma in situ (DCIS). Despite its flat growth pattern,
the degree of nuclear pleomorphism warrants categorization of this lesion as high-grade
DCIS and not flat epithelial atypia.
Finally, some high-grade DCIS lesions exhibit a flat (“clinging”)

growth pattern. However, the marked nuclear pleomorphism seen in
these lesions is not a feature of FEA.6 The presence of such high-grade
nuclear features merits the designation of high-grade DCIS, even if the
cells comprise only a single cell layer (Fig. 4.21, e-Fig. 4.25).14 Such lesions
are rarely seen in the absence of other architectural patterns of high-grade
DCIS.
Pathology Workup and Management Recommendations

The appropriate pathology workup and clinical management of patients
whose biopsy specimens show columnar cell lesions and FEA are evolving
as information regarding these lesions accumulates. Recommendations
for the workup and management of these lesions when encountered in
either core-needle biopsy (CNB) or excision specimens are summarized
in Table 4.4.
Core-Needle Biopsy
The limited available data suggest that neither additional pathology
workup nor excision is required when either columnar cell change or
columnar cell hyperplasia is encountered in a CNB specimen. Results
from small retrospective studies have indicated that up to 40% of patients
with FEA on CNB have a worse lesion on excision.48-57 However, given
TABLE 4.4 Workup and Management Recommendations for Columnar

Cell Lesions and Flat Epithelial Atypia
Workup and Management Workup and Management

when Found in Core-Needle when Found in Excisional
Type of Lesion Biopsy Specimen Biopsy Specimen
Columnar cell • No additional levels • No additional levels

change
• Excision not required • No further treatment
required
Columnar cell • No additional levels • No additional levels
hyperplasia • Excision not required • No further treatment
required
Flat epithelial • Obtain multiple levels to • Obtain multiple levels
atypia look for features diagnostic to look for features
of ADH or DCIS diagnostic of ADH or
• Need for excision uncertain; DCIS
radiologic–pathologic • Submit all tissue
correlation suggested to
assess need for excision
ADH, atypical ductal hyperplasia; DCIS, ductal carcinoma in situ.
the methodologic limitations of these studies and the wide variation in the
reported upgrade rate, the need for routine surgical excision following a
diagnosis of FEA on CNB is uncertain. The 2011 WHO Working Group
recommended that in such cases, radiologic–pathologic correlation be
used to determine the need for surgical excision.6
Excisional Biopsy
There are no data to suggest that the presence of columnar cell change or
columnar cell hyperplasia in an excisional biopsy specimen requires fur-
ther pathologic evaluation or additional treatment. However, the presence
of FEA in an excisional biopsy specimen should prompt a careful search
for areas with diagnostic features of ADH or DCIS by obtaining additional
levels from the block or blocks containing the lesion and by the submis-
sion of the remainder of the breast tissue for histological examination.
There are several other considerations regarding FEA in excisional
biopsy specimens that merit discussion. When a proliferation that fulfills
the diagnostic criteria for ADH or DCIS is found to arise in a background
of FEA, it seems most prudent to manage the patient as one would man-
age ADH or DCIS in any other setting. However, there are two issues that
remain to be resolved when FEA is found to coexist with diagnostic areas
of DCIS, particularly in cases in which the cytologic features of the cells
comprising the FEA are similar or identical to those of the cells comprising
the diagnostic areas of DCIS. The first is whether or not the FEA should
be taken into consideration in determining the size or the extent of the
DCIS lesion and the second is whether or not the presence of FEA at the
excision margins is sufficient to consider the margins “positive,” requiring
further surgical resection. Given the available clinical outcome data, albeit
limited, we currently do not take into consideration foci of FEA when
determining the size of a coexistent DCIS lesion or in the evaluation of
the status of the margins of excision.
Another increasingly common problem is the management of
patients whose breast biopsies, after thorough examination, show FEA
without diagnostic areas of ADH or DCIS. Again, we would argue that
despite the fact that these lesions may well be composed of cells that are
identical to those seen in some forms of DCIS, the few available clinical
follow-up studies of these lesions suggest that they are associated with
a risk of subsequent breast cancer that is considerably lower than that
seen with fully developed forms of low-grade DCIS. Therefore, managing
patients with such lesions as if they had DCIS would result in the over-
treatment of many patients. Nevertheless, the identification of FEA in a
breast biopsy should serve as a “red flag,” alerting the pathologist to the
possible presence of coexisting ADH, DCIS, lobular neoplasia, and inva-
sive carcinoma (particularly tubular carcinoma), lesions for which clinical
management strategies are better defined.
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55. Lavoue V, Roger CM, Poilblanc M, et al. Pure flat epithelial atypia (DIN 1a) on core
needle biopsy: study of 60 biopsies with follow-up surgical excision. Breast Cancer Res
Treat. 2011;125(1):121-126.
56. Lee TY, Macintosh RF, Rayson D, Barnes PJ. Flat epithelial atypia on breast needle
core biopsy: a retrospective study with clinical-pathological correlation. Breast J.
2010;16(4):377-383.
57. Ingegnoli A, d’Aloia C, Frattaruolo A, et al. Flat epithelial atypia and atypical ductal
hyperplasia: carcinoma underestimation rate. Breast J. 2009;16(1):55-59.
5
Lobular Carcinoma In Situ and
Atypical Lobular Hyperplasia
Lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH)

are related lesions most often characterized by a proliferation of small,
loosely cohesive, neoplastic epithelial cells within the terminal duct
lobular units (TDLUs); they differ only in the degree of TDLU involve-
ment by the neoplastic cells. These lesions have traditionally been con-
sidered markers of a generalized (bilateral) increase in breast cancer risk.
However, recent evidence suggests that at least some examples represent
direct breast cancer precursors.
Some authors have advocated grouping ALH and LCIS together
under the single term lobular neoplasia.1 The purported advantages to this
approach are that it removes the word “carcinoma” from the diagnosis of an
in situ lesion and that it eliminates the need to make the morphologic dis-
tinction between ALH and LCIS, which in some cases is problematic and
somewhat arbitrary. However, the major disadvantage of this approach is
that it combines into one category lesions that, although parts of a spectrum,
differ in the magnitude of the associated breast cancer risk.2 Therefore, it
remains clinically useful to continue to distinguish ALH from LCIS.3
Lobular Carcinoma in Situ

LCIS is a relatively uncommon lesion. In the premammographic era, it
was found in 0.5% to 3.6% of otherwise benign breast biopsies. Although
this lesion is more frequently encountered in biopsies performed because
of mammographic microcalcifications, the histologically identified calci-
fications are most often located in normal breast tissue adjacent to areas
of LCIS.4 The age range in which LCIS is encountered is broad, but it is
most common in younger women. The mean age at diagnosis is usually
reported to be between 44 and 46 years and 80% to 90% of women are
premenopausal. Multicentricity in the ipsilateral breast has been identified
in 60% to 80% of cases. Bilaterality has been reported in 25% to 30%.4
136
LOBULAR CARCINOMA IN SITU AND ATYPICAL LOBULAR HYPERPLASIA ——— 137
In the premammographic era, LCIS was always an incidental finding in
breast tissue removed because of another abnormality. Most LCIS identi-
fied in biopsies performed because of mammographic microcalcifications is
also incidental. However, in a small proportion of cases, the mammograph-
ically identified microcalcifications are associated with the LCIS itself.5,6
Gross Pathology
There are no grossly identifiable abnormalities attributable to LCIS.
Histopathology
In TDLUs involved by the classical form of LCIS, the acini are filled with
and distended by a solid proliferation of small cells with small, uniform,
round-to-oval nuclei that have relatively homogeneous chromatin and
nucleoli that are inconspicuous to absent. Mitoses are infrequent (Fig. 5.1,
e-Fig. 5.1). At least half of the acini in a lobule must be filled with and
distended by this cell population in order to qualify for a diagnosis of
LCIS; lesser degrees of involvement warrant a diagnosis of ALH (see the
subsequent text). The assessment of lobular distension is to some degree
subjective and there is no gold standard by which to determine its pres-
ence. One practical approach is to compare the caliber of involved acini
with that of uninvolved acini, although the caliber of the latter may be
quite variable in some cases. The cells of LCIS are most often loosely
cohesive. In some cases, residual lumina may be observed in the involved
acini; however, the LCIS cells themselves do not polarize around these
extracellular lumina. This form of LCIS, with small cells with small,
A
FIGURE 5.1 Lobular carcinoma in situ (LCIS). A: Low-power view illustrating several
enlarged terminal duct lobular units in which the acini are filled with and distended by a
population of uniform, small cells. B: The cells are loosely cohesive and have small, uniform
nuclei with homogeneous chromatin; nucleoli are not evident. These are type A LCIS cells.
B
uniform nuclei, was referred to as type A by Haagensen et al.1 However,

Haagensen, Azzopardi, and others noted that some LCIS lesions may be
characterized by cells that show more abundant cytoplasm and slightly
more variation in cell and nuclear size and shape and by the presence of
nucleoli; these have been referred to as type B cells (Fig. 5.2, e-Fig. 5.2).1
A
FIGURE 5.2 Lobular carcinoma in situ (LCIS). A: The acini of this lobule are filled with solid
proliferation of relatively uniform cells. B: These cells are poorly cohesive and exhibit mild
nuclear variability and occasional prominent nucleoli. These are type B LCIS cells.
B
In some instances, type A and type B cells coexist within a single space
(Fig. 5.3). Regardless of cell or nuclear size, the cytoplasm of LCIS cells is
typically pale to lightly eosinophilic. In almost all cases of LCIS, at least
some cells contain intracytoplasmic vacuoles that may contain an eosino-
philic mucin globule (Fig. 5.4). These vacuoles may be so subtle that spe-
cial histochemical stains for mucin are required for their demonstration.
At the other end of the spectrum, the vacuoles may be large enough to
FIGURE 5.3 Lobular carcinoma in situ with a mixture of smaller, central type A cells and
larger, peripheral type B cells.
FIGURE 5.4 Lobular carcinoma in situ. Many of the cells contain small intracytoplasmic
vacuoles, some of which contain an eosinophilic globule.
produce signet ring cell forms (Fig. 5.5). The cells of LCIS typically show
loss of cell membrane expression of the adhesion molecule E-cadherin
(see the subsequent text).7-10
In about three-quarters of the cases, the cells of LCIS involve the
terminal ducts and/or extralobular ducts.3 The growth of the cells within
these ducts may be solid but is more often pagetoid (i.e., the LCIS cells are
FIGURE 5.5 Lobular carcinoma in situ. In this case, the cells have signet ring cell
morphology, with large intracytoplasmic, mucin-filled vacuoles that displace the nuclei
to the cell periphery.
FIGURE 5.6 Lobular carcinoma in situ (LCIS) with pagetoid involvement of a duct. The
LCIS cells are present between the duct basement membrane and an attenuated layer of
residual native duct epithelium.
insinuated between the duct basement membrane and the native ductal epi-
thelial cells) (Fig. 5.6, e-Fig. 5.3). Some ducts involved by LCIS have irregu-
lar outer contours with the formation of protruding buds that produce an
appearance resembling a “clover leaf” (Fig. 5.7, e-Fig. 5.4).3 Although some
authors believe that ductal involvement alone is sufficient for a diagnosis
of LCIS, others render a diagnosis of ductal involvement by ALH when
diagnostic changes of LCIS are not concurrently identified in the lobules.11
FIGURE 5.7 Lobular carcinoma in situ with duct involvement in a “clover leaf” pattern.
The outer layer of myoepithelial cells is retained in the acini and

ducts involved by LCIS, but may be attenuated. In some cases, scattered
myoepithelial cells are admixed with the neoplastic epithelial cells within
the involved spaces.
In addition to involving lobular acini and ducts, LCIS may involve
a variety of lesions including usual ductal hyperplasia, ductal carcinoma
in situ (DCIS), fibroadenomas, intraductal papillomas, columnar cell
lesions/flat epithelial atypia, benign sclerosing lesions (such as sclerosing
adenosis, radial scars, and complex sclerosing lesions), and collagenous
spherulosis (Fig. 5.8, e-Fig. 5.5). The involvement of these lesions by LCIS
B
FIGURE 5.8 Lobular carcinoma in situ involving a radial scar. A: At low power, the central
fibroelastotic nidus of the radial scar can be appreciated. The surrounding, radially distrib-
uted ductal-lobular structures show a solid epithelial proliferation. B: At higher power, the
cells comprising the epithelial proliferation have the characteristic cytologic features of
lobular carcinoma in situ.
FIGURE 5.9 Pleomorphic lobular carcinoma in situ. The cells show variation in nuclear
size and shape and irregularity of the nuclear membranes.
may be solid, pagetoid, or both, and the resulting patterns can create diag-
nostic problems (see the Differential Diagnosis section).
In some cases, the nuclear, cytoplasmic, and/or architectural fea-
tures deviate from the classical appearances of LCIS described previ-
ously. Pleomorphic LCIS is characterized by nuclear pleomorphism with
at least a two- to threefold variation in nuclear size, nuclear membrane
irregularity, and variably prominent nucleoli (Fig. 5.9, e-Fig. 5.6).3,7,9,10,12-14
In some cases of pleomorphic LCIS, the cells have apocrine features with
abundant, eosinophilic cytoplasm (Fig. 5.10, e-Fig. 5.7). Mitoses may be
FIGURE 5.10 Pleomorphic lobular carcinoma in situ. In this case, the cells have apocrine
features, with abundant eosinophilic cytoplasm.
observed and may be numerous. Foci of central, comedo-type necrosis

may be present in the involved spaces, and this necrotic debris may under-
go calcification (Fig. 5.11). The combination of nuclear pleomorphism,
mitoses, and central necrosis often raises the possibility of high-grade
DCIS (see the Differential Diagnosis section). As for classical LCIS, the
cells of pleomorphic LCIS typically show loss of cell membrane expres-
sion of E-cadherin.7,13,14
Cytoplasmic alterations that may be seen in LCIS include clear cell
change (Fig. 5.12) and apocrine change,15 which may be seen in both pleo-
morphic LCIS as mentioned previously and in otherwise classical types of
B
FIGURE 5.11 Pleomorphic lobular carcinoma in situ. A: Some of the ducts show comedo
necrosis and calcification. B: At high power, nuclear pleomorphism and mitotic activity are
evident. Although the histologic features are worrisome for high-grade DCIS, the loose
cellular cohesion and intracytoplasmic vacuoles in some of the cells are clues to the cor-
rect diagnosis. C: Immunostain for E-cadherin shows no expression of this protein in the
tumor cells, consistent with a lobular phenotype.
C
LCIS (Fig. 5.13, e-Fig. 5.8). In some cases, the cells have a myoid appear-
ance, with dark, eccentric nuclei and cytoplasmic eosinophilia similar to
features that characterize rhabdomyoblasts (Fig. 5.14).
Variant architectural alterations may be seen. Some cases exhibit a
mosaic growth pattern in which the cells are cohesive and have distinct cell
borders (rather than the usual loosely cohesive pattern) (Fig. 5.15). In other
cases, the lesion is composed of cells with the cytologic features of classical
LCIS (either type A or type B cells), but the acini are markedly distended
and foci of comedo necrosis may be present (Fig. 5.16, e-Fig. 5.9).9,10,14,16
These lesions have sometimes been referred to as “florid LCIS.” The
involvement of collagenous spherulosis by LCIS produces a pseudocribri-
form pattern that mimics cribriform pattern DCIS.14,17
FIGURE 5.12 Lobular carcinoma in situ with clear cell change.

FIGURE 5.13 Lobular carcinoma in situ with apocrine change.
FIGURE 5.14 Lobular carcinoma in situ with myoid cells resembling rhabdomyoblasts.
FIGURE 5.15 Lobular carcinoma in situ with cohesive, mosaic pattern of cell growth.
Distinct cell borders are evident.
A
FIGURE 5.16 Lobular carcinoma in situ (LCIS) with comedo necrosis. A: Several ducts
contain a solid proliferation of cells with foci of central, comedo-type necrosis. B: At high
power, the cells have the cytologic features of classical LCIS. C: E-cadherin immunostain
demonstrating loss of E-cadherin expression in the neoplastic cells supporting a lobular
phenotype.
C

The cells of classical LCIS have a low proliferative rate, are typically
strongly and diffusely estrogen receptor (ER) positive, and rarely, if
ever, show HER2 overexpression or gene amplification or p53 gene
alterations.3,7 Although the cells of pleomorphic LCIS are also usually
ER positive, some cases demonstrate weaker ER expression than classical

LCIS and some are ER negative (particularly those with prominent apo-
crine features). In addition, these lesions commonly have a moderate to
high proliferative rate, may show HER2 protein overexpression (Fig. 5.17)
and gene amplification, may exhibit p53 protein accumulation suggestive
of p53 mutation, and typically express androgen receptor.13,18
B
FIGURE 5.17 Pleomorphic lobular carcinoma in situ. H&E-stained section (A) and cor-
responding HER2 immunostain (B), the latter demonstrating strong (3+) HER2 protein
overexpression.
As noted previously, one of the most characteristic features of the

cells of LCIS (including classical and pleomorphic types) is the loss of
expression of the cell adhesion molecule E-cadherin (Fig. 5.18, see also
Figs. 5.11C and 5.16C, e-Fig. 5.10). In addition, loss of expression or
abnormal cellular localization of other molecules in the E-cadherin–
catenin cell adhesion complex is also observed (see the Differential
Diagnosis section). This likely provides the molecular basis for the poor
cellular cohesion that characterizes these lesions. As in invasive lobular
carcinomas, molecular mechanisms resulting in loss of E-cadherin expres-
sion include loss of heterozygosity on chromosome 16q22.1, the site of the
E-cadherin gene accompanied by other events such as E-cadherin gene
mutation or silencing of gene expression by promoter methylation.7,8,19
However, as will be discussed subsequently, not all examples of LCIS
show complete absence of E-cadherin staining by immunohistochemistry.
Studies of classical examples of LCIS using comparative genomic
hybridization (CGH) and array-based CGH have indicated that losses
at 16q and gains at 1q are characteristic features of these lesions.
Pleomorphic LCIS and so-called florid LCIS also exhibit 16q losses and
1q gains, but some show more complex genomic alterations than classical
LCIS and are characterized by more numerous chromosomal losses and
gains and more frequent amplifications, suggesting that they are geneti-
cally more advanced lesions.18 Of note, 16q losses are also commonly seen
in flat epithelial atypia, atypical ductal hyperplasia, low-grade DCIS, and
low-grade invasive breast cancers, providing a genetic link between LCIS
and lesions in the low-grade ductal neoplasia pathway.7,8,10
FIGURE 5.18 Loss of expression of E-cadherin in lobular carcinoma in situ (LCIS). The LCIS
cells (left) are E-cadherin negative, whereas the epithelial cells of a normal terminal duct
lobular unit (right) show strong membrane staining for E-cadherin.

Long-term follow-up studies have indicated that LCIS is associated with
an approximately seven- to tenfold increase in breast cancer risk compared
with women in the reference population. The absolute risk for a woman
with LCIS developing breast cancer is approximately 1% per year and this
risk persists for more than 25 years. Some studies of patients with “lobular
neoplasia” have suggested a lower breast cancer risk than this, but these
studies included cases of both LCIS and ALH. Most studies with long-term
follow-up (>15 years) have indicated that the risk of subsequent cancer is
approximately equal in both breasts, although in some studies ipsilateral
breast cancers predominate, at least within the first 5 to 10 years.3,4,20
Features that might identify patients with LCIS who are particularly
likely to develop invasive breast cancer have not been consistently identified.
A positive family history in women <40 years of age, maximal distension of
involved spaces, a mixture of type A and B cells, >10 involved spaces, and
focal E-cadherin staining have all been reported to be associated with a
greater risk of cancer development.4,21 However, the association between
these features and the development of invasive breast cancer is not sufficient-
ly strong or reproducible to be of value in clinical practice. Histologic and
cytologic features have been used to divide LCIS into three grades (lobular
intraepithelial neoplasia 1, 2, and 3).22 The grading of LCIS emphasizes the
heterogeneity of lesions within this category and may have merit. However,
this grading system requires validation in clinical follow-up studies.
LCIS has long been considered to simply represent a breast cancer
risk factor rather than a direct breast cancer precursor. Arguments sup-
porting LCIS as a risk factor include the bilateral nature of the breast
cancer risk and the fact that in most studies, the majority of breast cancers
that develop in women with LCIS are invasive ductal carcinomas of no
special type. However, invasive lobular carcinomas are much more preva-
lent among the cancers that develop in these women than in the general
population (accounting for 23% to 75% of the cancers). In addition, coex-
istent LCIS and invasive lobular carcinomas frequently exhibit the same
genetic alterations, suggesting a precursor–product relationship.23 These
data suggest that at least some LCIS represent direct breast cancer pre-
cursors.7,8,23 At the present time, however, it is not possible to determine
which LCIS lesions are more likely to act as risk indicators and which
are more likely to act as precursors. Therefore, the most appropriate
management for patients with LCIS is close observation (with or without
treatment with selective ER modulators, such as tamoxifen or raloxifene).
It is not necessary to assess or report upon the status of the microscopic
margins of excision in cases of classical LCIS.
The management of patients with LCIS variants such as pleomorphic
LCIS or LCIS with comedo necrosis is more problematic since the natural
history of these lesions is poorly understood.9,10,14 Anecdotal data suggest
that pleomorphic LCIS is more often associated with contemporaneous
invasive carcinoma than is the classical form of LCIS (e-Fig. 5.11). This
observation in association with the observations that these lesions have
“aggressive” cytologic features, have a high mitotic rate, and may have
HER2 and/or p53 gene abnormalities has led some to suggest that patients
with these lesions are more appropriately treated in a manner similar to
patients with DCIS rather than those with classical LCIS10 and that at a
minimum an attempt should be made to excise the lesion with negative mar-
gins. Thus, assessing and reporting on the status of the microscopic margins
of excision for the presence of these variant types of LCIS may have merit.
The management of patients with LCIS diagnosed on core-needle
biopsy is also an area of uncertainty. In a recent literature review, on
average 20% of patients with LCIS on a core-needle biopsy who under-
went surgical excision were found to have a “worse” lesion at excision.24
However, all of these studies had small numbers of patients and the range
of reported upgrade rates was wide (0% to 50%).24 Further, almost all stud-
ies addressing this issue have been retrospective, raising concerns about
possible selection bias with regard to which patients underwent excision.
There is general agreement that patients with LCIS on core-needle biopsy
who should undergo excision include those in whom the pathologic find-
ing of LCIS does not account for the mammographic abnormality, the
LCIS is accompanied by another lesion which by itself would warrant
excision (such as atypical ductal hyperplasia), and the features of LCIS
deviate from the classical type (such as pleomorphic LCIS and LCIS with
comedo necrosis).10,25 Although some have argued that patients with inci-
dentally detected foci of classical LCIS on a core-needle biopsy in whom
there is radiologic–pathologic concordance can be spared excision, others
have advocated excision for these patients as well.
The key features of LCIS are summarized in Table 5.1.
In most cases, the diagnosis of LCIS can be made on morphological
grounds alone employing the criteria described previously. However,
there are several situations in which the diagnosis is problematic.
lcis versus artifactual dyshesion.
In some instances, poor tissue fixation may
result in artifactual dyshesion of the epithelial cells lining normal ductal-
lobular structures or comprising benign lesions, such as a fibroadenoma
or usual ductal hyperplasia (Fig. 5.19, e-Fig. 5.12). This appearance could
result in the overdiagnosis of LCIS (or ALH). Careful examination of the
cells for features characteristic of LCIS, such as intracytoplasmic vacuoles
and pagetoid involvement, is helpful in making this distinction.
lcis versus benign cells. Several benign cell types may be mistaken for the
cells of LCIS. Myoepithelial cells surrounding normal lobular acini or
ducts may assume an epithelioid appearance, with abundant pale to clear
cytoplasm and prominent round nuclei, and this may produce a pattern
Table 5.1 Key Features of Lobular Carcinoma In Situ
Clinical Features
• Primarily premenopausal women
• Usually an incidental finding in breast biopsies performed for another
abnormality; rare cases with comedo necrosis may present with
mammographic microcalcifications
• Multicentricity in 60–80% of cases; bilaterality in 25–30%
• Associated with seven- to tenfold increase in breast cancer risk (absolute
risk ~1% per year)
Pathologic Features
Classical type:
• Lobular acini filled with and distended by solid proliferation of small,
loosely cohesive cells with small, bland nuclei
• May involve ducts in solid or pagetoid pattern
• Comedo necrosis rarely occurs
Pleomorphic type:
• Nuclear pleomorphism, with two- to threefold variation in nuclear size,
nuclear membrane irregularity, and variably prominent nucleoli
• Comedo necrosis may be seen
• Cells may show prominent apocrine features
• Distinction from high-grade DCIS may be problematic
• Loss of expression of E-cadherin characteristic of all forms of LCIS, but
E-cadherin expression may be seen in some cases (see text)
DCIS, ductal carcinoma in situ; LCIS, lobular carcinoma in situ.
mimicking pagetoid involvement by LCIS. However, these cells lack the

intracytoplasmic vacuoles and dyshesion of LCIS cells. Similarly, intraepi-
thelial histiocytes may on occasion be mistaken for pagetoid LCIS cells.
The small nuclei, foamy to granular cytoplasm, and lack of intracytoplas-
mic vacuoles distinguish these cells from the cells of LCIS (Fig. 5.20). In
problematic cases, stains for myoepithelial cell markers (such as calponin,
smooth muscle myosin heavy chain, and p63) and histiocyte markers
(such as CD68), respectively, may be necessary to resolve these two diag-
nostic problems.
classical lcis versus pleomorphic lcis. In some cases, it may be difficult to
distinguish classical LCIS composed of cells with larger, more variable
nuclei (type B cells) from pleomorphic LCIS. While the nuclei of the cells
of type B LCIS are larger and more variable than those in type A LCIS,
the variability in nuclear size and shape in these lesions is relatively subtle
FIGURE 5.19 Terminal duct lobular unit with poor tissue fixation. The epithelial cells have
a dyshesive appearance that mimics lobular carcinoma in situ (LCIS). However, diagnostic
cytologic features of LCIS are not present.
and the nuclei do not exhibit the two- to threefold (or greater) variation
in size and the nuclear membrane irregularities of pleomorphic LCIS. The
2011 WHO Working Group recommended that in cases in which there is
uncertainty, the lesion should be categorized as classical LCIS with type
B cells rather than as pleomorphic LCIS.3
FIGURE 5.20 Intraepithelial histiocytes mimicking pagetoid ductal involvement by lobu-

lar carcinoma in situ. The abundant, foamy cytoplasm and small nuclei are clues to the
correct diagnosis.
lcis versus alh. LCIS and ALH are composed of cells with identical cyto-
logic features and the distinction between the two lesions is based on
the extent of involvement of the TDLUs. If less than half of the acini in
a lobule show filling and distension by the neoplastic cell population or
if all the acini are involved but are not distended, a diagnosis of ALH is
warranted. Cases in which the cells have the cytologic features of pleo-
morphic LCIS are an exception to this rule. In such cases, a diagnosis of
pleomorphic LCIS is warranted even in the absence of acinar filling and
distension because there is no recognized entity of pleomorphic ALH.
lcis versus invasive carcinoma.The distinction between LCIS and invasive
carcinoma is usually not a problem. However, LCIS involving a preexist-
ing sclerosing lesion, such as a sclerosing adenosis, radial scar, or complex
sclerosing lesion (see Fig. 5.8), may produce diagnostic difficulties. This
differential diagnostic problem is considered in Chapter 7.
lcis versus dcis.Although the distinction between LCIS and DCIS is usu-
ally straightforward, there are cases that present diagnostic difficulties for
several reasons (see Chapter 3). The diagnosis in some such cases may
be resolved with careful attention to histologic details found on routine
H&E-stained sections, but others may require the use of adjunctive immu-
nostains to help arrive at the correct diagnosis. A number of markers may
be useful in the differential diagnosis of LCIS versus DCIS. The most
widely employed of these has been E-cadherin.26-28 As noted previously,
loss of expression of E-cadherin is a characteristic feature of LCIS. In
contrast, the cells of DCIS typically show strong, diffuse membrane stain-
ing for E-cadherin regardless of architectural pattern or nuclear grade.
Unfortunately, not all cases of LCIS show complete absence of E-cadherin
expression. In some cases, the level of expression may simply be reduced
compared with the level of expression in the surrounding normal epithe-
lial cells. In other cases, the LCIS cells show a fragmented, patchy, or
incomplete pattern of membrane staining for E-cadherin and may show
cytoplasmic staining (Fig. 5.21, e-Fig. 5.13). In still other cases, strong,
diffuse membrane staining for E-cadherin may be observed, similar to
that seen in DCIS.3 Thus, although the absence of E-cadherin expression
supports a diagnosis of LCIS, the presence of E-cadherin expression does
not necessarily preclude that diagnosis. It may be that the extent and pat-
tern of loss of E-cadherin expression in LCIS is related to the molecular
mechanism of E-cadherin inactivation in a given case.
In addition, in some cases, benign cells admixed with the LCIS cells
will show E-cadherin expression including myoepithelial cells, residual
normal ductal epithelial cells, and the cells of intraductal proliferative
lesions, such as usual ductal hyperplasia (Fig. 5.22). Care should be
taken not to misinterpret E-cadherin expression in these benign cells
as E-cadherin staining of the neoplastic cells of LCIS. Several other
markers have been proposed as useful in the distinction of LCIS from
B
FIGURE 5.21 Lobular carcinoma in situ with E-cadherin expression. A: The histologic
features of this in situ lesion are diagnostic of LCIS involving a duct. B: E-cadherin immu-
nostain shows variable membrane staining and perinuclear cytoplasmic staining for
E-cadherin in the neoplastic cells.
DCIS including β-catenin, high-molecular-weight cytokeratin (HMW-CK)

expression using antibody 34βE12, and p120 catenin.29,30 It has been sug-
gested that the presence of HMW-CK staining using the 34βE12 antibody
is characteristic of LCIS, whereas the absence of staining supports a diag-
nosis of DCIS. However, we have not found this antibody sufficiently reli-
able in this context to be of clinical use. Immunostaining for p120 catenin
B
FIGURE 5.22 Lobular carcinoma in situ (LCIS) and usual ductal hyperplasia (UDH) in the
same duct. A: The pale cells in the outer portion of this cellular proliferation are LCIS cells;
the cells comprising UDH are present in the center. B: E-cadherin immunostain demon-
strates strong membrane expression in some of the cells in this proliferation. However,
the E-cadherin staining is present in the cells of UDH and cytoplasmic processes of
myoepithelial cells; the LCIS cells are E-cadherin negative.
may be of value in the distinction of LCIS from DCIS.10,30 LCIS exhibits a

cytoplasmic staining pattern for p120 catenin; in contrast in DCIS, a cell
membrane staining pattern is observed. Thus, immunostaining for p120
catenin complements E-cadherin staining in the differential diagnosis of
LCIS (the cells of which show lack of membrane staining for E-cadherin
and cytoplasmic expression of p120 catenin) versus DCIS (the cells of
which exhibit membrane staining for both E-cadherin and p120 catenin)
(Fig. 5.23).
It should be emphasized that in some cases, the distinction between
LCIS and DCIS remains problematic even after careful histologic exami-
nation and after the application of these adjunctive immunostains. In such
cases, a diagnosis of in situ carcinoma with ductal and lobular features or
in situ carcinoma with indeterminate features may be most prudent. How
best to manage patients with such ambiguous in situ lesions (i.e., more like
LCIS or more like DCIS) is an unresolved issue.
Several situations in which problems in the distinction between
LCIS and DCIS occur merit specific comment:
A
FIGURE 5.23 Pleomorphic lobular carcinoma in situ with comedo necrosis. A: Medium-
power image shows several spaces that are filled with and distended by a solid prolifera-
tion of epithelial cells with focal comedo necrosis. While this appearance suggests ductal
carcinoma in situ, even at this power poor cellular cohesion is evident, a feature that
should raise the suspicion of a lobular lesion. B: High-power view demonstrates nuclear
pleomorphism, cellular dyshesion, and necrosis. C: Immunostain for E-cadherin demon-
strating absence of staining in the cells comprising this in situ lesion. D: Immunostain for
p120 catenin demonstrating cytoplasmic staining for this protein. The combination of
absence of staining for E-cadherin and cytoplasmic staining for p120 catenin supports a
lobular phenotype.
D
TABLE 5.2 Histologic Criteria Useful for Distinguishing between

Lobular Carcinoma In Situ (LCIS) and Small Cell, Solid Pattern Ductal
Carcinoma in Situ (DCIS) Involving the Terminal Duct Lobular Units
Feature LCIS DCIS
Loss of cohesion Present Absent

Intracytoplasmic vacuoles More common Less common
Pagetoid ductal involvement More common Less common
Microacini Absent Present
Polarization of cells at periphery Absent Present
• LCIS versus Small Cell, Solid DCIS: It may be quite difficult to

distinguish LCIS from low-grade DCIS with a solid growth pattern
when the latter lesion involves recognizable lobules. Histologic crite-
ria that are most useful in making this distinction are summarized in
Table 5.2 (Fig. 5.24, e-Fig. 5.14). However, none of these features is
entirely specific and even with the use of these criteria, some lesions
will defy unequivocal categorization. In such cases, adjunctive
immunostains for E-cadherin and other markers as noted previously
may be useful in arriving at the correct diagnosis.
A
FIGURE 5.24 Low-grade ductal carcinoma in situ (DCIS), solid pattern, involving a lobule.
A: Low-power view demonstrates acini filled with and distended by a population of small,
uniform cells. The differential diagnosis includes lobular carcinoma in situ and DCIS. B: At
high power, microacini are identified, supporting the diagnosis of DCIS.
B
• Pleomorphic LCIS versus High-Grade DCIS: This distinction may

also be quite difficult, particularly in cases of pleomorphic LCIS
that show comedo necrosis and prominent apocrine differentia-
tion resulting in large cell size (see Fig. 5.23). Features that favor a
diagnosis of pleomorphic LCIS are cellular dyshesion, the presence
of intracytoplasmic vacuoles, and the presence of classical LCIS in
adjacent TDLUs. In problematic cases, immunostains for E-cadherin
and the other markers noted previously may help resolve the issue.
However, how best to manage patients with pleomorphic LCIS is
uncertain.
• LCIS with Comedo Necrosis versus DCIS with Comedo Necrosis:
As noted previously, some examples of LCIS composed of classical
type A or B cells may show comedo necrosis in the involved spaces
and may, therefore, simulate DCIS (see Fig. 5.16, e-Fig. 5.8). The
recognition of the characteristic cytologic features of the LCIS cells
(particularly dyshesion and intracytoplasmic vacuoles) will lead to
the correct diagnosis. Again, in problematic cases, immunostains for
E-cadherin and other makers discussed previously should be of value
in arriving at the correct diagnosis.
• LCIS Involving Collagenous Spherulosis versus Cribriform Pattern
DCIS: When LCIS involves collagenous spherulosis, the resulting
appearance can mimic low-grade DCIS with a cribriform pattern
(Fig. 5.25, e-Fig. 5.15).13 Both lesions are characterized by the com-
bination of small cells with uniform nuclei and round, punched-out
spaces. Features favoring a diagnosis of LCIS involving collagenous
C
FIGURE 5.25 Lobular carcinoma in situ (LCIS) involving collagenous spherulosis. A: This
duct contains a proliferation that shows a combination of small, uniform cells and round,
punched-out spaces mimicking cribriform pattern ductal carcinoma in situ. However,
eosinophilic basement membrane material and myxoid material are present within the
spaces consistent with collagenous spherulosis. B: Immunostain for E-cadherin shows lack
of staining of the monomorphic epithelial cells of LCIS. Focal staining is seen in myoepi-
thelial cells surrounding the spaces. C: Calponin immunostain highlights myoepithelial cells
around the spaces; the LCIS cells are negative.
spherulosis are the presence within the spaces of eosinophilic

basement membrane material or myxoid material, the absence of
polarized epithelial cells around spaces, and the presence of intra-
cytoplasmic vacuoles within the neoplastic cells. In problematic
cases, immunostains for E-cadherin and/or myoepithelial markers
can aid this distinction. In LCIS involving collagenous spherulosis,
the monomorphic neoplastic cells are E-cadherin negative. The cells
surrounding the punched-out spaces are myoepithelial cells and stain
for markers, such as calponin, smooth muscle myosin heavy chain,
and p63. In contrast, the neoplastic cells of cribriform pattern DCIS
are E-cadherin positive and no myoepithelial cells are present within
the proliferation. It should be emphasized, however, that the myo-
epithelial cells in collagenous spherulosis also stain for E-cadherin;
care should be taken not to misinterpret these as E-cadherin-positive
neoplastic epithelial cells.
• Pagetoid LCIS versus Pagetoid DCIS: Pagetoid ductal involvement
is a common feature of LCIS. However, DCIS may also involve
ducts in a pagetoid pattern and the distinction between the two may
be difficult (Fig. 5.26, e-Fig. 5.16). Again, cellular dyshesion and the
presence of intracytoplasmic vacuoles favor LCIS, while cellular
cohesion and moderate- to high-grade nuclear atypia favor DCIS.
Immunostains for E-cadherin and other markers as noted previously
may be required to arrive at the correct diagnosis.
A
FIGURE 5.26 DCIS with pagetoid ductal involvement. A: The pattern mimics that seen
with pagetoid duct involvement by lobular carcinoma in situ. B: At high power, the cells
show moderate nuclear pleomorphism and cohesion (compare with Figs. 5.6 and 5.7).
B
Atypical Lobular Hyperplasia

ALH is always an incidental microscopic finding in breast tissue removed
for another abnormality. It is more commonly seen in breast biopsies
performed for mammographic microcalcifications than in those in which
the indication for biopsy is a palpable mass. However, like LCIS, ALH is
usually incidental in these biopsies and the histologically identified calci-
fications are most often in adjacent normal tissue.
Gross Pathology
ALH is not grossly identifiable.
Histopathology
ALH is characterized by a proliferation of small, poorly cohesive epithe-
lial cells in the TDLUs that are cytologically, immunophenotypically, and
genetically identical to those of LCIS. However, the degree of involvement
of the TDLUs is less extensive. All of the acini in a given TDLU may not
be involved by the process, and those acini that are involved show less
distension and expansion by the neoplastic cells than is seen in LCIS. In
fact, in some acini, the ALH cells are few and do not fill or obliterate the
lumen (Figs. 5.27-5.29, e-Figs. 5.17 and 5.18).
There is no sharp dividing line between ALH and LCIS, and diagnos-
tic criteria for this distinction vary among experts. We utilize the criteria of
Page et al. and require that at least one-half of the spaces in a given lobule
B
FIGURE 5.27 Atypical lobular hyperplasia. A: A portion of one terminal duct lobular unit
contains a cellular proliferation that only minimally distends the involved acini. B: Higher
power view shows small, monomorphic cells within the acini, cytologically identical to
those seen in lobular carcinoma in situ.
be filled with and distended by the characteristic cells to warrant a diagno-

sis of LCIS; cases with lesser degrees of involvement are given the diagno-
sis of ALH, including cases in which all of the acini are involved, but are
not distended.26 As with LCIS, the neoplastic cells may involve ducts. In
the absence of diagnostic changes of LCIS in the lobules, neoplastic cells
within ducts in this setting is considered ductal involvement by ALH.11
B
FIGURE 5.28 Atypical lobular hyperplasia. A: The terminal duct lobular unit on the left
contains a proliferation of small cells within the acini, but the caliber of these acini is simi-
lar to that of the acini in the adjacent uninvolved lobules. B: The cells are loosely cohesive
and have small, uniform nuclei, identical to those seen in lobular carcinoma in situ.

Clinical follow-up studies using strict histopathologic criteria to distin-
guish ALH from LCIS have indicated that the risk of subsequent breast
cancer is lower for ALH than for LCIS. Page et al. initially reported a six-
fold increase in risk for women with ALH when compared with those with
nonproliferative lesions.31 Most recently, this same group reported a lower
B
FIGURE 5.29 Atypical lobular hyperplasia. A: In this minimal example of atypical lobular
hyperplasia in atrophic breast tissue from a postmenopausal woman, there is involvement
of a single terminal duct lobular unit (bottom of field) that can be readily overlooked on
low-power examination. B: However, on higher power examination, the characteristic fea-
tures of atypical lobular hyperplasia are apparent.
relative risk (threefold increase) for women with ALH than that reported in
their prior studies.32 In an update from the Nurses’ Health study,33 women
with ALH had a relative risk for subsequent breast cancer of 5.5, similar to
that initially reported by Page et al., but higher than that reported in their
most recent update. The risk associated with ductal involvement by ALH
alone is lower than the risk associated with ALH involving both lobules
and ducts.11 Approximately 60% of breast cancers that develop in women
with ALH occur in the ipsilateral breast.32,33
The appropriate management of patients with ALH identified on
core-needle biopsy, as for patients with LCIS, is uncertain. On average,
approximately 16% of women with ALH on a core-needle biopsy are
found to have a “worse” lesion on subsequent excision, but the studies
on this subject suffer from the same limitations described previously for
patients with LCIS on core-needle biopsy.24
The most common differential diagnostic dilemma is the distinction of
ALH from LCIS; criteria to make this distinction are discussed above.
Several other differential diagnostic considerations for ALH are similar to
those discussed previously for LCIS, particularly ALH versus artifactual
cellular dyshesion and ALH in a benign sclerosing lesion versus invasive
carcinoma.
It should be noted that there is no generally recognized entity of
lobular hyperplasia. This term has been variously used to describe usual
ductal hyperplasia involving lobules or lobules with an increase in the
number of acinar units (a process that is more correctly referred to as
adenosis). Therefore, the term “lobular hyperplasia” should not be used
in clinical practice or in surgical pathology reports.
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breast: higher risk for subsequent invasive cancer predicted by more extensive disease.
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8. Lerwill MF. The evolution of lobular neoplasia. Adv Anat Pathol. 2006;13(4):157-165.
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10. Rakha EA, Ellis IO. Lobular breast carcinoma and its variants. Semin Diagn Pathol.
2010;27(1):49-61.
11. Page DL, Dupont WD, Rogers LW. Ductal involvement by cells of atypical lobular
hyperplasia in the breast: a long-term follow-up study of cancer risk. Hum Pathol.
1988;19(2):201-207.
12. Frost AR, Tsangaris TN, Silverberg SG. Pleomorphic lobular carcinoma in situ. Pathol
Case Rev. 1996;1:27.
13. Sneige N, Wang J, Baker BA, Krishnamurthy S, Middleton LP. Clinical, histopathologic,
and biologic features of pleomorphic lobular (ductal-lobular) carcinoma in situ of the
breast: a report of 24 cases. Mod Pathol. 2002;15(10):1044-1050.
14. Jacobs TW. Recently recognized variants of lobular carcinoma in situ (LCIS) with an
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211-219.
15. Eusebi V, Betts C, Haagensen DE Jr, Gugliotta P, Bussolati G, Azzopardi JG. Apocrine
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ultrastructural study. Hum Pathol. 1984;15(2):134-140.
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cases. Am J Surg Pathol. 2006;30(11):1445-1453.
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18. Chen YY, Hwang ES, Roy R, et al. Genetic and phenotypic characteristics of pleomor-
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21. Goldstein NS, Bassi D, Watts JC, Layfield LJ, Yaziji H, Gown AM. E-cadherin reactivity
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2008;132(6):979-983.
25. Rendi MH, Dintzis SM, Lehman CD, Calhoun KE, Allison KH. Lobular in-situ neopla-
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26. Maluf HM. Differential diagnosis of solid carcinoma in situ. Semin Diagn Pathol.
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implications. Am J Clin Pathol. 2001;115(1):85-98.
29. Bratthauer GL, Moinfar F, Stamatakos MD, et al. Combined E-cadherin and high
molecular weight cytokeratin immunoprofile differentiates lobular, ductal, and hybrid
mammary intraepithelial neoplasias. Hum Pathol. 2002;33(6):620-627.
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female breast. A long-term follow-up study. Cancer. 1985;55(11):2698-2708.
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lobular hyperplasia as a unilateral predictor of breast cancer risk: a retrospective cohort
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laterality of breast cancer risk according to histologic type of atypical hyperplasia: results
from the Nurses’ Health Study. Cancer. 2007;109(2):180-187.
6
Fibroepithelial Lesions
Some lesions of the breast present as discrete masses composed of both

stromal and epithelial components. Included within this category of
biphasic lesions are fibroadenomas and phyllodes tumors. In addition,
several other breast lesions present as well-defined nodules that possess
histologic features that may resemble fibroadenomas, including several
lesions categorized as “adenomas” and mammary hamartomas.
Fibroadenoma
Fibroadenomas are the most common benign tumors of the female breast.
They are most frequent in young women, especially those under 30 years,
but may be seen at any age. They generally present as a solitary, palpable,
firm, mobile mass and are typically <3 cm in size. Less frequently, multiple
synchronous or metachronous lesions occur, which may be unilateral or
bilateral. In addition, nonpalpable fibroadenomas may be detected by
mammography as a mass, microcalcifications, or both.
Fibroadenomas are easily shelled out surgically and, on gross exami-
nation, appear as firm, well-circumscribed, ovoid nodules that have a
smooth, bosselated outer surface and a tan-gray, bulging, lobulated cut sur-
face, often with visible slit-like spaces (Fig. 6.1). However, the gross appear-
ance may vary from soft and mucoid to extremely fibrotic and calcified.
Microscopically, fibroadenomas are well-circumscribed, but unen-
capsulated lesions characterized by a proliferation of both stromal and
glandular elements. In most fibroadenomas, the proportion of glands and
stroma is relatively consistent throughout the lesion. Two growth pat-
terns are recognized: an intracanalicular pattern, in which the glands are
distorted, stretched, and compressed by the proliferating stroma (Fig. 6.2,
e-Fig. 6.1), and a pericanalicular pattern, in which the stroma surrounds
glandular structures with open lumina (Fig. 6.3, e-Fig. 6.2). These patterns
often coexist and are not thought to have any clinical significance.
However, a fibroadenoma with a prominent intracanalicular pattern could
171
Fibroepithelial Lesions ——— 173
B
FIGURE 6.2 Fibroadenoma, intracanalicular pattern. A: The border of the lesion is
well-circumscribed. Glands are compressed and distorted by the stromal component.
B: Higher power view demonstrates benign glandular epithelium.
B
FIGURE 6.3 Fibroadenoma, pericanalicular pattern. A: In this lesion, the stroma surrounds
glands, which have open lumina. B: Higher power view demonstrates that the tumor is
well-demarcated from the surrounding tissue, but lacks a true capsule.
FIGURE 6.4 Fibroadenoma with prominent leaf-like pattern. The prominent intracanalicular
pattern in this case could result in the misinterpretation of this lesion as a benign phyllodes
tumor or an intraductal papilloma.
most patients who have fibroadenomas with prominent myxoid change

do not have this syndrome. In other cases, particularly in older women,
the stroma may be hyalinized and show calcifications (Fig. 6.7, e-Fig. 6.5).
Focal or diffuse stromal hypercellularity may be seen and when promi-
nent warrants a diagnosis of “cellular fibroadenoma” (Fig. 6.8, e-Fig. 6.6).
However, there are no agreed upon guidelines regarding how cellular the
stroma must be in order to warrant categorization as hypercellular. As will
be discussed later, lesions of this type must be distinguished from phyllodes
tumors. An uncommon feature within the stroma of fibroadenomas is the
presence of multinucleated giant cells (Fig. 6.9).4-6 These can produce a
striking low-power picture, but the cytologic features, although bizarre,
are benign and mitotic figures are not seen. These cells are identical to the
multinucleated giant cells that are occasionally seen in otherwise normal
breast stroma (see also Fig. 1.12). The stroma of fibroadenomas may con-
tain adipose tissue or areas of pseudoangiomatous stromal hyperplasia.
Heterologous stromal elements such as smooth muscle, cartilage, and
bone may also be seen, albeit rarely.
Fibroadenomas may undergo infarction; this occurs most frequently
during pregnancy and lactation.
Estrogen receptor (ER)β, but not ERα, is expressed in the stromal
cells of fibroadenomas,7 whereas the epithelium often shows variable
expression of ERα. The level of expression of stromal ERβ correlates
with young age and stromal cellularity.7 Progesterone receptor can be
expressed in both the epithelium and stroma.
B
FIGURE 6.5 Lobular carcinoma in situ involving a fibroadenoma. A: At low power,
virtually all of the glands in this lesion contain a cellular proliferation. B: High-power view
demonstrates the dyshesive, uniform epithelial cell population characteristic of lobular
carcinoma in situ.
FIGURE 6.6 Fibroadenoma with prominent myxoid stromal change.
FIGURE 6.7 Fibroadenoma with stromal hyalinization and calcifications.

FIGURE 6.8 Cellular fibroadenoma. This lesion exhibits more stromal cellularity than a
typical fibroadenoma, but lacks the cleft-like spaces, leaf-like projections, and periductal
stromal cell condensation of a phyllodes tumor.
A
FIGURE 6.9 Fibroadenoma with stromal giant cells. A: At lower power, cells with large,
hyperchromatic nuclei are evident in the stroma of this fibroadenoma. B: High-power
view reveals multinucleated stromal giant cells.
B
Fibroadenomas are benign lesions. Although they have traditionally

been treated with local excision, management by observation only is a rea-
sonable option when identified in core-needle biopsy specimens. Clinical
follow-up studies have indicated that women with fibroadenomas have a
slightly increased risk of subsequent breast cancer, which is comparable
to that seen in association with other proliferative lesions without atypia
(relative risk ˜1.5 to 2.0).8 The risk is higher among women with complex
fibroadenomas (see the subsequent text). Of note, the presence of atypical
hyperplasia in a fibroadenoma does not appear to be associated with the
same increased level of cancer risk as atypical hyperplasia in otherwise
normal breast tissue.9
The key features of fibroadenomas are summarized in Table 6.1.
TABLE 6.1 Key Features of Fibroadenoma
• Most often occurs in young women but can be seen at any age
• Grossly circumscribed, smooth, bosselated firm nodule; cut surface
lobulated with slit-like spaces
• Microscopically composed of relatively balanced proliferation of stromal
and epithelial elements in intracanalicular and/or pericanalicular patterns
• Epithelium may show usual ductal hyperplasia or apocrine metaplasia;
atypical hyperplasias and carcinomas in situ may rarely be seen
• Stroma may show myxoid change or hyalinization with or without
calcifications
Fibroadenoma variants
Complex Fibroadenoma
Fibroadenomas that contain cysts larger than 3 mm, sclerosing adenosis,
epithelial calcifications, or papillary apocrine change have been called
“complex fibroadenomas” (Fig. 6.10, e-Fig. 6.7).8 In one clinical follow-
up study, complex fibroadenomas were reported to be associated with a
greater subsequent breast cancer risk than fibroadenomas that lack such
changes (relative risk ˜3.0).8
Juvenile Fibroadenoma
Most fibroadenomas in young girls and adolescents have the appearance
of typical fibroadenomas as described previously. The term juvenile fibro-
adenoma has been used to describe fibroadenomas that occur predomi-
nantly in adolescents and are characterized by more stromal cellularity
and a greater degree of epithelial hyperplasia than seen in fibroadenomas
of the usual type (Fig. 6.11, e-Fig. 6.8). Juvenile fibroadenomas may
grow rapidly and may become extremely large and even produce marked
distortion of the breast.10 Some authors have used the term giant fibroad-
enoma to describe such large, juvenile fibroadenomas. However, others
have used “giant fibroadenoma” to describe typical fibroadenomas that
become very large.
FIGURE 6.10 Complex fibroadenoma. Several areas of sclerosing adenosis are evident in
this lesion.
B
FIGURE 6.11 Juvenile fibroadenoma. A: At low power, this tumor from a 14-year-old
girl has a pericanalicular pattern, epithelial proliferation, and increased stromal cellularity.
B: High-power view demonstrates the stromal cellularity.
FIGURE 6.12 Fibroadenomatous change. Changes similar to those seen in fibroadenomas

are present, but the lesion lacks the sharp circumscription of a fibroadenoma; one side
appears to blend into the surrounding breast tissue.
Fibroadenomatous Change (Fibroadenomatoid Hyperplasia)

Fibroadenomatous change or fibroadenomatoid hyperplasia is a term
used to describe histologic changes in the breast similar to those seen in
fibroadenomas, but in which no discrete mass is formed (Fig. 6.12).
Adenomas
A variety of lesions of the breast have been considered to represent
“adenomas.” Some (such as tubular adenomas) may be variants of fibro-
adenoma, whereas others are unrelated to fibroadenomas or to each other.
Tubular Adenoma
Tubular adenomas are well-demarcated lesions that have features in com-
mon with fibroadenomas.11 These relatively rare lesions usually occur in
young women. It is debatable whether tubular adenoma should be con-
sidered a separate entity or merely a variant of fibroadenoma in which
the epithelial elements predominate. On gross examination, like fibro-
adenomas, they are well-defined, but are softer and are characteristically
tan-brown. The hallmark of tubular adenomas is the presence of closely
packed round to oval glands or tubules, with little intervening fibrous
stroma (Fig. 6.13). The tubules are lined by a double cell layer, but the
myoepithelial cells are often inconspicuous. A stromal lymphocytic infil-
trate may be present.
FIGURE 6.13 Tubular adenoma. This sharply circumscribed nodule is composed of

benign, round to oval glands with little intervening stroma.
Lactating Adenoma (Nodular Lactational Hyperplasia)

This lesion consists of a relatively circumscribed breast mass that occurs
only in pregnancy and the postpartum period. Although some lesions with
these features may represent fibroadenomas in which the glands show
superimposed secretory features (Fig. 6.14), most appear to represent
FIGURE 6.14 Fibroadenoma with some glands showing lactational-like changes.

coalescence of hyperplastic lobules with lactational changes (Fig. 6.15,

e-Fig. 6.9).11,12 Therefore, these lesions are probably better regarded as foci
of nodular lactational hyperplasia than true adenomas. Focal or complete
infarction of such lesions may occur.
B
FIGURE 6.15 Lactating adenoma (nodular lactational hyperplasia). A: This circumscribed
lesion is composed of aggregates of hyperplastic lobules that exhibit lactational changes.
B: Higher power view demonstrates the characteristic features of lactating breast tissue.
Apocrine Adenoma
Lesions composed of a nodular aggregate of ducts or glands with promi-
nent papillary apocrine change and apocrine cysts have been termed
apocrine adenomas.13
Other Types of Adenoma
Ductal adenomas and pleomorphic adenomas appear to represent vari-
ants of intraductal papilloma and are discussed in Chapter 8.
Mammary Hamartoma
Mammary hamartoma is a term that has been used to describe a lesion
composed of mammary ducts, lobules, collagenous stroma, and adipose
tissue. These lesions have also been referred to as fibroadenolipomas and
adenolipomas. Although mammary hamartomas may be clinically appar-
ent and simulate a fibroadenoma, they are more often detected mammo-
graphically as a demarcated density, typically surrounded by a radiolucent
halo.14,15 These lesions are usually readily enucleated and grossly consist of
a smooth, well-circumscribed, usually ovoid or lenticular mass of tissue.
The appearance of the cut surface depends on the relative proportion of
the components. Lesions with more fibrous stroma may be indistinguish-
able from normal breast tissue, whereas those containing large amounts of
adipose tissue may resemble lipomas.16-18
Histologic examination shows a circumscribed but unencapsulated
nodule composed of breast ducts, lobules, fibrous stroma, and adipose
tissue admixed in varying proportions (Fig. 6.16, e-Fig. 6.10). In some
A
FIGURE 6.16 Mammary hamartoma. A: This well-circumscribed tumor is composed
primarily of fibrous stroma and mammary ducts and lobules. The adipose tissue
component is sparse. B: This hamartoma features a larger proportion of adipose tissue.
B
areas, these elements are haphazardly arranged, whereas in others, the

organization resembles that of normal breast tissue. The epithelium may
show apocrine metaplasia. Pseudoangiomatous stromal hyperplasia may
be present.17 Some lesions additionally feature smooth muscle cells in the
stroma; such lesions have been called “myoid hamartomas.”19 Chondroid
islands are rarely present in the fat; such lesions have been called “chon-
drolipomas.”18
Given that these lesions histologically resemble normal breast tis-
sue or breast tissue with non-specific benign changes, it is difficult if not
impossible to make the diagnosis of hamartoma without knowledge of the
clinical and/or mammographic findings.14,17,19 In particular, a definitive
diagnosis of this lesion in core-needle biopsy samples is not possible, but
hamartoma might be raised as a diagnostic possibility in the context of the
appropriate mammographic findings.20
Phyllodes Tumor
Phyllodes tumors are uncommon biphasic lesions that account for ≤1%
of all primary breast tumors.21 These lesions generally occur in an older
age group than fibroadenomas; most patients are middle aged or elderly.
Patients with phyllodes tumors often have a history of a rapidly enlarging
tumor, sometimes at the site of a pre-existing, long-standing mass.
Phyllodes tumors tend to be larger than fibroadenomas (average size
4 to 5 cm),21 but some fibroadenomas can be quite large, and conversely,
some phyllodes tumors may be small. Larger phyllodes tumors present
clinically as a firm, palpable mass; smaller lesions present mammographi-

cally as a circumscribed or lobulated density. Although malignant lesions
tend to be larger than benign variants, there is no consistent relationship
between tumor size and histologic evidence of malignancy.
Upon gross examination, phyllodes tumors are circumscribed masses
that may be multinodular. The cut surface typically consists of bulging
tan to gray tissue that may have a whorled appearance (Fig. 6.17). Clefts,
cystic spaces, or a cauliflower-like appearance may be evident, especially
in larger lesions. Foci of necrosis and hemorrhage may be seen; their pres-
ence is suggestive of malignancy.
Upon microscopic examination, phyllodes tumors are character-
ized by stromal hypercellularity and a prominent intracanalicular growth
pattern. Long, sometimes branching, cleft-like spaces and ducts, lined
by an inner epithelial and outer myoepithelial cell layer, are surrounded
by cellular stroma that is often more condensed around the clefts and
ducts. Frond-like projections of cellular stroma covered by epithelium
and myoepithelium protruding into epithelial-lined cystic spaces create a
leaf-like appearance (Figs. 6.18 and 6.19). The stroma may exhibit areas
of pseudoangiomatous stromal hyperplasia; multinucleated stromal giant
cells may rarely be present.6 The epithelial component shows a variety of
appearances. Varying degrees of usual ductal hyperplasia are common.
Squamous metaplasia is seen more often than in fibroadenomas (Fig. 6.20,
e-Fig. 6.11), but apocrine metaplasia is seen less frequently. Ductal or
FIGURE 6.17 Phyllodes tumor, cut surface. This well-circumscribed tumor measured
9 cm and is composed of fleshy, tan tissue with foci of hemorrhage. Yellow areas are
evident in the lower portion of this lesion. On histologic examination, this was a malignant
phyllodes tumor with foci of liposarcoma.
FIGURE 6.18 Phyllodes tumor. A: Leaf-like projections of mildly hypercellular stroma

covered by epithelium characterize this benign phyllodes tumor. B: In this malignant
phyllodes tumor, leaf-like projections are present within a cystic space. The stroma is
more cellular than in the benign phyllodes tumor shown in Fig. 6.18A.
lobular carcinoma in situ may rarely arise in the epithelial component.

Even less frequently, invasive carcinoma may develop.
Phyllodes tumors are most often classified as benign, borderline, or
malignant based on the assessment of several histologic features, includ-
ing the tumor border, stromal cellularity, stromal cell atypia, stromal cell
mitotic activity, presence of stromal overgrowth (defined as at least one
microscopic field seen at 4× magnification that contains only stroma
FIGURE 6.19 Phyllodes tumor demonstrating epithelial-lined ducts and cleft-like spaces sur-
rounded by a hypercellular stroma. Stromal cellularity is greatest around the ducts and clefts.
without associated epithelial elements), and presence of malignant heter-

ologous elements.21-24 However, assessment of some of these parameters
is subjective. In addition, the precise definitions of these features and the
cut-points for the level of mitotic activity that distinguishes among benign,
borderline, and malignant lesions have varied among authors.
FIGURE 6.20 Phyllodes tumor with squamous metaplasia of duct epithelium.

TABLE 6.2 WHO Criteria for Distinguishing Benign, Borderline,

and Malignant Phyllodes Tumors
Benign Borderline Malignanta
Tumor border Well-defined Well-defined; Infiltrative

may be focally
infiltrative
Stromal cellularity Cellular, usually Cellular, usually Cellular, usually
mild, may be moderate, may marked and
non-uniform be non-uniform diffuse
or diffuse or diffuse
Stromal cell atypia None to mild Mild or moderate Marked
Mitotic activity Usually few (<5 Usually frequent Usually abundant
per 10 HPFs) (5–9 per 10 HPFs) (≥10 per 10 HPFs)
Stromal overgrowth Absent Absent or very Often present
focal
Malignant Absent Absent May be present
heterologous
elements
Relative proportion 60–75% 15–20% 10–20%
of phyllodes
tumors
HPF, high-power field.

a
While these features are often observed in combination, they may not always be present
simultaneously. The presence of malignant heterologous elements is sufficient for a
diagnosis of malignant phyllodes tumor even in the absence of the other histologic criteria.
From Tan PH, Tse G, Lee A, Simpson J, Hanby A. Fibroepithelial tumours. In: Lakhani
SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ, eds. WHO Classification of
Tumours of the Breast. Lyon: IARC Press [in press].
The criteria for the classification of phyllodes tumors adopted by the

2011 WHO Working Group are summarized in Table 6.2.21 It should be
noted, however, that it is not uncommon for a phyllodes tumor to exhibit
features from more than one of these categories, and in such cases, clas-
sification may be particularly problematic and subjective. Furthermore,
while no one feature consistently defines a phyllodes tumor as malignant,
the presence of malignant heterologous elements is sufficient for a diag-
nosis of a malignant phyllodes tumor even in the absence of the other
features characteristic of malignant lesions.21
Benign phyllodes tumors are generally characterized by a well-
defined, circumscribed border, mild stromal hypercellularity, little or no
stromal cell atypia, and few stromal cell mitoses. The degree of stromal
cellularity is usually relatively consistent throughout the lesion, but foci
of stromal condensation are commonly seen around ducts and cleft-like
spaces (Fig. 6.21, e-Figs. 6.12–6.17). Stromal overgrowth, as defined
B
FIGURE 6.21 Benign phyllodes tumor. A: The tumor has a circumscribed border.
B: There is modest stromal hypercellularity with periductal condensation. C: The stromal
cell nuclei are relatively uniform in appearance.
C
earlier, is not present. Histologically benign heterologous stromal ele-

ments may be present, including adipose tissue, bone, cartilage, and
skeletal muscle. Benign phyllodes tumors may be difficult to distinguish
from cellular fibroadenomas. In problematic cases, the presence of long,
branching, cleft-like, epithelial-lined spaces with surrounding stromal
condensation, non-uniform distribution of glands and stroma, numerous
leaf-like projections into cystic spaces, and stromal cell mitoses favor a
diagnosis of phyllodes tumor. However, in some cases, the distinction
between these two lesions may be difficult to make with certainty. The
2011 WHO Working Group recommended that in cases in which there
is histological ambiguity, a diagnosis of cellular fibroadenoma should be
favored.
In malignant phyllodes tumors, the border is infiltrative, the
stroma is highly cellular, and the stromal cells show moderate to marked
nuclear pleomorphism and prominent mitotic activity (≥10 mitoses/10
high-power fields) (Fig. 6.22). Foci of stromal overgrowth are common
(Figs. 6.23 and 6.24, e-Figs. 6.18–6.20). Although the stroma most often
resembles a fibrosarcoma, heterologous differentiation may be seen
including liposarcoma, osteosarcoma, chondrosarcoma, and rhabdomyo-
sarcoma (Fig. 6.25). Malignant phyllodes tumors must be distinguished
from spindle cell carcinomas and primary breast sarcomas. Demonstration
of a benign epithelial component will help to establish the diagnosis of
phyllodes tumor, but this may require extensive sampling in some cases.
It should be noted that a sarcomatous lesion in the breast is more likely to
represent a malignant phyllodes tumor than a primary mammary sarcoma
FIGURE 6.22 Malignant phyllodes tumor. A: The stroma is highly cellular. B: The stromal
cells show marked nuclear pleomorphism.
or a metastatic sarcoma from another site. As discussed in Chapter 11,

cytokeratin stains may be necessary to define a malignant spindle cell
lesion as a spindle cell carcinoma.
Borderline phyllodes tumors are characterized by moderate stromal
cellularity (Fig. 6.26, e-Fig. 6.21A). Of note, the degree of cellularity is
FIGURE 6.23 Malignant phyllodes tumor with stromal overgrowth. This low-power field
(4× magnification) contains only stromal cells; no epithelial elements are present.
often heterogeneous, with some areas no more cellular than a fibroad-

enoma (Fig. 6.27). Stromal cell atypia is mild to moderate and stromal cell
mitoses are usually frequent (Fig. 6.28, e-Fig. 6.21B). The margin may be
circumscribed, but is often at least focally infiltrative (Fig. 6.29). Stromal
overgrowth is not present or very focal.
A
FIGURE 6.24 Malignant phyllodes tumor, invasive border. A: Stromal cells and glands
extend irregularly into the surrounding adipose tissue. B: Small nests of stroma and
glands are present in adipose tissue beyond the main lesion.
B
It is difficult to predict the clinical outcome of patients with phyl-

lodes tumors. The major clinical concern is local recurrence, and this may
be seen with benign, borderline, or malignant lesions. Therefore, com-
plete excision of the lesion is the primary therapeutic goal. In one large
literature review, the risk of local recurrence was 21%, 46%, and 65%
for patients with benign, borderline, and malignant lesions, respectively;
A
FIGURE 6.25 Malignant phyllodes tumor with liposarcoma. A: Foci of liposarcomatous
differentiation are evident on the left side of this image. B: Higher power demonstrates
lipoblasts.
B
FIGURE 6.26 Borderline phyllodes tumor with moderate to marked stromal

hypercellularity.
FIGURE 6.27 Borderline phyllodes tumor. The degree of stromal cellularity in this tumor
is variable.
FIGURE 6.28 Borderline phyllodes tumor. High-power view shows moderate stromal cell
atypia and a stromal cell mitosis.
FIGURE 6.29 Borderline phyllodes tumor. Much of the border of this tumor was
circumscribed; however, in this area, the stroma invades irregularly into the surrounding
adipose tissue.
these risks were considerably lower among patients treated with wide
local excision (8%, 29%, and 36%, respectively).25 However, some inves-
tigators have suggested that recurrence is more closely related to the ade-
quacy of excision than to the histologic features of the tumor.26 Recurrent
tumors may contain both stromal and epithelial components, although
there is often increased predominance of the stromal component.
Furthermore, the recurrence may exhibit more atypical characteristics
than the original lesion.
Distant metastases are uncommon. Even among those with histolog-
ically malignant lesions, the frequency of metastatic disease is only ˜20%
to 25%.23,26 Most tumors that metastasize have obviously sarcomatous
features and stromal overgrowth. The presence of malignant heterologous
elements appears to be indicative of a particularly poor prognosis.27
Metastases usually present after chest wall recurrence, generally consist
of only the stromal component, and are usually hematogenous. The most
common metastatic sites are lungs and bones. Axillary lymph node metas-
tases are rare.
At the present time, there are no biomarkers of sufficient prognos-
tic value to be used in routine practice. Markers of proliferation (such
as Ki67) and expression of other markers including p53, CD117 (c-kit),
epidermal growth factor receptor, and vascular endothelial growth factor
correlate with histologic category of phyllodes tumors (being highest in
malignant and lowest in benign lesions), but do not appear to be indepen-

dent predictors of clinical outcome.21,23,28-30
Fibroepithelial Lesions on Core-needle Biopsy

A diagnosis of fibroadenoma can usually be made readily on core-needle
biopsy, particularly when the edge of the lesion is present in the tissue
samples. Typical fibroadenomas diagnosed on core-needle biopsy can be
safely managed by observation alone, provided that the imaging studies
are concordant with the diagnosis.
Distinguishing between a cellular fibroadenoma and benign phyl-
lodes tumor may be particularly problematic in core-needle biopsy sam-
ples that contain a fibroepithelial lesion with a cellular stroma, especially
if it has an intracanalicular pattern. In such cases, if there is uncertainty
about the diagnosis, it is prudent to render a diagnosis of “fibroepithelial
lesion with increased stromal cellularity” and to recommend an excision
for further evaluation of the lesion.31-36 Other features of fibroepithelial
lesions on core-needle biopsy that should prompt concern and for which
excision should be recommended are an irregular border, stromal cell
atypia, and prominent stromal cell mitoses.37,38
The possibility of a phyllodes tumor should always be considered
when an atypical or malignant spindle cell lesion is identified in core-
needle biopsy samples, even if no benign epithelial component is evident.
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7
Adenosis and Sclerosing
Lesions
The term adenosis refers to a group of benign breast lesions that have in
common a pathologic increase in the number of mammary glandular units.
Some forms of adenosis are characterized by an increase in the number
of lobular acini without distortion of the lobular architecture (“simple
adenosis”). In other types, there is an accompanying stromal prolifera-
tion that compresses and distorts the glands (e.g., sclerosing adenosis).
Still other forms of adenosis are characterized by a haphazard, infiltrative
proliferation of glands, with little or no distortion (e.g., microglandular
adenosis [MGA], tubular adenosis, and secretory adenosis).
The term sclerosing lesions describes a group of proliferative breast
lesions in which benign glands are entrapped and distorted by fibrous or
fibroelastotic connective tissue. Included in this group are radial scars and
complex sclerosing lesions.
The importance of recognizing the various patterns of adenosis and
sclerosing lesions, and the reason they are considered together in this
chapter, is that they may be mistaken for invasive carcinoma, particularly
low-grade forms, such as tubular carcinoma and low-grade invasive ductal
carcinoma.
Sclerosing Adenosis
The most common form of adenosis is sclerosing adenosis, a lesion of the
terminal duct lobular units characterized by a lobulocentric proliferation
of glands and tubules accompanied by a stromal proliferation that pro-
duces variable glandular compression and distortion (Fig. 7.1, e-Fig. 7.1).
Sclerosing adenosis is usually an incidental microscopic finding;
however, in some instances, it may present as a mammographic abnormal-
ity (most often microcalcifications). Less commonly, the lesion presents as
a mammographic density or a palpable abnormality.
202
Adenosis and Sclerosing Lesions ——— 203
C
Figure 7.1 Sclerosing adenosis. A: Low-power view illustrating the relatively circumscribed,
lobulocentric nature of the proliferation. B: High-power view of one area of the lesion
showing several open glands lined by attenuated epithelium. The myoepithelial layer is difficult
to appreciate. C: Another area of the lesion showing compressed glands in fibrotic stroma.
Lesions of sclerosing adenosis may be single or multiple. The

glands and tubules comprising the proliferation are composed of benign,
often flattened epithelial cells surrounded by a myoepithelial cell layer.
Secretions may be present in gland lumina. The epithelial cells lack cyto-
logic atypia; however, a worrisome picture may be seen when there is
coexistent apocrine metaplasia (see subsequent text).1,2 The myoepithelial
cell component in some cases is conspicuous, but in others it is difficult to
appreciate on hematoxylin and eosin–stained sections. Even when incon-
spicuous on routinely stained sections, a myoepithelial cell layer around
the glands is readily demonstrated by immunostains for myoepithelial cell
markers such as calponin, smooth muscle myosin heavy chain, and p63
(Fig. 7.2).
Glandular compression and distortion is most marked at the center
of the lesion and may completely obliterate the lumina, resulting in the
appearance of solid cords of cells within a fibrous stroma, often with a
swirling pattern. Calcifications are frequently present in association with
the glands (Fig. 7.3, e-Fig. 7.2). Perineural invasion, although uncommon,
is a well-documented feature of sclerosing adenosis and should not be
taken as an indication of malignancy (Fig. 7.4).3 The key to the diagnosis
of sclerosing adenosis is low-power microscopic examination that demon-
strates the circumscribed, lobulocentric nature of the process. This feature
helps distinguish sclerosing adenosis from invasive carcinoma (Fig. 7.1A).
However, infrequently, invasive carcinomas form relatively circumscribed
foci, which at low power mimic the lobulocentric configuration of scleros-
ing adenosis (Fig. 7.5).
Figure 7.2 Sclerosing adenosis immunostained for smooth muscle myosin heavy chain
highlighting the myoepithelial cells around the glands.
Figure 7.3 Several calcifications are present in this example of sclerosing adenosis.
The terms nodular adenosis and adenosis tumor have been applied
to florid examples of sclerosing adenosis that results in a mammographic
mass or palpable lesion. This lesion may sometimes be seen as rounded,
pink, granular areas on gross examination. Microscopically, nodular
Figure 7.4 Perineural invasion in sclerosing adenosis. Benign glands are present adjacent
to nerve twigs.
B
Figure 7.5 Low-grade invasive ductal carcinoma mimicking sclerosing adenosis.
A: At low power, this relatively circumscribed focus of invasive carcinoma mimics the
lobulocentric configuration of sclerosing adenosis. B: Higher power view demonstrates
rounded glands with mild atypia of the epithelial cells; no myoepithelial cells are apparent.
C: Immunostain for smooth muscle myosin heavy chain shows absence of myoepithelial
cells around the glands supporting a diagnosis of invasive carcinoma (vascular smooth
muscle cells show expression of smooth muscle myosin heavy chain).
C
adenosis is composed of aggregated or coalescent foci of typical sclerosing

adenosis (Fig. 7.6, e-Fig. 7.3).
The epithelium of the glands of sclerosing adenosis may demonstrate
various proliferative lesions, including atypical hyperplasia and in situ
A
Figure 7.6 Nodular adenosis. A: Scanning magnification view illustrating an aggregate of
several focally coalescent areas of sclerosing adenosis. A nodular configuration is evident.
B: Higher power view illustrates variably compressed glands in the stroma, which is typical
of sclerosing adenosis.
B
c arcinoma (either ductal or lobular types) (Figs. 7.7 and 7.8, e-Figs. 7.4
and 7.5). Involvement by in situ carcinoma produces an appearance of
small nests, glands, or cords of neoplastic epithelial cells within a fibrotic
stroma and the distinction from invasive carcinoma may be quite difficult;
the use of myoepithelial cell immunostains may be required to confirm
the in situ nature of the process (Figs. 7.7 and 7.8). However, even when
involved by in situ carcinoma, the underlying lobulocentric configuration
A
Figure 7.7 Ductal carcinoma in situ involving sclerosing adenosis. A: The presence in the
stroma of small glands and nests containing malignant cells produces an appearance worri-
some for invasive carcinoma. B: Smooth muscle myosin heavy chain immunostain highlights
myoepithelial cells around the glands, which confirms the in situ nature of the process.
B
of sclerosing adenosis is retained, and it is important to recognize this in

order to arrive at the correct diagnosis.
Clinical follow-up studies have indicated that sclerosing adenosis is
associated with a 1.5- to 2-fold increase in the risk of the development of
subsequent breast cancer, which is similar to the level of risk associated with
other proliferative lesions without atypia.4 The presence of sclerosing ade-
nosis in a core-needle biopsy specimen does not require surgical excision.
The key features of sclerosing adenosis are summarized in Table 7.1.
A
Figure 7.8 Lobular carcinoma in situ involving sclerosing adenosis. A: Low-power view
illustrates that most of the adenotic glands are filled with a cellular proliferation largely
filling their lumina. B: The high-power appearance is that of compressed cords and nests of
monomorphic cells typical of lobular neoplasia in a fibrotic stroma, a pattern worrisome for
invasive carcinoma. C: Smooth muscle myosin heavy chain immunostain reveals myoepitheli-
al cells around the cellular cords and nests, which confirms the in situ nature of the process.
C
Table 7.1 Key Features of Sclerosing Adenosis
• Lobulocentric (circumscribed) proliferation of small glands and tubules with

variable compression and distortion by fibrotic stroma
• Glands and tubules surrounded by myoepithelial cell layer
• Associated calcifications common
• Epithelium typically cuboidal or flattened but may show apocrine
metaplasia (apocrine adenosis) or atypical apocrine changes (atypical
apocrine adenosis)
• May be involved by in situ carcinoma (ductal or lobular types), producing
an appearance that mimics invasive carcinoma
Apocrine Adenosis and Atypical Apocrine Adenosis

The term apocrine adenosis has been used to describe a variety of benign
breast lesions in which the epithelium exhibits apocrine cytology.5,6 We
and others have restricted this term to lesions that have the architectural
features of sclerosing adenosis but in which the epithelium shows apo-
crine metaplasia as characterized by enlarged cell size, abundant granu-
lar, eosinophilic cytoplasm, large round nuclei, and prominent nucleoli
(Fig. 7.9, e-Fig. 7.6).2 The nuclear enlargement and nucleolar prominence
can create the erroneous impression of cytologic atypia unless the apo-
crine nature of the process is recognized.
The term atypical apocrine adenosis is applied when the apocrine
cells show at least a threefold variation in nuclear size and nucleolar
enlargement (Fig. 7.10).2 However, the distinction from apocrine ductal
carcinoma in situ (DCIS) involving sclerosing adenosis is not clear-cut;
this is especially problematic in cases in which there is apocrine DCIS
elsewhere in the specimen.2,6 In equivocal cases, a diagnosis of “atypical
apocrine adenosis” or “atypical apocrine proliferation involving scleros-
ing adenosis” is preferable. If the lesion is at or near a margin of an exci-
sion specimen, a re-excision may be prudent to exclude the possibility of
adjacent diagnostic areas of apocrine DCIS. Finding such a lesion on a
core-needle biopsy is an indication for excision, although the frequency
with which a more advanced lesion is found on excision is not currently
known.
Figure 7.9 Apocrine adenosis. In this example of sclerosing adenosis, the epithelial cells
have granular, eosinophilic cytoplasm and uniform round nuclei characteristic of apocrine
metaplasia.
Figure 7.10 Atypical apocrine adenosis. The epithelial cells have eosinophilic cytoplasm
typical of apocrine metaplasia, but show nuclear pleomorphism with prominent, enlarged
nucleoli.
It should be evident that when apocrine epithelium is present in scle-

rosing adenosis, the combination of epithelial cells with enlarged nuclei
that have prominent nucleoli and glandular distortion may produce a
pattern mimicking invasive carcinoma. This is particularly true for atypi-
cal apocrine adenosis. In such cases, immunostains for myoepithelial cell
markers may be required to make this distinction.
The subsequent breast cancer risk associated with apocrine adenosis
and atypical apocrine adenosis has not been well-defined. In one study,
none of 47 patients with atypical apocrine adenosis developed cancer with
a mean follow-up of 35 months.1 In contrast, in two other studies of 37
patients each with mean follow-up periods of almost 9 and 14 years, respec-
tively, 3 patients developed carcinoma in one study and 4 in the other.2,7
Microglandular Adenosis
MGA is an uncommon form of adenosis characterized by an infiltrative,
nonlobulocentric proliferation of relatively uniform, small glands within
the mammary stroma and adipose tissue (Fig. 7.11, e-Figs. 7.7 and 7.8).8-11
This lesion typically presents as a palpable mass, but may also be detected
as mammographic microcalcifications or density or as an incidental
microscopic finding.
The glands of MGA are regular and round without angulation, are
not compressed by the stroma, and are lined by a single epithelial layer
(Fig. 7.11, e-Fig. 7.9). Although surrounded by basement membrane (as
demonstrated by electron microscopy and by immunostains for type IV
C
Figure 7.11 Microglandular adenosis. Small glands infiltrate fibrous (A) and fatty stroma
(B) in a haphazard manner. Eosinophilic secretions are evident in many of the gland
lumina. (C) High-power view illustrates that the glands are composed of a single layer
of cuboidal epithelial cells with amphophilic cytoplasm and small, regular nuclei. No sur-
rounding myoepithelial cells are present.
Figure 7.12 Microglandular adenosis immunostained for smooth muscle myosin heavy
chain. A myoepithelial layer is present around a normal duct (top of field), but no myo-
epithelial cells are seen around the glands of microglandular adenosis.
collagen and laminin), the glands lack an outer myoepithelial cell layer
(Fig. 7.12). Eosinophilic, periodic acid-Schiff–positive, diastase-resistant
secretory material is frequently seen within the lumina (Fig. 7.13), as are
calcium deposits. The epithelial cells are cuboidal or flattened without
apical snouting and have clear to amphophilic cytoplasm and round
nuclei with inconspicuous nucleoli. Strong immunoreactivity for S100
Figure 7.13 Microglandular adenosis. A periodic acid-Schiff stain highlights the luminal
secretions.
Figure 7.14 S100 protein stain demonstrates strong staining of the glands of
microglandular adenosis.
protein (Fig. 7.14) and cathepsin D and lack of expression of epithe-

lial membrane antigen, estrogen receptor (Fig. 7.15), and progesterone
receptor are characteristic features of the cells of MGA.12-14
MGA has long been considered to be a benign lesion despite its infil-
trative growth pattern and lack of a myoepithelial cell layer.8-11 However,
Figure 7.15 Microglandular adenosis immunostained for estrogen receptor (ER).

Epithelial cells of a normal duct show strong nuclear staining for ER (top of field). No ER
expression is seen in the microglandular adenosis.
atypical forms of this lesion have been described (atypical MGA) as well
as an association with invasive carcinoma, raising the possibility that
it may represent a non-obligate precursor lesion (see subsequent text).
In atypical MGA, the glands become more complex with connections
between them, formation of luminal bridges, and microcribriform nests.12-14
The epithelial cells begin to stratify, obliterating the lumens of the glands.
Cytologic atypia is often also present, and there is loss of luminal secre-
tions (Fig. 7.16, e-Fig. 7.10). Carcinoma can be seen in conjunction with
or arise in MGA,9,12-17 usually progressing through atypical MGA and/or
B
Figure 7.16 Atypical microglandular adenosis. A: Low-power view illustrates areas of
typical microglandular adenosis (upper and left) and atypical microglandular adenosis
in which the glands are filled with a cellular proliferation that obliterates most of the
lumens. B: High-power view demonstrates atypical epithelial cells filling the glands. A few
glands of typical microglandular adenosis are also evident in the upper part of the picture.
DCIS. The invasive carcinomas tend to retain some of the features of the
underlying MGA, such as an alveolar growth pattern and clear cytoplasm
as well as retention of the immunophenotypic profile (S100 protein and
cathepsin D positive; estrogen receptor and progesterone receptor nega-
tive).12 Uncommon histologic types of carcinoma reported in association
with MGA include adenoid cystic carcinoma as well as carcinomas with
basaloid, secretory, squamous, and chondroid or chondromyxoid features
(Fig. 7.17).18-20
Recent molecular data demonstrating similar genetic alterations and
a clonal relationship among coexistent MGA, atypical MGA, and invasive
carcinomas have provided further evidence to support the view that MGA
may represent a non-obligate precursor to invasive breast carcinoma and, in
particular, to carcinomas with a basal-like or triple negative phenotype.16,17
B
Figure 7.17 Carcinoma arising in microglandular adenosis. A: Low-power view
demonstrates an area of typical microglandular adenosis on the right side of this image.
On the left side, foci of ductal carcinoma in situ (DCIS) and invasive carcinoma are present.
B: Higher power view of a focus of DCIS with adjacent invasive carcinoma. C: Another area
of the same tumor showing tumor cells in a chondromyxoid matrix.
C
The differential diagnosis of MGA includes tubular carcinoma and

other types of adenosis. The key features distinguishing MGA from tubular
carcinoma are summarized in Table 7.2. Major features distinguishing MGA
from sclerosing adenosis are the infiltrative pattern, the non-compressed
nature of the glands, and the absence of a myoepithelial layer around
the glands in MGA. Secretory adenosis (see subsequent text) has many
histologic features in common with MGA, but there is retention of a
myoepithelial cell layer around the infiltrating glands.21
Treatment for MGA is complete excision with negative margins and
careful clinical follow-up. In some cases, the lesion is extensive, which
makes it difficult to obtain negative margins of excision.
Table 7.2 Key Features Useful for Distinguishing Microglandular

Adenosis from Tubular Carcinoma
Microglandular Tubular
Adenosis Carcinoma
Gland distribution Random Stellate

Gland shape Round Angular, tapered
ends
Apical cytoplasmic snouts No Yes
Luminal secretions Yes No
Basement membrane around glands Yes No
Stromal desmoplasia No Yes
Associated DCIS No Yes
S100 protein Positive Negative
ER/PR Negative Positive
DCIS, ductal carcinoma in situ; ER, estrogen receptor; PR, progesterone receptor.
Tubular Adenosis
Tubular adenosis is an unusual benign lesion, which may be misinterpreted
as carcinoma, particularly tubular carcinoma.22 This lesion lacks the circum-
scription of sclerosing adenosis, having only a vague lobulocentric appearance
on low-power examination. Tubular adenosis is composed of a haphazard
proliferation of elongated and branching tubules, which have both epithelial
and myoepithelial layers (Fig. 7.18). Glands cut in a cross section may have
a rounded appearance. Luminal secretions are usually present and microcal-
cifications are frequent. Tubular adenosis may be involved by DCIS. In such
cases, the haphazard arrangement of the glands combined with the atypical
cytologic features raises particular concern for invasive carcinoma.23 Hence,
B
Figure 7.18 Tubular adenosis. A: Low-power view showing the haphazard prolifera-
tion of elongated, branching tubules. B: High-power view illustrating myoepithelial cells
around the tubules. C: The myoepithelial cells surrounding the tubules are highlighted by
this smooth muscle myosin heavy chain immunostain.
C
immunohistochemistry to demonstrate myoepithelial cells may be helpful. No

further treatment is required following a diagnosis of tubular adenosis.
Secretory Adenosis
The term secretory adenosis has been used to describe a lesion architec-
turally similar to MGA.21 The lesion is characterized by small tubules and
glands, which have an infiltrative pattern on low-power examination and
contain luminal secretions as seen in MGA. However, in contrast to MGA,
myoepithelial cells are evident around the tubular structures (Fig. 7.19).
A
Figure 7.19 Secretory adenosis. A: Low-power view illustrating a haphazard, non-
lobulocentric proliferation of small glands. B: High-power view demonstrating round to
ovoid glands, with intraluminal eosinophilic secretion seen in one of the glands similar to
that seen in microglandular adenosis. C: Smooth muscle myosin heavy chain immunostain
highlights myoepithelial cells around the glands, a feature that distinguishes this lesion
from microglandular adenosis.
C
Blunt Duct Adenosis

The term blunt duct adenosis has been used to describe two histologically
different lesions. Some authors have described and illustrated as “blunt
duct adenosis” a lesion that appears to represent usual ductal hyperplasia
involving lobular acini and terminal ductules.24 Others have used this term
to describe a lesion characterized by enlarged lobular units with variably
dilated acini that have blunt contours and are often lined by columnar epi-
thelial cells, lesions now classified as columnar cell change and columnar
cell hyperplasia (see Chapter 4).25 Given the varying definitions of blunt
duct adenosis, we do not use this term in clinical practice.
Sclerosing Lesions: Radial Scars and Complex

Sclerosing Lesions
A variety of breast lesions are characterized by benign glands and tubules
entrapped and distorted by a fibrous or fibroelastotic connective tissue
stroma, often with accompanying adenosis, epithelial hyperplasia, and cyst
formation. The terms radial scar, radial sclerosing lesion, sclerosing papil-
lary proliferation, and complex sclerosing lesion, among others, have been
used for this histologically complex picture. We reserve the term radial scar
for those sclerosing lesions characterized by a central, sclerotic nidus from
which ducts and lobules radiate circumferentially. Sclerosing lesions with
a less organized appearance are categorized as complex sclerosing lesions.
Radial scars may be identified as an incidental finding in breast tissue
removed for another abnormality or may be large enough to be detected
by mammography. The mammographic appearance is typically that of a
spiculated mass and can mimic carcinoma.26,27
Radial scars are often multiple and may be bilateral. When large enough
to be apparent upon gross examination, they appear as firm, chalky white
lesions with an irregular stellate outline that may be difficult to distinguish
from carcinoma. Microscopically, radial scars show a central area of stromal
sclerosis and elastosis containing entrapped and variably distorted glands
and epithelial cell nests, an appearance that may simulate invasive carci-
noma. The sclerotic zone is typically paucicellular and hyalinized.28-30 A myo-
epithelial cell layer is present around the glands and epithelial nests, but may
be difficult to appreciate on routine sections and may require immunostains
for their demonstration. However, in our experience, even with immunos-
tains, myoepithelial cells are frequently identifiable only around some of the
glands or may show a reduction or even absence of staining for some myo-
epithelial cell markers.31 The central sclerotic zone is surrounded by radially
arranged ducts and lobules that show varying degrees of adenosis, epithelial
hyperplasia, papillomas, and cysts (Fig. 7.20, e-Figs. 7.11 and 7.12). Apocrine
metaplasia may be seen. Calcifications are often present within the lesion.
A
Figure 7.20 Radial scar. A: Low-power view demonstrates a central area of fibroelastotic
stroma containing entrapped glands and surrounded by radiating ducts with usual ductal
hyperplasia and cystic changes. B: High-power view of entrapped glands in the center of
the lesion. An outer myoepithelial layer is evident around some of the glands, but this is
easier to appreciate on a smooth muscle myosin heavy chain immunostain (C).
C
Complex sclerosing lesions are also characterized by zones of stro-

mal fibrosis and fibroelastosis containing entrapped and distorted glands
and accompanied by lobules and ducts with other changes such as adeno-
sis, hyperplasia, papillomas, cysts, and apocrine metaplasia. However, the
lesions are often larger and do not have the well-defined radial configura-
tion of radial scars (Fig. 7.21, e-Fig. 7.13). The histologic features of com-
plex sclerosing lesions show considerable overlap with those of sclerosing
papillomas (see Chapter 8); in fact, many such lesions likely represent a
late stage of sclerosing papilloma in which the distortion of the underlying
papillary structure precludes its recognition.
The epithelium of the glands in the sclerotic areas of radial scars
and complex sclerosing lesions may consist of only a single cell layer
with benign cytologic features or may show proliferative changes includ-
ing usual ductal hyperplasia, atypical ductal hyperplasia, atypical lobu-
lar hyperplasia, or DCIS or lobular carcinoma in situ. As for sclerosing
adenosis, involvement of radial scars and complex sclerosing lesions by
in situ carcinoma results in the appearance of neoplastic epithelial cells
within a fibrotic stroma. The distinction from invasive carcinoma may be
B
Figure 7.21 Complex sclerosing lesion. A: Low-power view illustrating numerous glands
within a fibroelastotic stroma. Surrounding ducts show varying degrees of epithelial
hyperplasia and cystic change. The pattern of this lesion is not as organized as that of a
radial scar (see Fig. 7.20). B: High-power view of glands from the sclerotic area shows that
they are surrounded by a myoepithelial cell layer.
particularly difficult and may require the use of myoepithelial cell marker
immunostains to define the nature of the process. However, as for radial
scars, the myoepithelial cells surrounding the glands within complex scle-
rosing lesions may show a reduction or absence of expression of one or
more myoepithelial cell markers.31 Although dense, paucicellular, fibrous,
or fibroelastotic stroma may be seen in association with some invasive
breast cancers, its presence should always prompt consideration of a
benign sclerosing lesion and is a helpful clue to the correct diagnosis.
The clinical significance of radial scars has long been a matter of
debate. However, there appears to be an increased frequency of carcinoma
Table 7.3 Key Features of Radial Scars/Complex Sclerosing Lesions
May mimic invasive carcinoma mammographically and upon gross and

microscopic examination
Radial scars
• Central fibroelastotic core with entrapped glands
• Glands surrounded by myoepithelial layer
• Peripheral ducts/lobules radiate circumferentially from central core and
show varying degrees of adenosis, hyperplasia, papillomas, and cysts
Complex sclerosing lesions
• Fibrotic or fibroelastotic stroma containing entrapped glands
• Glands surrounded by myoepithelial layer
• Associated ducts/lobules show varying degrees of adenosis, hyperplasia,
papillomas, and cysts
• Generally larger and with a less organized appearance than radial scars
and atypical hyperplasia in association with larger radial scars, particularly

in women older than 50 years.32 In addition, one clinical follow-up study
has suggested that these lesions are associated with a twofold increased
risk of subsequent breast cancer—independent of other benign histologic
changes.33 In two other studies, the increased breast cancer risk associated
with radial scars was observed primarily in women older than 50 years and
was largely attributable to the category of coexistent proliferative breast dis-
ease.34,35 The increase in breast cancer risk appears to be more pronounced in
the first 10 years following the biopsy demonstrating this lesion.35
Patients with radial scars and complex sclerosing lesions diagnosed
in excisional biopsy specimens require no further treatment in the absence
of coexistent atypical hyperplasia or carcinoma in situ. The management
of patients with radial scars detected on core-needle biopsy specimens is a
matter of debate (e-Fig. 7.14). Studies that have assessed the frequency with
which a worse lesion is found on excision following a core-needle biopsy
diagnosis of radial scar have been limited by small patient numbers and
possible selection bias. Most authorities agree, however, that the finding of
radial scar on a core-needle biopsy is an indication for excision.36-41
The key features of radial scars and complex sclerosing lesions are
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8
Papillary Lesions
Papillary lesions of the breast comprise a heterogeneous group. These

lesions have in common a growth pattern characterized by the presence of
finger-like projections or fronds of variable length and thickness that are
composed of central fibrovascular cores covered by epithelium. Although
the histologic identification of a breast lesion as “papillary” is usually
straightforward, the distinction among intraductal papilloma, papilloma
with atypia (atypical papilloma), papilloma with ductal carcinoma in situ
(DCIS), papillary DCIS, or even invasive papillary carcinoma may be a
source of diagnostic difficulty.
A few general principles apply to all papillary lesions. First, as will
be discussed in more detail, assessment of the presence and distribution of
myoepithelial cells in the lesion is one of the most helpful features in arriv-
ing at the correct diagnosis (Table 8.1). In some cases, this may require
the use of immunostains to myoepithelial cell proteins. Second, the ideal
method to examine an excisional biopsy specimen containing a suspected
intraductal papillary lesion involves carefully opening the involved duct
longitudinally using a pair of fine scissors until the tumor is exposed.
Identification of the lesion may be facilitated by the surgeon placing a
suture at the end of the involved duct nearest the nipple. Randomly slic-
ing through the excised tissue is not recommended as a small lesion may
be missed. Third, if a papillary lesion is suspected on gross examination, a
frozen section should not be performed because the distinction of benign
from atypical or malignant papillary lesions on frozen sections may be
extremely difficult. Moreover, freezing may produce tissue distortion and
artifacts that could preclude definitive categorization of the lesion on per-
manent sections.
228
Papillary Lesions ——— 229
Table 8.1 Distribution of Myoepithelial Cells in Papillary Lesions
Myoepithelial Cells
Myoepithelial Cells at the Periphery of
within Papillae Involved Spaces
Papilloma Present Present

Papilloma with Absent in atypical Present
atypia/DCIS areas; present in areas
of residual benign
papilloma
Papillary DCIS Absent Present
Encapsulated papillary Absent Absent
carcinoma
Solid papillary carcinoma Absent May be present or
absent
DCIS, ductal carcinoma in situ.
Intraductal Papilloma
Intraductal papillomas are benign lesions that can be divided into two
groups: central papillomas, which involve large ducts and are usually soli-
tary, and peripheral papillomas, which involve the terminal duct lobular
units and are usually multiple (Fig. 8.1).
A
Figure 8.1 Intraductal papillomas. A: Solitary, central papilloma. B: Multiple peripheral
papillomas.
B
Figure 8.1 (Continued)
Central papillomas are tumors of the major lactiferous ducts and are
most frequently observed in women 30 to 50 years of age. Patients usually
present with nipple discharge that may be bloody; on occasion, the lesion
reaches sufficient size to produce a palpable, subareolar mass. Peripheral
papillomas occur in somewhat younger patients and less often present
with nipple discharge or a mass.1 They may occasionally present as a
mammographic abnormality (microcalcifications or multiple densities).
Central papillomas are generally <1 cm in diameter, but occasionally
may be as large as 4 or 5 cm. On gross examination, they appear as tan-
pink, circumscribed nodules within a dilated duct or cyst. A frankly pap-
illary configuration may be apparent, but more typically the lesion has a
bosselated surface. The tumor may be attached to the wall of the involved
duct by a stalk or may be sessile. Peripheral papillomas are usually not
identifiable on gross examination.
On histologic examination, papillomas are composed of arborizing
fronds with well-developed fibrovascular cores (Fig. 8.1, e-Fig. 8.1). The
papillary fronds are covered by an inner myoepithelial cell layer and an
outer epithelial layer (Fig. 8.2, e-Fig. 8.2). The myoepithelial layer is vari-
ably prominent, but is always present. In problematic cases, myoepithelial
cells can be highlighted by immunostaining for actin, smooth muscle
myosin heavy chain, calponin, p63, or other myoepithelial cell markers
(Fig. 8.3, e-Fig. 8.3). Myoepithelial cells are also present at the periphery
of the involved duct(s) (Fig. 8.4, e-Fig. 8.3) (Table 8.1). The epithelium
of benign papillomas may consist of one or a few layers of cuboidal to
Figure 8.2 Intraductal papilloma. The papillary fronds consist of fibrovascular cores
covered by an inner myoepithelial cell layer and an outer epithelial cell layer.
Figure 8.3 Intraductal papilloma. Calponin immunostain highlights the myoepithelial

cell layer.
Figure 8.4 Intraductal papilloma. p63 immunostain demonstrates myoepithelial cells

within the papillae and around the periphery of the involved duct.
columnar cells or it may show varying degrees of usual ductal hyperplasia

(UDH). The epithelial hyperplasia may be extreme and may grow in a
contiguous fashion between adjacent papillae (Fig. 8.5, e-Fig. 8.4). In
some cases, the epithelial proliferation may in areas have the appear-
ance of atypical ductal hyperplasia (ADH) or DCIS (see subsequent text).
Apocrine metaplasia is frequent (Fig. 8.6, e-Fig. 8.5); squamous meta-
plasia may also be seen.2 Varying degrees of myoepithelial hyperplasia
may be observed in some cases (Fig. 8.7). The hyperplastic myoepithelial
cells can be epithelioid or spindle-shaped and may have abundant clear
cytoplasm. The myoepithelial cell component may be sufficiently promi-
nent that the foci resemble areas of adenomyoepithelioma (e-Fig. 8.6)
(see subsequent text). Collagenous spherulosis is yet another change that
may be seen in the epithelium of intraductal papillomas; this should not
be misinterpreted as an area of ADH or DCIS (Fig. 8.8, e-Fig. 8.7) (see
subsequent text).
The papillary fronds and/or the surrounding duct wall may show
varying degrees of stromal fibrosis and may contain entrapped glands
and/or solid epithelial cell nests. On occasion, the fibrosis is so exten-
sive that it distorts or obscures the underlying papillary architecture. In
such cases, the term sclerosing papilloma is appropriate. In the most
extreme cases, the features overlap with those of a ductal adenoma
Figure 8.5 Intraductal papilloma with usual ductal hyperplasia (UDH). This papilloma
shows a florid epithelial proliferation that fills the spaces between papillae. The
proliferation has the architectural and cytologic features of UDH.
Figure 8.6 Apocrine metaplasia in an intraductal papilloma.

B
Figure 8.7 Myoepithelial cell hyperplasia in an intraductal papilloma. A: Numerous
yoepithelial cells with clear cytoplasm are apparent. B: Smooth muscle myosin heavy
m
chain immunostain further highlights the myoepithelial cells.
B
Figure 8.8 Intraductal papilloma with collagenous spherulosis. A: Low-power view
illustrating prominent collagenous spherulosis (upper right). B: Higher power view
illustrating the characteristic features of collagenous spherulosis (see text).
(see subsequent text) or complex sclerosing lesion. The presence of

glands or epithelial nests within a fibrous stroma may produce a wor-
risome appearance that raises the question of an invasive carcinoma
(Fig. 8.9, e-Fig. 8.8). However, in benign intraductal papillomas with
sclerosis, myoepithelial cells are discernible around at least some of the
entrapped glands and epithelial nests, which is a feature supporting the
benign nature of this process. In addition, the stroma of these lesions
typically has a more hyalinized, sclerotic appearance than the stroma
associated with invasive carcinomas.
Benign papillomas may undergo infarction, particularly larger cen-
tral lesions; this may occur spontaneously or may be associated with trau-
ma, such as a needling procedure (fine-needle aspiration or core-needle
biopsy). Infarction is frequently associated with entrapment of benign
epithelium at the periphery of the lesion. The entrapped epithelium
may exhibit reactive cytologic atypia or squamous metaplasia (Fig. 8.10,
e-Fig. 8.9).3
Although the histologic features of peripheral papillomas are similar
to those of central papillomas, the epithelium of the peripheral lesions
more often shows foci of ADH and DCIS than that of solitary, central
papillomas.4,5
A
Figure 8.9 Intraductal papilloma with sclerosis (sclerosing papilloma). A: Low-power view
illustrates that the majority of this papilloma is replaced by dense collagen obliterating
the papillary architecture. B: High-power view illustrating entrapped glandular epithelium
within collagen.
B
Intraductal papillomas are benign lesions that are adequately treated

by excision. The risk of subsequent breast cancer associated with solitary
intraductal papillomas is similar to that of women with other prolif-
erative lesions without atypia (relative risk ˜2 compared with the general
A
Figure 8.10 Intraductal papilloma with infarction. A: At low power, necrosis and focal
areas of hemorrhage are apparent. B: High-power view of the periphery of the lesion
showing necrosis (right side of field) and epithelium with squamous metaplasia.
B
opulation). Multiple papillomas appear to be associated with a higher

p
risk of concurrent and subsequent carcinoma than do solitary, central
papillomas.1,5-7 The key features of intraductal papillomas are summarized
in Table 8.2.
Table 8.2 Key Features of Intraductal Papilloma
Clinical
• Age 30–50 years at presentation
• May be central or peripheral
• Central lesions most often present as nipple discharge or subareolar mass
Histologic
• Variably fibrotic fibrovascular cores covered by epithelial and myoepithelial
cells
• Epithelium consists of one to several layers of cuboidal to columnar cells,
but may exhibit usual ductal hyperplasia, atypical ductal hyperplasia
(papilloma with atypia), or DCIS (papilloma with DCIS)
• Apocrine metaplasia and/or squamous metaplasia may be seen, the latter
most often in association with infarction

Papilloma with Atypia (Atypical Papilloma)

and Papilloma with DCIS
Some intraductal papillomas exhibit monotonous areas of epithelial pro-
liferation that fulfill the combined architectural and cytologic criteria for
the diagnosis of ADH or low-grade DCIS (Figs. 8.11 and 8.12, e-Fig. 8.10).
These areas may involve the papilloma to varying degrees, but features of
a benign papilloma remain evident in part of the lesion. When DCIS is
present, it most often exhibits solid and/or cribriform patterns. Small foci
of necrosis may be observed (Fig. 8.12). Of note, myoepithelial cells are
absent in the foci of ADH or DCIS but remain identifiable in the areas
of residual benign papilloma and around the periphery of the involved
spaces (Fig 8.13) (Table 8.1). In addition, the epithelial cells comprising
the atypical foci lack expression of high-molecular-weight cytokeratins
(such as CK5/6) and typically show strong, diffuse expression of estrogen
receptor (Fig. 8.14).7 In fact, in problematic cases, the absence of high-
molecular-weight cytokeratin staining coupled with the presence of dif-
fuse staining for estrogen receptor is a useful adjunct to help distinguish
ADH or DCIS in a papilloma from UDH in a papilloma which typically
shows strong expression of high-molecular-weight cytokeratins (often in
a mosaic pattern) and patchy, variable expression of estrogen receptor.
A
Figure 8.11 Papilloma with atypia. A: At low power, most of the lesion can be seen
to consist of an intraductal papilloma without atypical features. However, in a few areas
(seen best in the lower right portion of this photograph), small foci of monomorphic
epithelial cells with a cribriform pattern are evident. B: Higher power view illustrates the
atypia characteristic of atypical ductal hyperplasia (lower right).
B
A
Figure 8.12 Papilloma with DCIS. A: Low-power view illustrates that a large portion
of the papilloma contains an epithelial proliferation with the architectural and cytologic
features of ductal carcinoma in situ (DCIS) growing in a solid and cribriform pattern (left
side). B: Higher power view to illustrate the DCIS. In this case, the DCIS has intermediate-
grade nuclei.
B
Figure 8.13 Papilloma with extensive involvement by ductal carcinoma in situ (DCIS).
Smooth muscle myosin heavy chain immunostain demonstrating myoepithelial cells lining
the fibrovascular cores of residual benign papilloma and at the periphery of the space.
Myoepithelial cells are not present within the areas of DCIS.
Figure 8.14 Papilloma with DCIS immunostained for cytokeratin (CK) 5/6. The neoplastic
epithelial cells are CK5/6 negative; CK5/6 highlights residual myoepithelial cells.
Criteria for distinguishing papilloma with atypia from papilloma with

DCIS have been varied. Some have been based on assessment of the size or
extent (i.e., number of millimeters) of the atypical proliferation within the
papilloma, whereas others have been based on the proportion of the pap-
illoma involved by the atypical proliferation.6,8 The 2011 WHO Working
Group recommended that size/extent criteria rather than proportion crite-
ria be utilized to distinguish papilloma with atypia (atypical focus <3 mm
in size) from DCIS involving a papilloma (≥3 mm of atypia), an approach
to which we subscribe.9 It is important to note that when the atypia within
the papilloma is of intermediate or high nuclear grade, a diagnosis of DCIS
involving a papilloma should be rendered regardless of extent.
The clinical significance of atypia or DCIS in a papilloma is not well-
defined. Some authors have reported a substantially increased risk (7.5-
fold) for the subsequent development of breast cancer, predominantly in
the ipsilateral breast,6 whereas others have found that the level of breast
cancer risk associated with papillomas with atypia was similar to that for
patients with ADH elsewhere in the breast (fourfold to fivefold) and that
the risk was approximately equal in both breasts.1 Breast cancer risk is
reported to be particularly high (sevenfold) among women with multiple
papillomas with atypia.1
The risk of subsequent breast cancer and local recurrence does not
appear to be related to the extent of atypia or DCIS within the papilloma.
In fact, the most important consideration is the presence of atypia or
DCIS in the surrounding breast tissue because this appears to be more

closely related to the risk of recurrence than the qualitative features or
extent of atypia within the papilloma itself.6,10
Given the foregoing information, papillomas with atypia and papil-
lomas with DCIS are best managed by complete excision with careful
follow-up. The surrounding breast tissue should be carefully evaluated for
the presence of ADH and DCIS because this should be the major feature
influencing management decisions.
Papillary DCIS
As indicated in Chapter 3, some DCIS lesions have a papillary growth
pattern, characterized by fibrovascular cores covered by neoplastic epi-
thelium. In our view, these lesions are fundamentally distinct from papil-
lomas with DCIS because they do not exhibit evidence of residual benign
papilloma. Features useful in distinguishing papillary DCIS from benign
intraductal papillomas are summarized in Table 8.3. In particular, in pap-
illary DCIS, the papillae are usually more delicate and less fibrotic than
those of intraductal papilloma. Additionally, the epithelium in papillary
DCIS is usually composed of a single cell population with a uniform
Table 8.3 Key Features Useful for Distinguishing Intraductal

Papilloma from Papillary Ductal Carcinoma In Situ
Intraductal
Papilloma Papillary DCIS
Cell types Epithelial and Epithelial only

myoepithelial
Cell orientation Haphazard Uniform, perpendicular
to fibrovascular stalks;
solid, cribriform, or
micropapillary patterns
may be present
Nuclei Normochromatic Hyperchromatic
Stroma of papillae Prominent; Delicate
fibrosis with
epithelial
entrapment
Apocrine metaplasia Present Absent
Proliferation in adjacent ducts Hyperplasia DCIS

Adapted from Kraus FT, Neubecker RD. The differential diagnosis of papillary tumors of
the breast. Cancer. 1962;15:444-455.
appearance (Fig. 8.15, e-Fig. 8.11). The epithelium may consist of one to
several layers of columnar cells with varying degrees of cellular stratifica-
tion or may show a more pronounced proliferation of uniform cells in
solid, cribriform, or micropapillary growth patterns. Contiguous growth of
B
Figure 8.15 Papillary ductal carcinoma in situ. A: Medium-power view illustrating
delicate fibrovascular cores. B: High-power view illustrating papillae covered by a single
population of stratified columnar epithelial cells. No myoepithelial cells are present.
Figure 8.16 Papillary ductal carcinoma in situ. In this case, there is a cribriform
proliferation of neoplastic epithelial cells that partially obliterate the spaces between
papillae. Residual fibrovascular cores are apparent.
the epithelium may partially or completely obliterate the spaces between

papillae, obscuring the underlying papillary architecture (Fig. 8.16). The
nuclei of the neoplastic epithelial cells are most often of low or interme-
diate grade. Some authors have described and illustrated the presence of
myoepithelial cells within the papillae of papillary DCIS, albeit in reduced
numbers when compared with intraductal papillomas.11,12 In our view,
lesions illustrated as “papillary DCIS” with myoepithelial cells in the
papillae most likely represent pre-existing benign intraductal papillomas
that have become extensively involved by DCIS rather than de novo papil-
lary DCIS. A layer of myoepithelial cells is present at the periphery of the
involved spaces, however, which is a feature that defines this as an in situ
process (Fig. 8.17, e-Fig. 8.12) (Table 8.1).
It should be noted that although most papillary DCIS have a single,
uniform cell population, others feature a dimorphic cell population in
which the second population consists of cells with abundant, pale cyto-
plasm that are most often in a basal location. These cells (“globoid cells”)
should not be mistaken for myoepithelial cells and can be distinguished
from them with immunohistochemical markers for epithelial cells (such
as low-molecular-weight cytokeratins) and myoepithelial cells if necessary
(Fig. 8.18, e-Fig. 8.13). The key features of papillary DCIS are summarized
in Table 8.4.
Figure 8.17 Papillary ductal carcinoma in situ. Smooth muscle myosin heavy chain
immunostain demonstrates a myoepithelial cell layer at the periphery of the involved
space but not within the papillary proliferation.
Figure 8.18 Papillary ductal carcinoma in situ with dimorphic cell population. In addition
to the neoplastic columnar epithelial cells covering the papillae, a second population of
cells with pale cytoplasm is evident (“globoid” cells), primarily in a basal location. Although
they superficially resemble myoepithelial cells, they are in fact a second population of
neoplastic epithelial cells.
Table 8.4 Key Features of Papillary Ductal Carcinoma In Situ
• Delicate fibrovascular cores covered by monotonous, often stratified

population of columnar epithelial cells with low or intermediate nuclear
grade
• Myoepithelial cells not present in papillae, but present at the periphery of
involved spaces
• Epithelial proliferation may assume cribriform, solid, and micropapillary
growth patterns
• Some cases characterized by dimorphic cell population
Encapsulated Papillary Carcinoma

Traditionally considered to be a variant of DCIS and termed intracystic or
encysted papillary carcinoma, the lesion that is now referred to as encap-
sulated papillary carcinoma13 is characterized by a circumscribed nodule
of papillary carcinoma surrounded by a fibrous capsule. Some lesions
appear to be present within a cystically dilated duct. Most frequently
found in elderly women, these lesions usually present as a subareolar mass
with or without nipple discharge. Encapsulated papillary carcinoma may
occur alone, but more often the surrounding breast tissue contains foci
of low or intermediate nuclear grade DCIS, usually with a cribriform or
micropapillary pattern.14,15
On gross examination, these lesions appear as a circumscribed,
friable, or bosselated mass that may appear to be within a cystic space.
Microscopically, they are characterized by one or occasionally several
nodules of papillary carcinoma surrounded by a thick fibrous capsule
(Fig. 8.19, e-Fig. 8.14). The histologic appearance of the papillary pro-
liferation can have any of the features described previously for papillary
DCIS (e-Fig. 8.15). In addition, it is not uncommon to find entrapped
neoplastic epithelial cells within the fibrous capsule, which is a feature
that may be misinterpreted as invasive carcinoma. Myoepithelial cells
are not present in the papillae of encapsulated papillary carcinomas.
However, in contrast to papillary DCIS in which there are myoepithelial
cells at the periphery of the involved spaces, recent studies have failed to
demonstrate a layer of myoepithelial cells at the periphery of the tumor
nodules of most encapsulated papillary carcinomas (Fig. 8.20, e-Fig.
8.16) (Table 8.1).15-18 This observation raises the possibility that many of
these lesions, long considered variants of DCIS, may in fact be a form of
low-grade invasive carcinoma with an expansile growth pattern or part
of a spectrum of progression from in situ to invasive disease.15,16,18,19 The
finding of axillary lymph node metastases in patients with encapsulated
papillary carcinoma that do not show evidence of frank invasive carci-
noma provides further support for this concept.20 Regardless of whether
Figure 8.19 Encapsulated papillary carcinoma. Low-power view illustrating the papillary
proliferation surrounded by a fibrous capsule. The papillae are covered by a single,
uniform cell population and lack myoepithelial cells.
Figure 8.20 Encapsulated papillary carcinoma immunostained for p63. No myoepithelial

cells are seen within the papillae or at the periphery of the lesion. An adjacent normal
duct is surrounded by a layer of p63-positive myoepithelial cells.
Figure 8.21 Encapsulated papillary carcinoma with an adjacent focus invasive ductal
carcinoma.
these lesions are in situ or invasive in nature, however, outcome studies

have demonstrated that they are associated with an excellent prognosis
with adequate local therapy alone.19,21-23 Therefore, it is most prudent to
continue to manage patients with these lesions as they are currently man-
aged (i.e., similar to patients with DCIS) and to avoid categorization of
such lesions as frankly invasive papillary carcinomas.
Areas of unequivocal invasive carcinoma (most often invasive ductal
carcinoma) may be seen in association with encapsulated papillary carci-
nomas. These can range from microinvasive to larger foci (Fig. 8.21). To
avoid confusion with entrapped epithelium, the putative invasion should
be clearly present beyond the fibrous capsule of the lesion.
Given the controversy about the nature of encapsulated papillary
carcinomas, there is currently no universal agreement as to what T stage
should be assigned to these lesions. When frankly invasive carcinoma
is present in association with an encapsulated papillary carcinoma, we
believe it is most prudent to report only the size of the frankly invasive
component as the tumor (T) size for staging purposes. The 2011 WHO
Working Group recommended that encapsulated papillary carcinomas
that lack areas of conventional invasive carcinoma be staged and man-
aged as in situ lesions (Tis). The key features of encapsulated papillary
carcinoma are summarized in Table 8.5.
Table 8.5 Key Features of Encapsulated Papillary Carcinoma
Clinical
• Older age at presentation
• Presents with nipple discharge or subareolar mass
Histologic
• One or more nodule(s) of papillary carcinoma surrounded by thick fibrous
capsule
• Delicate papillae covered by monotonous, often stratified population of
columnar epithelial cells of low or intermediate nuclear grade
• Papillary, cribriform, and solid growth patterns may be seen
• Myoepithelial cells absent both within and surrounding the papillary nodules
• May represent a form of low-grade invasive cancer with expansile growth
pattern rather than an in situ lesion
• Foci of frankly invasive carcinoma (most often invasive ductal carcinoma)
may be seen
Solid Papillary Carcinoma

Solid papillary carcinoma, historically considered to be a variant of
DCIS, presents in older women (seventh and eighth decades) as histolog-
ically circumscribed, solid nodules of neoplastic epithelial cells that are
typically ovoid or spindle-shaped and may have a streaming appearance
similar to that seen in UDH (e-Fig. 8.17).19,24,25 Discrete papillae are not
apparent; the underlying papillary structure is represented by a network
of fibrovascular cores among the solid cellular proliferation (Fig. 8.22,
e-Fig. 8.18). The cells may have endocrine features, with granular eosin-
ophilic cytoplasm, fine nuclear chromatin, and immunoreactivity for
chromogranin and synaptophysin. Intracellular and extracellular mucin
production are common features (Fig. 8.23), and areas of invasive muci-
nous carcinoma may be seen in association with these lesions. Other
types of invasive carcinoma may also be seen.25 Features that distinguish
these lesions from UDH include a uniform cell population, polarization
of the cells around fibrovascular cores and fenestrations, mucin produc-
tion, and absence of staining of the neoplastic cells for cytokeratin 5/6.26
An absence of myoepithelial cells within the cellular proliferation
is characteristic. Lack of myoepithelial cells around the periphery of the
neoplastic nodules has also been reported in some cases, which raises the
possibility that at least some of these lesions represent circumscribed nests
of invasive carcinoma rather than variants of DCIS (Fig. 8.24, e-Fig. 8.19)
(Table 8.1).19,25 The identification in metastatic foci of tumor with a
morphologic appearance identical to that of solid papillary carcinomas
B
Figure 8.22 Solid papillary carcinoma. A: Portions of two circumscribed nodules of
solid papillary carcinoma are seen in this photograph. The nodules are composed of a
uniform population of ovoid- to spindle-shaped epithelial cells growing in a solid pattern.
Fibrovascular cores are evident. The pattern of the proliferation superficially resembles
that seen in usual ductal hyperplasia. B: Higher power view to illustrate the uniformity of
the cell population.
Figure 8.23 Solid papillary carcinoma with extracellular mucin production.
Figure 8.24 Solid papillary carcinoma. Smooth muscle myosin heavy chain immunostain
demonstrates an absence of myoepithelial cells within and surrounding this nodule of
solid papillary carcinoma. Vascular smooth muscle cells and pericytes within the fibrovas-
cular stroma are highlighted by this antibody.
raises further concern that at least some of these lesions represent invasive
rather than in situ carcinomas.19,24,25
In practice, it may be very difficult on H&E-stained sections alone
to determine if a solid papillary carcinoma is entirely in situ, entirely
invasive, or composed of a mixture of in situ and invasive components. In
such cases, immunostains for myoepithelial cells may be helpful in resolv-
ing this issue. Solid papillary carcinomas in which the cell nests exhibit
a complete or partial peripheral myoepithelial cell layer should be con-
sidered in situ lesions. At the other end of the spectrum, the presence of
nests of solid papillary carcinoma with irregular borders that are present
in a geographic, jigsaw pattern coupled with the absence of myoepithelial
cells around the nests is considered by some to be indicative of invasive
carcinoma (Fig. 8.25).27 Unfortunately, even with the use of myoepithe-
lial cell immunostains, the precise categorization of some solid papillary
carcinomas remains problematic. The 2011 WHO Working Group recom-
mended that if there is uncertainty about the presence of invasion, the
lesion should be regarded as in situ for staging and management purposes.
Follow-up studies have indicated that solid papillary carcinomas without
coexisting areas of conventional invasive carcinoma appear to have an
indolent clinical course.19,24,25
A
Figure 8.25 Solid papillary carcinoma. A: Tumor cell nests with irregular borders
arranged in a geographic, jigsaw pattern are indicative of invasive carcinoma. B: p63
immunostain from another area of this case demonstrates the absence of myoepithelial
cells around tumor cell nests.
B
Invasive Papillary Carcinoma

Invasive papillary carcinomas are tumors in which the invasive cell nests
consist of papillae with fibrovascular cores that are covered by malignant
epithelial cells (Fig. 8.26). These lesions are reported to be associated with
A
Figure 8.26 Invasive papillary carcinoma. A: Low-power view showing tumor cells
arranged in irregular nests, many of which have a frankly papillary configuration. B: Higher
power view demonstrating fibrovascular cores covered by cytologically atypical tumor cells.
B
a favorable prognosis,28 but frankly invasive carcinomas of the breast with

a papillary pattern are exceptionally rare. More often, areas of conven-
tional types of invasive carcinoma (such as invasive ductal or mucinous
carcinomas) are seen in association with papillary DCIS, encapsulated
papillary carcinomas, or solid papillary carcinomas;25,29 these lesions
should not be categorized as invasive papillary carcinomas.29
Papillary Lesions on Core-needle Biopsy

Excision is required when an atypical papillary lesion or papillary car-
cinoma is present in a core-needle biopsy specimen. However, the
need for surgical excision in patients with benign intraductal papilloma
in core-needle biopsy samples (Fig. 8.27) is an unresolved issue. The
reported frequency of upgrade on excision (to ADH, DCIS, or invasive
cancer) following a diagnosis of benign papilloma on core-needle biopsy
ranges from 0% to 25%.30-33 However, the studies that have addressed this
are characterized by small patient numbers and potential selection bias
with regard to which patients underwent surgical excision. Some studies
have suggested that patients with a benign papilloma on a core-needle
biopsy may not require excision, particularly if the imaging studies are
concordant with that diagnosis.33 Given the limitations of the available
data, however, we currently recommend that patients with benign papil-
loma diagnosed on core-needle biopsy undergo excision for complete
evaluation of the lesion. Possible exceptions to this recommendation are
cases with an incidentally identified “micropapilloma” that is completely
encompassed within a core-needle biopsy fragment (Fig. 8.28).34
Figure 8.27 Core-needle biopsy with intraductal papilloma.
A
Figure 8.28 Core-needle biopsy with a micropapilloma. Low-power (A) and higher
power (B) views showing that this small, benign papilloma appears to be completely
contained within the core-needle biopsy specimen.
B
Lesions Considered to be Variants of Intraductal

Papilloma
Ductal Adenoma
Ductal adenomas are circumscribed nodules composed of epithelial cell
nests and glands within a sclerotic stroma and surrounded by a dense
fibrous capsule, the latter presumably representing a fibrotic duct wall
(Fig. 8.29). Myoepithelial cells surround the epithelial elements and may
be inconspicuous or prominent. Areas of apocrine metaplasia, cyst for-
mation, sclerosing adenosis, and epithelial hyperplasia may also be seen.
Distortion of the epithelial elements by the sclerotic stroma may result
in a pseudoinfiltrative pattern (Fig. 8.30). The stroma may show myxoid
change and, rarely, cartilaginous metaplasia, such that the features over-
lap with those of a pleomorphic adenoma (see subsequent text). Ductal
adenomas are thought to represent highly sclerotic variants of intraductal
papillomas in which the underlying papillary architecture has been com-
pletely obliterated.
Pleomorphic Adenoma
Pleomorphic adenomas, also known as benign mixed tumors, rarely occur
in the breast and are histologically similar to those seen in the salivary
gland.35-39 They are characterized by an admixture of luminal epithelial
Figure 8.29 Ductal adenoma. At low power, the lesion consists of a circumscribed
nodule with a sclerotic rim. The stroma contains epithelial cells in nests and glands.
Figure 8.30 Ductal adenoma. Higher power view of the center of a ductal adenoma
illustrating benign glands within a densely fibrotic stroma.
and myoepithelial cells embedded in a mucinous and chondromyxoid

stroma in which pseudocartilaginous as well as true chondroid and
osteoid change may occur. The epithelial cells can be arranged as nests,
cords, or tubules; the nuclei are bland. The myoepithelial cells are usu-
ally more polygonal and either surround the epithelial component or are
dispersed singly throughout the stromal matrix (Fig. 8.31, e-Fig. 8.20). The
cellularity of the lesion can vary substantially. On occasion, pleomorphic
adenoma-like areas are seen in association with intraductal papillomas,
which supports the view that they are papilloma variants (Fig. 8.32). In
addition, as noted earlier, similar areas may be seen in ductal adenomas.
Adenomyoepithelioma
Adenomyoepitheliomas are typically multinodular, lobulated lesions
composed of a combination of epithelial and myoepithelial elements
(Fig. 8.33, e-Fig. 8.21).40 Myoepithelial cells comprise a prominent com-
ponent of the lesion and may be clear and polygonal or spindle-shaped
(Figs. 8.34 and 8.35, e-Fig. 8.22). Often, there is a prominent component
of epithelial hyperplasia and papillomatosis.41 The epithelial component
may show apocrine, squamous, or sebaceous differentiation.42 In other
cases, the myoepithelial cell component may be so prominent that epi-
thelial cells are difficult to appreciate. Tavassoli43 described three variants
of adenomyoepithelioma: the spindle cell type in which the predominant
Figure 8.31 Pleomorphic adenoma. At low power, the tumor consists of a circum-
scribed nodule composed of benign glands within a variably fibrotic and chondromyxoid
stroma.
Figure 8.32 Pleomorphic adenoma (right) arising in association with an intraductal

papilloma (left).
Figure 8.33 Adenomyoepithelioma. At low power, a relatively circumscribed nodule

composed of epithelial cells forming glands and nests is apparent. The spaces between
the epithelial cells are occupied by myoepithelial cells.
Figure 8.34 Adenomyoepithelioma. Small glands composed of epithelial cells with

eosinophilic cytoplasm are surrounded by myoepithelial cells with clear cytoplasm.
Figure 8.35 Adenomyoepithelioma. In this lesion, the myoepithelial cells between the
glands have a spindle shape.
pattern of the myoepithelial cells is spindled with few epithelial lined

spaces within the lesion; the tubular pattern that is characterized by a pro-
liferation of rounded tubules with unusually prominent and hyperplastic
myoepithelial cells; and the lobulated pattern, which is composed of solid
nests of myoepithelial cells proliferating around compressed epithelial

lined spaces. A thick fibrous capsule may occasionally surround adeno-
myoepitheliomas and central areas of sclerosis and even necrosis may
be present. Immunostains for myoepithelial cells, such as p63, calponin,
and smooth muscle myosin heavy chain, may be helpful in confirming
the diagnosis of adenomyoepithelioma. However, it should be noted that
the myoepithelial cells in these lesions may show reduction or absence of
expression of one or more of these markers,40 indicating that these myo-
epithelial cells may exhibit an aberrant phenotype.
Most adenomyoepitheliomas appear to represent variants of intra-
ductal papilloma. In fact, as noted earlier, adenomyoepitheliomatous foci
may be seen in intraductal papillomas, and adenomyoepitheliomas may
have a prominent papillary epithelial proliferation. Some adenomyoepi-
theliomas appear to represent foci of adenosis in which the myoepithelial
cell component is particularly prominent.
Adenomyoepitheliomas are benign and are adequately treated by
complete local excision. Incomplete excision, particularly in the tubular
variant, has been associated with recurrence of these lesions.43 Rarely, the
epithelial component, myoepithelial component, or both becomes malig-
nant. The malignant component is typically characterized by an infiltra-
tive growth pattern, marked cytologic atypia, and numerous mitoses. Foci
identifiable as invasive ductal carcinoma or metaplastic carcinoma may
sometimes be seen; in other cases, the malignant component shows a
myoepithelial phenotype or is undifferentiated. In still other cases, there
may be foci of malignancy, which exhibit a combined epithelial and myo-
epithelial phenotype. Such lesions have been variously termed malignant
adenomyoepithelioma, epithelial–myoepithelial carcinoma (when both
components are malignant), and adenomyoepithelioma with carcinoma.42
These malignant lesions have been associated with both local recurrence
and distant metastases.42,44,45 At the other end of the spectrum, lesions
composed exclusively of benign myoepithelial cells (“myoepitheliomas”)
have also been reported.
Collagenous Spherulosis
Collagenous spherulosis is discussed here because it is commonly seen in
intraductal papillomas, although it can also be seen in other lesions (such
as UDH, ADH, adenosis, radial scars, and complex sclerosing lesions)
as well as in lobules and small ducts.46 The hallmark of this lesion is the
presence within the lumina of hyaline, acellular, eosinophilic spherules or
fibrillary, amorphous material, which may either be eosinophilic or have a
more basophilic, mucoid appearance (Figs. 8.8 and 8.36).47 These intralu-
minal deposits are composed of basement membrane components (type IV
collagen and laminin) and ground substance. Myoepithelial cells surround
the lumina and the deposits and are typically compressed, elongated, or
spindle-shaped. Calcifications may be present in areas of collagenous
spherulosis; thus, the lesion may be detected mammographically.48
Figure 8.36 Collagenous spherulosis involving a small duct. Amorphous, eosinophilic

spherules and mucoid deposits are present within the lumina.
The importance of recognizing this entity is to appreciate its benign

nature and to distinguish it from carcinoma because the features can be
confused with those of DCIS, adenoid cystic carcinoma, or signet ring cell
carcinoma. Lobular carcinoma in situ (LCIS) may involve areas of col-
lagenous spherulosis. In this situation, the appearance may mimic that of
cribriform pattern DCIS (see Chapter 5).49 Immunostains for E-cadherin
and/or myoepithelial markers can aid in identification of the lesion as
collagenous spherulosis involved by LCIS and facilitate its distinction
from DCIS. It may occasionally be difficult to distinguish collagenous
spherulosis from adenoid cystic carcinoma, particularly in small samples
such as core-needle biopsies. One report suggested that in problematic
cases, this distinction can be made using immunostains for calponin,
smooth muscle myosin heavy chain, and c-kit (CD117). According to this
report, collagenous spherulosis shows expression of calponin and smooth
muscle myosin heavy chain in the myoepithelial cells and lacks epithelial
cell staining for c-kit (CD117), whereas the myoepithelial cells of adenoid
cystic carcinomas lack staining for calponin and smooth muscle myosin
heavy chain and the epithelial cells are c-kit positive.50 However, the reli-
ability of these immunostains to make this distinction requires further
verification.
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and malignant papillary lesions of the breast. Am J Surg Pathol. 1983;7(5):451-461.
12. Raju UB, Lee MW, Zarbo RJ, Crissman JD. Papillary neoplasia of the breast: immuno-
histochemically defined myoepithelial cells in the diagnosis of benign and malignant
papillary breast neoplasms. Mod Pathol. 1989;2(6):569-576.
13. Collins L, O’Malley F, Visscher D, Moriya T, Ichihara S, Reis-Filho J. Encapsulated
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WHO Classification of Tumours of the Breast. Lyon: IARC Press 2012;106-107.
14. Carter D, Orr SL, Merino MJ. Intracystic papillary carcinoma of the breast. After mas-
tectomy, radiotherapy or excisional biopsy alone. Cancer. 1983;52(1):14-19.
15. Collins LC, Carlo VP, Hwang H, Barry TS, Gown AM, Schnitt SJ. Intracystic papillary
carcinomas of the breast: a reevaluation using a panel of myoepithelial cell markers. Am
J Surg Pathol. 2006;30(8):1002-1007.
16. Wynveen CA, Nehhozina T, Akram M, et al. Intracystic papillary carcinoma of the
breast: an in situ or invasive tumor? Results of immunohistochemical analysis and clini-
cal follow-up. Am J Surg Pathol. 2011;35(1):1-14.
17. Esposito NN, Dabbs DJ, Bhargava R. Are encapsulated papillary carcinomas of the
breast in situ or invasive? A basement membrane study of 27 cases. Am J Clin Pathol.
2009;131(2):228-242.
18. Hill CB, Yeh IT. Myoepithelial cell staining patterns of papillary breast lesions:
from intraductal papillomas to invasive papillary carcinomas. Am J Clin Pathol.
2005;123(1):36-44.
19. Rakha EA, Gandhi N, Climent F, et al. Encapsulated papillary carcinoma of the breast:
an invasive tumor with excellent prognosis. Am J Surg Pathol. 2011;35(8):1093-1103.
20. Mulligan AM, O’Malley FP. Metastatic potential of encapsulated (intracystic) papillary
carcinoma of the breast: a report of 2 cases with axillary lymph node micrometastases.
Int J Surg Pathol. 2007;15(2):143-147.
21. Harris KP, Faliakou EC, Exon DJ, Nasiri N, Sacks NP, Gui GP. Treatment and outcome
of intracystic papillary carcinoma of the breast. Br J Surg. 1999;86(10):1274.
22. Leal C, Costa I, Fonseca D, Lopes P, Bento MJ, Lopes C. Intracystic (encysted) papillary
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Pathol. 1998;29(10):1097-1104.
23. Lefkowitz M, Lefkowitz W, Wargotz ES. Intraductal (intracystic) papillary carcinoma
of the breast and its variants: a clinicopathological study of 77 cases. Hum Pathol.
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24. Maluf HM, Koerner FC. Solid papillary carcinoma of the breast. A form of intraductal
carcinoma with endocrine differentiation frequently associated with mucinous carci-
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2006;30(4):501-507.
26. Rabban JT, Koerner FC, Lerwill MF. Solid papillary ductal carcinoma in situ versus
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keratin 5/6. Hum Pathol. 2006;37(7):787-793.
27. Visscher D, Collins L, O’Malley F, Badve S, Reis-Filho J. Solid papillary carcinoma. In:
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National Surgical Adjuvant Breast Project (protocol no. 4). VI. Invasive papillary cancer.
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29. Tse G, Moriya T, Niu Y. Invasive papillary carcinoma. In: Lakhani SR, Ellis IO, Schnitt
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34. Lee KA, Zuley ML, Chivukula M, Choksi ND, Ganott MA, Sumkin JH. Risk of malig-
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9
Microinvasive Carcinoma
Microinvasive carcinoma is characterized by the extension of cancer cells

beyond the basement membrane of the ductal–lobular system into the
adjacent tissue, with no focus more than 0.1 cm in greatest dimension.
Lesions that fulfill this definition are staged as T1mi.1 According to the
7th edition of the American Joint Commission on Cancer (AJCC) Cancer
Staging Manual, when there are multiple foci of microinvasion, the
pathologist should attempt to quantify the number of foci and the range
of their sizes, including the largest, but should not report the size of the
tumor as the sum of the sizes.1
There are no clinical or radiologic features that distinguish microinvasive
carcinoma in association with ductal carcinoma in situ (DCIS) from pure
DCIS of equivalent size and grade.
Gross Pathology
Microinvasive carcinomas cannot, by definition, be identified on gross
pathologic examination and are typically detected during microscopic
examination of specimens containing DCIS.
Histopathology
Foci of microinvasive carcinoma are most often seen in association
with large areas of high-grade DCIS, but may also be seen with DCIS of
any grade or with lobular carcinoma in situ.2-4 Rarely, foci of microin-
vasive carcinoma are identified in the absence of coexistent carcinoma
in situ. The presence of periductal stromal desmoplasia and periduc-
tal lymphoid infiltrates and the involvement of lobules in association
267
with high-grade DCIS should heighten the suspicion of microinvasion.

However, these features are commonly present in association with
high-grade DCIS without demonstrable microinvasion; therefore, their
presence alone cannot be depended upon to make this distinction.
The cells comprising microinvasive foci associated with DCIS
typically have the same cytologic features as the cells comprising the
DCIS itself and may be present as single cells, small, solid cell clusters,
or glands. Although the AJCC criteria define an upper boundary for
microinvasive carcinoma (i.e., 0.1 cm), there is no universal agreement
on the lower boundary or minimum criteria for identifying microinva-
sion. Page and Anderson5 require “more than a single collection of cells
outside the lobular unit or immediate periductal area.” Fisher6 indicates
that the suspicious focus should comprise a “recognized type of invasive
cancer.” Elston and Ellis7 state that “only when unequivocal invasion is
seen outside the specialized lobular stroma should microinvasive carci-
noma be diagnosed.” The definition offered by Silver and Tavassoli8 is
less restrictive and recognizes as microinvasive any tumor cells singly
and in clusters in the periductal stroma. de Mascarel et al.2 recognize
two types of microinvasion, those characterized by the presence of sin-
gle infiltrating tumor cells and those characterized by infiltrating tumor
cell clusters.
We believe that it is most prudent to consider as microinvasion any
tumor cells singly or in small nests within the stroma that are clearly not
present within pre-existing ductal–lobular structures or within a benign
sclerosing lesion, even if these cells are in the stroma immediately adja-
cent to ducts and lobules (Figs. 9.1–9.7, e-Figs. 9.1–9.6). Although the
nuclear grade of the neoplastic cells comprising the microinvasive foci
can be readily assessed, the extent of these foci is, by definition, limited
and this often precludes accurate assessment of a combined histologic
grade.
A diagnosis of microinvasion should only be rendered in the pres-
ence of unequivocal histologic findings supporting that diagnosis. This is
particularly important in core-needle biopsy samples because a diagno-
sis of microinvasion in a core-needle biopsy is commonly viewed as an
indication for sentinel node biopsy or other forms of axillary lymph node
examination, whereas a diagnosis of pure DCIS will not result in axillary
node examination if the DCIS is of limited extent.
The key features of microinvasive carcinoma are summarized in
Table 9.1.
Microinvasive Carcinoma ——— 269
B
FIGURE 9.1 Microinvasive carcinoma. A: Low-power view demonstrates numerous ducts
with high-grade ductal carcinoma in situ, some of which are surrounded by a mononucle-
ar cell infiltrate. In addition, an area with small tumor cell nests in a desmoplastic stroma
is evident (arrows). B: High-power view demonstrates that these irregular tumor cell nests
lack a surrounding myoepithelial cell layer, consistent with stromal invasion. Given the
invasive pattern of these cell nests and the small size of this area (<0.1 cm), a diagnosis of
microinvasive carcinoma is warranted.
B
FIGURE 9.2 Microinvasive carcinoma. A: Low-power view illustrating an irregular,
non-lobulocentric collection of fused glands in the stroma (arrow) in association with an
area of ductal carcinoma in situ. This focus measures <0.1 cm in size. B: Higher power
view of the microinvasive focus.
B
FIGURE 9.3 Microinvasive carcinoma. A: Low-power view illustrating high-grade ductal
carcinoma in situ with a prominent stromal mononuclear cell infiltrate. Even at this
magnification, a few nests of tumor cells with irregular contours are seen within the
inflammatory infiltrate (arrows). B: Higher power view of one of the nests demonstrating
its invasive nature.
B
FIGURE 9.4 Microinvasive carcinoma. A: This focus of ductal carcinoma in situ is
surrounded by a dense lymphoid infiltrate. To the right of the duct, a few tumor cells,
singly and in small nests, are present admixed with the lymphocytes (arrow). B: Higher
power view demonstrating the neoplastic cells within the lymphocyte-rich stroma.
B
FIGURE 9.5 Microinvasive carcinoma. A: This example of microinvasive carcinoma is
characterized by a few irregular clusters of neoplastic cells in the stroma adjacent to foci
of ductal carcinoma in situ (arrow). B: Higher power view of microinvasive focus.
B
FIGURE 9.6 Microinvasive carcinoma associated with non–high-grade ductal carcinoma
in situ at low (A) and higher (B) power. In this case, the microinvasive focus consists of
grade 1 invasive ductal carcinoma.
FIGURE 9.7 Microinvasive lobular carcinoma associated with lobular carcinoma in situ.
TABLE 9.1 Key Features of Microinvasive Carcinoma
• Most commonly seen in association with large, high-grade DCIS

• Neoplastic cells or cell nests within stroma, clearly not within pre-existing
ductal–lobular structures or within a benign sclerosing lesion; no focus
more than 0.1 cm in greatest size
• Patterns in DCIS commonly mistaken for microinvasion include
• Involvement of lobules
• Branching of involved ducts
• Distortion of involved ducts or acini by fibrosis
• DCIS involving benign sclerosing processes such as sclerosing adenosis,
radial scars, and complex sclerosing lesions
• Crush artifact
• Cautery effect
• Artifactual displacement of DCIS cells into stroma or adipose tissue due
to specimen manipulation or prior needling procedure
• Immunostains for myoepithelial cell markers and cytokeratin often helpful
in distinguishing mimics from true microinvasion

FIGURE 9.8 Immunostain for HER2 protein in a case of high-grade ductal carcinoma in
situ (DCIS) with microinvasion. Both the DCIS and microinvasive focus show strong (3+)
HER2 protein overexpression.
Biomarkers
Immunostains for estrogen receptor, progesterone receptor, and HER2
should be performed in all cases of microinvasive carcinoma. However,
the microinvasion may no longer be present on the slides recut for these
biomarker studies. In such cases, the immunostain results for the asso-
ciated DCIS should be reported and can be used as a surrogate for the
marker studies on the microinvasive focus or foci because the expression
of these markers in the accompanying DCIS almost always mirrors that in
the areas of microinvasion (Fig. 9.8, e-Fig. 9.7).

A variety of definitions have been used for microinvasion in the past.
Some of these definitions have included lesions that would currently be
considered frankly invasive carcinomas. As a result, it is difficult to draw
firm conclusions regarding the frequency of axillary lymph node involve-
ment or clinical outcome among patients with microinvasion.
The reported frequency of axillary lymph node involvement in
patients given a diagnosis of microinvasive carcinoma ranges from 0%
to 28%.4,9 More recent studies have indicated that sentinel lymph node
involvement is seen in up to 14% of patients with microinvasion.10-14 The
sentinel lymph node deposits are often micrometastases or isolated tumor
cells. Although some studies have suggested that disease-free survival
and overall survival for patients with microinvasive carcinoma is similar
to that of patients with DCIS of equivalent size and grade, others have
suggested that clinical outcome is intermediate between that of patients
with pure DCIS and those with frankly invasive cancer.2,4,15 These differ-
ences are probably due to differences in the definitions of microinvasion
used in these various studies.
It is likely that when the current AJCC definition for microinvasion is
used, the frequency of axillary lymph node involvement will be quite low.
Moreover, local recurrence and survival rates will likely be similar for patients
with DCIS and microinvasion and those with pure DCIS of similar extent
and grade because some patients categorized as having pure DCIS will have
undetected foci of microinvasive (or even frankly invasive) carcinoma due to
the practical limitations of tissue sampling. Therefore, the management algo-
rithm for patients with large areas of DCIS with and without microinvasion
should be similar and should include a sentinel lymph node biopsy.
The identification of microinvasion in a lesion that is primarily DCIS can
be difficult because a variety of patterns in DCIS may be misconstrued
as microinvasion. These include (a) DCIS involving lobules (“canceriza-
tion” of lobules) (Fig. 9.9, e-Fig. 9.8); (b) branching of involved ducts
(Fig. 9.10); (c) distortion or entrapment of involved ducts or acini by
fibrosis (Fig. 9.11); (d) inflammation present in association with and
obscuring involved ducts or acini; (e) crush artifact; (f) cautery effect; (g)
artifactual displacement of DCIS cells into the surrounding stroma or
adipose tissue due to tissue manipulation or a prior needling procedure
(Fig. 9.12, e-Fig. 9.9); and (h) DCIS involving benign sclerosing processes
FIGURE 9.9 Ductal carcinoma in situ extending into the lobular acini (arrow). The pattern
produced by the lobular involvement should not be mistaken for microinvasive carcinoma.
FIGURE 9.10 Ductal carcinoma in situ with duct branching. The small tongue of tumor
cells on the right side of the duct (arrow) represents a duct branch and should not be
misinterpreted as microinvasion.
such as radial scars, complex sclerosing lesions, and sclerosing adenosis

(Fig. 9.13, e-Fig. 9.10).16
Obtaining additional H&E-stained levels may help to define the
nature of the process in problematic cases. In many cases, immuno
stains for myoepithelial cells are of greater value for distinguishing true
microinvasion from its mimics. Cancerization of lobules, duct branching,
duct distortion, and DCIS involving adenosis are all distinguished from
true microinvasion by the presence of myoepithelial cells around the
involved spaces. In contrast, microinvasive foci lack a myoepithelial cell
FIGURE 9.11 Ductal carcinoma in situ distorted by stromal fibrosis. The irregular duct
contours should not be mistaken for microinvasion.
FIGURE 9.12 Displaced tumor cells and necrotic debris within adipose tissue adjacent to
the ductal carcinoma in situ. There is no stromal reaction to these cells, which were most
likely displaced by tissue manipulation.
layer around the neoplastic cell nests. A variety of myoepithelial cell mark-
ers have been advocated for this purpose (Fig. 9.13).17-20 However, the
available myoepithelial cell markers vary in their sensitivity and specificity,
and the use of a panel is advised.21 We most often use a combination of
calponin, smooth muscle myosin heavy chain, and p63 for this purpose.
Double immunostaining for cytokeratin and a myoepithelial marker, such
A
FIGURE 9.13 Ductal carcinoma in situ (DCIS) involving sclerosing adenosis. A: Numerous
small solid nests and glands composed of neoplastic cells are present in a desmoplastic
stroma adjacent to DCIS, raising the suspicion of microinvasion. B: A smooth muscle myosin
heavy chain immunostain demonstrates a myoepithelial cell layer around the nests and
glands, supporting the in situ nature of this process.
B
as p63, may be particularly helpful in this setting because this circumvents

the problem of basing a diagnosis of microinvasion solely on a negative
result (i.e., absence of staining for myoepithelial cell markers) by highlight-
ing the epithelial cells of the microinvasive focus (Fig. 9.14, e-Fig. 9.11).
FIGURE 9.14 Double immunostain for cytokeratin (red cytoplasmic stain) and p63
(brown nuclear stain) in a case of ductal carcinoma in situ (DCIS) with microinvasion. Ducts
containing DCIS are surrounded by p63-positive myoepithelial cells. In contrast, the focus
of microinvasion shows staining only for cytokeratin; there are no associated p63-positive
myoepithelial cells.
References
1. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010.
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Breast ductal carcinoma in situ with microinvasion: a definition supported by a long-
term study of 1248 serially sectioned ductal carcinomas. Cancer. 2002;94(8):2134-2142.
3. Ross DS, Hoda SA. Microinvasive (T1mic) lobular carcinoma of the breast: clinico-
pathologic profile of 16 cases. Am J Surg Pathol. 2011;35(5):750-756.
4. Pinder S, Ellis I, Schnitt S, Tan PH, Rutgers E, Morrow M. Microinvasive carcinoma. In:
5. Page DL, Anderson TJ. Diagnostic Histopathology of the Breast. Edinburgh: Churchill
Livingstone; 1987.
6. Fisher ER. Pathobiological considerations relating to the treatment of intraductal carci-
noma (ductal carcinoma in situ) of the breast. CA Cancer J Clin. 1996;47:52-64.
7. Elston CE, Ellis IO. The Breast. Edinburgh: Churchill Livingstone; 1998.
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1998;82(12):2382-2390.
9. Guth AA, Mercado C, Roses DF, Darvishian F, Singh B, Cangiarella JF. Microinvasive
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from ductal carcinoma in situ with microinvasion. Cancer. 1999;85(11):2439-2443.
11. Klauber-DeMore N, Tan LK, Liberman L, et al. Sentinel lymph node biopsy: is it indi-
cated in patients with high-risk ductal carcinoma-in-situ and ductal carcinoma-in-situ
with microinvasion? Ann Surg Oncol. 2000;7(9):636-642.
12. Intra M, Zurrida S, Maffini F, et al. Sentinel lymph node metastasis in microinvasive
breast cancer. Ann Surg Oncol. 2003;10(10):1160-1165.
13. Yi M, Krishnamurthy S, Kuerer HM, et al. Role of primary tumor characteristics in
predicting positive sentinel lymph nodes in patients with ductal carcinoma in situ or
microinvasive breast cancer. Am J Surg. 2008;196(1):81-87.
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10
Invasive Breast Cancer
Invasive breast cancers constitute a heterogeneous group of lesions. The

vast majority are adenocarcinomas; their histopathologic classification
is based upon the growth pattern and cytologic features of the tumor.
Although the most common types are designated “ductal” and “lobular,”
this distinction is not meant to indicate the site of origin within the mam-
mary ductal system. Most invasive breast cancers arise in the terminal duct
lobular unit, regardless of histologic type.1
Mammographic screening has had a dramatic impact on the nature
of invasive breast cancers encountered in clinical practice. Mammography
results not only in the detection of smaller invasive breast cancers and
fewer cancers with axillary lymph node involvement but also in more spe-
cial type cancers (particularly tubular carcinomas) and cancers of lower
histological grade.2-4
At the present time, histopathology remains the basis for the clas-
sification of invasive breast cancers. However, knowledge gained from
molecular studies will likely result in modification of the existing his-
topathologic classification system. Several molecular subtypes of breast
cancer identified through gene expression profiling studies have been
recognized for over a decade. Most notable among these are the luminal
A, luminal B, HER2, and basal-like types.5-9 Other molecular subtypes
identified in at least some studies include normal breast-like, molecular
apocrine, and claudin-low groups (see subsequent text).9,10 Given that
clinicians are thinking increasingly in terms of these molecular subtypes
in formulating treatment recommendations,11 pathologists must become
familiar with this terminology. Therefore, molecular subtypes will be men-
tioned briefly in the subsequent discussion of histologic types of breast
cancer where appropriate; these will be discussed in more detail later in
this chapter.
282
INVASIVE BREAST CANCER ——— 283
Invasive Ductal Carcinoma (Invasive Carcinoma

of no Special Type)
Invasive ductal carcinomas are the most common type of invasive breast
cancer, accounting for up to 70% to 75% of the cases in some series.
These tumors comprise a heterogeneous group with regard to pathologic
features and clinical course and are characterized histologically by the
lack of sufficient features to warrant categorization as any of the special
type tumors. For this reason, the WHO classification designates these
tumors as invasive carcinomas of no special type.12
Invasive ductal carcinomas usually present as a palpable tumor and/or
mammographic abnormality; the latter is most often a spiculated mass
with or without associated microcalcifications.
Gross Pathology
The classical macroscopic appearance of invasive ductal carcinoma is
that of a scirrhous carcinoma, characterized by a firm, sometimes rock-
hard mass, which on a cut section has a gray-white to tan, gritty surface
(Fig. 10.1). This consistency and appearance is due to the desmoplastic
tumor stroma and not the neoplastic cells themselves. Invasive ductal
carcinomas composed primarily of tumor cells with little desmoplastic
stromal reaction are grossly tan and soft. Although most invasive ductal
cancers have a stellate or spiculated contour with irregular peripheral
margins, some are grossly well circumscribed.
FIGURE 10.1 Gross appearance of an invasive ductal carcinoma. The tumor is composed
of tan-gray tissue with irregular borders.
Histopathology
The microscopic appearance of invasive ductal carcinomas is highly
heterogeneous with regard to growth pattern, cytologic features, mitotic
activity, stromal desmoplasia, and extent of associated ductal carcinoma
in situ (DCIS). Variability in histologic features may be seen within a sin-
gle case. The tumor cells may be arranged as well-formed glandular struc-
tures; as nests, cords, or trabeculae of various sizes; or as solid sheets. Foci
of necrosis are evident in some cases and may be extensive. Cytologically,
the tumor cells range from those that show little deviation from normal
breast epithelial cells to those exhibiting marked cellular pleomorphism
and nuclear atypia. Mitotic activity can range from undetectable to brisk.
The degree of gland formation, nuclear atypia, and mitotic activity are
considered together in determining the combined histologic grade, an
important prognostic factor (see the Prognostic Factors section) (Fig. 10.2,
e-Fig. 10.1). Stromal desmoplasia is inapparent to minimal in some cases.
At the other end of the spectrum, some tumors show such prominent
stromal desmoplasia that the tumor cells constitute only a minor com-
ponent of the lesion. Similarly, some invasive ductal carcinomas have
no identifiable component of DCIS, whereas in others, the DCIS is the
predominant component of the tumor. Associated stromal lymphoid or
lymphoplasmacytic infiltrates range from absent to so marked that they
obscure the tumor cells. Finally, the microscopic border of these cancers
may be infiltrating, pushing, circumscribed, or mixed.
A
FIGURE 10.2 Histologic heterogeneity of invasive ductal carcinomas. A: Histologic
grade 1 invasive ductal carcinoma. B: Histologic grade 2 invasive ductal carcinoma.
C: Histologic grade 3 invasive ductal carcinoma.
C
Biomarkers and Molecular Pathology

Although the expression of innumerable biomarkers has been studied in
invasive breast cancers over the last several decades, at the present time,
only three are universally used in daily practice: estrogen receptor (ER),
progesterone receptor (PR), and HER2. The expression of these markers is
highly variable in invasive ductal carcinomas, as might be anticipated from
their histologic heterogeneity. In most contemporary series, approximately
70% to 80% of invasive ductal carcinomas are ER positive and 10% to

15% show HER2 protein overexpression and gene amplification. Invasive
ductal carcinomas characteristically show cell membrane expression of
E-cadherin, although the level of expression may be reduced in some
cases.13 Given their histologic heterogeneity, it should not be surpris-
ing that invasive ductal carcinomas exhibit a wide spectrum of genetic/
genomic alterations as well as heterogeneity with regard to molecular
subtypes as defined by gene expression profiling.14
The prognosis is highly variable in this heterogeneous group of tumors and
is related to a variety of factors including lymph node status, tumor size,
histologic grade, and lymphovascular invasion (LVI) (see the Prognostic
and Predictive Factors section).
The diagnosis of invasive ductal carcinoma is one of exclusion; as noted
above, these tumors lack sufficient histologic features to qualify for cat-
egorization as any of the special type tumors described later.
Invasive Lobular Carcinoma

Invasive lobular carcinomas account for approximately 5% to 15% of
invasive breast carcinomas and are the second most common type.15 The
variation in incidence is related at least in part to differences in diagnostic
criteria in different studies. In addition, the increase in frequency of inva-
sive lobular carcinomas in more recent series may be related to the use of
postmenopausal hormone replacement therapy.16
Invasive lobular carcinomas are characterized by multifocality in
the ipsilateral breast and appear to be more often bilateral than other
types of invasive breast cancer (reported range of bilaterality 6% to 47%).
However, some studies have shown the incidence of subsequent contra-
lateral breast cancer among patients with invasive lobular carcinoma to be
similar to that of patients with invasive ductal carcinoma.17-19
Lobular carcinoma in situ (LCIS) coexists with invasive lobular car-
cinoma in 70% to 80% of the cases.17,20,21
Invasive lobular carcinoma may present as a palpable mass or as a mam-
mographic abnormality, with characteristics similar to those of invasive
ductal carcinomas. However, both the findings on physical examination
and the mammographic appearance of invasive lobular carcinomas may
be quite subtle. On physical examination, there may be only a vague area
of thickening or induration without definable margins. Mammographic
findings may be equally subtle, with many invasive lobular carcinomas
appearing as poorly defined areas of asymmetric density with architectural
distortion and others revealing no mammographic abnormalities, even in

the presence of a palpable mass. In fact, the extent of the tumor may be
substantially underestimated by both physical examination and mammog-
raphy. While the use of magnetic resonance imaging has been advocated
to more clearly define the lesion extent in patients with invasive lobular
carcinoma, the high sensitivity and low specificity of this technique may
result in overestimation of tumor size in some cases.22
Gross Pathology
Some invasive lobular carcinomas appear as firm, gritty, gray-white
masses, indistinguishable from invasive ductal carcinomas. However, in
other cases, no mass is grossly evident and the breast tissue may have only
a rubbery consistency. In still other cases, no abnormality is evident on
visual inspection or upon palpation of the involved breast tissue and the
presence of carcinoma is revealed only upon microscopic examination.23
Histopathology
Invasive lobular carcinomas as a group show distinctive cytologic features
and patterns of tumor cell infiltration of the stroma. The classical form
is characterized by small, relatively uniform neoplastic cells that invade
the stroma singly and in a single-file pattern, which results in the forma-
tion of linear strands.24 These cells frequently encircle mammary ducts
in a concentric pattern (Fig. 10.3, e-Fig. 10.2). Furthermore, the tumor
A
FIGURE 10.3 Invasive lobular carcinoma. A: The tumor cells invade the stroma in linear
strands. B: In this tumor, the neoplastic cells encircle a benign duct in a concentric
pattern. C: The cells of classical invasive lobular carcinoma are small and have small,
uniform nuclei. Intracytoplasmic vacuoles are evident in a few cells.
C
cells may infiltrate the breast stroma and adipose tissue in an insidious
fashion, invoking little or no desmoplastic stromal reaction and with little
disruption of the background architecture. The nuclei of the neoplastic
cells are usually small, show little variation in size, and are often eccen-
tric. Mitotic figures are infrequent. The cells often contain intracytoplas-
mic lumina, which may contain an eosinophilic globule. In some cells,
these lumina may be large enough to impart a signet ring cell appearance.
However, in the classical form of invasive lobular carcinoma, cells with a
FIGURE 10.4 E-cadherin immunostain of invasive lobular carcinoma showing loss of

expression in the tumor cells. In contrast, the cells lining a benign duct show strong
membrane staining for E-cadherin.
signet ring configuration comprise only a small proportion of the tumor

cell population.
Many examples of invasive lobular carcinoma (as well as LCIS) are
characterized histologically by tumor cells that are loosely cohesive. The
molecular basis for this feature is the loss of expression of E-cadherin
on the tumor cell membranes, which, in turn, is due to the combina-
tion of loss of heterozygosity on chromosome 16q22.1 (the region of
the E-cadherin gene) accompanied by mutations in the gene encoding
this protein or silencing of gene expression by promoter methylation
(Fig. 10.4). Loss of E-cadherin expression by immunohistochemistry
(IHC) may be a helpful adjunct in distinguishing lobular from ductal-type
carcinomas in problematic cases.25-29 However, approximately 15% of
invasive lobular carcinomas exhibit E-cadherin expression (Fig. 10.5).30,31
Therefore, an invasive breast carcinoma that has the histologic features
of an invasive lobular carcinoma but is E-cadherin positive should not be
classified as an invasive ductal carcinoma. The expression of E-cadherin
in such cases is considered to be aberrant and is often accompanied by
abnormalities in expression of other molecules in the cadherin-catenin
cell adhesion complex.30,31
Variant forms of invasive lobular carcinoma differ from the classical
form with regard to architectural and/or cytologic features.24,32-34 In the
solid and alveolar variants, the cells comprising the tumor have features
FIGURE 10.5 Invasive lobular carcinoma with E-cadherin expression. A: Low-power view
showing the tumor cells infiltrating the stroma in a single-file pattern characteristic of
invasive lobular carcinoma. B: At high power, the cytologic features characteristic of
invasive lobular carcinoma are evident including uniform, eccentrically placed nuclei
and occasional intracytoplasmic vacuoles. C: E-cadherin immunostain showing strong
membranous staining of the tumor cells.
characteristic of the classical form of invasive lobular carcinoma, but dif-

fer from the classical form with regard to the growth pattern of the tumor
cells. In the solid variant, the neoplastic cells grow in large confluent
sheets with little intervening stroma (Fig. 10.6, e-Fig. 10.3). The alveo-
lar variant is characterized by tumor cells that grow in groups of 20 or
more cells separated from one another by a delicate fibrovascular stroma
(Fig. 10.7). A trabecular variant has also been described, but there is
considerable overlap between this pattern and that seen in the classical
form of invasive lobular carcinoma. In the pleomorphic variant, the neo-
plastic cells infiltrate the stroma singly and in linear strands as in classical
invasive lobular carcinoma, but are larger, exhibit more nuclear variation
than that seen in the classical form, and may show apocrine features
(Fig. 10.8, e-Fig. 10.4).35-38 Although signet ring cells can be seen in the
classical type of invasive lobular carcinoma as well as in some examples
of invasive ductal carcinoma, tumors that are composed of a prominent
component of signet ring cells that otherwise have the characteristic
features of invasive lobular carcinoma are considered to represent the
signet ring cell variant of invasive lobular carcinoma.39,40 Histiocytoid
carcinoma is a variant of invasive lobular carcinoma in which the
tumor cells have a histiocyte-like appearance with abundant foamy,
pale, eosinophilic cytoplasm and mild nuclear atypia (Fig. 10.9).41-43
The cells stain for gross cystic disease fluid protein (GCDFP), consistent
with apocrine differentiation.
FIGURE 10.6 Invasive lobular carcinoma, solid variant. The cells are similar to those of the
classical type, but grow in a solid sheet.
FIGURE 10.7 Invasive lobular carcinoma, alveolar variant. The tumor cells grow in groups
separated by a delicate fibrovascular stroma.
B
FIGURE 10.8 Invasive lobular carcinoma, pleomorphic variant. A: Tumor cells infiltrate
the stroma singly and in linear strands. B: The cells are larger and show more nuclear
pleomorphism than those of classical invasive lobular carcinoma (compare with
Fig. 10.3C). Many of the cells have intracytoplasmic vacuoles.

Classical invasive lobular carcinomas typically show expression of ER and
PR and rarely show HER2 overexpression or gene amplification. Although
pleomorphic lobular carcinomas are also frequently ER and PR positive,
FIGURE 10.9 Invasive lobular carcinoma, histiocytoid variant. The tumor cells have
abundant pale to foamy cytoplasm and are difficult to distinguish from histiocytes.
they may show HER2 protein overexpression and gene amplification.43 As

noted earlier, absence of cell membrane E-cadherin expression is a char-
acteristic and arguably the defining feature of invasive lobular carcinomas,
both classical and variant types. The cells of invasive lobular carcinomas
also show altered expression of other proteins in the cadherin–catenin
complex and, in particular, show cytoplasmic rather than membrane
staining for p120 catenin.44 As with LCIS, invasive lobular carcinomas
typically show losses on chromosomal arm 16q and gains at 1q. While the
majority of invasive lobular carcinomas are classified as luminal A in gene
expression profiling studies, some cluster within the luminal B, HER2,
and even basal-like groups.14
The prognosis of patients with invasive lobular carcinoma as a group has
not consistently been shown to differ from that of patients with invasive
ductal carcinoma as a whole. However, the classical type may be associ-
ated with a more favorable outcome than variant types and than invasive
ductal carcinomas. Available evidence suggests that the pleomorphic
variant and the signet ring cell variant (when defined as tumors in which
>10% of the neoplastic cells are of the signet ring cell type) appear to be
associated with a poor clinical outcome.12,35-39
A number of studies have noted differences in the pattern of meta-
static spread between invasive lobular and invasive ductal carcinomas.15
In particular, metastases to the lungs, liver, and brain parenchyma appear

to be less common in patients with lobular than with ductal cancers. In
contrast, lobular carcinomas have a greater propensity to metastasize to
the leptomeninges, peritoneal surfaces, and retroperitoneum and to the
gastrointestinal tract, reproductive organs, and bone. In fact, the major-
ity of the cases of carcinomatous meningitis in patients with metastatic
breast cancer occur in patients with lobular cancers. Peritoneal metastases
may appear as numerous small nodules studding the peritoneal surfaces
in a manner similar to that seen in ovarian carcinoma. Metastases to the
stomach can produce an appearance that simulates an infiltrative (linitis
plastica) type of primary gastric carcinoma. Involvement of the uterus may
result in vaginal bleeding, whereas a metastatic tumor in the ovary may
produce ovarian enlargement and the appearance of a Krukenberg tumor.
In some classical invasive lobular carcinomas, the cells are widely dis-
persed in normal-appearing breast stroma, without evidence of a des-
moplastic stromal response. As a result, the tumor cells may be entirely
overlooked on low-power examination or they may be mistaken for
scattered mononuclear inflammatory cells. The solid variant of invasive
lobular carcinoma may in some instances be difficult to distinguish from a
lymphoma since both may show poorly cohesive sheets of relatively uni-
form cells. Histologic cues favoring lobular carcinoma are the presence of
intracytoplasmic vacuoles and areas in which the cells infiltrate the stroma
in the characteristic linear pattern, particularly at the edges of the lesion.
In problematic cases, immunostains for cytokeratin, hormone receptors,
and lymphoid markers are helpful in arriving at the correct diagnosis.
The pleomorphic variant of invasive lobular carcinoma may be difficult
to distinguish from a high-grade invasive ductal carcinoma in which the
cell nests are compressed and distorted. Stromal invasion in linear strands
or as single cells, the presence of intracytoplasmic vacuoles, and absence
of cell membrane E-cadherin expression favor a lobular phenotype. The
histiocytoid variant may be difficult to distinguish from reactive histiocytic
infiltrates, including those associated with fat necrosis. Immunostains for
cytokeratin, hormone receptors, and CD68 are valuable adjuncts in mak-
ing this distinction.
Invasive Carcinomas with Ductal and Lobular Features

A small proportion of invasive breast cancers (approximately 5%) are not
readily classifiable as either ductal or lobular.12 Some such lesions have
distinct areas of invasive ductal carcinoma and invasive lobular carcinoma
(Fig. 10.10, e-Fig. 10.5); these are best classified as mixed invasive ductal
and invasive lobular carcinomas. Others have features that are interme-
diate between those of invasive ductal and invasive lobular carcinomas
(Fig. 10.11).
FIGURE 10.10 Mixed invasive ductal and invasive lobular carcinoma. Distinct areas of
invasive ductal carcinoma (left) and invasive lobular carcinoma (right) are evident.
FIGURE 10.11 Invasive carcinoma with ductal and lobular features. The tumor is
composed of small cells with uniform nuclei growing in both irregular nests and linear
strands. The features are not clearly diagnostic of either invasive ductal carcinoma or
invasive lobular carcinoma.
FIGURE 10.12 Tubulolobular carcinoma. The tumor consists of both linear strands of
neoplastic cells and round glandular structures.
Tubulolobular carcinoma is a distinctive type of invasive breast

cancer with both ductal and lobular features. In these lesions, some of
the tumor cells invade the stroma in the linear strands characteristic of
the classical form of invasive lobular carcinoma, whereas others form
small tubules. The tubules tend to have rounded to ovoid contours and
are smaller and less angulated than those seen in tubular carcinoma
(Fig. 10.12, e-Fig. 10.6). Although tubulolobular carcinomas have tradi-
tionally been considered to be variants of invasive lobular carcinoma,
recent studies have indicated that the cells comprising these lesions
consistently show membranous expression of E-cadherin, suggesting that
tubulolobular carcinomas are variants of invasive ductal rather than lobu-
lar carcinoma.45 However, given that some invasive lobular carcinomas
exhibit E-cadherin staining,30,31 the presence of E-cadherin expression
in tubulolobular carcinomas is in our view insufficient proof that these
lesions are variants of ductal rather than lobular carcinoma.
Tubular Carcinoma
Tubular carcinoma is a special type cancer that is associated with limited
metastatic potential and an excellent prognosis. Prior to the widespread
use of screening mammography, tubular carcinomas accounted for <4%
of all breast cancers.46 However, these tumors account for a much higher
proportion of cancers detected in mammographically screened popula-
tions, with incidence rates ranging from 7.7% to 27%.47,48
Historically, tubular carcinomas were detected as palpable lesions.
However, the majority (60% to 70%) now present as nonpalpable mam-
mographic abnormalities. Not infrequently, tubular carcinomas are dis-
covered incidentally in biopsies performed for unrelated reasons.
When a mammographic abnormality is present, it is usually a mass
lesion and is only occasionally associated with microcalcifications. The
majority of tubular carcinomas have spiculated margins and cannot be
distinguished radiologically from invasive ductal carcinomas.
Gross Pathology
Grossly, tubular carcinomas are firm, spiculated lesions that are indistin-
guishable from invasive ductal carcinomas.
Histopathology
Tubular carcinomas are characterized by a haphazard proliferation of
well-formed glands or tubules composed of a single layer of epithelial cells
without a surrounding myoepithelial cell layer. These tubules tend to be
ovoid in shape and have sharply angular contours with tapering ends and
open lumens. The cells comprising these tubules are characterized by low-
grade nuclei and often exhibit apical cytoplasmic “snouts.” The stroma
of tubular carcinomas usually has desmoplastic features, and prominent
elastosis may be present in some cases (Fig. 10.13, e-Fig. 10.7).49 There is
now general agreement that >90% of the tumor should exhibit this char-
acteristic morphology to be categorized as a “pure” tubular carcinoma;
tumors with <90% tubular elements are referred to by some as “mixed”
tubular carcinomas.46
The majority of tubular carcinomas have an associated component of
DCIS. This is usually of low nuclear grade with cribriform and micropapil-
lary patterns. In addition, flat epithelial atypia is often found in associa-
tion with tubular carcinomas (see Chapter 4). LCIS and atypical lobular
hyperplasia may also be observed.
Some studies have suggested that the frequency of multifocality and
multicentricity in tubular carcinoma is higher than in invasive ductal car-
cinomas.
Tubular carcinomas are virtually always ER and PR positive. In addi-
tion, these carcinomas rarely, if ever, show HER2 overexpression or gene
amplification.50 These tumors fall within the luminal A molecular subtype
in gene expression profiling studies.14

Patients with tubular carcinoma have an excellent prognosis.51,52 In fact,
in some series, the prognosis is similar to that of age-matched women
B
FIGURE 10.13 Tubular carcinoma. A: Low-power view illustrates a haphazard proliferation
of well-formed glands in a desmoplastic stroma. B: High-power view demonstrates ovoid
tubules, some with pointed ends. Apical cytoplasmic snouts are evident in many of the
cells forming the tubules. The nuclei are low grade.
ithout breast cancer.52 Axillary lymph node metastases have been report-
w
ed in up to 15% of patients with these tumors and this is related to the
tumor size (e-Fig. 10.7C).53 When tubular carcinoma does metastasize to
axillary lymph nodes, usually one and seldom more than three nodes are
involved. Several studies have concluded that even the presence of nodal
disease in patients with tubular carcinoma does not affect disease-free or
overall survival.50,53
Because these lesions are composed of well-formed glands, several benign
lesions must be considered in the differential diagnosis including scle-
rosing adenosis, radial scars/complex sclerosing lesions, microglandular
adenosis, and tubular adenosis. In some cases, the distinction of tubular
carcinoma from these other lesions may be difficult on histologic grounds
alone and adjunctive immunostains may be necessary in order to arrive
at the correct diagnosis. In particular, stains for myoepithelial cells are of
value in distinguishing tubular carcinoma from benign sclerosing lesions
(i.e., sclerosing adenosis and radial scars/complex sclerosing lesions)
and from tubular adenosis. Myoepithelial cell stains are not helpful in
distinguishing tubular carcinoma from microglandular adenosis since
the glands in both of these lesions lack an outer myoepithelial cell layer.
However, immunostains for S-100 protein and ER are helpful in this dis-
tinction (see Chapter 7).
Tubular carcinomas must also be distinguished from grade 1 inva-
sive ductal carcinomas of NST. In general, the glands of grade 1 invasive
ductal carcinomas do not have the ovoid shape, pointed ends, and apical
cytoplasmic snouts that characterize the glands of tubular carcinoma. This
distinction is important since the prognosis of tubular carcinomas is better
than that of grade 1 invasive ductal carcinomas.51,52
Invasive Cribriform Carcinoma

Invasive cribriform carcinoma is a well-differentiated cancer associated
with a favorable prognosis. It is uncommon, accounting for approximately
1% to 3.5% of invasive breast cancers.46,54,55
The tumor may present as a palpable mass, but is often clinically occult
and detected by mammography as a spiculated mass with or without
microcalcifications.
Gross Pathology
No distinctive gross features of invasive cribriform carcinoma have been
described.
Histopathology
Invasive cribriform carcinomas are characterized by small tumor cells
with little nuclear pleomorphism that invade the stroma as cribriform
or fenestrated cellular islands that resemble cribriform pattern DCIS.
B
FIGURE 10.14 Invasive cribriform carcinoma. A: The tumor is composed of fenestrated
cell nests with contours that vary from smooth to angulated and irregular. B: p63
immunostain demonstrates an absence of myoepithelial cells around the invasive tumor
cell nests. In contrast, a p63-positive myoepithelial cell layer is present around small
benign ducts.
The contour of these islands varies from smooth to angulated (Fig. 10.14,

e-Fig. 10.8). These tumors often show admixtures of other histologic
patterns of invasive breast cancer, particularly tubular carcinoma,
which is seen in approximately 20% of the cases. In about 80% of the
cases, there is an associated component of DCIS, usually with a cribri-

form pattern.

Invasive cribriform carcinomas are characteristically positive for ER and
more than two-thirds are positive for PR. These tumors typically lack
HER2 protein overexpression and gene amplification46 and belong to the
luminal A molecular subtype.14

Approximately 14% of patients have axillary lymph node metastases. As
mentioned previously, invasive cribriform carcinoma has an excellent
prognosis, with 10-year survival rates of >90% being reported. The prog-
nosis of patients with pure invasive cribriform carcinomas is better than
that of patients in whom the cribriform component is mixed with other
histologic types.46,54,55
The major differential diagnostic consideration for invasive cribriform car-
cinoma is cribriform pattern DCIS. Further, in some lesions characterized
by a cribriform pattern, it may be difficult to determine the relative pro-
portions of invasive cribriform carcinoma and cribriform DCIS. Invasive
cribriform carcinoma has a haphazard distribution and infiltrates between
ducts and lobules, whereas DCIS maintains the normal ductal and lobular
architecture. In contrast to cribriform DCIS where the involved spaces
have smooth, rounded contours, at least some of the infiltrating islands
of invasive cribriform carcinoma have irregular, sharp, and angulated
borders. The stroma in invasive cribriform carcinoma tends to be des-
moplastic, whereas there is a lack of associated stromal change in most
cribriform DCIS. Lastly, the nests of invasive cribriform carcinomas lack
myoepithelial cells surrounding the glandular islands, whereas a periph-
eral myoepithelial cell layer is present in cribriform pattern DCIS. If these
cells cannot be appreciated on hematoxylin and eosin–stained sections,
immunostains for myoepithelial cell markers may be used to aid in this
distinction; this approach may also be used to help define the relative
proportions of invasive carcinoma and DCIS.
Invasive cribriform carcinomas must also be distinguished from
adenoid cystic carcinomas, which are commonly characterized by crib-
riform tumor cell nests. The presence in adenoid cystic carcinomas of a
dual epithelial/myoepithelial cell population and intraluminal mucoid
and/or basement membrane material are useful clues to the correct
diagnosis because these features are not seen in invasive cribriform
carcinoma. Furthermore, adenoid cystic carcinomas are typically ER
negative, whereas invasive cribriform carcinomas are virtually always
ER positive.
Mucinous Carcinoma
Mucinous carcinoma (also known as colloid carcinoma) is another special
type cancer that is associated with a relatively favorable prognosis. These
tumors are uncommon and in most series account for approximately 2%
of invasive breast carcinomas.56
Mucinous carcinomas occur over a wide age range. In a recent review of
over 11,000 mucinous carcinomas from the SEER database, the median
age was 71 years (range 25 to 85 years)57; this median age is higher than
that of patients with invasive ductal carcinomas of NST. Patients with
mucinous carcinoma may present with palpable tumors. However, since
the introduction of widespread screening mammography, a substantial
proportion of patients with mucinous carcinoma (30% to 70%) present
with nonpalpable mammographic lesions.58,59 Mammographically, muci-
nous carcinomas are most often circumscribed or lobulated masses that
are rarely associated with calcification.
Gross Pathology
Mucinous carcinomas typically have a circumscribed or bosselated con-
tour, a variably soft, gelatinous consistency, and a glistening cut surface.
Histopathology
The hallmark of mucinous carcinomas is extracellular mucin production.
However, the extent of extracellular mucin varies from tumor to tumor.
Typically, tumor cells in small clusters are dispersed within pools of
extracellular mucin, which may be traversed by thin fibrous septae con-
taining thin-walled blood vessels. On occasion, the cells assume a glan-
dular, trabecular, sheet-like, papillary, or micropapillary configuration.
The nuclei are generally of low or intermediate grade; rarely, high-grade
nuclear features are present. This characteristic histology should comprise
at least 90% of the tumor (or 100% according to some) to qualify for
the diagnosis of mucinous carcinoma.56 Mucinous carcinomas with foci
of carcinoma that have nonmucinous features are classified as “mixed”
mucinous tumors. The cellularity of mucinous carcinomas is variable,
with some tumors being highly cellular (type B mucinous carcinomas)
and others paucicellular (type A mucinous carcinomas) (Figs. 10.15 and
10.16, e-Fig. 10.9).60 The type B carcinomas frequently exhibit endocrine
differentiation as defined by either cytoplasmic argyrophilic granules or
immunoreactivity for the endocrine markers chromogranin or synap-
tophysin.60-62 Mucinous carcinomas are often accompanied by a DCIS
component, which may have a micropapillary, papillary, cribriform, or
solid pattern. Rarely comedo necrosis is present. The DCIS may also
exhibit prominent extracellular mucin production.
B
FIGURE 10.15 Mucinous carcinoma. A: At low power, the tumor consists of a relatively
circumscribed mucin pool containing numerous nests of neoplastic epithelial cells. B:
High-power view to demonstrate cytologic detail. In this case, the tumor cells have low-
grade nuclei.
FIGURE 10.16 Mucinous carcinoma. This tumor is paucicelluar and is composed primarily
of extracellular mucin; only a few scattered tumor cell nests are present.

Mucinous carcinomas are typically ER positive and about 70% are PR
positive. In addition, mucinous carcinomas usually do not overexpress
the HER2 protein or show HER2 gene amplification.50 These tumors are
characterized by relatively few chromosomal losses and gains and show
relatively little genomic instability.63 Mucinous carcinomas cluster within
the luminal A molecular subtype in gene expression profiling studies.14
However, expression signatures of type A mucinous carcinomas are dis-
tinct from those of type B lesions, the latter having an expression profile
similar to that of carcinomas with endocrine features.64
In the SEER database review of over 11,000 patients with mucinous car-
cinoma noted above, 12% of patients had axillary nodal metastases at
presentation.57 The frequency of nodal involvement is related to tumor
size; axillary lymph node involvement is exceptionally rare in mucinous
carcinomas <1 cm in size.50 Patients with pure mucinous carcinoma gen-
erally have a favorable prognosis. In the large SEER review,57 5-, 10-, 15-,
and 20-year survival rates were 94%, 89%, 85%, and 81%, respectively,
for patients with mucinous carcinoma compared with 82%, 72%, 66%,
and 62%, respectively, for patients with invasive ductal carcinoma of no
special type. Late systemic recurrences (>25 years after diagnosis) may
be seen.50,57 Nodal involvement is the most important adverse prognostic

factor in these patients.57 The prognostic importance of endocrine dif-
ferentiation in mucinous carcinomas is not sufficiently established to be
considered a standard prognostic feature.
Mucinous carcinomas have rarely been associated with unusual
metastatic manifestations, including mucin embolism resulting in fatal
cerebral infarcts and pseudomyxoma peritonei.65-67
The differential diagnosis of mucinous carcinoma includes other mucin-
producing lesions of the breast, particularly mucocele-like lesions.
Mucocele-like lesions are characterized by cystically dilated, mucin-filled
ducts, often associated with rupture and extravasation of mucin into the
stroma. The epithelium lining the ducts may be attenuated or show a
spectrum of proliferative changes ranging from hyperplasia to atypical
ductal hyperplasia to DCIS (Figs. 10.17 and 10.18).68-70 In some cases,
strips or clusters of epithelium may become detached from the duct walls
and lie free within mucin pools; the distinction from mucinous carcinoma
may be difficult in such cases, particularly if the epithelial strips or clus-
ters are derived from DCIS (Fig. 10.19, e-Fig. 10.10). Features favoring a
mucocele-like lesion with epithelial detachment are a linear configuration
of the epithelium (resembling a duct lining) and the presence of associ-
ated myoepithelial cells; the latter may require immunostains for their
FIGURE 10.17 Mucocele-like lesion. This lesion is composed of variably dilated mucin-
filled ducts with foci of stromal mucin extravasation. The epithelium lining the ducts is
attenuated.
FIGURE 10.18 Mucocele-like lesion with atypical ductal hyperplasia.
emonstration. However, in some cases, particularly those associated

d
with DCIS, it may not be possible to definitively distinguish a mucocele-
like lesion with detached epithelium from mucinous carcinoma. In addi-
tion, the distinction between mucinous carcinoma and mucocele-like
lesion may be difficult or impossible on core-needle biopsy. Given that
some mucinous carcinomas feature abundant mucin with few neoplastic
cell clusters, it is not possible to exclude a mucinous carcinoma in core-
needle biopsy samples that contain stromal mucin pools, even if they are
devoid of neoplastic cell nests. Excision should be recommended in such
cases for definitive evaluation.
Mucinous cystadenocarcinoma is another mucin-producing lesion
of the breast that must be distinguished from mucinous carcinomas (see
the subsequent text).71 Several other lesions may also enter into the dif-
ferential diagnosis of mucinous carcinoma including fibroadenoma with
prominent myxoid stroma, myxoma, neurofibroma with prominent myx-
oid change, and matrix-producing metaplastic carcinoma.
medullary carcinoma and Carcinomas

with Medullary features
Medullary carcinomas are rare and in our experience account for <1%
of all invasive breast cancers. The pathologic diagnosis of this tumor is
subject to considerable interobserver variability.72,73 Lesions with some but
not all of the features of medullary carcinoma have been variously termed
B
FIGURE 10.19 Mucocele-like lesion with stripped epithelium. A: Low-power view
illustrates mucin pools, within which are strands of epithelium derived from the duct
lining. B: The epithelium is cytologically benign. This appearance should not be mistaken
for mucinous carcinoma.
“atypical medullary carcinomas,” “invasive carcinomas with medullary

features,” and “invasive ductal carcinomas with medullary features.” In
view of the difficulties in reproducibly applying the diagnostic criteria for
medullary carcinoma, the 2011 WHO Working Group recommended that
medullary carcinomas, atypical medullary carcinomas, and invasive ductal
carcinomas with medullary features be grouped together as “carcinomas

with medullary features.”74
Tumors in this group usually present at a younger age than patients with
other breast cancers. This is at least partially explained by the fact that
some patients with these tumor harbor BRCA1 germline mutations (see
the Pathologic Features of Hereditary Breast Cancer section). The major-
ity of patients present with a palpable mass. Although some patients
exhibit axillary lymphadenopathy at the time of presentation, histologic
examination of the lymph nodes in such cases typically reveals benign
reactive changes rather than metastatic carcinoma.
In mammographic studies, most medullary carcinomas appear as a
fairly well-defined mass unassociated with calcifications.75 However, a
significant proportion of the cases of medullary carcinoma are associated
with an ill-defined margin. Moreover, the majority of mammographically
well-circumscribed cancers are invasive ductal carcinomas of no special
type rather than medullary carcinomas.76
Gross Pathology
Upon gross examination, medullary carcinomas are well-circumscribed,
soft, tan-brown to gray tumors that bulge above the cut surface of the
specimen. A multinodular appearance may be appreciated in some cases.
Areas of hemorrhage, necrosis, or cystic degeneration may be present.
Histopathology
Several similar but distinct classification systems for the histologic diagno-
sis of medullary carcinomas have been proposed.77-80 All of these classifica-
tion schemes recognize the following attributes of medullary carcinomas,
but the relative importance and the mandatory nature of each are stressed
to a different degree: (a) syncytial growth pattern of the tumor cells in
more than 75% of the tumor, (b) admixed lymphoplasmacytic infiltrate,
(c) microscopic circumscription, (d) grade 2 or 3 nuclei, and (e) absence
of glandular differentiation (Fig. 10.20, e-Fig. 10.11). Tumors that lack a
variable number of these characteristics (depending on the system used)
have been classified in these systems as “atypical medullary carcinoma” or
invasive ductal carcinoma.
Medullary carcinomas may show foci of hemorrhage, necrosis, cystic
degeneration, and various types of metaplasia of the tumor cells, most
often squamous metaplasia. In some tumors, the neoplastic cells may
exhibit bizarre cytologic features with marked nuclear atypia and multi-
nucleated giant cell forms. There is usually little or no associated DCIS.
Carcinomas in this group are typically negative for ER and PR and lack
HER2 protein overexpression and gene amplification (“triple negative”).
B
FIGURE 10.20 Medullary carcinoma. A: The tumor is well circumscribed and composed
of a syncytium of epithelial cells with an associated lymphoplasmacytic infiltrate. B: High-
power view demonstrates high-grade cytologic atypia of the tumor cells, with nuclear
pleomorphism and an abnormal mitosis. Scattered lymphocytes and plasma cells are also
evident.
They variably express basal cytokeratins (CK5/6, 14, and 17) and epi-
dermal growth factor receptor (EGFR). These tumors show considerable
genomic instability. Most breast cancers in women with germline BRCA1
mutations have medullary features, and many sporadic carcinomas with
these features exhibit somatic inactivation of this gene by one of several
different molecular mechanisms. Mutations of the p53 tumor suppressor

gene are especially common. Medullary carcinomas and carcinomas with
medullary features typically cluster within the basal-like group in gene
expression profiling studies.14
Although studies have differed in the histologic criteria employed, most
indicate that the incidence of axillary lymph node metastases is lower in
patients with medullary carcinomas than in those with atypical medullary
carcinomas or invasive ductal carcinomas with medullary features.
Outcome data for patients with medullary carcinoma are confounded
by the use of differing classification systems and interobserver variability.
These tumors have traditionally been thought of as having a more favor-
able prognosis than invasive ductal carcinomas of NST; however, a more
favorable prognosis has not been observed in all studies. Most deaths
occur within 5 years after diagnosis. Data from one large clinical cohort
with long-term follow-up suggested that the prognosis of these tumors is
similar to that of grade 3 invasive ductal carcinomas with a prominent
lymphoplasmacytic infiltrate, but better than that of grade 3 invasive duc-
tal carcinomas without a prominent lymphoplasmacytic infiltrate.81
The absence of nesting of the large neoplastic cells, the minimal stroma,
and the admixture of lymphocytes and plasma cells may create an appear-
ance that raises the question of lymphoma. In such cases, immunostains
for cytokeratin are of value in defining the epithelial nature of the malig-
nant cells. In addition, the lymphoplasmacytic infiltrate and circumscrip-
tion of these tumors may create difficulty in distinguishing a medullary
carcinoma from a metastasis in an intramammary lymph node. However,
medullary carcinomas lack the capsule and other underlying architectural
features of lymph nodes.
Given the poor interobserver reproducibility in the diagnosis of
medullary carcinoma and the overlap of medullary carcinomas, atypical
medullary carcinomas, and invasive ductal carcinomas with medullary
features with regard to their histologic features, biomarker expression,
genomic alterations, and molecular subtype, there is a growing trend
away from separating these tumors from each other. As noted above, the
2011 WHO Working Group recommended that these tumors be grouped
together within a single category of “carcinomas with medullary features,”
thereby eliminating the need to distinguish among them.74
Invasive Micropapillary Carcinoma

Invasive micropapillary carcinoma accounts for <2% of invasive breast
carcinomas in pure form. It is more common to see foci of invasive
micropapillary carcinoma admixed with other histologic types, particu-
larly invasive ductal carcinomas of NST. Patients with this tumor type
c ommonly have axillary lymph node metastases at presentation and have

a relatively poor prognosis.82-87
Patients may present with a palpable mass or with a mammographically
detected lesion without features that permit their distinction from other
types of breast cancers.
Gross Pathology
No distinguishing gross features have been described. The median size
reported for invasive micropapillary carcinoma is significantly larger than
invasive ductal carcinomas of NST.
Histopathology
These lesions are characterized by clusters of cells in a micropapil-
lary or tubular–alveolar arrangement, which appear to be suspended in
clear spaces. These micropapillary clusters, unlike true papillary lesions,
lack fibrovascular cores. The cells in these clusters have an “inside-out”
arrangement, with the apical surface polarized to the outside, toward
the stroma (Fig. 10.21). This feature can be highlighted using an immu-
nostain for epithelial membrane antigen (EMA) (Fig. 10.22). The overall
appearance of invasive micropapillary carcinoma may mimic serous pap-
illary carcinomas of the ovary or may simulate LVI. True LVI has been
A
FIGURE 10.21 Invasive micropapillary carcinoma. A: Medium-power view illustrates
tumor cells in glands and nests, most of which appear to be within clear spaces. B: In this
example, the glands and nests are composed of cells with intermediate-grade nuclei.
B
FIGURE 10.22 Invasive micropapillary carcinoma immunostained for epithelial membrane

antigen (EMA). Intense EMA immunoreactivity is seen around the outside of the glands,
emphasizing the “inside-out” pattern or reverse polarity of the cells.
reported in 33% to 67% of cases and may be extensive. It may be difficult

to determine if particular nests of tumor cells in clear spaces represent
foci of invasive micropapillary carcinoma or LVI. Cytologically, the cells
comprising the invasive micropapillary carcinoma usually have low- to
intermediate-grade nuclei. The majority of tumors (~70%) are associated

with a DCIS component with micropapillary and cribriform patterns.
Invasive micropapillary carcinomas may occur in pure form or may
be admixed with invasive ductal carcinoma of NST or, in a minority of
cases, with mucinous carcinoma (e-Fig. 10.12).86 It is not clear if tumors
with both invasive micropapillary and mucinous components should be
classified as mixed lesions or as mucinous variants of invasive micropapil-
lary carcinoma.

The majority of invasive micropapillary carcinomas are ER positive (~60%
to 100%) and almost half are PR positive. HER2 protein overexpression
has been observed in up to one-third of reported cases.88 Most invasive
micropapillary carcinomas are classified as luminal A or luminal B sub-
types in gene expression profiling studies.14

Up to 75% of patients with invasive micropapillary carcinomas have axil-
lary lymph node metastases at the time of initial presentation.82-87 The
frequency of lymph node involvement is similar for pure invasive micro-
papillary carcinomas and for those lesions in which an invasive micro-
papillary pattern constitutes only a minor component of a breast cancer.
Therefore, it is important that the pathologist recognize and report an
invasive micropapillary component in an invasive breast cancer, even if
present as a minor component.
Although carcinomas with an invasive micropapillary component
typically present with higher stage disease than patients with invasive car-
cinoma of NST (i.e., they are more likely to have positive axillary lymph
nodes), the prognosis of these two groups is similar when adjusted for
stage.83,84
Artifactual retraction of the stroma around nests of invasive ductal carci-
nomas of NST can produce an appearance that resembles invasive micro-
papillary carcinoma. However, in such cases, the tumor cells lack the
reverse polarity characteristic of the tumor cell nests of invasive micro-
papillary carcinoma. An EMA immunostain may be helpful in resolving
the problem in difficult cases. The nests of invasive ductal carcinoma
will show EMA staining on the inner surfaces of the cells, whereas the
nests of invasive micropapillary carcinoma exhibit EMA reactivity on the
outside edges.
Metastatic carcinomas with a micropapillary pattern (such as those
originating in the ovaries, lungs, and bladder) should be considered in
the appropriate clinical setting. DCIS will be absent in cases of metastatic
micropapillary carcinoma.
Metaplastic Carcinoma
Metaplastic carcinomas represent a morphologically heterogeneous group
of invasive breast cancers in which a variable portion of the glandular
epithelial cells comprising the tumor has undergone transformation into
an alternate cell type, either a nonglandular epithelial cell type (e.g.,
squamous cell) or a mesenchymal cell type (e.g., spindle cell, chondroid,
osseous, and myoid).89 In some cases, particularly in spindle cell and squa-
mous cell carcinomas, the metaplastic elements may occur in pure form
without an identifiable component of adenocarcinoma. There is no uni-
formly agreed upon classification scheme or terminology for these tumors.
Metaplastic carcinomas are uncommon, representing <1% of all
breast cancers. The prognostic implications of metaplastic carcinomas are
difficult to define and are probably related to the type of metaplasia pres-
ent, as discussed later.
Patients with metaplastic carcinoma are similar to patients with invasive
carcinoma of NST with regard to their age at presentation, the manner
in which their tumors are detected, and the location within the breast in
which these tumors arise.90,91 Most patients present with a single palpable
lesion that not infrequently is associated with rapid growth of short dura-
tion. Skin fixation and fixation to deep tissues has been noted in a sub-
stantial minority of patients.
The mammographic appearance of metaplastic carcinoma is not spe-
cific. Most are fairly circumscribed, non-calcified lesions, which in many
cases appear benign.92 Some show both a circumscribed portion and a
spiculated portion, which in one study correlated with the metaplastic and
invasive epithelial components, respectively. Foci of osseous metaplasia
may be detected mammographically in a subset of cases.
Gross Pathology
The gross appearance of metaplastic carcinomas is not distinctive, and
these tumors can either be well circumscribed or show an indistinct or
irregular border. Cystic degenerative changes are not infrequent in lesions
with squamous differentiation. In general, metaplastic carcinomas tend
to be relatively large tumors, compared with invasive carcinomas of NST,
with a mean size of 3.9 cm (range 1.2 to 10 cm).93,94
Histopathology
Microscopically, metaplastic carcinomas constitute a heterogeneous
group of lesions. While there is no universally accepted classification
system, the 2011 WHO Working Group developed a descriptive classifica-
tion for these lesions.89 In this classification, the categories of metaplastic
carcinoma include squamous cell carcinoma, metaplastic carcinoma
with mesenchymal differentiation, low-grade adenosquamous carcinoma,
s pindle cell carcinoma, and fibromatosis-like metaplastic carcinoma.

Spindle cell carcinoma and fibromatosis-like metaplastic carcinoma are
discussed in Chapter 11; the remainder will be discussed here.
squamous cell carcinoma. Foci of squamous differentiation may be seen
admixed with invasive carcinomas of no special type but are more com-
monly seen in association with medullary carcinomas and carcinomas
with medullary features. Pure squamous cell carcinomas of the breast
are rare. In pure squamous cell carcinomas, the squamous differentiation
can range from well to poorly differentiated. In some tumors composed
primarily of squamous cells, there is prominent cystic degeneration.89,95
In such cases, parts of the tumor may be composed of squamous epithe-
lial-lined cysts resembling benign epidermal inclusion cysts (Fig. 10.23,
e-Fig. 10.13). In the acantholytic variant of squamous cell carcinoma,
irregular spaces lined by squamous cells can simulate vascular spaces and
lead to an erroneous diagnosis of angiosarcoma. Spindle cell differentia-
tion is frequently seen in association with squamous differentiation.
metaplastic carcinomas with mesenchymal differentiation.
The most frequent
mesenchymal (heterologous) elements seen in metaplastic carcinomas are
cartilage and bone.89,96 The chondroid and osseous components in these
tumors may appear histologically benign or frankly malignant, resembling
chondrosarcoma and osteosarcoma, respectively (Figs. 10.24 and 10.25,
FIGURE 10.23 Metaplastic carcinoma, squamous type. This tumor is composed primarily
of a squamous epithelial-lined cyst. A few nests of malignant squamous cells extend into
the adjacent stroma.
B
FIGURE 10.24 Metaplastic carcinoma with chondroid differentiation. A: H&E-stained
section. B: Cytokeratin immunostain demonstrating cytoplasmic staining of many of the
tumor cells.
e-Fig. 10.14). If the mesenchymal component predominates, the differen-

tial diagnosis must include a malignant phyllodes tumor with heterolo-
gous elements and stromal overgrowth as well as a pure sarcoma, either
primary or metastatic. The correct diagnosis in such cases may require
extensive tissue sampling in order to demonstrate epithelial elements
FIGURE 10.25 Metaplastic carcinoma with osseous differentiation.
(such as glands, solid epithelial cell nests, or squamous differentiation) or

a component of DCIS. In some cases, immunostains for epithelial mark-
ers, such as cytokeratin, may be required for proper diagnosis. It should
be noted, however, that cytokeratin immunoreactivity may be focal and a
panel of anticytokeratin antibodies may be required to demonstrate cyto-
keratin positivity. In our experience, broad-spectrum cytokeratin antibod-
ies (such as antibody MNF116) and antibodies to high-molecular-weight/
basal cytokeratins (such as antibody 34βE12 and antibodies to CK5/6)
are the most sensitive for the detection of cytokeratin expression in this
setting. However, not all metaplastic carcinomas with mesenchymal dif-
ferentiation show expression of epithelial markers, and in cases in which
there is no histological evidence of epithelial differentiation, no DCIS, and
no cytokeratin expression, an unequivocal distinction from a malignant
phyllodes tumor with heterologous elements or a pure sarcoma may not
be possible. Focal cytokeratin staining in the stromal cells of phyllodes
tumors may further complicate this distinction.97
low-grade adenosquamous carcinoma. Low-grade adenosquamous carci-
nomas are an unusual subtype of metaplastic carcinoma that appear to
represent a distinct clinicopathologic entity.98-100 These tumors may arise
de novo or in association with preexisting benign sclerosing processes,
such as complex sclerosing lesions, sclerosing papillomas, and adeno-
myoepitheliomas.100 Low-grade adenosquamous carcinomas are typically
smaller than other metaplastic carcinomas, with a median size between 2
and 2.8 cm (range 0.5 to 8.6 cm). They exhibit a firm, yellow cut surface
with irregular borders. Histologically, they are composed of a variable
B
FIGURE 10.26 Low-grade adenosquamous carcinoma. A: The tumor is composed of
well-formed glands and squamous epithelial nests in a fibrous stroma. B: High-power view
illustrates bland cytologic features of both the glandular and squamous components.
dmixture of well-formed glands and solid cords of cells with squamous

a
differentiation that are arranged in a haphazard, infiltrative pattern. The
glands often show elongated, compressed lumens, which may suggest
syringomatous differentiation (Fig. 10.26, e-Fig. 10.15). Microcysts filled
with keratinaceous material may be present. The stroma may be composed
of bland spindle cells that produce a fibromatosis-like appearance or may

be more collagenized. Concentration of cellular stroma around tumor cell
nests is a characteristic feature. Stromal lymphocytic infiltrates are present
in most cases. In some cases, the spindle cell stroma is more cellular and
shows cytologic atypia, suggesting progression to a higher grade spindle
cell carcinoma. Using immunostains for myoepithelial cell markers (p63,
smooth muscle myosin, CD10, and calponin), myoepithelial cells may
be demonstrated around some tumor glands and cell nests in either a
continuous or a discontinuous pattern or they may be completely absent;
variability is observed even within individual cases. A lamellar pattern
of stromal cell staining around glands is seen on smooth muscle myosin
and calponin immunostains, and stronger cytokeratin staining of luminal
epithelial cells than surrounding basally located cells is characteristic.101
The differential diagnosis of low-grade adenosquamous carcinoma
includes syringomatous adenoma of the nipple (see Chapter 15), reac-
tive squamous metaplasia, and tubular carcinoma. These lesions may be
locally aggressive, but have a relatively good prognosis when compared
with other metaplastic carcinomas.100
The vast majority of metaplastic carcinomas are ER, PR, and HER2 nega-
tive (“triple negative”). Many express basal cytokeratins (CK5/6, 14, and
17), EGFR, and p63, although expression of these markers may be quite
focal. Expression by some of these tumors of markers usually associated
with a myoepithelial phenotype (such as smooth muscle actin) blurs
the distinction between metaplastic carcinomas and myoepithelial car-
cinomas (see Chapter 11). Some metaplastic carcinomas cluster in the
basal-like group and others in the claudin-low group in gene expression
profiling studies.14 These tumors typically show complex genomic altera-
tions and considerable genomic instability. p53 mutations are particularly
common.89
The outcome of patients with metaplastic carcinomas is difficult to deter-
mine since most studies are retrospective and come from referral centers.
Moreover, some studies combine different types of metaplastic carcinoma
and analyze the outcome as a single group. Available data suggest that
some forms (e.g., low-grade adenosquamous carcinoma and low-grade
fibromatosis-like metaplastic carcinoma) are associated with a good prog-
nosis, whereas others are associated with a poor prognosis.
The reported frequency of axillary lymph node metastases in patients
with metaplastic carcinomas as a group is lower than that for patients
with invasive carcinomas of no special type of equivalent size and grade.89
Metastatic dissemination to distant sites may occur in the absence of
lymph node metastases, particularly to the lungs and brain. Some studies
have suggested that the clinical behavior of metaplastic carcinomas with
little or no recognizable epithelial component is more similar to that of

a sarcoma than conventional types of mammary carcinoma. Metastatic
lesions may demonstrate an epithelial phenotype, metaplastic phenotype,
or both.89
The differential diagnostic considerations vary with the type of meta-
plastic carcinoma. A pure or predominantly squamous lesion must be
distinguished from a tumor originating in the mammary skin or cutaneous
appendages. The differential diagnosis of spindle cell carcinomas and of
metaplastic carcinomas with mesenchymal/heterologous differentiation is
discussed in Chapters 11 and 13, respectively.
Adenoid Cystic Carcinoma

Adenoid cystic carcinoma is a morphologically distinct form of invasive
breast carcinoma associated with an excellent prognosis.102 This rare
lesion accounts for <0.1% of all breast cancers.103
The median age of patients with adenoid cystic carcinoma varies among
studies, but is usually in the sixth or early seventh decade with a wide age
range reported. These tumors present as a palpable mass, with the major-
ity of lesions discovered in the subareolar or central region of the breast.
Skin involvement has been reported in rare cases.
Mammographically, adenoid cystic carcinomas can appear as well-
defined lobulated masses, ill-defined masses, or spiculated lesions. Some
present with mammographic microcalcifications, whereas others are
mammographically occult.
Gross Pathology
The reported size range of adenoid cystic carcinomas is broad. Grossly,
these tumors are usually circumscribed and nodular; however, the micro-
scopic extent of the lesion may be appreciably greater than the grossly
evident lesion in 50% to 65% of cases.
Histopathology
Histologically, these tumors are similar to adenoid cystic carcinomas
that arise in the salivary glands and are composed of epithelial cells with
variable degrees of glandular, squamous, and sebaceous differentiation,
myoepithelial/basaloid cells, and characteristic collections of acellular,
eosinophilic basement membrane material.104-107 The epithelial compo-
nent can assume variable architectural patterns including solid, cribri-
form, tubular, and trabecular configurations (Fig. 10.27, e-Fig. 10.16).
Both true lumens and pseudolumens are present. The true lumens are
surrounded by cytokeratin 7–positive epithelial cells that tend to have
B
FIGURE 10.27 Adenoid cystic carcinoma. A: Cribriform pattern. B: Trabecular pattern.
more abundant eosinophilic cytoplasm than the basaloid cells. The pseu-
dolumens contain myxoid material or eosinophilic spherules composed
of basement membrane components (type IV collagen and laminin) and
are surrounded by myoepithelial/basaloid cells with scant cytoplasm and
hyperchromatic nuclei. These cells show variable staining for a variety
of myoepithelial cell markers (e.g., p63, smooth muscle myosin heavy
B
FIGURE 10.28 Adenoid cystic carcinoma, solid type with basaloid features. A: This
tumor consists of a relatively uniform population of small cells with scant cytoplasm.
B: Immunostain for cytokeratin 7 highlights glandular epithelial cells forming ductal
structures within the solid cell nests. C: Immunostain for p63 highlights the basaloid cells.
The glandular luminal cells are p63 negative (center of field).
chain, calponin, and basal cytokeratins). A solid variant of adenoid cystic

carcinoma in which virtually all of the cells display prominent basaloid
features has also been described (Fig. 10.28, e-Fig. 10.17).108 Associated
DCIS with adenoid cystic features is seen in a minority of cases, but may
C
be difficult to distinguish from circumscribed nests of invasive adenoid

cystic carcinoma. Perineural invasion is also seen in some cases and may
be prominent. LVI is only rarely identified. Adenoid cystic carcinoma
may develop in a background of microglandular adenosis109 and has also
been reported to arise in association with low-grade adenosquamous
carcinoma and adenomyoepithelioma.110
These tumors are usually ER and PR negative and typically lack HER2
protein overexpression and gene amplification (“triple negative”). 111
Expression of CD117 (c-kit) is a characteristic feature of adenoid cystic
carcinoma112,113 but is not specific for this tumor type. Adenoid cystic car-
cinomas of the breast (and salivary gland) are characterized by a recurrent
translocation t(6;9)(q22-23;p23-24) that results in an MYB-NFIB fusion
gene.114 These tumors belong to the basal-like group in gene expression
profiling studies.14
Patients with adenoid cystic carcinoma have an excellent prognosis. Only
rare instances of axillary lymph node metastases have been reported. It
has been suggested that the solid variant of adenoid cystic carcinoma with
basaloid features has a greater propensity for lymph node metastases than
other types, but this is based on the study of a small number of cases.108
Distant metastases are also infrequent, and death due to adenoid cystic
carcinoma is exceedingly rare. Some authors have advocated grading

these tumors using a system similar to that employed for grading adenoid
cystic carcinomas of salivary glands and have reported that the grading
provides prognostically useful information.106 The prognostic utility of this
grading system, however, has been disputed by others.105
Some of the growth patterns seen in adenoid cystic carcinomas may raise
the differential diagnosis of in situ or invasive cribriform carcinoma or
benign conditions, such as collagenous spherulosis. In contrast to inva-
sive cribriform carcinoma, which is composed of a single epithelial cell
population, adenoid cystic carcinomas are composed of a dual population
of epithelial and myoepithelial cells. In addition, intraluminal basement
membrane material is seen in adenoid cystic carcinomas, but not in inva-
sive cribriform carcinomas. Finally, invasive cribriform carcinomas are
positive for ER and PR, whereas adenoid cystic carcinomas are typically
negative for these receptors. Although myoepithelial cells are present in
association with cribriform pattern DCIS, they are limited to the periphery
of the involved ducts and are not intimately admixed with the epithelial
cells as in adenoid cystic carcinoma. The distinction of adenoid cystic
carcinoma from collagenous spherulosis may be difficult because of the
presence in both of myxoid material and eosinophilic spherules composed
of basement membrane material. However, collagenous spherulosis is
not infiltrative and is confined to preexisting ducts, lobules, or epithelial
proliferative lesions (see Chapter 8). The solid variant of adenoid cystic
carcinoma with basaloid features may be difficult to distinguish from a
variety of other lesions including high-grade invasive ductal carcinoma,
small cell carcinoma, solid papillary carcinoma, and even lymphoma.
Identification of foci of basement membrane material and the demonstra-
tion of a dual epithelial–myoepithelial cell population by IHC will lead to
the correct diagnosis.
Carcinomas with NEUROendocrine features

Some invasive breast cancers show evidence of neuroendocrine differen-
tiation at the morphologic level, histochemical level, immunohistochemi-
cal level, or some combination of these.115-121 In addition, in rare instances,
breast carcinomas can secrete hormonal products that cause clinical
symptoms.
With the exception of the very rare functioning neuroendocrine tumor,
which results in clinical manifestations due to hormone production and
secretion, these tumors present in a manner similar to other breast cancers
without distinctive clinical or mammographic features.
Gross Pathology
These tumors are not associated with distinctive gross characteristics, and
the reported mean size in most studies is similar to invasive cancers of no
special type.
Histopathology
Neuroendocrine differentiation may be demonstrated by histochemical or
immunohistochemical stains in up to 30% of invasive carcinomas of no
special type as well as in some special type tumors, particularly mucinous
carcinomas and solid papillary carcinomas.
With regard to tumors that show histologic evidence of neuroen-
docrine differentiation by light microscopy, several distinct morphologic
subtypes are recognized. Primary tumors morphologically indistinguish-
able from carcinoid tumors occurring elsewhere in the body (designated
neuroendocrine carcinoma, well differentiated in the most recent WHO
classification)121 can arise in the breast and comprise <1% of all breast
cancers. These tumors must be distinguished from metastatic carcinoids,
which occasionally involve the breast (Fig. 10.29, e-Fig. 10.18).115-120 The
presence of DCIS in the region of the tumor can assist with this differ-
ential diagnosis. In equivocal cases, a clinical evaluation to rule out an
alternate primary site may be required. At the other end of the neuroen-
docrine spectrum are primary breast carcinomas that are indistinguishable
from small cell carcinomas (designated neuroendocrine carcinoma, poorly
differentiated/small cell carcinoma in the most recent WHO classifica-
tion)121-123 or large cell neuroendocrine carcinomas124 at other sites. Again,
these tumors must be distinguished from metastatic small cell or large cell
neuroendocrine carcinomas involving the breast, and a clinical evaluation
to rule out an alternate primary site, such as the lung, may be required.
There is only limited information regarding the expression of biomarkers
in invasive carcinomas with neuroendocrine differentiation. Available
data suggest that these tumors are most commonly ER and PR positive
and lack HER2 overexpression.121 Mucinous and solid papillary carci-
nomas with neuroendocrine differentiation cluster within the luminal
A molecular subtype in gene expression profiling studies.14 There are no
available data on the molecular subtypes of tumors that have histologic
features of primary carcinoid tumors or small or large cell neuroendocrine
carcinomas of the breast.
There appears to be no significant difference in the incidence of axillary
lymph node metastases in patients with carcinomas with neuroendocrine
differentiation compared with patients with invasive ductal carcinoma
of NST. On the other hand, as may be expected based on the behavior
of small cell carcinoma arising from other sites, most but not all reports
B
FIGURE 10.29 Invasive carcinoma with neuro endocrine features. A: This tumor is
composed of glands and solid cell nests with small, uniform nuclei. B: Immunostain for
synaptophysin shows cytoplasmic reactivity in the tumor cells.
indicate an aggressive clinical course in patients with primary small cell

carcinoma of the breast.121
The major differential diagnostic consideration is metastasis of an endo-
crine tumor arising in an extramammary site. In some cases, it may be
ifficult to distinguish a well-differentiated endocrine tumor from an

d
invasive lobular carcinoma with a solid growth pattern because of the
uniformity of the cell population in both tumors. In such cases, immunos-
tains for E-cadherin, chromogranin, and synaptophysin may be of help in
arriving at the correct diagnosis.
Carcinomas with apocrine Differentiation

Although many invasive breast cancers show some evidence of apocrine
differentiation, <1% of invasive breast carcinomas demonstrate pure
apocrine features (i.e., possess the cytologic characteristics of apocrine
epithelial cells throughout the tumor).125-128
Patients with apocrine carcinomas are similar in age and mode of presen-
tation to patients with invasive carcinoma of NST. The mammographic
characteristics of apocrine carcinomas are not distinctive.76
Gross Pathology
No distinctive gross findings are associated with apocrine carcinoma, and
the size distribution is similar to invasive carcinomas of NST.
Histopathology
Apocrine differentiation, characterized by cells with abundant, foamy
to granular eosinophilic cytoplasm and round nuclei with prominent
nucleoli, may occur in invasive ductal carcinomas, invasive lobular
carcinomas, and other breast cancer types.128-130 Thus the term invasive
apocrine carcinoma comprises a heterogeneous group. Therefore, inva-
sive carcinomas with pure apocrine cytology are probably best character-
ized according to the underlying histologic pattern (i.e., invasive ductal
carcinoma with apocrine features and invasive lobular carcinoma with
apocrine features) (Fig. 10.30, e-Fig. 10.19).

Carcinomas with apocrine features are ER and PR negative but show
expression of androgen receptor.131 These tumors also show immunostain-
ing for GCDFP.132 HER2 overexpression and gene amplification have been
reported in about 40% to 50% of cases. Although a “molecular apocrine”
signature has been identified in gene expression profiling studies, only
about half of the carcinomas that show histologic evidence of apocrine
differentiation show this signature. The remainder belong to the luminal
and HER2 molecular subtypes. These molecular data provide further evi-
dence that carcinomas with apocrine features on histologic examination
do not represent a distinct entity.133
B
FIGURE 10.30 Invasive carcinoma with apocrine features. A: The cells invade the stroma
in nests of varying size. B: The tumor cells have abundant granular eosinophilic cytoplasm.

The prognosis of invasive carcinomas with apocrine cytology does
not appear to differ from that of invasive ductal carcinomas of NST
with regard to the frequency of axillary lymph node involvement or
prognosis.134
In some cases, the foamy or granular nature of the cytoplasm may produce
an appearance mimicking a histiocytic infiltrate or a granular cell tumor,
respectively. Immunostains for cytokeratin will mark the cells of apocrine
carcinoma and distinguish them from histiocytes and the cells of a granu-
lar cell tumor.
Invasive Papillary Carcinoma

Invasive papillary carcinomas are rare lesions reportedly associated with
a favorable prognosis. They are discussed in Chapter 8.
Inflammatory Carcinoma
Inflammatory carcinoma is a form of locally advanced breast cancer
characterized by erythema, edema, induration, warmth, and tenderness of
the mammary skin, resulting in a “peau d’orange” appearance.135-137 The
pathologic correlate of this clinical presentation is the presence of tumor
emboli in dermal lymphovascular spaces (Fig. 10.31). The clinical findings
are presumed to be due to lymphatic obstruction by the tumor emboli. No
significant inflammatory cell infiltration is present; the term inflammatory
refers to the clinical appearance of the skin.
It is important to note that skin biopsies from patients with the
clinical diagnosis of inflammatory carcinoma do not always demonstrate
FIGURE 10.31 Biopsy of the skin of the breast from a patient with clinical findings
consistent with inflammatory carcinoma. Tumor emboli are present in dermal lymphatic
spaces.
dermal lymphovascular tumor emboli, possibly due to the limitations of

tissue sampling; obtaining additional levels through the tissue block may
be prudent in such cases.138 Conversely, dermal LVI may be seen in the
absence of these clinical findings; therefore, this histologic finding in and
of itself is insufficient for a diagnosis of inflammatory carcinoma.139
The invasive carcinoma in the breast is most often a high-grade
invasive ductal carcinoma of no special type, but inflammatory carcinoma
may also be seen in association with other histologic types. Up to 50%
of cases are ER and PR negative and about 40% show HER2 overexpres-
sion or gene amplification. In some cases, inflammatory carcinoma may
be the presenting sign of cancer recurrence (“secondary inflammatory
carcinoma”).
Inflammatory carcinoma was previously associated with a very poor
prognosis. However, the combined use of neoadjuvant chemotherapy and
radiation therapy followed by mastectomy has dramatically improved the
outcome for these patients.136,137
In summary, inflammatory carcinoma is not a pathologic diagnosis;
it is a clinical diagnosis with a pathologic correlate. Although the presence
of dermal LVI supports the diagnosis of inflammatory carcinoma in the
appropriate clinical setting, a diagnosis of “inflammatory carcinoma” per
se is not appropriate in a surgical pathology report.
Miscellaneous Rare Invasive Breast Cancers
Secretory Carcinoma
Secretory carcinoma is a rare tumor that accounts for <0.01% of all breast
cancers. It is discussed in Chapter 17.
Invasive Carcinoma with Osteoclast-Like Giant Cells
Invasive carcinoma with osteoclast-like giant cells is characterized by
an invasive epithelial component with admixed giant cells, which mor-
phologically resemble osteoclasts and have the phenotypic features of
histiocytes on immunohistochemical and ultrastructural analysis.140,141
The clinical features of patients with these tumors and their location
within the breast are similar to patients with invasive ductal carcinomas
of NST. Invasive carcinoma with osteoclast-like giant cells is associated
with a benign appearance both mammographically and grossly, due to
the presence of circumscribed borders. On macroscopic examination,
these lesions are typically circumscribed, fleshy, and brown in color due
to recent and remote hemorrhage and benign vascular proliferation.
The epithelial component of the tumor is usually moderately to poorly
differentiated invasive ductal carcinoma, but osteoclast-like giant cells
have also been reported in invasive lobular carcinomas and most other
special type cancers (Fig. 10.32, e-Fig. 10.20).142-145 Foci of hemorrhage
and hemosiderin deposition are typically present. Although the prognostic
FIGURE 10.32 Invasive carcinoma with osteoclast-like giant cells. The tumor is a high
grade invasive ductal carcinoma, composed of sheets of tumor cells with vesicular nuclei
that have variably prominent nucleoli. Several giant cells with abundant eosinophilic
cytoplasm and multiple small nuclei (resembling osteoclasts) are admixed with the tumor
cells.
significance of this unusual lesion is not known with certainty, available

evidence suggests that these tumors do not appear to be any more or less
aggressive than breast cancers of NST and that the prognosis is related to
the characteristics of the carcinoma itself.
Lipid-Rich and Glycogen-Rich Carcinomas
Variable amounts of lipid and/or glycogen are commonly present in the
cytoplasm of breast cancer cells. However, a small proportion of breast
carcinomas are characterized by tumor cells that contain abundant lipid
or abundant glycogen within their cytoplasm. These lesions have been
termed lipid-rich carcinomas and glycogen-rich carcinomas, respectively.
On routine light microscopy, the tumor cells comprising these lesions
show vacuolated or clear cell cytoplasmic features. However, neither
lipid-rich nor glycogen-rich carcinomas appear to be distinct clinico-
pathologic entities, and the importance of recognizing these lesions lies
in the fact that they may mimic other forms of malignancy, particularly
metastatic renal cell carcinoma.146
Pleomorphic Carcinoma
Pleomorphic carcinoma is a variant of high-grade invasive ductal car-
cinoma in which at least 50% of the tumor cells show marked nuclear
pleomorphism, bizarre giant cell forms, and a high mitotic rate. Areas of
necrosis and cavitation occur in larger tumors. Lymph node involvement
is seen in about 50% of patients at the time of presentation. Biomarker
studies reveal that most of these tumors are negative for ER and PR.147 The
prognosis is poor, but it is not clear that it is any worse than that of other
grade 3 invasive ductal carcinomas of similar size and stage.
Invasive Carcinoma with Choriocarcinomatous Features
Invasive carcinoma with choriocarcinomatous features is an exceedingly
rare form of breast cancer. Only two reports have described the pres-
ence of choriocarcinomatous elements (i.e., trophoblastic differentiation)
admixed with conventional breast carcinomas.148,149 The choriocarcino-
matous component was associated with invasive ductal carcinoma in one
case and metastatic mucinous carcinoma in the second. The choriocarci-
nomatous elements in these tumors produce human chorionic gonadotro-
pin. If choriocarcinomatous features are encountered in a breast tumor,
the differential diagnosis should include choriocarcinoma metastatic to
the breast, as several such cases have been reported.
Mucinous Cystadenocarcinoma
Mucinous cystadenocarcinoma is a rare variant of invasive breast car-
cinoma, which is morphologically indistinguishable from mucinous
cystadenocarcinoma of the ovary or pancreas (e-Fig. 10.21).71 Although
these tumors may be associated with the extravasation of mucin, they are
otherwise morphologically distinct from conventional mucinous carci-
noma. The importance of recognizing these tumors is that they must be
distinguished from metastatic lesions in the breast, particularly those of
ovarian origin. The prognostic significance of primary mucinous cystad-
enocarcinoma of the breast is currently unknown.
Pathologic Features of Hereditary Breast Cancer

Approximately 5% to 10% of breast cancers are caused by mutations in
high-penetrance breast cancer susceptibility genes.150-153 Cancers that arise
in women with mutations in the BRCA1 and BRCA2 genes have been the
best characterized with regard to their pathologic features.154
The majority of breast cancers that develop in women with BRCA1
germline mutations are invasive ductal carcinomas of no special type, but
medullary carcinomas and carcinomas with medullary features are more
common in women with BRCA1 mutations than among women with
BRCA2 mutations or sporadic breast cancers.150,154-156 Individual histo-
logic features associated with BRCA1 mutations include high histologic
grade, high mitotic rate, solid sheets of tumor cells with little gland for-
mation, a prominent lymphocytic infiltrate, geographic zones of necrosis,
and pushing borders (Fig. 10.33).150,151,154-161 In addition, when compared
with sporadic breast cancers, BRCA1-related cancers are more often ER,
B
FIGURE 10.33 BRCA1-associated breast cancer. A: Low-power view demonstrates a
circumscribed border and geographic zones of necrosis within the tumor. B: High-power
view illustrates marked cytologic atypia and numerous mitoses. This tumor was negative
for ER, PR, and HER2 (“triple negative”) and is characteristic of tumors with a basal-like
phenotype.
PR, and HER2 negative (“triple negative”) and have a basal-like immuno-
phenotype (characterized by tumor cell expression of basal cytokeratins
5/6, 14, and 17, EGFR, and P-cadherin, among other biomarkers) and
cluster within the basal-like group in gene expression profiling stud-
ies.150,157,159,160,162,163 These features are similar to those seen in sporadic bas-
al-like breast cancers (see the subsequent text), tumors in which somatic
inactivation of BRCA1 has been identified.
Genotype–phenotype correlations are less clear in BRCA2 mutation
carriers than in those with BRCA1 mutations. Some studies suggested
that certain histologic types such as tubular, tubulolobular, lobular, and
pleomorphic lobular carcinomas are more common among BRCA2 muta-
tion carriers than among controls.150,155 However, the largest study to date
of BRCA2 mutation carriers did not confirm this association.164 In fact,
in that study, cancers in BRCA2 mutation carriers were predominantly
invasive ductal carcinomas of high histologic grade. Of interest, these
high-grade cancers were more likely to be ER positive than grade-matched
controls.164
At this time, no reproducibly identifiable histologic features have
been observed in breast cancers from women with other inherited disor-
ders associated with an increased breast cancer risk such as Li-Fraumeni
syndrome, ataxia telangiectasia, or Cowden syndrome.
Prognostic and Predictive Factors

A prognostic factor is one that is useful for assessing patient outcome,
whereas a predictive factor provides information on the likelihood of
response to a given therapeutic modality.165 There has long been inter-
est in identifying biological, molecular, and genetic markers that may be
useful in assessing the prognosis and predicting treatment response in
patients with invasive breast cancer, and this remains an area of active
research. Traditional pathologic factors (such as axillary lymph node
status, tumor size, histologic type, histologic grade, and LVI) in conjunc-
tion with hormone receptor status and HER2 status remain the principal
means for assessing prognosis and determining the likelihood of thera-
peutic response in patients with breast cancer. However, molecular tests
are being used increasingly as adjuncts to assess prognosis and guide
therapy.
Axillary Lymph Node Status
There is uniform agreement that the status of the axillary lymph nodes
is the single most important prognostic factor for patients with breast
cancer; disease-free and overall survival decrease as the number of posi-
tive lymph nodes increases.166 As discussed in Chapter 18, axillary lymph
node metastases are categorized as macrometastases, micrometastases,
and isolated tumor cells (ITCs). It has long been known that macrome-
tastases (i.e., those over 2 mm) are associated with an adverse clinical
outcome. However, the clinical significance of micrometastases and ITCs

(considered together in some studies as “occult metastases”) has been a
matter of uncertainty and controversy. Most studies evaluating their clini-
cal importance have been retrospective and were not initially designed to
address this question. The results from two recent clinical trials have pro-
vided the best available data regarding the clinical implications of these
small lymph node deposits. In the NSABP B32 trial, overall survival at
5 years was 95.8% for patients without and 94.6% for those with occult
metastases (absolute survival difference 1.2%).167 The investigators in this
study concluded that while this difference was statistically significant (P =
0.03), this small difference is not clinically important. In the ACOSOG
Z0010 study, the 5-year overall survival was 95.7% and 95.1% for those
without and with occult metastases, respectively; this difference was not
statistically significant.168 These results have led to the recommendation
that attempts to identify ITC and micrometastases in axillary lymph nodes
be abandoned.169,170
Tumor Size
After lymph node status, tumor size represents the next most important
prognostic factor for patients with breast cancer. The current American
Joint Commission on Cancer (AJCC) staging system for tumor size (T) is
shown in Table 10.1.135,171 Even among patients with breast cancers 1 cm
and smaller (T1a and T1b), size represents an important prognostic factor
for axillary lymph node involvement and outcome.172 The manner in which
the pathologic tumor size is measured varies among pathologists. Some
report the size of the macroscopically identified tumor. Others report the
microscopic size of the invasive component only or a microscopic size
that includes both the invasive and the in situ components. Prior stud-
ies have shown that, particularly for small breast cancers, there is often
poor correlation between the tumor size determined by gross pathologic
examination and the size of the invasive component as determined by
measurement from the histologic sections. Moreover, it is the size of the
invasive component that is the most clinically significant determinant of
outcome.173 In fact, the AJCC Cancer Staging Manual indicates that the
microscopically determined pT should be based on measuring only the
invasive component.135 Therefore, when there is a discrepancy between
the gross tumor size and the microscopic size, particularly of small breast
cancers, it is the microscopic size of the invasive component of the tumor
that takes precedence and that should be reported and used for pathologic
staging. Of course, for larger tumors in which a complete cross section
of the lesion cannot be represented on any one microscopic slide, the
macroscopic tumor size measurement should be used. Determination of
tumor size may be particularly problematic for cases in which most of the
invasive tumor was removed by a prior core-needle biopsy. In such cases,
determining the size from the pre-core biopsy imaging studies, particularly
ultrasound, may provide the most accurate assessment.
Table 10.1 American Joint Commission on Cancer System for Tumor

Size (T) Staging in Breast Cancer
Tx Primary tumor cannot be assessed

T0 No evidence of primary tumor
Tis Carcinoma in situ
Tis (DCIS) Ductal carcinoma in situ
Tis (LCIS) Lobular carcinoma in situ
Tis (Paget) Paget disease of the nipple not associated with invasive
cancer and/or carcinoma in situ in the underlying breast
parenchyma
T1 Tumor ≤20 mm in greatest dimension
T1mi Microinvasion ≤1 mm in greatest dimension
T1a >1 mm but ≤5 mm in greatest dimension
T1b >5 mm but ≤10 mm in greatest dimension
T1c >10 mm but ≤20 mm in greatest dimension
T2 Tumor >20 mm but ≤50 mm in greatest dimension
T3 Tumor >50 mm in greatest dimension
T4 Tumor of any size with direct extension to chest wall or
skin (ulceration or skin nodules; invasion of the dermis
alone does not qualify as T4)
T4a Extension to chest wall, not including only pectoralis
muscle adherence/invasion
T4b Ulceration and/or ipsilateral satellite nodules and/or edema
(including peau d’orange) of the skin, which do not meet
the criteria for inflammatory carcinoma
T4c Both T4a and T4b above
T4d Inflammatory carcinoma
Adapted from AJCC Cancer Staging Manual Seventh Edition. New York, NY:
Springer; 2010.
Histologic Type
Some histologic types of breast cancer are associated with a particu-
larly favorable clinical outcome.174,175 Special type tumors that have
consistently been shown to have an excellent prognosis include tubular,
invasive cribriform, mucinous, and adenoid cystic carcinomas. Moreover,
the 20-year recurrence-free survival of special type tumors 1.1 to 3.0 cm
in size is similar to that of invasive ductal carcinomas 1 cm and smaller
(87% and 86%, respectively).175 Strict diagnostic criteria for these special
type cancers must be employed in order to observe the favorable outcome
reported for these lesions.
Histologic Grade
The importance of tumor grading as a prognostic factor in patients with
breast cancer has been clearly demonstrated in numerous clinical out-
come studies.176 In fact, tumor grading has been shown to be of prognos-
tic value even in patients with breast cancers 1 cm and smaller.172 The
grading method in most widespread clinical use at the present time is
the Nottingham combined histologic grading system.176,177 In this system,
the degree of tubule formation, nuclear grade, and mitotic rate are each
assigned a value of 1 to 3; these values are then added together to produce
numerical scores from 3 to 9 (Table 10.2). Tumors with total scores of 3 to
5 are categorized as grade 1, those with scores of 6 and 7 are grade 2, and
those with scores of 8 and 9 are grade 3 (see Fig. 10.2). Long-term follow-
up studies have repeatedly documented that the risk of distant metastases
and survival are worst in grade 3 tumors and best in grade 1 tumors, inde-
pendent of lymph node status and tumor size.176
The use of histologic grading has been recommended for all types of
invasive breast cancer. However, histologic grade partially defines some
histologic types (for example, tubular carcinomas are by definition grade 1
and medullary carcinomas are grade 3 lesions). Nonetheless, for some
special type tumors, particularly lobular and mucinous carcinomas, the
combination of histologic type and grade provides a more accurate assess-
ment of prognosis than does histologic type alone.176,178
Histologic grade also provides useful information with regard to
response to chemotherapy and is, therefore, a predictive factor as well as
a prognostic indicator. The results of several studies have suggested that
the presence of high histologic grade is associated with a better response
to chemotherapy than low histologic grade in both the adjuvant and neo-
adjuvant settings.179
Table 10.2 Nottingham System for Determining Combined Histologic

Grade of Invasive Breast Cancer
Point Value
1 2 3
Tubules >75% 10–75% <10%

Nuclear grade Low Intermediate High
Mitosesa 0–5 5–10 >10
Cutoffs will vary depending on microscopic field area.

a
Grade 1: cumulative score 3, 4, or 5.

Grade 2: cumulative score 6 or 7.
Grade 3: cumulative score 8 or 9.
A frequent criticism of the use of histologic grading is that this assess-

ment is subjective and, as a consequence, prone to considerable interob-
server variability. However, recent studies have indicated that the use of
strict criteria and guidelines for histologic grading can result in acceptable
levels of interobserver agreement and have also identified areas that might
benefit from refinement.176
Lymphovascular Invasion
The presence of tumor emboli in lymphovascular spaces has been shown
in numerous studies to be an important and independent prognostic fac-
tor. The identification of LVI is of particular importance in patients with
T1, node-negative breast cancers, since this finding may permit the iden-
tification of a subset of patients at increased risk for axillary lymph node
involvement and distant metastasis in this otherwise favorable group.180,181
The vast majority of small vascular spaces that contain tumor emboli are
lymphatic spaces; only a minority are blood vessels.182
Strict criteria should be used to define the presence of LVI
(Figs. 10.34 and 10.35, e-Fig. 10.22).183-185 In particular, LVI must be dis-
tinguished from tumor cell nests within artifactual tissue spaces that form
as the result of shrinkage or retraction of the surrounding stroma during
tissue processing (Fig. 10.36, e-Fig. 10.23). To avoid this pitfall, assess-
ment for LVI is best performed in peritumoral tissue. Histologic features
FIGURE 10.34 Lymphovascular invasion. A tumor embolus is present within a thin-walled

vascular space in association with other vascular structures.
B
FIGURE 10.35 Lymphovascular invasion. A: Multiple tumor emboli are present within
thin-walled vascular spaces in the interlobular stroma. B: High-power view illustrates one
of these tumor emboli within an endothelial-lined space.
that are helpful for identifying bona fide LVI and distinguishing it from
retraction artifact are summarized in Table 10.3.
Immunostains for a variety of vascular and lymphatic endothelial
cell markers have been used in an attempt to improve the accuracy of
detection of LVI. Of these, the D2-40 antibody to podoplanin, which
FIGURE 10.36 Stromal retraction around nests of invasive tumor cells producing an
appearance simulating lymphovascular invasion. There are no endothelial cells lining these
spaces.
specifically recognizes lymphatic endothelial cells, appears to be the most

valuable (Fig. 10.37).182,186,187
The broad range in reported incidence of LVI (from under 5%
to over 50% of breast cancers) is due to a number of factors including
variations in patient population, differences in diagnostic criteria for LVI,
methodology used to detect LVI, and interobserver variability.
ER and PR Status
ER and PR represent weak prognostic factors for patients with breast can-
cer, but these receptors are the strongest predictive factors for response
to endocrine therapy. In current practice, ER and PR status are most
Table 10.3 Histologic Features Most Useful for Identifying True

Lymphovascular Invasion
• Lymphovascular invasion is best assessed in peritumoral tissue

• Tumor cells present in endothelial-lined spaces
• Configuration of tumor cells often does not conform to shape of the space
• Present in location of normal lymphovascular spaces
• In association with other vascular structures
• Periductal
• Interlobular stroma
FIGURE 10.37 Immunostain for podoplanin using antibody D2-40 highlights lymphatic
endothelial cells. Two of these spaces contain tumor cells.
often determined by IHC performed on paraffin sections. ER and PR

assays should be performed on all invasive breast cancers and ER should
be performed on all cases of DCIS using validated assays in accordance
with the guidelines recently published by the American Society of Clinical
Oncology (ASCO) and College of American Pathologists (CAP).188
How best to score ER and PR immunostains and report the results
has been a matter of debate for decades.189 The recent ASCO/CAP guide-
lines require that reports of ER and PR assays include the percentage of
tumor cells showing nuclear staining and the intensity of staining (strong,
medium, and weak); combining these two parameters into a score (such
as the Allred score)190 is optional. Carcinomas are considered positive for
ER and PR when at least 1% of tumor cells show nuclear staining.188,191 An
adequate internal positive control consisting of normal breast epithelial
cells that show staining for the receptors is required, particularly for the
interpretation of an ER or PR result as negative (Fig. 10.38).
HER2 Status
The analysis of breast cancer specimens for HER2 protein overexpression
and/or gene amplification is now standard practice.192,193 HER2 is a prog-
nostic factor for outcome in both node-negative and node-positive patients
and is a predictive factor for response to certain chemotherapeutic and
antiendocrine agents. However, the major clinical reason to assess HER2
status is to help select patients for treatment with HER2-targeted therapy
with agents such as trastuzumab (Herceptin) and lapatinib (Tykerb).
B
FIGURE 10.38 Estrogen receptor (ER) immunostains. A: ER-positive breast cancer.
Virtually all of the tumor cells show intense nuclear staining. B: ER-negative breast cancer.
The tumor cells lack nuclear staining for ER. In contrast, epithelial cells of a benign duct
show strong ER staining and serve as an internal positive control.
Assessment of HER2 protein overexpression using IHC and HER2

gene amplification using fluorescence in situ hybridization (FISH)
are the methods most commonly employed in clinical practice today
(Fig. 10.39).192 A detailed discussion of the pros and cons of each of these
B
FIGURE 10.39 HER2-positive breast cancer. A: HER2 immunostain demonstrates intense
membrane staining of all tumor cells in a chicken-wire pattern indicating HER2 protein
overexpression (3+). B: Fluorescence in situ hybridization assay using a dual-probe system.
Red signals denote HER2 gene copies and green signals denote copies of chromosome
17. The average ratio of red to green signals per nucleus is >2.2; therefore, this tumor
shows HER2 gene amplification.
techniques is beyond the scope of this text and the interested reader
should consult recent reviews on this subject.192,193
HER2 assays should be performed and interpreted according to the
guidelines published by ASCO/CAP.193 Using these guidelines, a tumor
should be considered HER2 positive if at least 30% of the tumor cells
show strong, circumferential membrane staining using a validated IHC
method, show a HER2/CEP17 (centromere enumeration probe 17) ratio
of more than 2.2 using a validated dual-probe system (i.e., a system that
includes FISH probes for the HER2 gene and CEP17), or show >6 HER2
signals/cell using a single-probe system (i.e., one that includes a FISH
probe for the HER2 gene only). More recently, a requirement to report the
presence of heterogeneity for HER2 gene amplification has been added to
the originally published ASCO/CAP guidelines.194 Genetic heterogeneity
in this setting is defined as the presence of more than 5% but less than
50% of tumor cells that show a HER2/CEP17 ratio of >2.2 using a dual-
probe system or >6 HER2 signals using a single-probe system.
Other Factors
A number of other histologic factors have been reported to have prog-
nostic value in patients with invasive breast cancer. The proliferation
rate, assessed by a variety of methods over the years, has been repeatedly
demonstrated to be an important prognostic factor in patients with breast
cancer.166 Immunostaining for the Ki67 antigen is now the most widely
used of these methods. However, the routine clinical application of Ki67
immunostains to assess prognosis and to predict chemotherapy benefit
in patients with breast cancer has been limited by wide variation in assay
techniques and interpretation of results. To overcome these limitations,
detailed recommendations were recently published in an attempt to stan-
dardize preanalytical and analytical variables, scoring, and interpretation
of Ki67 immunostaining results.195
Blood vessel invasion (i.e., invasion of veins and arteries) has been
reported to have an adverse effect on clinical outcome. However, there is
a broad range in the reported incidence of blood vessel invasion, ranging
from under 5% to almost 50%.196
The relationship between clinical outcome and the extent of mono-
nuclear inflammatory cell infiltrate in association with invasive breast
cancers has also been investigated. The prognostic significance of this
finding is controversial, with some studies noting an adverse effect on
clinical outcome and others observing either no significant effect or a
beneficial effect.81
Perineural invasion is only infrequently observed in invasive breast
cancers (e-Fig. 10.24). This phenomenon is often seen in association with
LVI and it has not been shown to be an independent prognostic factor.
The extent of DCIS associated with invasive cancers has also been
studied as a potential prognostic factor. The presence of an extensive intra-
ductal component is a prognostic factor for local recurrence in patients
treated with breast-conserving surgery and radiation therapy when the sta-
tus of the excision margins is unknown. However, it is not an independent
prognostic factor when the margin status is taken into consideration.197
The extent of associated DCIS has not been reproducibly shown to be a
prognostic factor for distant metastasis or overall survival.197,198
Numerous other factors have also been reported to have prognostic
importance in patients with breast cancer including ploidy, various onco-
genes and tumor suppressor genes (most notably p53), angiogenesis, and
proteases and protease inhibitors, to name just a few. None of these has
proven to be of sufficient value to be incorporated into routine clinical
practice.
Combining Prognostic Factors
Several authors have developed prognostic indices that take into account
various combinations of prognostic factors. The best known of these is the
Nottingham Prognostic Index, which takes into consideration tumor size,
lymph node status, and histologic grade. This index has been used to strat-
ify patients with breast cancer into good, moderate, and poor prognostic
groups, with annual mortality rates of 3%, 7%, and 30%, respectively.199
Molecular Prognostic and Predictive Tests
Although the evaluation of individual prognostic and predictive factors
has permitted the identification of clinically distinct subgroups of patients
with breast cancer, there is a pressing need to develop a comprehensive
profile of the biological and molecular characteristics of a tumor that
may aid in the assessment of prognosis and the prediction of response to
various therapeutic modalities in individual patients. The tools of modern
molecular biology, such as microarray technology and next-generation
sequencing, may ultimately provide such an assessment by permitting
high-throughput, parallel analysis of hundreds or thousands of param-
eters. A detailed discussion of molecular prognostic tests is beyond the
scope of this chapter. However, two molecular tests that are now com-
mercially available merit particular comment.
OncotypeDX (Genomic Health, Inc.) is a reverse transcriptase
polymerase chain reaction–based assay that can be performed on paraf-
fin sections. It is based on analysis of the expression of 21 genes and
provides a “recurrence score” that correlates with outcome. Although
it was initially used to assess prognosis in ER-positive, node-negative
patients treated with tamoxifen,200-202 recent data have indicated that
the recurrence score is an equally valuable prognostic factor for distant
recurrence in ER-positive patients treated with aromatase inhibitors203
and in ER-positive, node-positive patients204 as well as a prognostic fac-
tor for locoregional recurrence.205 However, in current clinical practice,
this assay is most often used as a predicitive factor, i.e., to predict to the
likelihood of chemotherapy benefit in selected women with ER-positive
breast cancer.206 MammaPrint (Agendia) is a molecular prognostic test
that utilizes expression array analysis of 70 genes to identify patients with
good and poor prognostic signatures.207-209 At the present time, this assay
requires fresh frozen tumor tissue, but it will soon be possible to perform it
on paraffin sections. Although these tests are already being used in patient
management, their ultimate value will be determined by the results of pro-
spective clinical trials that are currently underway (the TAILORx trial to
study OncotypeDX and the MINDACT trial to study MammaPrint).
Finally, while evaluation of breast cancer genomes using next-
generation sequencing is currently in its early stages, this technique will
undoubtedly provide new insights into breast cancer biology and permit
further personalization of breast cancer treatment.210,211
Molecular Classification of Breast Cancer

As noted earlier in this chapter, studies of breast cancers using gene
expression profiling have identified several major breast cancer sub-
types.5-9,212 The best characterized of these have been designated luminal
A, luminal B, HER2, and basal-like. These subtypes differ with regard to
their patterns of gene expression, clinical features, response to treatment,
and outcome. The key features of these breast cancer subtypes are sum-
marized in Table 10.4.
One of the most novel findings to have emerged from these studies
has been the characterization of basal-like breast cancers as a distinct
group. These tumors are invasive ductal carcinomas that feature high
histologic grade, solid architecture, absence of tubule formation, high
mitotic rate, a stromal lymphocytic infiltrate, a pushing border, geographic
zones of necrosis and/or a central fibrotic focus, and little or no associ-
ated DCIS (e-Fig. 10.25).213-216 Moreover, these tumors are typically ER,
PR, and HER2 negative (“triple negative”) and show expression of basal
cytokeratins, EGFR, and other basal-related genes. Basal-like carcinomas
are especially common in African American women and are associated
with a poor prognosis. However, heterogeneity has been identified even
within this subgroup. Of note, approximately 80% of BRCA1-associated
breast cancers cluster with the basal-like group in gene expression profil-
ing studies (see Fig. 10.33). It is important to remember that not all tumors
that are basal-like by gene expression profiling are triple negative and not
all triple-negative cancers are basal-like by gene expression profiling and
so these two terms should not be used synonymously.216,217 The overlap
between triple-negative breast cancers and breast cancers that are basal-
like in expression profiling studies is approximately 70% to 80%.
Other breast cancer subtypes that have been identified in gene
expression profiling studies include the molecular apocrine type (char-
acterized by activation of genes in the androgen receptor pathway), the
claudin-low type (characterized by high expression of genes involved in
epithelial–mesenchymal transition and stem cell features), and a normal
breast-like type (although this group is poorly characterized and may
represent an artifact of contamination of tumor samples by normal breast
epithelium and stroma).9
Table 10.4 Major Molecular Categories of Breast Cancer Determined

by Gene Expression Profiling
Molecular Category
Luminal HER2 Basal
Gene High expression High expression High expression of

expression of hormone of HER2 and basal epithelial
patterns receptors and other genes in genes, basal
associated genes amplicon cytokeratins
(luminal A > Low expression Low expression
luminal B) of ER and of ER and
associated associated genes
genes Low expression of
HER2
Clinical ~70% of invasive ~15% of invasive ~15% of invasive
features breast cancers breast cancers breast cancers
ER/PR positive ER/PR negative Most ER/PR/HER2
Luminal B tends Most overexpress negative
to be of higher HER2 BRCA1 gene
histologic grade More likely to be dysfunction
than luminal A high grade and common
Some overexpress node positive (germline
HER2 mutations,
(subset of somatic
luminal B) alterations)
Particularly
common in
African American
women
Treatment Respond to Respond to No response to
response endocrine HER2-targeted endocrine
and therapy therapy (e.g., therapy or HER2-
outcome (response may trastuzumab, targeted therapy
be different for lapatinib) Sensitivity to
luminal A and Respond to platinum-based
luminal B) anthracycline- chemotherapy
Response to based and PARP
chemotherapy chemotherapy inhibitors under
variable Generally poor investigation
(luminal B > prognosis Generally poor
luminal A) prognosis,
Generally favorable especially within
prognosis the first 5 years
ER, estrogen receptor; PR, progesterone receptor; PARP, poly(ADP ribose) polymerase.
Table 10.5 Immunophenotyping to Approximate Molecular Subtype

Using Six Biomarkers
Most Common Biomarker Profile
Luminal A ER+ and/or PR+, HER2-, Ki67 <14%

Luminal B ER+ and/or PR+, HER2-, Ki67 ≥14%
or
ER+ and/or PR+ and HER2+ (luminal-
HER2)
HER2 ER- and PR-, HER2+
Basal-like ER-, PR-, HER2-, CK5/6+ and/or
EGFR+
ER, estrogen receptor; PR, progesterone receptor.

Data from Brenton JD, Carey LA, Ahmed AA, Caldas C. Molecular classification and
molecular forecasting of breast cancer: ready for clinical application? J Clin Oncol.
2005;23(29):7350-7360; Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical
and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin
Cancer Res. 2004;10(16):5367-5374; Cheang MCU, Chia SK, Voduc D, et al. Ki67 index,
HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst.
2009;101(10):736-750.
At the present time, the clinical value of determining the breast

cancer molecular subtype and categorizing breast cancers beyond their
histopathologic features and ER, PR, and HER2 status has not been
established. However, these three biomarkers in combination with sev-
eral other markers can be used to approximate the molecular category of
breast cancer as defined by gene expression profiling (Table 10.5).6,218,219
Extramammary Malignancies Metastatic

to the Breast
Secondary tumor deposits in the breast may derive from the contralat-
eral breast or from virtually any nonmammary site.220-222 In one series,
metastases to the breast from nonmammary malignancies comprised
1.2% of all malignancies diagnosed in the breast.223 However, this series
was from a referral center, so this likely represents an overestimate of
the frequency of metastases to the breast. Because many nonmammary
malignancies can mimic the features of usual or unusual types of primary
breast tumors, it can be very difficult to distinguish between the two in a
subset of cases, particularly when there is no history of a prior nonmam-
mary malignancy. Nevertheless, this distinction is critical for appropriate
patient management.
Metastatic lesions involving the breast almost never occur in the
absence of metastases to other sites, even when the breast metastasis
is the first clinically detected site. When metastases are detected in the
breast, a solitary, unilateral lesion is present in 85% of cases; multiple
lesions are present in 10% of cases, and diffuse involvement of the breast
occurs in 5% of cases.224 The presence of tumor in ipsilateral axillary
lymph nodes does not necessarily imply that the malignancy is a primary
breast tumor, as metastatic deposits simultaneously involving the breast
and axillary lymph nodes are not infrequent.224
Although metastatic lesions in the breast can mimic the mammo-
graphic appearance of primary breast cancers, they are more likely to be
multiple and bilateral and exhibit well-defined margins without evidence
of spiculation.224,225 Mammographic microcalcifications associated with
metastatic lesions are rare, but have been reported in association with
metastatic ovarian tumors. On ultrasound examination, metastatic tumors
involving the breast are usually round or ovoid masses with some degree
of lobulation and variable internal echoes.
Metastatic tumors to the breast have a variable gross appearance,
depending on the type of metastasis. In general, however, these lesions
may be single or multiple and are generally well demarcated from the
surrounding breast parenchyma. The histologic and cytologic appear-
ance of these neoplasms is related to the site of origin of the primary
tumor. Metastatic lesions most frequently described in the breast include
malignant melanoma, lung carcinoma, carcinoid tumors from a variety of
primary sites, and, in men, prostate carcinoma. Less frequent metastases
to the breast include ovarian carcinoma, gastric carcinoma, renal cell car-
cinoma, thyroid carcinoma, various malignant tumors from the head and
neck, various types of sarcoma, colorectal carcinoma, medulloblastoma,
neuroblastoma, malignant mesothelioma, carcinoma of the urinary blad-
der, endometrial carcinoma, cervical carcinoma, chloroma, and chorio-
carcinoma (Fig. 10.40, e-Fig. 10.26).222,226
To a variable degree, the histologic features of many of the afore-
mentioned tumors may mimic a primary breast carcinoma. Therefore, it
is important that the pathologist consider the possibility of metastasis in
cases with unusual clinical, mammographic, or pathologic features. It is
also imperative that any relevant information (such as a history of prior
malignancy or simultaneous unexplained masses occurring elsewhere) is
conveyed to the pathologist. If a tumor displays unusual histologic find-
ings, which raise the possibility of a metastasis, the pathologist may opt
to additionally sample the tumor to look for areas more typical of primary
breast carcinoma and for foci of associated DCIS. In addition, immunos-
tains for a variety of markers may be helpful in defining a tumor as being
of mammary or nonmammary origin.226 The antibody panel chosen for
this purpose will vary depending upon the specific differential diagnosis.
Markers most useful for confirming that a tumor is of breast origin are
ER, cytokeratin 7, GCDFP, and mammaglobin; however, these all vary
in their sensitivity and/or specificity, and the staining results need to be
interpreted with this caveat in mind.222
FIGURE 10.40 Metastatic renal cell carcinoma (conventional clear cell type) involving the
breast.
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11
Spindle Cell Lesions
A variety of reactive and neoplastic lesions of the breast are characterized

by a proliferation of spindle cells (Table 11.1).1-5 When any spindle cell
lesion is encountered in the breast, the diagnosis of spindle cell carcinoma
(a type of metaplastic carcinoma) should always be considered and that
diagnosis should not be dismissed unless there is histologic and/or immu-
nophenotypic evidence to exclude it. The possibility of a phyllodes tumor
should also be given consideration because the epithelial component may
be difficult to identify in some cases, particularly in malignant lesions
characterized by prominent stromal overgrowth or in small biopsy sam-
ples (see Chapter 6). In fact, the definitive categorization of any spindle
cell lesion of the breast may be difficult or impossible due to the limited
sampling afforded by core-needle biopsy; therefore, a cautious approach
regarding the diagnosis of spindle cell lesions based on core-needle biopsy
specimens is prudent.
Many spindle cell lesions that occur in other anatomic sites may be
seen in the breast. This chapter will focus on those lesions that are most
likely to be encountered in clinical practice or that produce particular
diagnostic difficulties.
Spindle Cell Carcinoma

As noted in Chapter 10, some carcinomas of the breast included within
the broader category of metaplastic carcinoma are composed of spindle
cells. These tumors may occur in pure spindle cell form or may consist
primarily of spindle cells with associated glandular, squamous, or het-
erologous elements (most often chondroid or osseous). Tumors of this
type have been variously designated metaplastic carcinoma, sarcomatoid
carcinoma, and spindle cell carcinoma.1-3,5-10 Spindle cell carcinomas are
uncommon and account for <1% of invasive breast cancers.
Upon gross examination, the tumors are most often gray or white,
firm masses that are frequently circumscribed. Microscopically, the appear-
ance of the spindle cells can vary from bland to highly pleomorphic and
may show fascicular, fasciitis-like, storiform, or haphazard growth patterns
363
Table 11.1 Major Differential Diagnostic Considerations of Spindle Cell

Lesions of the Breast, Based on Cytologic Appearance of Spindle Cells
Bland spindle cells

• Scar
• Fibromatosis
• Myofibroblastoma
• Pseudoangiomatous stromal hyperplasia (fascicular type)
• Adenomyoepithelioma
• Spindle cell (metaplastic) carcinoma
Atypical spindle cells
• Spindle cell (metaplastic) carcinoma
• Malignant phyllodes tumor
• Nodular fasciitis
• Primary sarcoma
• Metastatic sarcoma
• Metastatic spindle cell (sarcomatoid) carcinoma
• Metastatic malignant melanoma
( Fig. 11.1, e-Figs. 11.1–11.3). The mitotic rate is highly variable. The borders
of the lesion are usually infiltrative, with entrapment of mammary ducts
and lobules and irregular infiltration of adjacent adipose tissue (Fig. 11.2),
but some cases exhibit pushing margins. Higher grade lesions tend to
obliterate the normal breast architecture. In some cases, the spindle cells
aggregate into small clusters that exhibit a more epithelioid appearance or
merge with an overt epithelial component. Areas suggestive of vascular
spaces may sometimes be seen (Fig. 11.3, e-Fig. 11.4) and areas of squa-
mous differentiation are not infrequent (Fig. 11.4, e-Fig. 11.5). Small foci
with heterologous chondroid or osseous differentiation may be observed.
Foci of conventional types of invasive breast carcinoma and/or duc-
tal carcinoma in situ (DCIS) may be seen in association with the spindle
cell component and, when present, provide useful clues to the epithelial
nature of the tumor (Fig. 11.5, e-Fig. 11.6). However, in pure spindle cell
carcinomas without morphologic evidence of an epithelial component
or associated DCIS, immunohistochemical stains for cytokeratin and
other markers may be required to arrive at the correct diagnosis.4,10,11 It
should be noted, however, that cytokeratin immunoreactivity may be
quite focal and a panel of anticytokeratin antibodies may be required to
demonstrate cytokeratin positivity. In our experience, broad-spectrum
cytokeratin antibodies (such as antibody MNF116) and antibodies to
high-molecular-weight/basal cytokeratins (such as antibody 34βE12 or
antibodies to cytokeratin 5/6) are the most sensitive for the detection of
Spindle Cell Lesions ——— 365
C
FIGURE 11.1 Spindle cell carcinoma at low (A), medium (B), and high (C) magnifications.
This tumor is highly cellular and is composed of interlacing fascicles of highly atypical
spindle cells with numerous mitotic figures, including atypical mitoses. There is no histologic
evidence of epithelial differentiation.
FIGURE 11.2 Spindle cell carcinoma. At the border of the lesion, there is irregular infiltra-
tion of adjacent adipose tissue producing a “lace-like” pattern.
cytokeratin expression in this setting (Figs. 11.6 and 11.7, e-Fig. 11.7).4,9 The
neoplastic cells also commonly express p63 as well as vimentin, smooth
muscle actin, and muscle-specific actin (Fig. 11.8, e-Fig. 11.8). Expression
by these tumors of basal cytokeratins, p63, actins, and other markers com-
monly associated with myoepithelial cells12-14 supports a basal epithelial
and/or myoepithelial phenotype for these tumors and blurs the distinction
between spindle cell carcinomas and lesions that have been previously
FIGURE 11.3 Spindle cell carcinoma with pseudovascular spaces.

FIGURE 11.4 Spindle cell carcinoma with foci of squamous differentiation.
categorized as myoepithelial carcinomas or malignant myoepitheliomas.

In fact, this distinction now appears to be one of semantics.15 Recent gene
expression profiling studies have demonstrated that some of these tumors
have a basal-like phenotype and cluster in the “basal-like” group, whereas
others show features of epithelial–mesenchymal transition and cluster in
the “claudin low” group.16 Spindle cell carcinomas are typically negative
for estrogen receptor and progesterone receptor expression and for HER2
protein overexpression (triple negative).
FIGURE 11.5 Spindle cell carcinoma with foci of overt epithelial differentiation.
The presence of an epithelial component is a clue to the correct categorization of this
predominantly spindle cell lesion as a spindle cell carcinoma.
B
FIGURE 11.6 Cytokeratin expression in spindle cell carcinomas. A: In some spindle cell
carcinomas such as the one depicted here, almost all of the tumor cells show cytokeratin
expression. B: In other cases, as shown in this image, only a minority of the tumor
cells show cytokeratin expression, even with the most sensitive and broad-spectrum
anticytokeratin antibodies. Both of these cases were immunostained using broad-spectrum
cytokeratin antibody MNF116.
C
FIGURE 11.7 Spindle cell carcinoma with foci of glandular differentiation. A: H&E stain.
B: Immunostain for cytokeratin using antibodies AE1/AE3 demonstrates reactivity of the
glandular component, but no reactivity of the spindle cell component. C: Immunostain
for cytokeratin using broad-spectrum cytokeratin antibody MNF-116 demonstrates
staining of both the glandular and spindle cell components of the tumor.
FIGURE 11.8 Spindle cell carcinoma. This p63 immunostain demonstrates reactivity in
most of the tumor cell nuclei.
One type of spindle cell carcinoma worthy of particular note is the

low-grade fibromatosis-like metaplastic carcinoma.17,18 These lesions,
which may arise either de novo or in association with papillomas
and benign sclerosing lesions,19 are composed of bland spindle cells
resembling those seen in scars or fibromatosis (Fig. 11.9). In contrast
to the cells of scars or fibromatosis, however, the spindle cells com-
prising these lesions show expression of cytokeratin, and some cases
show epithelioid cell clusters or small foci of squamous differentiation.
These tumors have been reported to be associated with a high rate of
local recurrence. Although no instances of metastasis were observed in
the initial report of these cases,17 regional and distant metastases have
subsequently been reported in a small proportion of patients with these
lesions.18
Spindle cell carcinomas are rarely associated with axillary lymph
node metastases. Recent studies suggest a poorer prognosis than for
conventional mammary carcinomas,9 and some have suggested that the
clinical behavior of these tumors, particularly those that lack or have a
minimal recognizable epithelial component, is more akin to that of sarco-
mas than carcinomas.8
Given the wide range of appearances of spindle cell carcinomas, the
differential diagnosis is broad and includes all of the other spindle cell
lesions discussed in this chapter as well as malignant phyllodes tumors
with prominent stromal overgrowth. It is important to note that a malig-
nant spindle cell tumor of the breast is much more likely to represent a
spindle cell carcinoma or a malignant phyllodes tumor than a sarcoma.
B
FIGURE 11.9 Fibromatosis-like metaplastic carcinoma. A: This spindle cell carcinoma
shows relatively low cellularity and abundant stromal collagen. In addition, the nuclei have
a bland appearance. B: An immunostain for cytokeratin 5/6 confirms the epithelial nature
of these tumor cells.
FIGURE 11.10 Cytokeratin immunostain in spindle cell carcinoma. In this case, only a few
tumor cells show keratin positivity.
As noted earlier, the presence of areas of overt epithelial differentiation

and/or associated DCIS is a valuable clue to the diagnosis of spindle cell
carcinoma. However, in cases without such features, the demonstration of
cytokeratin and/or p63 expression by the neoplastic cells may be required
to arrive at the correct diagnosis. The extent of cytokeratin or p63 expres-
sion needed to categorize a spindle cell lesion as a spindle cell carcinoma
has not been defined. The 2011 WHO Working Group recommended that
unequivocal expression of cytokeratin or p63 in any proportion of cells in
a pure spindle cell lesion is sufficient to categorize the lesion as a spindle
cell carcinoma (Fig. 11.10).10
The key features of spindle cell carcinoma are summarized in Table 11.2.
Table 11.2 Key Features of Spindle Cell Carcinoma
• May consist of a pure population of spindle cells or primarily of spindle

cells admixed with a minor epithelial component (glandular or squamous)
• Foci of overt epithelial differentiation and/or ductal carcinoma in situ are
clues to correct diagnosis
• Appearance of spindle cells ranges from bland (fibromatosis-like) to highly
pleomorphic
• Small component of heterologous elements may be present (especially
chondroid or osseous)
• Diagnosis may require use of a panel of cytokeratin immunostains
B
The spindle cells of fibromatosis show immunostaining for actin;

desmin and S100 protein expression can also be seen, but usually in
only a minority of cells.2 Nuclear expression of β-catenin is seen in about
three-quarters of the cases, and this may be a useful diagnostic adjunct
(Fig. 11.13).22 However, nuclear β-catenin expression is not specific for
fibromatosis and may also be seen in the stromal cells of phyllodes tumors
and in metaplastic carcinomas.23
FIGURE 11.13 Fibromatosis. Immunostain for β-catenin shows nuclear staining of the
tumor cells.
B
A
FIGURE 11.12 Fibromatosis, core-needle biopsy. A: This relatively paucicellular spindle
cell lesion features abundant collagen. Lymphoid infiltrates are present at the edge of the
lesion. B: Higher power view showing the border of the lesion with bland spindle cells in a
collagenous matrix and peripheral lymphoid aggregates.
B
The spindle cells of fibromatosis show immunostaining for actin;

desmin and S100 protein expression can also be seen, but usually in
only a minority of cells.2 Nuclear expression of β-catenin is seen in about
three-quarters of the cases, and this may be a useful diagnostic adjunct
(Fig. 11.13).22 However, nuclear β-catenin expression is not specific for
fibromatosis and may also be seen in the stromal cells of phyllodes tumors
and in metaplastic carcinomas.23
FIGURE 11.13 Fibromatosis. Immunostain for β-catenin shows nuclear staining of the
tumor cells.
Table 11.3 Key Features of Fibromatosis
• Clinical and radiographic appearance may be mistaken for carcinoma

• Bland spindle cells in long, sweeping fascicles
• Infiltration of adjacent tissue with entrapment of breast ducts and lobules
• May be difficult to distinguish histologically from scarring and
fibromatosis-like metaplastic carcinoma
• Nuclear staining for β-catenin may be a useful diagnostic adjunct in
problematic cases
• Wide local excision required to prevent local recurrence
The two lesions that most commonly enter into the differential diag-
nosis of fibromatosis are scarring from prior trauma (including surgery)
and fibromatosis-like metaplastic carcinoma. The presence of hemosiderin
deposition, fat necrosis, histiocytes, and foreign body giant cells and the
absence of long fascicles and entrapment of breast ducts and lobules at the
periphery favor a diagnosis of scar. However, in patients with fibromatosis
who have had prior surgery, it may be difficult or impossible to distinguish
areas of post-surgical scarring from residual fibromatosis, and this may
create particular problems in the assessment of the excision margins.
Arguably the most important differential diagnostic consideration is a
fibromatosis-like metaplastic carcinoma because these lesions are by defini-
tion deceptively bland.17, 18 Useful clues to the diagnosis of fibromatosis-like
metaplastic carcinomas include the identification of foci in which the cells
have an epithelioid appearance and the presence of cytokeratin or p63
expression by the spindle cells.
Other lesions that may enter into the differential diagnosis of fibro-
matosis are nodular fasciitis and spindle cell sarcomas. Features useful in
distinguishing nodular fasciitis from fibromatosis are discussed later (see
the section “Nodular Fasciitis”). Sarcomas are usually more cellular than
fibromatosis and show nuclear pleomorphism and mitotic activity, includ-
ing atypical mitoses.
The major clinical concern in patients with fibromatosis is local
recurrence, which is seen in 20% to 30% of cases. Local recurrences most
often occur within the first 3 years after diagnosis and appear to be associ-
ated with inadequate excision.24
The key features of fibromatosis are summarized in Table 11.3.
Myofibroblastoma
Myofibroblastomas are uncommon benign tumors of the breast. Early
reports suggested that these lesions were more frequent in men than in
women. However, myofibroblastomas have been identified with increas-
ing frequency by screening mammography, and they now appear to occur
equally frequently in females and males.2,25-29 While these lesions occur

over a broad age range, they are seen most often in postmenopausal
women and older men.28 Clinically, myofibroblastomas are typically
slowly growing, circumscribed, mobile masses that are usually mistaken
for fibroadenomas on physical examination and mammography.
Gross examination reveals a rubbery, firm, round, oval, or lobu-
lated nodule, with a bulging, homogenous gray to pink, whorled cut
surface. A variety of patterns may be seen histologically. In the classi-
cal type, the tumor is circumscribed, but does not have a true capsule.
The spindle cells comprising the lesion are uniform in appearance, have
bland oval nuclei, and are arranged as short fascicles admixed with bands
of hyalinized, brightly eosinophilic collagen. Mitoses are usually not
observed. Variable amounts of fat are typically present within the lesion,
as are mast cells and patchy perivascular lymphoplasmacytic infiltrates
(Fig. 11.14, e-Fig. 11.10). The stroma may show myxoid change, smooth
muscle differentiation, or chondroid metaplasia. Several variants of myo-
fibroblastoma have been described.28,29 The collagenized variant features
abundant stromal collagen and little cellularity (Fig. 11.15, e-Fig. 11.11),
whereas in the cellular variant, the ratio of cells to stroma is higher than
in the classical type (Fig. 11.16). An infiltrative variant has been described
in which the tumor margins are irregular and entrap normal mammary
glandular structures and adipose tissue. In the myxoid variant, stromal
myxoid change is particularly prominent. The deciduoid variant is charac-
terized by large cells with abundant cytoplasm arranged in nests or in solid
or trabecular patterns. In the lipomatous variant, the lesion is composed
A
FIGURE 11.14 Myofibroblastoma. A: Low-power view. The tumor border is
circumscribed. Spindle cells, collagen bands, fat, and patchy lymphoid infiltrates are
evident. B: High-power view demonstrates short fascicles of cytologically bland spindle
cells admixed with bands of hyalinized collagen.
B
A
FIGURE 11.15 Myofibroblastoma, collagenized variant. A: Low-power view. As in the
classical type of myofibroblastoma, the tumor is well-circumscribed and consists of
spindle cells, stromal collagen, and adipose tissue. However, this lesion shows more
abundant collagen and less cellularity. B: High-power view shows the predominance of
dense collagen and the relative paucity of spindle cells.
B
FIGURE 11.16 Myofibroblastoma, cellular variant. The ratio of spindle cells to stroma is
higher than that seen in the classical type.
primarily of the adipose tissue component. Finally, some myofibroblasto-

mas are composed partially or predominantly of cells with an epithelioid
appearance arranged in clusters, cords, alveolar groups, and linear strands
(epithelioid variant). When this pattern predominates, the histologic fea-
tures may raise concern for an invasive carcinoma, particularly invasive
lobular carcinoma (Fig. 11.17, e-Fig. 11.12).
B
FIGURE 11.17 Myofibroblastoma, epithelioid variant. A: This medium-power view shows
nests and cords of epithelioid cells in a dense collagenous stroma. B: At high power, the
epithelioid nature of the cells is even more evident. The appearance of strands of epitheli-
oid cells in the stroma in this case simulates invasive lobular carcinoma.
FIGURE 11.18 Myofibroblastoma, CD34 immunostain. The majority of the tumor cells are
CD34 positive.
Cases with nuclear pleomorphism have also been reported (atypical

myofibroblastoma), but cytologic atypia in this setting does not seem to
have clinical importance.
The cells of myofibroblastoma typically show expression of CD34
(Fig. 11.18), vimentin, and desmin, with more variable positivity for actin,
bcl-2, and CD99.28 Expression of estrogen, progesterone, and androgen
receptors is common (Fig. 11.19).2,28-30 Estrogen and progesterone receptor
expression in an epithelioid myofibroblastoma may compound the confu-
sion with invasive carcinoma.
FIGURE 11.19 Myofibroblastoma, estrogen receptor immunostain. Virtually all of the

tumor cells show strong nuclear expression of estrogen receptor.
Table 11.4 Key Features of Myofibroblastoma
• Firm, mobile mass; clinically and radiographically may be mistaken for

fibroadenoma
• Histologically circumscribed, but not encapsulated
• Short fascicles of uniform spindle cells with oval nuclei between bands of
hyalinized collagen
• Variable amounts of fat
• Mast cells and patchy lymphoid infiltrates common
• Variants:
• Collagenized
• Cellular
• Infiltrative
• Myxoid
• Deciduoid
• Lipomatous
• Atypical
• Epithelioid (may mimic invasive carcinoma, particularly lobular carcinoma)
The key features of myofibroblastoma are presented in Table 11.4.

Given the variable appearance of myofibroblastoma, it should not
be surprising that the differential diagnosis is broad and includes a vari-
ety of reactive and benign spindle cell lesions, spindle cell sarcoma, and
carcinoma (Table 11.5).28 A few of these are worthy of particular note.
The histologic features of myofibroblastoma overlap with those of spindle
Table 11.5 Lesions to Consider in the Differential Diagnosis

of Myofibroblastoma
• Reactive and benign spindle cell lesions

• Nodular fasciitis
• Solitary fibrous tumor
• Spindle cell lipoma
• Peripheral nerve sheath tumors
• Smooth muscle tumors
• Fascicular pseudoangiomatous stromal hyperplasia
• Spindle cell sarcomas
• Carcinomas
• Spindle cell/metaplastic carcinoma
• Other types of carcinoma (particularly invasive lobular carcinoma, which
can be mimicked by epithelioid variant of myofibroblastoma)
cell lipoma. Furthermore, these two tumors share genetic abnormalities,

which suggests a close relationship between them.28-31 Pseudoangiomatous
stromal hyperplasia (PASH) may exhibit foci of increased cellularity, with a
fascicular arrangement of myofibroblasts that produces a myofibroblastoma-
like appearance (see Chapter 12). This suggests that PASH and myofibro-
blastomas represent two ends of a spectrum of myofibroblastic lesions.
As with other spindle cell lesions, spindle cell carcinoma should be given
consideration in the differential diagnosis.
Myofibroblastomas are benign and are adequately treated by local
excision.
Nodular Fasciitis
Nodular fasciitis is uncommonly seen in the breast, but is particularly
important to recognize because it may clinically, radiographically, and
histologically mimic a malignant tumor.2 Lesions of nodular fasciitis may
occur either in the subcutaneous tissue of the breast or in the mammary
parenchyma. As in other sites, nodular fasciitis in the breast presents as a
rapidly growing mass that may be painful or tender and disappears spon-
taneously within a few months.
The histologic features are identical to those of nodular fasciitis else-
where. The lesion is generally well-circumscribed, but not encapsulated,
and is composed of plump spindle cells arranged in short fascicles and
whorls. The nuclei have prominent nucleoli, but are relatively uniform in
appearance. Mitotic figures are readily identifiable and may be numerous.
The appearance of these spindle cells (which are fibroblasts and myofi-
broblasts) has been likened to that of fibroblasts grown in tissue culture.
The stroma is typically loose and myxoid and may show cystic change.
Extravasated erythrocytes and patchy lymphoid infiltrates are common
features (Fig. 11.20, e-Fig. 11.13). Lymphoid aggregates may be present,
especially at the periphery of the lesion. The cellularity of the lesions
varies; early lesions are highly cellular, whereas regressing lesions show
less cellularity and more stromal collagen deposition. Mammary ducts
and lobules are usually not present within the lesion. The myofibroblasts
comprising nodular fasciitis typically express actin, but this may be focal.
Desmin expression is also occasionally seen.
The major differential diagnostic considerations are malignant spin-
dle cell tumors (including spindle cell carcinomas and sarcomas) and fibro-
matosis. Nodular fasciitis lacks the nuclear atypia of sarcomas and most
spindle cell carcinomas and does not have the long, sweeping fascicles and
infiltrative edge of fibromatosis. Furthermore, in contrast to spindle cell
carcinomas, the cells of nodular fasciitis lack cytokeratin expression.
Although nodular fasciitis will spontaneously regress, the clinical
presentation of growing mass in the breast virtually always prompts a
biopsy or excision. Local excision is adequate treatment.
The key features of nodular fasciitis are presented in Table 11.6.
B
FIGURE 11.20 Nodular fasciitis. A: Medium-power view illustrates spindle cells in a myx-
oid matrix with foci of extravasated erythrocytes. B: At high power, the spindle cells have
a “tissue culture” appearance and are characterized by vesicular nuclei with prominent
nucleoli. One mitotic figure is evident in this field, but mitoses may be numerous.
Table 11.6 Key Features of Nodular Fasciitis
• Presents clinically as a rapidly growing mass

• Cellularity varies; may be highly cellular
• Plump spindle cells with “tissue culture” appearance growing in short
fascicles and whorls
• Mitotic figures may be numerous
• Stroma typically myxoid with extravasated erythrocytes and patchy
lymphoid infiltrates; regressing lesions show variable collagenization
Spindle Cell Sarcomas

When a spindle cell sarcoma is identified in the breast, it is more likely
to represent the stromal component of a malignant phyllodes tumor than
a pure sarcoma. Therefore, the histologic identification of a spindle cell
sarcoma should prompt careful evaluation of the lesion for the presence
of an epithelial component, which, in turn, will lead to the diagnosis of
malignant phyllodes tumor.
Among the pure sarcomas of the breast, the most common is angio-
sarcoma (see Chapter 12). Other types of sarcoma may also rarely be seen.
In addition, sarcomas from other sites may rarely metastasize to the breast.
Other Lesions with Spindle Cell Morphology

In some adenomyoepitheliomas, the myoepithelial cells have a predomi-
nantly or exclusively spindle cell appearance (see Chapter 8). In addition,
in some cases of PASH, myofibroblastic proliferation is prominent and
may resemble areas seen in myofibroblastoma (see Chapter 12). Finally,
some non-sarcomatous malignant tumors metastatic to the breast may
have a spindle cell appearance, such as sarcomatoid renal cell carcinoma
and malignant melanoma.
References
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2. McMenamin ME, DeSchryver K, Fletcher CD. Fibrous lesions of the breast: a review. Int
J Surg Pathol. 2000;8(2):99-108.
3. Tse GM, Tan PH, Lui PC, Putti TC. Spindle cell lesions of the breast—the pathologic
differential diagnosis. Breast Cancer Res Treat. 2008;109(2):199-207.
4. Lee AH. Recent developments in the histological diagnosis of spindle cell carcinoma,
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Breast Pathology. Philadelphia, PA: W.B. Saunders; 2009:375-390.
6. Wargotz ES, Deos PH, Norris HJ. Metaplastic carcinomas of the breast. II. Spindle cell
carcinoma. Hum Pathol. 1989;20(8):732-740.
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nitions for biphasic and monophasic sarcomatoid mammary carcinomas. Semin Diagn
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8. Davis WG, Hennessy B, Babiera G, et al. Metaplastic sarcomatoid carcinoma of the
breast with absent or minimal overt invasive carcinomatous component: a misnomer.
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Pathol. 2006;30(3):300-309.
10. Reis-Filho JS, Lakhani SR, Gobbi H, Sneige N. Metaplastic carcinoma. In: Lakhani SR,
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metaplastic spindle cell carcinoma, phyllodes tumor and fibromatosis of the breast. Hum
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14. Reis-Filho JS, Milanezi F, Steele D, et al. Metaplastic breast carcinomas are basal-like
tumours. Histopathology. 2006;49(1):10-21.
15. Schmitt F, Tan PH, Dabbs D, Jones L. Myoepithelial and epithelial-myoepithelial
lesions. In: Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ, eds. WHO
16. Weigelt B, Kreike B, Reis-Filho JS. Metaplastic breast carcinomas are basal-like breast
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12
Vascular Lesions
Vascular lesions of the breast are a heterogeneous group. Most can be

readily categorized histologically as benign or malignant. However, vascu-
lar lesions with atypical but not frankly malignant features have also been
described. This chapter discusses the spectrum of vascular lesions that occur
in the breast as well as pseudoangiomatous stromal hyperplasia (PASH), a
lesion with a histologic appearance that simulates a vascular lesion.
Benign Vascular Lesions

Benign vascular lesions of the mammary parenchyma are relatively
uncommon and several categories have been recognized including peri-
lobular hemangioma, hemangioma (capillary, cavernous, and complex
types), venous hemangioma, and angiomatosis. In addition, a variety of
benign vascular lesions can involve the mammary subcutaneous tissue.1-4
The major clinical importance of these lesions is that they must be
distinguished from angiosarcoma. In general, benign vascular lesions are
circumscribed and lack the interanastomosing channels and the endothe-
lial proliferation and atypia that characterize angiosarcomas.5 However,
some angiosarcomas have areas that are extremely well-differentiated and
simulate benign blood vessels. Conversely, some benign vascular lesions
may show atypical cytologic or architectural features.6 For these reasons,
the distinction between a benign vascular lesion and low-grade angiosar-
coma may be impossible if the lesion is not completely excised or has only
been sampled by a core-needle biopsy.
Perilobular hemangiomas are the most common vascular lesions
of the breast. Their reported frequency ranges from as low as 1.2% to as
high as 11% of breast specimens.7,8 They are capillary hemangiomas that
are, by definition, of microscopic size and identified incidentally. They
consist of a circumscribed collection of small, thin-walled, variably ectatic
vascular spaces lined by relatively inconspicuous, flattened endothelial
cells that lack cytologic atypia. Despite their designation as “perilobular,”
387
they may involve the intralobular stroma, interlobular stroma, or both

(Fig. 12.1, e-Fig. 12.1). Rarely, perilobular hemangiomas exhibit endothe-
lial cell atypia (“atypical perilobular hemangioma”).1
Hemangiomas are benign vascular lesions that are large enough to be
detected clinically or mammographically.1 In general, they are microscopi-
cally well-circumscribed and lack endothelial cell atypia. However, in some
cases, vessels extend into the surrounding breast parenchyma or adipose
B
FIGURE 12.1 Perilobular hemangioma. A: Low-power view demonstrating a circumscribed
collection of small, ectatic blood vessels in association with a lobule. B: At high power, the
thin vessel walls and inconspicuous nature of the endothelial cells are apparent. This lesion
was an incidental microscopic finding.
Vascular Lesions ——— 389
tissue, which produces a worrisome appearance resembling low-grade

angiosarcoma. Mammary hemangiomas have been subcategorized as cav-
ernous (featuring dilated blood vessels filled with erythrocytes), capillary
(characterized by compact, sometimes lobular collections of small blood
vessels that resemble a pyogenic granuloma), and complex (composed of a
mixture of dilated vessels as seen in the cavernous type and small vessels as
seen in the capillary type) (Fig. 12.2, e-Fig. 12.2). As with vascular lesions
in other sites, thrombosis may occur; organizing thrombi may exhibit
B
FIGURE 12.2 Hemangioma, capillary type. A: This lesion was large enough to be detected
as a mammographic density and is composed of erythrocyte-filled small blood vessels in
the inter- and intralobular stroma and adipose tissue. B: The vessels are discrete without
interanastomoses and are lined by an inconspicuous endothelial cell layer.
apillary endothelial hyperplasia, which produces a pattern that may be

p
misinterpreted as an angiosarcoma (Fig. 12.3).9 In addition, some lesions
with features otherwise characteristic of benign hemangiomas exhibit
atypical changes, such as endothelial cell atypia or focally anastomosing
vascular channels (“atypical hemangiomas”).6
Venous hemangiomas are rare lesions consisting of vascular
structures that contain muscular walls of varying thickness. Again, the
B
FIGURE 12.3 Papillary endothelial hyperplasia. A: Low-power view of a breast core-needle
biopsy showing a circumscribed nodule that consists of a large blood vessel containing
an organizing thrombus with papillary endothelial cell hyperplasia. B: High-power view
of an area of papillary endothelial cell hyperplasia demonstrating a complex pattern of
anastomosing blood vessels with prominent, hyperchromatic endothelial cells that could
be mistaken for a low-grade angiosarcoma.
endothelial cells lining these spaces are relatively inconspicuous and lack
cytologic atypia.4
Angiomatosis is also a rare lesion composed of dilated, anastomosing
vascular spaces that are similar to angiomatoses in other sites. The walls of
these spaces may contain sparse, smooth muscle fibers and lymphocytes.
Endothelial cell atypia is not present (Fig. 12.4, e-Fig. 12.3). Although
these are benign lesions, they extend around mammary ducts and lobules
and often involve large areas of the breast. In addition, angiomatosis lacks
FIGURE 12.4 Angiomatosis. A: Scanning magnification demonstrates anastomosing

vascular structures dissecting through the mammary stroma. B: At high power, the
endothelial cells are flattened and lack cytologic atypia.
the circumscription that characterizes most other benign vascular lesions,

and the distinction from a low-grade angiosarcoma may be difficult.2
Angiosarcoma
Angiosarcomas are the most frequent primary sarcomas of the breast, but
are still very uncommon and account for <0.05% of breast malignancies.
They may arise spontaneously (primary angiosarcoma) or following radia-
tion therapy for breast cancer (secondary angiosarcoma). Although angio-
sarcomas that develop after radiation may involve the mammary skin,
breast parenchyma, or both, cutaneous angiosarcomas are more common
than those involving the mammary parenchyma in the post-radiation set-
ting.10-13 Angiosarcomas may also arise in the arm following radical mas-
tectomy as the result of chronic lymphedema (Stewart-Treves syndrome);
however, this is rarely seen in current practice where radical mastectomies
are uncommonly performed.14
The age range at presentation of patients with angiosarcomas is
broad, but patients with primary angiosarcomas are usually younger
(median age 35 to 40 years) than those with post-radiation angiosarcomas
(median age 59 to 69 years).
Angiosarcomas of the mammary parenchyma present as a painless
mass; those that involve the skin may appear as areas of blue or violaceous
discoloration.
On gross examination, the tumors range in size from <1 cm to
>20 cm; most cases are >2 cm. Angiosarcomas most often appear as hem-
orrhagic masses (Fig. 12.5); larger tumors may have areas of necrosis or
cystic degeneration. Smaller lesions may not appear grossly hemorrhagic.
On microscopic examination, angiosarcomas are characterized by
interanastomosing vascular spaces that dissect through the mammary
FIGURE 12.5 Angiosarcoma. This hemorrhagic mass involves the mammary parenchyma
and extends into the overlying skin.
stroma and adipose tissue and surround and invade lobules, disrupting the
normal lobular architecture. The vascular spaces are lined by endothelial
cells that show nuclear hyperchromasia. Variable degrees of stromal eryth-
rocyte extravasation are present. In many angiosarcomas, the vascular
spaces at the invasive edge of the tumor may appear extremely bland and
may be difficult to distinguish from benign blood vessels.
Angiosarcomas have been divided into low, intermediate, and high
grade based on a combination of histologic features (Table 12.1).5 Low-
grade angiosarcomas are characterized by well-formed, anastomosing vas-
cular channels that contain varying numbers of erythrocytes. Endothelial
cell nuclear hyperchromasia is present, but mitoses are absent or scant.
Papillary endothelial cell tufting and solid areas are absent (Figs. 12.6 and
12.7, e-Fig. 12.4). Some low-grade angiosarcomas are composed of vessels
that have a capillary-like appearance. Intermediate-grade lesions show
increased cellularity with endothelial cell tufts and papillary formations
and/or the presence of solid spindle cell foci with few or no vascular lumi-
na. Mitotic figures may be present in the more cellular areas (Fig. 12.8).
High-grade angiosarcomas exhibit prominent tufts and papillations com-
posed of cytologically malignant endothelial cells with readily identifiable
mitoses. Solid spindle cell areas with little or no vascular lumen formation
are often present, as are foci of stromal hemorrhage (“blood lakes”) and
necrosis (Fig. 12.9, e-Fig. 12.5). In some high-grade angiosarcomas, the
endothelial cells have an epithelioid appearance, and these lesions may be
difficult to distinguish from carcinomas (Fig. 12.10).15 It should be noted
that the grade may vary within a given lesion.
In the past, grading of angiosarcomas was thought to have prognos-
tic importance. In the most widely cited study to address the relationship
between grade and outcome, the 5-year survival was 76%, 70%, and 15% for
low-, intermediate-, and high-grade angiosarcomas, respectively.16 However,
TABLE 12.1 Histologic Features Used for Grading Angiosarcomas
Angiosarcoma Grade
Feature Low Intermediate High
Endothelial tufting Minimal Present Prominent

Papillary formations Absent Focal Prominent
Solid and spindle cell foci Absent Absent/minimal Present
Mitoses Rare/absent Present in Numerous
papillary areas
Blood lakes Absent Absent Present
Necrosis Absent Absent Present
Modified from Donnell RM, Rosen PP, Lieberman PH, et al. Angiosarcoma and other
vascular tumors of the breast. Am J Surg Pathol. 1981;5(7):629-642.
B
FIGURE 12.6 Angiosarcoma, low grade. A: Well-formed, interanastomosing vascular spaces
are apparent. Erythrocyte extravasation is present in the stroma. B: The endothelial cells
lining the vascular channels show mild nuclear hyperchromasia, but there is no evidence of
endothelial cell tufting.
a more recent study failed to demonstrate a relationship between grade of

angiosarcoma and outcome, similar to angiosarcomas at other sites.17
Angiosarcomas require complete excision and are most often treated
by mastectomy. Axillary lymph node involvement is rare. The most common
sites of metastatic spread are the lungs, liver, contralateral breast, other skin
and soft tissue locations, and bone.13 The prognosis is generally poor, with a
B
FIGURE 12.7 Angiosarcoma, low grade. A: This photograph illustrates the invasive edge
of the lesion, consisting of well-formed vascular structures. B: At high power, these blood
vessels are difficult to distinguish from normal vessels.
median recurrence-free survival rate less than 3 years and a median overall
survival less than 6 years.13 Some authors have reported that the prognosis
of post-irradiation angiosarcomas is worse than that of primary angiosarco-
mas, but all series are limited by the small numbers of patients.18
Several features of post-radiation angiosarcomas of the breast merit
particular comment. The interval between radiation and the development
FIGURE 12.8 Angiosarcoma, intermediate grade. This tumor consists of a combination of

well-formed vascular spaces and more solid spindle cell areas.
A
FIGURE 12.9 Angiosarcoma, high grade. A: Low-power view illustrating a relatively
solid cellular proliferation and areas of stromal hemorrhage (“blood lakes”). A few poorly
formed vascular structures are present at the lower right. B: High-power view demon-
strates endothelial cell tufting and papillary structures. The endothelial cells have enlarged,
vesicular nuclei with prominent nucleoli.
B
A
FIGURE 12.10 High-grade angiosarcoma, epithelioid type. A: The tumor cells have a
polygonal appearance and form cords and nests simulating a carcinoma. B: Immunostain
for cytokeratin showing absence of tumor cell staining. C: Immunostain for CD31 showing
intense tumor cell positivity.
C
of angiosarcoma is substantially shorter (median 5 to 6 years) than that

noted for other radiation-related malignancies in which the time between
irradiation and malignancy is often 10 years or more.13 Some post-
radiation angiosarcomas have developed within ≤2 years after radiation.
In addition, although all grades of angiosarcoma have been recognized
in this setting, most have intermediate- or high-grade areas. Further,
the degree of nuclear atypia in these lesions is often out of proportion
to the structural grade of the lesion (Fig. 12.11).10 Finally, recent studies
have shown that post-radiation angiosarcomas commonly show MYC
amplification.19-21 This feature appears to distinguish these lesions from
non–radiation-associated angiosarcomas and from atypical vascular
lesions, both of which lack amplification of this oncogene.20,21 Whether
identification of MYC amplification will be of value diagnostically for
B
FIGURE 12.11 Post-irradiation cutaneous angiosarcoma. A: Irregularly shaped, intercon-
necting vessels are present in the dermal collagen. B: Although the vascular structures are
relatively well-formed, the endothelial cells are highly atypical.
istinguishing post-radiation angiosarcomas from atypical vascular lesions

d
in histologically ambiguous cases remains to be determined.
Although the diagnosis of angiosarcoma is straightforward in most
cases, diagnostic problems may arise. Differential diagnostic considerations
for low-grade angiosarcomas include hemangiomas of various types,
angiolipomas, papillary endothelial hyperplasia, atypical vascular lesions,
and PASH. It has been suggested that the Ki67 proliferation rate can be used
to distinguish between low-grade angiosarcoma and hemangioma in prob-
lematic cases.22 While the Ki67 proliferation rate is significantly higher for
low-grade angiosarcomas as a group than for hemangiomas as a group, the
utility of Ki67 staining in making this distinction in an individual case is less
certain. High-grade angiosarcomas, particularly those in which the endothe-
lial cells have a more epithelioid appearance, may be difficult to distinguish
from carcinomas. In addition, as described in Chapter 11, some spindle cell
carcinomas demonstrate pseudovascular spaces that may mimic angiosar-
coma. In problematic cases, immunostains for endothelial markers (such as
factor VIII–related antigen, CD31, CD34, and D2-40) and epithelial markers
(such as cytokeratin) may be necessary to distinguish between angiosarcoma
and carcinoma. It should be noted, however, that some angiosarcomas
exhibit cytokeratin expression; therefore, cytokeratin antibodies should
never be used in isolation in this setting. Finally, high-grade angiosarcomas
may be difficult to distinguish from other types of spindle cell sarcoma.
Atypical Vascular Lesions

Atypical vascular lesions have been described in the skin of the breast and,
less frequently, the mammary parenchyma in women who have been treated
with conservative surgery and radiation therapy for breast cancer.10,23-27
These lesions typically present as small papules or plaques with pink, red,
or brown discoloration. The atypical vascular lesions originally described
by Fineberg and Rosen are characterized by a relatively circumscribed col-
lection of dilated vascular spaces in the dermis that often have complex,
branching contours and interanastomosing areas. Dissection between bun-
dles of dermal collagen may be focally present. The vascular spaces are most
often lined by a single layer of plump endothelial cells that have prominent
nuclei. However, prominent nucleoli and mitotic figures are absent. Some of
the vascular spaces contain thin projections of stroma covered by endothelial
cells. Erythrocytes are rarely seen within these vascular spaces, and red blood
cell extravasation into the surrounding dermis is not present. In addition, a
chronic inflammatory cell infiltrate is often present, although this may be
sparse in some cases (Fig. 12.12). Subsequent authors have divided atypical
vascular lesions into a lymphatic type and a vascular type.26 The lymphatic
type, which is more common, is similar to the original atypical vascular
lesions of Fineberg and Rosen.23 The less common vascular type is composed
of small, irregularly dispersed, often blood-filled, capillary-sized vessels lined
by prominent endothelial cells and surrounded by pericytes. These lesions
superficially resemble capillary hemangiomas, but the vessels do not have a
lobulocentric configuration and may show endothelial cell atypia.26
Diagnostic criteria useful for distinguishing between atypical vascular
lesions and cutaneous angiosarcoma are presented in Table 12.2. However,
some cases may defy definitive categorization.10,25,26 As noted above,
MYC amplification has been reported to be present in post-radiation
angiosarcomas but not in atypical vascular lesions,20,21 but in our view it is
B
FIGURE 12.12 Atypical vascular lesion of skin following radiation therapy for breast
cancer (lymphatic type). A: Low-power view illustrates dilated, branching vascular spaces
within the dermal collagen. B: The endothelial cells lining these spaces are plump, but
there is no nuclear hyperchromasia; cellular tufting is absent.
premature to use the presence or absence of MYC amplification to make

this distinction in routine clinical practice at present.
The natural history and malignant potential of atypical vascular
lesions that lack criteria for the diagnosis of angiosarcoma are unknown.
Although most patients reported to date have had a benign clinical course,
up to one-third of patients develop additional lesions, and rare instances
of progression to angiosarcoma have been observed.10,23,25-27
TABLE 12.2 Criteria to Distinguish between Cutaneous Angiosarcoma

and Atypical Vascular Lesionsa
Atypical Vascular
Angiosarcoma Lesion
Relative circumscription Absent Present
Interanastomosing vessels Present May be present
Dissection of dermal collagen Present Absent or focally
present
Infiltration of subcutaneous tissue Present May be present
Blood lakes Present (high-grade Absent
lesions)
Stromal projections into lumen Absent Present
Chronic inflammation May be present Present
Cytologic features
Papillary endothelial hyperplasia Present Absent
Cytologic atypia Mild, moderate, or Absent to mild
marked
Prominent nucleoli Present Absent
Mitotic figures Present Absent
a
These features are most useful for distinguishing between angiosarcoma and the
lymphatic type of atypical vascular lesions.23,26
Modified from Fineberg S, Rosen PP. Cutaneous angiosarcoma and atypical vascular
lesions of the skin and breast after radiation therapy for breast carcinoma. Am J
Clin Pathol. 1994;102(6):757-763 and Rosen PP. Rosen’s Breast Pathology. 3rd ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2009.
Pseudoangiomatous stromal hyperplasia (PASH)

PASH is a benign myofibroblastic proliferation that simulates a vascular
lesion.28-30 It is commonly seen as an incidental microscopic finding in
breast biopsies but may present as a palpable or radiographic mass.31 In one
study, at least one focus of PASH was identified in 23% of breast speci-
mens.29 PASH may also be seen in association with other breast lesions,
particularly fibroadenomas and phyllodes tumors, and is commonly pres-
ent in conjunction with gynecomastia. Almost all female patients are
premenopausal. The association of PASH with gynecomastia and the
preferential occurrence in premenopausal women suggest that hormonal
factors may be involved in the development and/or growth of these lesions.
On gross examination, PASH that presents as a palpable or mam-
mographic mass appears as a circumscribed, smooth nodule that on cut
section has a homogeneous tan to gray appearance. The slit-like spaces
that characterize fibroadenomas are not seen.
Microscopic examination reveals complex interanastomosing spaces

in a dense collagenous, keloid-like stroma. Some of the spaces have
spindle-shaped myofibroblasts at their margins that simulate endothelial
cells. The spaces are usually empty but may contain a few erythrocytes
(Fig. 12.13, e-Fig. 12.6). Occasionally, multinucleated giant cells are
B
FIGURE 12.13 Pseudoangiomatous stromal hyperplasia. A: At low power, slit-like, anasto-
mosing spaces are present in dense collagenous stroma. B: Myofibroblasts are present at
the edges of the spaces and resemble endothelial cells.
resent in the stroma (Fig. 12.14), and cytologic atypia and mitotic activ-
p
ity of the myofibroblasts may rarely be seen; the clinical significance of
these findings is uncertain.32 In some cases, the myofibroblasts aggregate
into fascicles and may produce patterns similar or identical to areas seen
in myofibroblastomas, an appearance that has been termed fascicular
PASH (Fig. 12.15, e-Fig. 12.7). Ducts present in areas of PASH may
show micropapillary hyperplasia of the epithelium similar to that seen in
gynecomastia.31
B
FIGURE 12.14 Pseudoangiomatous stromal hyperplasia (PASH) with multinucleated
myofibroblasts A: This lesion has features typical of PASH, but in this case occasional
cells lining the cleft-like spaces show multinucleation (arrow). B: High-power view of a
multinucleated myofibroblast.
The myofibroblasts of PASH show staining for vimentin and usually

for CD34; they are variably reactive for smooth muscle actin and desmin.
These cells commonly exhibit nuclear reactivity for progesterone receptor,
but not estrogen receptor.
B
FIGURE 12.15 Pseudoangiomatous stromal hyperplasia (PASH) with cellular foci.
A: In this case, in addition to foci of typical PASH, there is an area in which the
myofibroblasts aggregate into fascicles (lower left). B: At high power, the fascicular
focus has an appearance resembling areas seen in myofibroblastomas.
PASH is a benign lesion that is adequately treated by local excision.

Patients with a diagnosis of PASH on a core-needle biopsy do not require
surgical excision, provided that the diagnosis of PASH is concordant
with the findings on imaging studies.31 A recent follow-up study demon-
strated that patients with PASH do not have an increase in their risk of
subsequent breast cancer.33 The major importance of PASH is that it must
be distinguished histologically from a true vascular lesion, specifically,
angiosarcoma.
References
1. Jozefczyk MA, Rosen PP. Vascular tumors of the breast. II. Perilobular hemangiomas
and hemangiomas. Am J Surg Pathol. 1985;9(7):491-503.
2. Rosen PP. Vascular tumors of the breast. III. Angiomatosis. Am J Surg Pathol.
1985;9(9):652-658.
3. Rosen PP. Vascular tumors of the breast. V. Nonparenchymal hemangiomas of mam-
mary subcutaneous tissues. Am J Surg Pathol. 1985;9(10):723-729.
4. Rosen PP, Jozefczyk MA, Boram LH. Vascular tumors of the breast. IV. The venous
hemangioma. Am J Surg Pathol. 1985;9(9):659-665.
5. Donnell RM, Rosen PP, Lieberman PH, et al. Angiosarcoma and other vascular tumors
of the breast. Am J Surg Pathol. 1981;5(7):629-642.
6. Hoda SA, Cranor ML, Rosen PP. Hemangiomas of the breast with atypical histological
features. Further analysis of histological subtypes confirming their benign character. Am
J Surg Pathol. 1992;16(6):553-560.
7. Rosen PP, Ridolfi RL. The perilobular hemangioma. A benign microscopic vascular
lesion of the breast. Am J Clin Pathol. 1977;68(1):21-23.
8. Lesueur GC, Brown RW, Bhathal PS. Incidence of perilobular hemangioma in the
female breast. Arch Pathol Lab Med. 1983;107(6):308-310.
9. Branton PA, Lininger R, Tavassoli FA. Papillary endothelial hyperplasia of the breast:
the great impostor for angiosarcoma: a clinicopathologic review of 17 cases. Int J Surg
Pathol. 2003;11(2):83-87.
10. Weaver J, Billings SD. Postradiation cutaneous vascular tumors of the breast: a review.
11. Fraga-Guedes C, Gobbi H, Mastropasqua MG, Botteri E, Luini A, Viale G. Primary and
secondary angiosarcomas of the breast: a single institution experience. Breast Cancer
Res Treat. 2011;132(3):1081-1088.
12. Scow JS, Reynolds CA, Degnim AC, Petersen IA, Jakub JW, Boughey JC. Primary
and secondary angiosarcoma of the breast: the Mayo Clinic experience. J Surg Oncol.
2010;101(5):401-407.
13. Fletcher CFS, MacGrogan G. Angiosarcoma. In: Lakhani SR, Ellis IO, Schnitt SJ, Tan
PH, van de Vijver MJ, eds. WHO Classification of Tumours of the Breast. Lyon: IARC
Press 2012;135-136.
14. Heitmann C, Ingianni G. Stewart-Treves syndrome: lymphangiosarcoma following mas-
tectomy. Ann Plast Surg. 2000;44(1):72-75.
15. Macias-Martinez V, Murrieta-Tiburcio L, Molina-Cardenas H, Dominguez-Malagon H.
Epithelioid angiosarcoma of the breast. Clinicopathological, immunohistochemical, and
ultrastructural study of a case. Am J Surg Pathol. 1997;21(5):599-604.
16. Rosen PP, Kimmel M, Ernsberger D. Mammary angiosarcoma. The prognostic
significance of tumor differentiation. Cancer. 1988;62(10):2145-2151.
17. Nascimento AF, Raut CP, Fletcher CD. Primary angiosarcoma of the breast: clinicopath-
ologic analysis of 49 cases, suggesting that grade is not prognostic. Am J Surg Pathol.
2008;32(12):1896-1904.
18. Luini A, Gatti G, Diaz J, et al. Angiosarcoma of the breast: the experience of the
European Institute of Oncology and a review of the literature. Breast Cancer Res Treat.
2007;105(1):81-85.
19. Manner J, Radlwimmer B, Hohenberger P, et al. MYC high level gene amplification is
a distinctive feature of angiosarcomas after irradiation or chronic lymphedema. Am J
Pathol. 2010;176(1):34-39.
20. Guo T, Zhang L, Chang NE, Singer S, Maki RG, Antonescu CR. Consistent MYC and
FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-
associated atypical vascular lesions. Genes Chromosomes Cancer. 2011;50(1):25-33.
21. Mentzel T, Schildhaus HU, Palmedo G, Buttner R, Kutzner H. Postradiation cutaneous
angiosarcoma after treatment of breast carcinoma is characterized by MYC amplifica-
tion in contrast to atypical vascular lesions after radiotherapy and control cases: clini-
copathological, immunohistochemical and molecular analysis of 66 cases. Mod Pathol.
2012;25(1):75-85.
22. Shin SJ, Lesser M, Rosen PP. Hemangiomas and angiosarcomas of the breast: diag-
nostic utility of cell cycle markers with emphasis on Ki-67. Arch Pathol Lab Med.
2007;131(4):538-544.
23. Fineberg S, Rosen PP. Cutaneous angiosarcoma and atypical vascular lesions of
the skin and breast after radiation therapy for breast carcinoma. Am J Clin Pathol.
1994;102(6):757-763.
24. Requena L, Kutzner H, Mentzel T, Duran R, Rodriguez-Peralto JL. Benign vascular
proliferations in irradiated skin. Am J Surg Pathol. 2002;26(3):328-337.
25. Brenn T, Fletcher CD. Radiation-associated cutaneous atypical vascular lesions and
angiosarcoma: clinicopathologic analysis of 42 cases. Am J Surg Pathol. 2005;29(8):
983-996.
26. Patton KT, Deyrup AT, Weiss SW. Atypical vascular lesions after surgery and radiation
of the breast: a clinicopathologic study of 32 cases analyzing histologic heterogeneity
and association with angiosarcoma. Am J Surg Pathol. 2008;32(6):943-950.
27. Gengler C, Coindre JM, Leroux A, et al. Vascular proliferations 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. 2007;109(8):
1584-1598.
28. Vuitch MF, Rosen PP, Erlandson RA. Pseudoangiomatous hyperplasia of mammary
stroma. Hum Pathol. 1986;17(2):185-191.
29. Ibrahim RE, Sciotto CG, Weidner N. Pseudoangiomatous hyperplasia of mam-
mary stroma. Some observations regarding its clinicopathologic spectrum. Cancer.
1989;63(6):1154-1160.
30. Powell CM, Cranor ML, Rosen PP. Pseudoangiomatous stromal hyperplasia (PASH).
A mammary stromal tumor with myofibroblastic differentiation. Am J Surg Pathol.
1995;19(3):270-277.
31. Ferreira M, Albarracin CT, Resetkova E. Pseudoangiomatous stromal hyperplasia tumor:
a clinical, radiologic and pathologic study of 26 cases. Mod Pathol. 2008;21(2):201-207.
Wilkins; 2009.
33. Degnim AC, Frost MH, Radisky DC, et al. Pseudoangiomatous stromal hyperplasia and
breast cancer risk. Ann Surg Oncol. 2010;17(12):3269-3277.
13
Other Mesenchymal Lesions
Most pathologic entities in the breast arise from the epithelium. However,
the components of the mammary stroma may also give rise to various
lesions which, in general, are similar in appearance to comparable lesions
seen at other sites.
Many benign and malignant mesenchymal lesions that occur else-
where in the body have been described in the breast. Only those more
frequent or important from the point of view of differential diagnosis are
described in this chapter.
Benign Mesenchymal Lesions

Lipoma
Lipomas of the breast present clinically and radiographically as circum-
scribed soft tissue masses. Given that adipose tissue is a normal compo-
nent of breast stroma and can be abundant, a diagnosis of lipoma of the
breast is difficult in the absence of a low-power appearance of a nodule
of mature adipose tissue surrounded by a capsule. In fact, we rarely make
this diagnosis in our clinical practice.
Angiolipomas also occur in the breast. As for angiolipomas else-
where, the distinguishing feature is the presence within a lipomatous tumor
of small blood vessels containing fibrin thrombi within a delicate fibrous
stroma (Fig. 13.1, e-Fig. 13.1). Cellular angiolipomas are characterized by
a cellular spindle cell proliferation in which the vessels may be collapsed
and difficult to appreciate and in which the adipose tissue component
may be sparse (Fig. 13.2).1,2 In addition, these lesions can exhibit cytologic
atypia and rare mitoses.2 The appearance of blood vessels in adipose tis-
sue as seen in angiolipomas may raise the concern for a vascular lesion,
including angiosarcoma, particularly in core-needle biopsy samples. Often
excision is required to render a definitive diagnosis, particularly for cellular
angiolipoma.2 Other lipoma variants, such as fibrolipoma and spindle cell
lipoma, have also been described in the breast.3
408
Other Mesenchymal Lesions ——— 409
B
FIGURE 13.1 Angiolipoma. A: The tumor is composed of mature adipocytes with an admix-
ture of small blood vessels within a fibrous stroma. B: The presence of fibrin thrombi in the
vessels is a characteristic feature.
It should be noted that lipomatous tumors submitted to the

athologist as specimens from the breast are, in fact, frequently from the
p
subcutaneous tissue overlying the breast rather than from the mammary
parenchyma per se.
B
FIGURE 13.2 Cellular angiolipoma. A: In this core-needle biopsy specimen, the tumor has
a vaguely lobulated border (lower left corner) and is composed of bland spindle cells and
small blood vessels. No adipose tissue component is evident. B: On higher power view,
many fibrin thrombi are apparent within blood vessel lumina.
Some authors have described adenolipomas in which normal mam-

mary glandular structures are incorporated within the substance of an
apparent lipoma. These lesions are probably better categorized as hamar-
tomas (see Chapter 6).
Granular Cell Tumor

Granular cell tumors are uncommonly found in the breast but, when
present, can simulate carcinoma on clinical examination, imaging studies,
and gross pathologic examination.4-6 These tumors occur more commonly
in African-American than in Caucasian women6,7 and typically appear
between puberty and menopause, implicating hormonal factors in their
development. Granular cell tumors of the breast most commonly occur
in the upper, inner quadrant in contrast to carcinomas, which occur most
frequently in the upper, outer quadrant. Patients present with a palpable
mass that may be associated with skin retraction or fixation to skeletal
muscles of the chest wall.
Gross examination reveals a gray-white to tan firm tumor that may
be gritty when cut; these features further give the impression of carcinoma.
Microscopically, these lesions are identical to granular cell tumors in other
sites, consisting of a poorly circumscribed, infiltrative proliferation of cells in
which the most characteristic feature is prominent granularity of the cyto-
plasm (Fig. 13.3, e-Fig. 13.2). Upon electron microscopic examination, these
granules correspond to secondary lysosomes. The nuclei are small and uni-
form and lack the features of malignancy. The differential diagnosis of granu-
lar cell tumor includes fat necrosis and other processes with an accumulation
of histiocytes (such as duct ectasia), as well as invasive carcinomas. Granular
cell tumors are positive for S100 protein (Fig. 13.3), negative for cytokeratin,
and negative for estrogen receptor and progesterone receptor expression.
A
FIGURE 13.3 Granular cell tumor. A: Cells with abundant eosinophilic granular cytoplasm
infiltrate the breast tissue. Note the compressed duct at the center of this field. B: High-
power view demonstrates the small nuclei and cytoplasmic granularity that characterize
the cells comprising this lesion. C: S100 protein immunostain demonstrates strong tumor
cell reactivity.
C
Granular cell tumors are almost invariably benign and are ade-
quately treated by local excision.6 Rare cases of malignant granular cell
tumors have been reported in both the breast and extramammary sites.
Although initially considered to be myogenic in nature (hence, their
earlier designation as granular cell myoblastomas), ultrastructural and
immunohistochemical evidence has proven that these are of neurogenic
origin.4,8
Neural Lesions
Neurofibromas and neurilemomas (Schwannomas) are benign nerve
sheath tumors that are most frequently seen in the breast in patients with
neurofibromatosis and are most common in the areolar area (e-Fig. 13.3).9
Other benign neural tumors that have been described in the breast include
neurothekeoma10 and nerve sheath myxoma.11 Diagnostic difficulty does
not usually arise in excisional biopsy specimens, but core-needle biopsy
specimens may pose a problem due to sampling limitations.
Myxoma
Myxomas are benign mesenchymal lesions that can rarely occur in the
breast. Grossly, myxomas are well-circumscribed lesions with a glistening
cut surface. On microscopic examination, there is an abundant, hypo-
cellular myxoid stroma containing scattered spindle cells with vesicular
nuclei and scant cytoplasm (Fig. 13.4).12 The importance of this lesion is
in its association with Carney complex.13 Myxomas may pose a diagnostic
problem when sampled by core-needle biopsy. The major differential diag-
nostic considerations include mucinous carcinoma, mucocele-like lesion,
fibroadenoma with myxoid stroma, and the myxoid variant of nodular
fasciitis. Some metaplastic carcinomas may also show a myxoid stroma
and this possibility should be ruled out with cytokeratin and p63 immu-
nostains when necessary.
Inflammatory Myofibroblastic Tumor
Inflammatory myofibroblastic tumor may rarely present as a breast mass.
Grossly, these lesions are usually firm, circumscribed nodules that have a
gray-white to yellow cut surface. On histologic examination, bland myo-
fibroblasts are arrayed in interlacing fascicles with admixed lymphocytes
and plasma cells.14,15 The tumor cells are positive for smooth muscle actin
and negative for cytokeratin. These tumors have rarely been reported to
recur following inadequate excision.14 Other spindle cell lesions of the
breast, in particular, spindle cell carcinoma, are the main differential diag-
nostic considerations.
Other Benign Mesenchymal Neoplasms
Leiomyomas are uncommon in the breast but can occur in the region
of the nipple16 and even more rarely in the substance of the breast.17,18
Chondrolipomatous, chondro-osseous, and osseous tumors are very rare.19
These latter tumors are composed entirely of mature mesenchymal tissue,
although normal mammary epithelium may occasionally be incorporated
within them.
Periductal Stromal Sarcoma
These rare, low-grade, biphasic tumors are characterized by a proliferation
of stromal spindle cells around benign epithelial components.20 While this
B
FIGURE 13.4 Myxoma. A: This circumscribed nodule is composed largely of myxoid
ground substance. No glands are present, which is a feature that distinguishes this lesion
from a fibroadenoma with prominent myxoid stromal change. B: Higher power view
demonstrates scattered spindle cells and a few blood vessels in the myxoid stroma.
lesion is thought to be related to phyllodes tumor, it lacks the architectural

organization associated with those tumors. Periductal stromal sarcoma
most commonly presents as a breast mass in perimenopausal or post-
menopausal women. Histologically, the tumor appears multinodular, with
the stromal proliferation cuffing ducts and lobules in a pericanalicular
growth pattern (Fig 13.5). Myxomatous change in the stromal component

can occur.21 Infiltration of the stromal cells into the surrounding adipose
tissue is often present. Cytologic atypia and mitotic figures (≥3/10 high-
power fields) can be seen in the stromal component. Local recurrences
have been observed among the few cases reported; as such excision with
negative margins is recommended.20 Lesions with the architectural fea-
tures described above but in which the stromal cells lack cytologic atypia
and have a mitotic count <3/10 high-power fields have been termed peri-
ductal stromal hyperplasia.20
B
FIGURE 13.5 Periductal stromal sarcoma. A: A cellular stromal proliferation surrounds
ducts and lobules and extends into the adjacent adipose tissue. B: At higher power, cyto-
logic atypia and mitotic figures can be seen in the stromal component.
Malignant Mesenchymal Lesions (Primary Breast

Sarcomas)
Primary sarcomas of the breast other than angiosarcomas are extremely
rare.22-24 Some sarcomas arise in the chest wall and secondarily involve the
breast, particularly those that develop following irradiation; these may be
mistaken for primary breast sarcomas.
A sarcomatous-appearing tumor in the breast is far more likely to be
a metaplastic carcinoma or a malignant phyllodes tumor than a primary
sarcoma. Therefore, before concluding that any breast tumor is a primary
sarcoma, efforts should be made to exclude metaplastic carcinoma by
extensively sampling the tumor to identify foci of conventional invasive
mammary carcinoma and/or ductal carcinoma in situ and by performing
immunostains using multiple anticytokeratin antibodies (see Chapter 11).
The possibility of phyllodes tumor should be excluded by extensively
examining the lesion to identify the benign epithelial component that
characterizes these lesions.
After angiosarcoma, the second most common type of primary mam-
mary sarcoma is liposarcoma.24,25 However, virtually any type of sarcoma
that occurs elsewhere in the body may occur in the breast as a primary
lesion, including fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma,
malignant peripheral nerve sheath tumor, and osteosarcoma (Fig. 13.6,
e-Fig. 13.4).22-24,26 In addition, metastatic sarcomas from other sites may be
A
FIGURE 13.6 Osteosarcoma of the breast. A: This tumor consists of a poorly defined
proliferation of spindle and epithelioid cells with abundant osteoid formation. Extensive
sectioning failed to demonstrate a benign epithelial component, which is the key feature
distinguishing this lesion from a phyllodes tumor with osteosarcomatous differentiation.
In addition, the neoplastic cells were cytokeratin-negative, which is a feature useful in
distinguishing this lesion from a metaplastic carcinoma. B: High-power view demonstrates
the neoplastic cells and osteoid production.
B
encountered in the breast, including synovial sarcoma. These sarcomatous

lesions are all histologically similar to those encountered in other loca-
tions. Recently, a lesion termed mammary not otherwise specified–type
sarcoma was described, characterized by expression of CD10 and, in
some cases, myoepithelial markers.27
References
1. Kahng HC, Chin NW, Opitz LM, Pahuja M, Goldberg SL. Cellular angiolipoma of the
breast: immunohistochemical study and review of the literature. Breast J. 2002;8(1):
47-49.
2. Kryvenko ON, Chitale DA, VanEgmond EM, Gupta NS, Schultz D, Lee MW.
Angiolipoma of the female breast: clinicomorphological correlation of 52 cases. Int J
Surg Pathol. 2011;19(1):35-43.
3. Smith DN, Denison CM, Lester SC. Spindle cell lipoma of the breast. A case report.
Acta Radiol. 1996;37(6):893-895.
4. Damiani S, Dina R, Eusebi V. Eosinophilic and granular cell tumors of the breast. Semin
Diagn Pathol. 1999;16(2):117-125.
5. Scaranelo AM, Bukhanov K, Crystal P, Mulligan AM, O’Malley FP. Granular cell tumour
of the breast: MRI findings and review of the literature. Br J Radiol. 2007;80(960):
970-974.
6. Papalas JA, Wylie JD, Dash RC. Recurrence risk and margin status in granular cell
tumors of the breast: a clinicopathologic study of 13 patients. Arch Pathol Lab Med.
2011;135(7):890-895.
7. Adeniran A, Al-Ahmadie H, Mahoney MC, Robinson-Smith TM. Granular cell tumor of
the breast: a series of 17 cases and review of the literature. Breast J. 2004;10(6):528-531.
8. Ingram DL, Mossler JA, Snowhite J, Leight GS, McCarty KS Jr. Granular cell tumors
of the breast. Steroid receptor analysis and localization of carcinoembryonic antigen,
myoglobin, and S100 protein. Arch Pathol Lab Med. 1984;108(11):897-901.
9. Bongiorno MR, Doukaki S, Arico M. Neurofibromatosis of the nipple-areolar area: a
case series. J Med Case Reports. 2010;4:22.
10. Mertz KD, Mentzel T, Grob M, Pfaltz M, Kempf W. A rare case of atypical cellular neu-
rothekeoma in a 68-year-old woman. J Cutan Pathol. 2009;36(11):1210-1214.
11. Wee A, Tan CE, Raju GC. Nerve sheath myxoma of the breast. A light and electron
microscopic, histochemical and immunohistochemical study. Virchows Arch A Pathol
Anat Histopathol. 1989;416(2):163-167.
12. Magro G, Cavanaugh B, Palazzo J. Clinico-pathological features of breast myxoma:
report of a case with histogenetic considerations. Virchows Arch. 2010;456(5):581-586.
13. Carney JA, Toorkey BC. Myxoid fibroadenoma and allied conditions (myxomatosis) of
the breast. A heritable disorder with special associations including cardiac and cutane-
ous myxomas. Am J Surg Pathol. 1991;15(8):713-721.
14. Khanafshar E, Phillipson J, Schammel DP, Minobe L, Cymerman J, Weidner N.
Inflammatory myofibroblastic tumor of the breast. Ann Diagn Pathol. 2005;9(3):
123-129.
15. Hill PA. Inflammatory pseudotumor of the breast: a mimic of breast carcinoma. Breast
J. 2010;16(5):549-550.
16. Nascimento AG, Karas M, Rosen PP, Caron AG. Leiomyoma of the nipple. Am J Surg
Pathol. 1979;3(2):151-154.
17. Boscaino A, Ferrara G, Orabona P, Donofrio V, Staibano S, De Rosa G. Smooth muscle
tumors of the breast: clinicopathologic features of two cases. Tumori. 1994;80(3):
241-245.
18. Minami S, Matsuo S, Azuma T, et al. Parenchymal leiomyoma of the breast: a case report
with special reference to magnetic resonance imaging findings and an update review of
literature. Breast Cancer. 2011;18(3):231-236.
19. Lugo M, Reyes JM, Putong PB. Benign chondrolipomatous tumors of the breast. Arch
Pathol Lab Med. 1982;106(13):691-692.
20. Burga AM, Tavassoli FA. Periductal stromal tumor: a rare lesion with low-grade sarco-
matous behavior. Am J Surg Pathol. 2003;27(3):343-348.
21. Tomas D, Jankovic D, Marusic Z, Franceschi A, Mijic A, Kruslin B. Low-grade periduc-
tal stromal sarcoma of the breast with myxoid features: Immunohistochemistry. Pathol
Int. 2009;59(8):588-591.
22. Adem C, Reynolds C, Ingle JN, Nascimento AG. Primary breast sarcoma: clinico-
pathologic series from the Mayo Clinic and review of the literature. Br J Cancer.
2004;91(2):237-241.
23. Callery CD, Rosen PP, Kinne DW. Sarcoma of the breast. A study of 32 patients with
reappraisal of classification and therapy. Ann Surg. 1985;201(4):527-532.
24. Surov A, Holzhausen HJ, Ruschke K, Spielmann RP. Primary breast sarcoma: preva-
lence, clinical signs, and radiological features. Acta Radiol. 2011;52(6):597-601.
25. Austin RM, Dupree WB. Liposarcoma of the breast: a clinicopathologic study of 20
cases. Hum Pathol. 1986;17(9):906-913.
26. Silver SA, Tavassoli FA. Primary osteogenic sarcoma of the breast: a clinicopathologic
analysis of 50 cases. Am J Surg Pathol. 1998;22(8):925-933.
27. Leibl S, Moinfar F. Mammary NOS-type sarcoma with CD10 expression: a rare entity
with features of myoepithelial differentiation. Am J Surg Pathol. 2006;30(4):450-456.
14
Miscellaneous Rare Lesions
A wide variety of reactive, benign, and malignant lesions occurring else-

where in the body have been described in the breast. This chapter will
focus on a few of these rare entities that are well-documented and that
must be distinguished from more commonly encountered breast lesions.
Amyloid Tumor
Amyloid deposits may be seen in the breast of patients with predisposing
systemic diseases. Primary amyloid tumors limited to the breast are rare.1
Patients present with a painless mass, which is typically 2 to 3 cm in size.
Grossly, amyloid tumors are usually single nodules that have a firm, gray
or white, shiny cut surface. Microscopic examination reveals the char-
acteristic eosinophilic, homogenous deposits of amyloid in fibroadipose
tissue, in vessel walls, and in and around ducts and lobules. The latter
is associated with atrophy and obliteration of these glandular elements.
Calcifications may be present.1,2 Careful clinical evaluation is required
to distinguish between primary and secondary amyloid deposition.
Treatment is by excisional biopsy.
Wegener Granulomatosis
Wegener granulomatosis presenting in the breast is unusual. Most
patients have other evidence of this systemic disease. Within the breast,
Wegener granulomatosis usually presents as a tender mass that may
involve the overlying skin, which suggests inflammatory carcinoma.
If a surgical excision is performed, the typical features of necrotizing
vasculitis are seen, along with acute and chronic inflammation of the
breast stroma. Areas of infarction may be present with granulomas at the
periphery of the infarcted areas.3,4 This lesion must be distinguished from
419
other more common causes of inflammation and granuloma formation

(see Chapter 2).
Tumors Of Lymphoid And Hematopoietic Cells

Lymphoma
Lymphomas in the breast may be due to secondary involvement by dis-
seminated lymphoma or may represent a primary lesion. Secondary mam-
mary involvement by lymphoma should be excluded before a diagnosis of
primary breast lymphoma is made.
Primary lymphomas of the breast are uncommon, accounting for
<1% of all malignant mammary neoplasms. They typically appear grossly
as circumscribed masses, with a tan-white, fleshy cut surface. Foci of hem-
orrhage or necrosis may be present.
On histologic examination, primary breast lymphomas are almost
always of non-Hodgkin type, but Hodgkin disease may rarely involve the
breast as well.5,6 Among the non-Hodgkin lymphomas, diffuse large B-cell
lymphoma is the most common type.5,7,8 but other categories of lympho-
mas have also been reported to occur as primary lesions in the breast
including Burkitt lymphoma (which may present with massive bilateral
breast enlargement),5 extranodal marginal B-cell lymphomas arising from
mucosa-associated lymphoid tissue (MALT lymphomas),5,9,10 follicular
lymphomas (Fig. 14.1, e-Fig. 14.1), lymphoblastic lymphomas, T-cell
lymphomas,11 and most recently implant-associated anaplastic large cell
lymphomas (ALCLs; see subsequent text).12-16
Large cell lymphomas must be distinguished from poorly differenti-
ated carcinomas, including invasive carcinomas with medullary features.
In addition, some lymphomas have an appearance reminiscent of the solid
variant of invasive lobular carcinoma.17 In cases in which the lymphoma
cells are arranged in a linear pattern or cords, the appearance may resem-
ble the classical type of invasive lobular carcinoma. In problematic cases,
immunostains for lymphoid and epithelial markers and hormone recep-
tors are valuable adjuncts for arriving at the correct diagnosis. Low-grade
lymphomas must be distinguished from chronic inflammatory infiltrates,
such as those seen in lymphocytic mastopathy (see Chapter 2) and from
intramammary lymph nodes.
Implant-associated ALCL is a recently described primary T-cell
lymphoma of the breast occurring in women with prosthetic implants.12-16
Patients typically present with a late-onset seroma or capsule-associated
contracture. The median age at presentation is 51 years (range 28 to 87
years), with a median time to development of ALCL of 8 years (range
1 to 23 years) following implant placement. There does not appear to
be a predilection for a particular implant type (i.e., saline vs. silicone;
textured vs. smooth) or with the indication for the implant. Microscopic
examination of the seroma fluid or the fibrous capsule reveals proliferation
of a relatively cohesive population of large, pleomorphic blasts. ALCL is
Miscellaneous Rare Lesions ——— 421
B
FIGURE 14.1 Primary breast lymphoma, B-cell, follicular type. A: A nodular lymphoid
infiltrate is present and involves the interlobular and intralobular stroma. B: High-power
view shows a mixture of centrocytes and centroblasts.
composed of cells of T-cell or null lineage with expression of CD30 and

is further subcategorized based on the presence or absence of expression
of anaplastic lymphoma kinase (ALK). The vast majority of implant-
associated ALCLs are ALK-negative.12 Once the diagnosis is certain,
removal of the implant is recommended. Limited data suggest that this
lymphoma is relatively indolent, though there are reports of cases with an
TABLE 14.1 Key Features of Primary Breast Lymphoma
• Diagnosis should not be made unless secondary mammary involvement by

disseminated lymphoma is excluded
• Grossly appears as circumscribed nodules with tan-white, fleshy cut surface
• Diffuse large B-cell lymphoma most common type
• Distinction from carcinoma may be problematic
• The growth pattern of some lymphomas may simulate solid or classical
variants of invasive lobular carcinoma
• Large cell lymphomas may be difficult to distinguish from poorly
differentiated carcinomas (including carcinomas with medullary features)
• Immunostains for epithelial and lymphoid markers and hormone
receptors are of value in distinguishing carcinoma from lymphoma in
problematic cases
• Low-grade lymphomas must be distinguished from chronic inflammatory
infiltrates
• Anaplastic large cell lymphomas reported in association with breast implants
aggressive clinical course. It is important to exclude systemic ALCL before

rendering a diagnosis of implant-associated ALCL; the former scenario
may account for some of the cases with a more aggressive clinical course.18
The key features of primary breast lymphomas are summarized in
Table 14.1.
Plasma Cell Dyscrasias
The breast may be involved in patients with multiple myeloma either as a
manifestation of disseminated disease or as local extension from a lesion
in an adjacent rib. Solitary extramedullary plasmacytomas of the breast
may also occur. These lesions present as a circumscribed tan, brown mass
that may range in size from 2 to 4 cm.19 Histologic findings are the same as
those seen in neoplastic plasma cell proliferations elsewhere in the body.
Rosai–Dorfman Disease
The rare occurrence of this lesion within the breast has been well-docu-
mented.20,21 Patients present with a breast mass that may mimic carcinoma
clinically and radiologically. Axillary lymph node involvement has also been
reported.21 On gross examination, the breast tissue contains single or multiple
nodules with circumscribed to lobulated borders that on cut section show a
gray-tan surface. Histologically, the lesions are composed of poorly defined,
sometimes multinodular aggregates of large histiocytes with an associated
polymorphous background of mature lymphocytes and plasma cells. Many
of the histiocytes exhibit lymphophagocytosis. Differential diagnostic con-
siderations include granulomatous mastitis as well as other histiocytic pro-
cesses.20 Patients with this disease usually have an indolent clinical course.
Other Hematopoietic Lesions

Infrequently, the breast is involved by leukemia of either lymphoid or
myeloid types. Involvement by chronic lymphocytic leukemia (CLL)/small
lymphocytic lymphoma (SLL) may be mistaken for chronic inflammatory
cell infiltrates (Fig. 14.2, e-Fig. 14.2). Further, involvement of the breast
and/or axillary lymph nodes by CLL/SLL may occur in women with inva-
sive breast cancer in which case the two lesions coexist (Fig. 14.3).
FIGURE 14.2 Chronic lymphocytic leukemia involving the breast. A: At low power, there
are stromal aggregates of lymphocytes that could be mistaken for chronic inflammation.
B: High-power view demonstrates the uniform population of small lymphocytes charac-
teristic of chronic lymphocytic leukemia.
B
FIGURE 14.3 Chronic lymphocytic leukemia/small lymphocytic lymphoma and invasive
lobular carcinoma. A: At low power, there are stromal aggregates of small lymphocytes
adjacent to the characteristic single-file infiltration pattern of invasive lobular carcinoma.
B: At high power, the cells comprising the carcinoma are readily apparent as is the
monotonous appearance of the small lymphocytes.
The term pseudolymphoma, as in other organs, has been used to

describe a florid reactive inflammatory cell infiltrate characterized by a
polymorphic lymphoid cell population with germinal center formation.22,23
Immunohistochemistry or flow cytometry may be helpful in demonstrating
the polyclonal nature of the cells, which distinguishes this process from a
lymphoma.
Extramedullary hematopoiesis has been reported in the breast in
patients with myelofibrosis and myeloid metaplasia (Fig. 14.4, e-Fig. 14.3)
and in the nipple fluid of infants presenting with bloody nipple discharge.24
Recent reports have noted the occurrence of extramedullary hematopoiesis
in the breast and axillary lymph nodes following neoadjuvant chemother-
apy for breast cancer.25,26
Cutaneous Appendageal and Salivary Gland–Type

Tumors
A variety of benign and malignant tumors similar in appearance to tumors
of the skin appendages and salivary glands have been reported to occur
in the breast.27 Among cutaneous appendageal-type tumors, in addi-
tion to syringomatous lesions (see Chapter 15), there have been reports
of eccrine spiradenoma, eccrine acrospiroma, clear cell hidradenoma,
apocrine hidradenoma, and syringocystadenoma papilliferum, as well as
tumors with sebaceous differentiation, including sebaceous carcinomas.28
A
FIGURE 14.4 Extramedullary hematopoiesis. A: At medium power, there is a cellular
infiltrate in the mammary stroma and adipose tissue. B: High-power view demonstrates
erythroid and myeloid precursors and a megakaryocyte. This patient had myelofibrosis
with myeloid metaplasia.
B
With regard to salivary gland–type tumors, in addition to pleomorphic

adenomas (see Chapter 8), adenoid cystic carcinomas (see Chapter 10),
and myoepithelial lesions, acinic cell carcinomas and mucoepidermoid
carcinomas have been reported to occur in the breast.29,30
Melanocytic Lesions
Benign and malignant melanocytic lesions may occur in the skin of the
breast as at any other site. When a pigmented lesion is located on the skin
of the nipple-areolar complex, care must be taken to exclude Paget dis-
ease because the cells of this disorder may acquire melanin pigment (see
Chapter 15). There have been a few reports of primary malignant mela-
nomas of the breast as well as tumors of the breast that show combined
features of invasive ductal carcinoma and malignant melanoma. In addi-
tion, the cells of conventional invasive mammary carcinomas that invade
the skin and disrupt the dermoepidermal junction may contain melanin
pigment. However, most melanocytic tumors of the breast are metastases
from malignant melanoma arising in extramammary sites.31
References
1. Luo JH, Rotterdam H. Primary amyloid tumor of the breast: a case report and review of
the literature. Mod Pathol. 1997;10(7):735-738.
2. McMahon RF, Connolly CE. Amyloid breast tumor. Am J Surg Pathol. 1987;11(6):488.
3. Jordan JM, Rowe WT, Allen NB. Wegener’s granulomatosis involving the breast. Report
of three cases and review of the literature. Am J Med. 1987;83(1):159-164.
4. Veerysami M, Freeth M, Carmichael AR, Carmichael P. Wegener’s granulomatosis of the

breast. Breast J. 2006;12(3):268-270.
5. Gholam D, Bibeau F, El Weshi A, Bosq J, Ribrag V. Primary breast lymphoma. Leuk
Lymphoma. 2003;44(7):1173-1178.
6. Brustein S, Filippa DA, Kimmel M, Lieberman PH, Rosen PP. Malignant lymphoma of
the breast. A study of 53 patients. Ann Surg. 1987;205(2):144-150.
7. Brogi E, Harris NL. Lymphomas of the breast: pathology and clinical behavior. Semin
Oncol. 1999;26(3):357-364.
8. Talwalkar SS, Miranda RN, Valbuena JR, Routbort MJ, Martin AW, Medeiros LJ.
Lymphomas involving the breast: a study of 106 cases comparing localized and dissemi-
nated neoplasms. Am J Surg Pathol. 2008;32(9):1299-1309.
9. Cohen PL, Brooks JJ. Lymphomas of the breast. A clinicopathologic and immunohisto-
chemical study of primary and secondary cases. Cancer. 1991;67(5):1359-1369.
10. Lamovec J, Jancar J. Primary malignant lymphoma of the breast. Lymphoma of the
mucosa-associated lymphoid tissue. Cancer. 1987;60(12):3033-3041.
11. Gualco G, Chioato L, Harrington WJ Jr, Weiss LM, Bacchi CE. Primary and second-
ary T-cell lymphomas of the breast: clinico-pathologic features of 11 cases. Appl
Immunohistochem Mol Morphol. 2009;17(4):301-306.
12. Popplewell L, Thomas SH, Huang Q, Chang KL, Forman SJ. Primary anaplastic
large-cell lymphoma associated with breast implants. Leuk Lymphoma. 2011;52(8):
1481-1487.
13. Li S, Lee AK. Silicone implant and primary breast ALK1-negative anaplastic large cell
lymphoma, fact or fiction? Int J Clin Exp Pathol. 2009;3(1):117-127.
14. Thompson PA, Lade S, Webster H, Ryan G, Prince HM. Effusion-associated anaplastic
large cell lymphoma of the breast: time for it to be defined as a distinct clinico-patholog-
ical entity. Haematologica. 2010;95(11):1977-1979.
15. Miranda RN, Lin L, Talwalkar SS, Manning JT, Medeiros LJ. Anaplastic large cell
lymphoma involving the breast: a clinicopathologic study of 6 cases and review of the
literature. Arch Pathol Lab Med. 2009;133(9):1383-1390.
16. de Jong D, Vasmel WL, de Boer JP, et al. Anaplastic large-cell lymphoma in women with
breast implants. JAMA. 2008;300(17):2030-2035.
17. Bobrow LG, Richards MA, Happerfield LC, et al. Breast lymphomas: a clinicopathologic
review. Hum Pathol. 1993;24(3):274-278.
18. Aladily TN, Medeiros LJ, Alayed K, Miranda RN. Breast implant-associated anaplastic
large cell lymphoma: a newly recognized entity that needs further refinement of its defi-
nition. Leuk Lymphoma. 2012;53(4):749-750.
19. Taylor L, Aziz M, Klein P, Mazumder A, Jagannath S, Axelrod D. Plasmacytoma in
the breast with axillary lymph node involvement: a case report. Clin Breast Cancer.
2006;7(1):81-84.
20. Green I, Dorfman RF, Rosai J. Breast involvement by extranodal Rosai-Dorfman disease:
report of seven cases. Am J Surg Pathol. 1997;21(6):664-668.
21. Tenny SO, McGinness M, Zhang D, Damjanov I, Fan F. Rosai-Dorfman disease present-
ing as a breast mass and enlarged axillary lymph node mimicking malignancy: a case
report and review of the literature. Breast J. 2011;17(5):516-520.
22. Lin JJ, Farha GJ, Taylor RJ. Pseudolymphoma of the breast. I. In a study of 8,654 con-
secutive tylectomies and mastectomies. Cancer. 1980;45(5):973-978.
23. Salman WD, Al-Dawoud A, Howat AJ, Twaij Z. Lymphoid tissue in the breast: a histo-
logical conundrum. Histopathology. 2007;51(4):572-573.
24. Pampal A, Gokoz A, Sipahi T, Dogan H, Ergur AT. Bloody nipple discharge in 2 infants
with interesting cytologic findings of extramedullary hematopoiesis and hemophagocy-
tosis. J Pediatr Hematol Oncol. 2012;34(3):229-231.
25. Wang J, Darvishian F. Extramedullary hematopoiesis in breast after neoadjuvant chemo-

therapy for breast carcinoma. Ann Clin Lab Sci. 2006;36(4):475-478.
26. Millar EK, Inder S, Lynch J. Extramedullary haematopoiesis in axillary lymph nodes
following neoadjuvant chemotherapy for locally advanced breast cancer—a potential
diagnostic pitfall. Histopathology. 2009;54(5):622-623.
27. Sapino A, Sneige N, Eusebi V, Michal M. Salivary gland/skin, adnexal type carcinoma.
In: Lakhani S, Ellis I, SJ S, Tan P-H, van de Vijver MJ, eds. WHO Classification of
Tumors of the Breast. Lyon: IARC Press 2012;55.
28. Panico L, D’Antonio A, Chiacchio R, Delrio P, Petrella G, Pettinato G. An unusual,
recurring breast tumor with features of eccrine spiradenoma: a case report. Am J Clin
Pathol. 1996;106(5):665-669.
29. Foschini MP, Krausz T. Salivary gland-type tumors of the breast: a spectrum of benign
and malignant tumors including “triple negative carcinomas” of low malignant potential.
30. Sapino A, Sneige N, Eusebi V. Mucoepidermoid carcinoma. In: Lakhani S, Ellis I, SJ S,
Tan P-H, Van de Vijver MJ, eds. WHO Classification of Tumors of the Breast. Lyon:
IARC Press 2012;58.
31. Ellis IO, Collins LC, Ichihara S, MacGrogan G. Invasive carcinomas of no special type.
In: Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ, eds. WHO Classification
of Tumors of the Breast. Lyon: IARC Press 2012;34-38.
15
Nipple Disorders
The nipple can be affected by a variety of inflammatory and neoplastic

conditions that affect the skin, cutaneous appendages, and subcutane-
ous tissue elsewhere in the body. In addition, accessory (supernumerary)
nipples may be found anywhere along the milk lines, which in embryonic
life extend from the axilla to the groin. These accessory nipples consist
microscopically of normal nipple components, including lactiferous ducts
and smooth muscle, and may also contain mammary glandular tissue in
the deep dermis.
The remainder of this chapter will focus on the most clinically
important disorders of the nipple. Normal anatomy and histology of the
nipple is discussed in Chapter 1.
Squamous Metaplasia of Lactiferous

Ducts (SMOLD)
The keratinizing squamous epithelium of the skin normally invaginates
into the nipple duct orifices for approximately 1 to 2 mm (Fig. 15.1,
e-Fig. 15.1). However, if this epithelium extends more deeply into a
nipple duct, keratin may accumulate, filling and obstructing the duct
and creating a lesion analogous to an epidermal inclusion cyst. Rupture
of the duct will result in the extrusion of keratinaceous debris into
the stroma, eliciting a foreign body giant cell inflammatory reaction.
Secondary bacterial colonization and infection may occur. This condi-
tion, known as SMOLD (also known as Zuska disease and recurrent
subareolar abscess), presents as a red and painful mass near the nipple
that may be interpreted clinically to be an abscess.1 It may occur at any
age and is highly associated with a history of smoking. Antibiotic ther-
apy and/or incision and drainage procedures are generally ineffective.
Treatment requires complete excision of the affected duct or ducts, with
429
FIGURE 15.1 Keratinizing squamous epithelium extending into the superficial aspect of
a lactiferous duct. This is a normal finding. However, extension of squamous epithelium
more deeply into lactiferous ducts can result in keratin accumulation and duct obstruction,
setting the stage for duct rupture and stromal inflammation.
wedge resection of the nipple. Failure to adequately excise the area may
result in multiple recurrences or formation of a fistulous tract.1,2
The initial surgical procedure in patients with SMOLD is often inci-
sion and drainage of a presumptive abscess. Specimens from this type of
procedure typically consist of fragments of subareolar breast tissue, with
or without subcutaneous tissue and/or skin, and show a mixed inflam-
matory infiltrate and foreign body giant cell reaction. Areas of abscess
formation may be present. The findings of inflammation and foreign body
giant cell reaction are not specific. However, in the appropriate clinical
context, these findings should raise the suspicion of SMOLD and should
prompt careful histologic evaluation for the presence of keratinaceous
debris within the inflammatory infiltrate and for ducts with squamous
metaplasia and/or intraluminal keratin, which are the defining features of
this disorder. Diagnostic features of SMOLD are more often seen in sub-
sequent excision specimens than in specimens from incision and drainage
procedures because more tissue is available for histologic examination
(Figs. 15.2–15.4, e-Figs. 15.2–15.5). The key features of SMOLD are sum-
Nipple Disorders ——— 431
FIGURE 15.2 Squamous metaplasia of lactiferous ducts (SMOLD). In this example of

SMOLD, squamous metaplasia is evident in several nipple ducts. The duct to the left of
center is filled with and distended by keratinaceous material.
FIGURE 15.3 Squamous metaplasia of lactiferous ducts. The epithelium of this large
duct shows squamous metaplasia, and there are intraluminal flakes of keratin and
inflammatory cells. The surrounding stroma shows acute and chronic inflammation
(courtesy of Dr. Susan Lester).
B
FIGURE 15.4 High-power view of subareolar breast tissue from an incision and drainage
procedure from a patient who presented clinically with what was thought to be a
subareolar abscess. A subsequent excision demonstrated diagnostic features of squamous
metaplasia of lactiferous ducts (SMOLD). A: This specimen shows an inflammatory infiltrate
composed of neutrophils, plasma cells, lymphocytes, and foreign body giant cells. Although
these findings are not specific, they should raise the possibility of SMOLD in the appropriate
clinical setting (courtesy of Dr. Susan Lester). B: In this case, a few keratin flakes can be
identified in the inflammatory cell infiltrate (arrows).
TABLE 15.1 Key Features of Squamous Metaplasia of Lactiferous

Ducts
• May occur at any age

• Highly associated with history of smoking
• Squamous metaplasia of duct epithelium; keratin in duct lumens
• Mixed stromal inflammatory infiltrate with foreign body giant cell reaction;
abscess formation may be present
• Keratinaceous debris may be present in stromal inflammatory infiltrate
Nipple Adenoma
Nipple adenoma is a relatively uncommon entity that may be mistaken
for carcinoma. The condition has also been called florid papillomatosis
of the nipple, florid adenomatosis, subareolar duct papillomatosis, and
erosive adenomatosis. It is most common in the fifth to six decades,
but may be seen in women of any age and also occurs in men. Patients
present with soreness, ulceration, and swelling of the nipple and occa-
sionally with discharge; the clinical presentation may simulate Paget
disease.3,4
The gross appearance is usually that of an ill-defined, firm nod-
ule. Microscopically, nipple adenomas have a wide range of histologic
appearances. In general, these lesions are characterized by a relatively
circumscribed proliferation of benign glands and ducts in a variably
fibrotic stroma (Fig. 15.5, e-Fig. 15.6). The glands may grow in an
adenosis-like pattern characterized by a proliferation of relatively
simple glands or they may be expanded and distorted by prominent
papillary hyperplasia and/or usual ductal hyperplasia. The hyperplasia
sometimes has gynecomastoid features, and foci of necrosis may be seen
(Figs. 15.6–15.8, e-Figs. 15.7–15.10). Apocrine metaplasia or squamous
metaplasia may be present. Stromal sclerosis around glands or in assoc
iation with papillary intraductal hyperplasia may result in epithelial
entrapment and distortion and a pseudoinfiltrative pattern. However,
as with other benign lesions, the glands and ducts of nipple adeno-
mas are surrounded by a myoepithelial cell layer. Rosen and Caicco4
described three distinct growth patterns of nipple adenoma: adenosis,
papillomatosis, and sclerosing papillomatosis. However, these are often
mixed and do not appear to have any prognostic significance. Of note,
glandular epithelium may extend onto the surface of the nipple, replac-
ing the squamous epithelium and producing clinically an erythematous,
eroded appearance that may be mistaken for Paget disease (Fig. 15.9,
e-Fig. 15.11). The key histologic features of nipple adenoma are sum-
B
FIGURE 15.5 Nipple adenoma. A: Scanning magnification. Within the nipple stroma,
there is a relatively well-circumscribed collection of ducts with varying degrees of epithelial
hyperplasia. B: Higher power view illustrates usual ductal hyperplasia in one of these ducts.
B
FIGURE 15.6 Nipple adenoma. A: This lesion shows both an adenosis pattern (left) and a
papillomatosis pattern (right). B: Higher power view of adenosis-like area showing variably
distorted glands in a fibrotic stroma.
FIGURE 15.7 Nipple adenoma with prominent papillary hyperplasia of duct epithelium.
The lesion is benign, but recurrence may be seen if incompletely

excised. Occasional cases of coexistent or subsequent carcinoma have
been reported.4,5 The criteria used to identify in situ or invasive carcinoma
in association with a nipple adenoma are the same as those used else-
where in the breast.
A
FIGURE 15.8 A: In this nipple adenoma, many of the glands show gynecomastoid
hyperplasia. B: Higher power view of gynecomastoid hyperplasia.
B
Nipple adenomas with a prominent adenotic pattern need to

be distinguished from tubular carcinomas and from syringomatous
adenomas. Distinction from tubular carcinoma may be aided in prob-
lematic cases by immunostaining for myoepithelial cells, which are
present around the glands and ducts of nipple adenomas, but not
FIGURE 15.9 Nipple adenoma. In this lesion, glandular epithelium extends to the surface
of the nipple, replacing the squamous epithelium.
TABLE 15.2 Key Features of Nipple Adenoma
• Most common in fifth and sixth decades, but can occur at any age
• Relatively circumscribed glandular proliferation involving nipple stroma
• Glands may be simple and grow in an adenosis-like pattern and/or show
varying degrees of papillary hyperplasia and/or usual ductal hyperplasia
• Stromal fibrosis may entrap glandular epithelium resulting in a
pseudoinfiltrative pattern
• Glandular epithelium may extend onto the nipple surface, replacing
squamous epithelium and clinically simulating Paget disease
carcinomas. The distinction of nipple adenoma from syringomatous

adenoma is discussed below. Those nipple adenomas showing promi-
nent papillary hyperplasia with marked ductal expansion must be dis-
tinguished from a central intraductal papilloma. The latter is confined
to a single dilated lactiferous duct and is more well-circumscribed than
a nipple adenoma.
Syringomatous Adenoma
This rare tumor typically presents as a mass in the nipple and/or subareo-
lar region. The reported age range of patients with this lesion is broad;
the average age is about 40 years. Histologically, the lesion is composed
of an infiltrative proliferation of small glandular or tubular structures,
solid islands or cords of cells, and squamous nests and cysts, set within a
fibrous stroma that can show myxoid or hyaline change. The glands often
have angulated contours, a teardrop shape, or comma-shaped extensions,
similar to that seen in syringomatous tumors of the skin and salivary
glands (Figs. 15.10 and 15.11, e-Figs. 15.12–15.14). Although the glands
may be composed of two or more cell layers, a definite myoepithelial
cell layer cannot be identified. The cells have small, uniform nuclei, and
mitotic figures are not usually evident. Infiltration between nipple ducts
and smooth muscle bundles is characteristic, and the infiltrating glands
may extend into the subareolar breast tissue. Perineural invasion may be
seen.6,7 The key features of syringomatous adenoma are summarized in
Table 15.3.
Despite their infiltrative nature, these lesions behave in a benign
manner, and patients with syringomatous adenoma appear to be ade-
quately treated with complete local excision. However, this may require
removal of the entire nipple.
Syringomatous adenomas share histological features with low-
grade adenosquamous carcinomas;8,9 whether these two lesions repre-
sent the same or different processes is an unresolved issue. The major
B
FIGURE 15.10 Syringomatous adenoma. A: Low-power view demonstrating numerous
small ducts and glands infiltrating between lactiferous ducts and through smooth muscle
bundles. B: Some of the glands are ovoid, whereas others have irregular contours and
comma-like extensions.
istinguishing feature is the location in the breast: syringomatous

d
adenomas arise in the nipple and may secondarily involve subareolar
breast tissue, whereas low-grade adenosquamous carcinomas arise more
peripherally in the breast parenchyma and rarely involve the subareolar
breast tissue or nipple.4,5 One possible explanation for this difference in
FIGURE 15.11 Syringomatous adenoma. Most of the epithelium of this gland shows
squamous metaplasia.
anatomic distribution is that syringomatous adenomas actually represent

lesions arising in cutaneous appendages of the nipple-areolar complex,
whereas low-grade adenosquamous carcinomas represent tumors of the
mammary parenchyma per se.
Syringomatous adenoma may also be confused with tubular carci-
noma. The presence of ovoid glands with tapering ends and the presence
of associated ductal carcinoma in situ (DCIS) characterize tubular carci-
noma, whereas irregularly shaped glands, squamous metaplasia, and the
absence of associated DCIS are features that characterize syringomatous
adenoma. Finally, syringomatous adenomas are distinguished from nipple
adenomas by their infiltrative pattern, the characteristic shape of the
glands, the presence of squamous cysts, the lack of prominent epithelial
hyperplasia and papillomatosis, and the absence of extension onto the
skin surface.
TABLE 15.3 Key Features of Syringomatous Adenoma
• Infiltrative lesion composed of small glands, some with irregular contours

(including teardrop shapes and comma-like extensions), solid nests, and
squamous cysts
• Invasion between lactiferous ducts and smooth muscle bundles
• Perineural invasion may be seen
Paget Disease
Paget disease is seen in about 1% to 4% of patients with breast carcinoma
and is characterized by the presence of malignant glandular epithelial cells
within the epidermis of the nipple and/or areola. Most commonly, it pres-
ents clinically as an eczematous, red, weeping, and often crusted lesion.
However, it may be clinically occult and detected only during histologic
examination of the nipple or areola.
Upon microscopic examination, the epidermis is permeated by
malignant cells arranged singly or in groups, which are often more numer-
ous in the basal region (Figs. 15.12 and 15.13, e-Fig. 15.15). Rarely, the
FIGURE 15.12 Paget disease of the nipple. A: Scattered malignant glandular epithelial
cells are present in the epidermis. There is dermal chronic inflammation. B: High-power
view demonstrating cytologic features of Paget cells. These cells have large nuclei with
prominent nucleoli and pale, amphophilic cytoplasm.
FIGURE 15.13 Paget disease of the nipple. In this case of Paget disease, the malignant
cells are so numerous that they almost replace areas of the epidermis.
Paget cells form tubular structures. The cells may be sparse or they may
be so numerous that they replace most of the keratinocytes in areas of
the epidermis. Paget cells have large nuclei, prominent nucleoli, and
abundant pale, amphophilic cytoplasm, which often contains mucin. The
cytoplasm may also contain melanin pigment.10 Mitotic figures may be
observed. Because of shrinkage artifact, the cells sometimes appear to lie
within intraepidermal lacunae. Paget cells may involve the epithelium of
cutaneous appendages as well as the epidermis. The underlying dermis
shows variable degrees of telangiectasia and chronic inflammation.
Paget cells show expression of low-molecular-weight cytokeratins,
such as cytokeratin 7.11-13 These cells also show cytokeratin staining using
antibodies AE1/AE3 and CAM 5.2, but they lack expression of cytokeratin
20. Paget cells express epithelial membrane antigen and commonly
show HER2 protein overexpression. They may also show expression of
carcinoembryonic antigen (CEA), estrogen receptor, progesterone recep-
tor, androgen receptor, gross cystic disease fluid protein, and S100 protein
(Fig. 15.14, e-Figs. 15.16 and 15.17).11,13-15
An underlying breast carcinoma is found in >95% of patients
with Paget disease. This is nearly always of ductal type and may be
either purely DCIS (typically of high nuclear grade with associated
comedo necrosis) or a combination of DCIS and invasive carcinoma.
Occasionally, the associated DCIS is confined to a single duct beneath
the nipple, but it is often more widespread.16 Rarely, an underlying

carcinoma cannot be found, even after extensive tissue sampling; the
presumption in such cases is that the disease arose in and is confined to
the epidermis.
B
FIGURE 15.14 Paget cells demonstrating immunoreactivity with cytokeratin antibodies
CAM 5.2 (A) and cytokeratin 7 (B). Note the absence of staining of the surrounding
keratinocytes. Paget cells usually show HER2 protein overexpression (C) and variable
expression of gross cystic disease fluid protein (D).
D
Patients who present with Paget disease should be evaluated for the
presence of an underlying breast carcinoma. Those with very limited disease
may be candidates for breast-conserving treatment.17,18 Paget disease in and of
itself has no prognostic significance when associated with an invasive breast
cancer. The key features of Paget disease are summarized in Table 15.4.
The differential diagnosis of Paget disease cells includes malignant
lesions, such as malignant melanoma and squamous cell carcinoma in
TABLE 15.4 Key Features of Paget Disease
• Broad age range (26–88 years)

• Seen in 1–4% of patients with breast cancer
• Presents clinically as an eczematous, weeping area on the nipple/areola
• High-grade malignant glandular epithelial cells present within the nipple
epidermis
• Associated underlying high-grade DCIS or both DCIS and invasive
carcinoma present in almost all cases
• Paget cells show expression of low-molecular-weight cytokeratins and
epithelial membrane antigen, usually show overexpression of HER2 protein,
and show variable expression of ER/PR, gross cystic disease fluid protein,
CEA, and S100 protein
• Differential diagnosis includes malignant melanoma, Bowen disease, clear
keratinocytes, and Toker cells
CEA, carcinoembryonic antigen; DCIS, ductal carcinoma in situ; ER, estrogen receptor;
PR, progesterone receptor.
situ (Bowen disease), both of which rarely occur in the nipple, as well as
benign intraepidermal cells with cytoplasmic clearing that may be either
keratinocytes (Fig. 15.15, e-Fig. 15.18) or Toker cells (Figs. 15.16 and
15.17, e-Fig. 15.19).11,13,14 In problematic cases, histochemical stains for
mucin or immunohistochemical stains may be needed to distinguish Paget
FIGURE 15.15 Clear cells in the nipple. These cells with cytoplasmic clearing are
keratinocytes. In some cells, a clear vacuole is present that displaces the nucleus,
simulating signet ring cells. These cells have small, bland nuclei, and histochemical
stains for cytoplasmic mucin are negative.
B
FIGURE 15.16 Toker cells. A: Toker cells are benign cells with pale cytoplasm present in
the nipple epidermis, singly and in small clusters. B: At high power, the nuclei of Toker cells
are bland and lack prominent nucleoli. These cells show cytoplasmic staining for cytokera-
tin 7 (C) and nuclear staining for estrogen receptor (D). Toker cells share immunopheno-
typic features with Paget cells, but are distinguished from them by their benign cytology.
D
B
FIGURE 15.17 Toker cell hyperplasia. A: Toker cells are present singly and in small
nests within the nipple epidermis. The bland cytology characteristic of Toker cells is
retained. B: Mucicarmine stain. In contrast to the cells of Paget disease, Toker cells lack
intracytoplasmic mucin as demonstrated in this negative mucicarmine stain.
TABLE 15.5 Most Frequent Histochemical and Immunohistochemical

Staining Patterns of Paget Disease and Its Mimics (11–15)
Paget Malignant Squamous Cell

Disease Melanoma Carcinoma In Situ Toker Cells
Mucin + – – –
Cytokeratin 7 + – – +
EMA + – +/– +
HER2 + – – +/–
ER/PR +/– – – +/–
GCDFP +/– – – –
S100 +/– + – +/–
HMB45 – + – NA
+, usually present.
–, usually absent.
+/–, may be present or absent.
NA, no information available.
cells from the other cell types (Table 15.5). Of note, however, Paget cells
and Toker cells have many immunophenotypic similarities.11,13 In fact, it
has been suggested that Toker cells may represent the cell of origin for the
rare cases of Paget disease without an identifiable underlying carcinoma.
References
1. Lester S. Subareolar abscess (Zuska’s disease): a specific disease entity with specific
treatment and prevention strategies. Pathol Case Rev. 1999;4(5):189-193.
2. Meguid MM, Oler A, Numann PJ, Khan S. Pathogenesis-based treatment of recurring
subareolar breast abscesses. Surgery. 1995;118(4):775-782.
3. Perzin KH, Lattes R. Papillary adenoma of the nipple (florid papillomatosis, adenoma,
adenomatosis). A clinicopathologic study. Cancer. 1972;29(4):996-1009.
4. Rosen PP, Caicco JA. Florid papillomatosis of the nipple. A study of 51 patients, includ-
ing nine with mammary carcinoma. Am J Surg Pathol. 1986;10(2):87-101.
5. Jones MW, Tavassoli FA. Coexistence of nipple duct adenoma and breast carcinoma:
a clinicopathologic study of five cases and review of the literature. Mod Pathol.
1995;8(6):633-636.
6. Jones MW, Norris HJ, Snyder RC. Infiltrating syringomatous adenoma of the nipple. A
clinical and pathological study of 11 cases. Am J Surg Pathol. 1989;13(3):197-201.
7. Rosen PP. Syringomatous adenoma of the nipple. Am J Surg Pathol. 1983;7(8):739-745.
8. Rosen PP, Ernsberger D. Low-grade adenosquamous carcinoma. A variant of metaplas-
tic mammary carcinoma. Am J Surg Pathol. 1987;11(5):351-358.
9. Van Hoeven KH, Drudis T, Cranor ML, Erlandson RA, Rosen PP. Low-grade adeno-
squamous carcinoma of the breast. A clinocopathologic study of 32 cases with ultra-
structural analysis. Am J Surg Pathol. 1993;17(3):248-258.
10. Tang X, Umemura S, Kumaki N, et al. A case report of pigmented mammary Paget’s
disease mimicking nevus of the nipple. Breast Cancer. 2011 (e-pub).
11. Lundquist K, Kohler S, Rouse RV. Intraepidermal cytokeratin 7 expression is not
restricted to Paget cells but is also seen in Toker cells and Merkel cells. Am J Surg
Pathol. 1999;23(2):212-219.
12. Smith KJ, Tuur S, Corvette D, Lupton GP, Skelton HG. Cytokeratin 7 staining in mam-
mary and extramammary Paget’s disease. Mod Pathol. 1997;10(11):1069-1074.
13. Yao DX, Hoda SA, Chiu A, Ying L, Rosen PP. Intraepidermal cytokeratin 7 immuno-
reactive cells in the non-neoplastic nipple may represent interepithelial extension of
lactiferous duct cells. Histopathology. 2002;40(3):230-236.
14. Kohler S, Rouse RV, Smoller BR. The differential diagnosis of pagetoid cells in the epi-
dermis. Mod Pathol. 1998;11(1):79-92.
15. Liegl B, Horn LC, Moinfar F. Androgen receptors are frequently expressed in mammary
and extramammary Paget’s disease. Mod Pathol. 2005;18(10):1283-1288.
16. Chaudary MA, Millis RR, Lane EB, Miller NA. Paget’s disease of the nipple: a ten year
review including clinical, pathological, and immunohistochemical findings. Breast
Cancer Res Treat. 1986;8(2):139-146.
17. Chen CY, Sun LM, Anderson BO. Paget disease of the breast: changing patterns of inci-
dence, clinical presentation, and treatment in the U.S. Cancer. 2006;107(7):1448-1458.
18. Lagios MD, Westdahl PR, Rose MR, Concannon S. Paget’s disease of the nipple.
Alternative management in cases without or with minimal extent of underlying breast
carcinoma. Cancer. 1984;54(3):545-551.
16
Male Breast Lesions
Normal Histology
The adult male breast, like the female breast, is composed of glandular
epithelial elements embedded in a stroma composed of varying amounts
of fibrous tissue and adipose tissue. However, in contrast to the female
breast, the epithelial components of the male breast consist primarily of
branching ducts and terminal ductules with minimal, if any, acinar forma-
tion (Fig. 16.1, e-Fig. 16.1). Lobular development has been reported in
males with Klinefelter syndrome and in other conditions associated with
high serum estrogen.
Gynecomastia
Gynecomastia is the most common lesion of the male breast. Although
this is sometimes seen in association with known endocrine abnor-
malities and the use of certain drugs (including digitalis, spironolactone,
tricyclic antidepressants, and marijuana) or topical agents (such as lav-
ender and possibly tea tree oils), in most cases the etiology is unknown.
Gynecomastia occurs most often around the age of puberty or in old age.
The process may be either localized or generalized and can be unilateral
or bilateral. Gynecomastia is also very common in male newborns as a
result of in utero exposure to maternal estrogens.
The histologic appearance varies with the duration of the condition.
In all stages, the number of ducts is increased, and there may be duct dila-
tation. Early in the disease, the periductal stroma is loose, vascular, and
cellular and contains varying numbers of lymphocytes and plasma cells.
The duct epithelium may show hyperplasia with a characteristic pattern
of tapering tufts protruding into the lumen, a pattern similar to that some-
times seen in benign epithelial hyperplasia in women and in the epithelial
component of many juvenile fibroadenomas (Fig. 16.2, e-Fig. 16.2). In the
451
FIGURE 16.1 Normal male breast. There are scattered ducts in a fibroadipose stroma.
Note the absence of lobules.
A
FIGURE 16.2 A: Gynecomastia, early stage, characterized by an increased number of
ducts surrounded by a loose periductal stroma. B: A few tapering tufts of epithelium
protrude into a duct lumen.
Male Breast Lesions ——— 453
B
later stage, there is progressive periductal fibrosis and stromal hyalinization

(Fig. 16.3), and the epithelium undergoes atrophy (Table 16.1).1 Apocrine
metaplasia may be seen in either early or later stages. Squamous metaplasia
is most common in the early phase. Pseudoangiomatous stromal hyperpla-
sia may be seen in any phase and may be prominent (Fig. 16.4).2 Lobule
FIGURE 16.3 Gynecomastia, fibrous stage, with periductal fibrosis.

TABLE 16.1 Key Features of Gynecomastia
Clinical
• Most common at puberty and in old age
• May be unilateral or bilateral
• Most often idiopathic
Histologic
Early stage
• Loose periductal stroma
• Mixed chronic inflammatory infiltrate often present
• Epithelial hyperplasia with cell tufting and protrusion into duct lumens
Late stage
• Fibrosis and hyalinization of periductal stroma
• Atrophy of ductal epithelium
formation may be seen, and the lobules may even show lactational-like
changes (Fig. 16.5).
The epithelial hyperplasia seen in the early stages of gynecomastia
can be quite florid and may on occasion produce a worrisome appear-
ance with solid, cribriform, or papillary growth patterns. In some cases,
the combined architectural and cytologic features may be sufficient to
FIGURE 16.4 Pseudoangiomatous stromal hyperplasia in gynecomastia.

FIGURE 16.5 Abortive lobule formation in gynecomastia.
arrant a diagnosis of atypical ductal hyperplasia (Fig. 16.6, e-Fig. 16.3)

w
or to raise the possibility of ductal carcinoma in situ (DCIS). However,
the subsequent breast cancer risk associated with such atypical intraductal
proliferations in the setting of gynecomastia (and in the male breast in
general) is unknown. Therefore, in our view, the threshold for rendering a
diagnosis of DCIS in this setting should be high.
FIGURE 16.6 Atypical ductal hyperplasia in gynecomastia.

Other Benign Lesions

Other benign lesions that have been reported to occur in the male breast
include fibroadenoma, phyllodes tumor, intraductal papilloma, duct
ectasia, myofibroblastoma, lymphocytic mastopathy/diabetic mastopathy,
cavernous hemangioma, and pseudoangiomatous stromal hyperplasia.
The histologic appearance of these lesions is similar to that seen in the
female breast.
Carcinoma of the Male Breast

Carcinoma of the breast in men is uncommon and accounts for approxi-
mately 0.6% of all breast cancers. The carcinomas may be either in situ or
invasive. Both lesions tend to occur in a somewhat older age group than
in women, with the peak in the sixth decade for DCIS and the seventh
decade for invasive carcinomas.3 Clinical gynecomastia has not been
shown to be a risk factor for carcinoma. However, an increased inci-
dence of breast cancer in men with Klinefelter syndrome has long been
recognized.4,5 Other causes of hypoandrogenism, such as testicular injury
and infertility, have also been reported to be associated with develop-
ment of male breast carcinoma. Hyperestrogenemia, such as that seen in
liver disease, is also considered to be a risk factor for breast carcinoma in
males. The proportion of men with breast carcinoma who have a positive
family history varies from 4% to 21%, depending upon the population
studied. Most are associated with mutations in the BRCA2 breast cancer
susceptibility gene.6,7 It should be noted that breast cancers arising in
men with BRCA2 germline mutations do not differ from sporadic breast
cancers with respect to size, histologic grade, or tumor stage; however,
when compared with sporadic male breast cancers, BRCA2-associated
cancers present at a younger age and have a poorer overall survival
(Table 16.2).8
DCIS of the male breast tends to be retroareolar in location and
nodular and/or cystic and often presents with nipple discharge. Papillary
DCIS is the most frequent histologic pattern, with lesions of low and
intermediate nuclear grade predominating.9 Cribriform, micropapillary,
and solid architectural patterns have also been reported. High-grade DCIS
lesions with comedo necrosis are most often seen in association with
invasive carcinomas.
Men with invasive breast carcinomas tend to present with larger
tumors and at a higher stage than women with breast cancer. The vast
majority of male breast carcinomas are invasive ductal carcinomas that
are similar in histologic appearance to those seen in women (Fig. 16.7,
e-Figs. 16.4 and 16.5). These tumors are typically estrogen receptor posi-
tive and progesterone receptor positive (Fig. 16.8),10-12 and most are also
positive for androgen receptor expression.13 Reports vary on the frequency
of HER2 protein overexpression, but this seems to be less common than
TABLE 16.2 Risk Factors for Male Breast Cancer
Conditions with increased serum estrogen:

Liver disease
Obesity
Antiandrogen therapy (prostate cancer)
Exogenous estrogen therapy (transsexuals)
Conditions with decreased serum androgen:
Klinefelter syndrome
Testicular injury/infertility
Occupational exposure to extreme high temperatures
Drugs/exogenous agents:
Digitalis
Tricyclic antidepressants
Marijuana
Lavender oil
Tea tree oil
Radiation:
Chest wall radiation
Hereditary:
BRCA2 mutation carriers
Cowden syndrome (PTEN mutation)
CHEK2 mutation carriers
FIGURE 16.7 Invasive ductal carcinoma of the male breast.

FIGURE 16.8 Immunostain for estrogen receptor in male breast cancer, which
demonstrates strong nuclear staining.
in female breast cancers.13 The prognosis, when adjusted for number of

positive axillary lymph nodes, tumor size, and histologic grade, is similar
in male and female patients (Table 16.3).10,14
The second most frequently reported type of invasive mammary
carcinoma in males is papillary carcinoma. As with invasive ductal
carcinomas, papillary carcinomas in males have the same histologic
features as those seen in women, with large papillary nests composed of
a monotonous proliferation of atypical epithelial cells covering fibrovas-
cular cores and lacking a myoepithelial cell layer. Other special types of
mammary carcinoma, such as invasive micropapillary, mucinous, medul-
lary, tubular, and apocrine carcinoma, may also be seen in men, but are
uncommon.15
As with female breast cancer, male breast cancers also demon-
strate distinct molecular subtypes. Utilizing immunohistochemistry as
a surrogate for gene expression profiling studies, luminal A and B and
basal-like cancers have been identified in two small series of male breast
carcinomas.16,17
Both in situ and invasive lobular carcinomas have been reported in
the male breast, but are extremely uncommon.14 Paget disease may also be
seen in men.18 The key features of male breast cancer are summarized in
Table 16.3.
TABLE 16.3 Key Features of Male Breast Cancer
• Older males (seventh decade)

• Presents at higher stage than female cancers, but prognosis similar to
females when matched for stage
• Invasive ductal type most common
• Papillary carcinoma common
• Other types rare
• Typically estrogen receptor positive, progesterone receptor positive, and
androgen receptor positive
• HER2 positivity less common than in female breast cancer
Metastasis to the Male Breast

Metastases to the male breast are seen most often with tumors that com-
monly metastasize to the female breast, such as renal cell carcinoma, mel-
anoma, and lymphoma. Of particular note is the occurrence of metastatic
prostate carcinoma because this may mimic primary breast carcinoma
(Fig. 16.9). Furthermore, in men with prostate cancer, the associated epi-
thelial hyperplasia secondary to antiandrogen or estrogen therapies may
be misinterpreted as associated DCIS. Immunostains for prostate-specific
FIGURE 16.9 Metastatic prostate carcinoma involving the breast. Tumor cells in nests
and glands infiltrate around a residual normal duct.
FIGURE 16.10 Metastatic prostate carcinoma demonstrating strong cytoplasmic staining

for prostate-specific antigen.
antigen and prostatic acid phosphatase may be particularly helpful in

distinguishing prostatic carcinoma metastatic to the breast from primary
breast carcinoma (Fig. 16.10).
References
1. Bannayan GA, Hajdu SI. Gynecomastia: clinicopathologic study of 351 cases. Am J Clin
Pathol. 1972;57(4):431-437.
Wilkins; 2009.
3. Anderson WF, Jatoi I, Tse J, Rosenberg PS. Male breast cancer: a population-based
comparison with female breast cancer. J Clin Oncol. 2010;28(2):232-239.
4. Jackson AW, Muldal S, Ockey CH, O’Connor PJ. Carcinoma of male breast in associa-
tion with the Klinefelter syndrome. BMJ. 1965;5429:223-225.
5. Brinton LA. Breast cancer risk among patients with Klinefelter syndrome. Acta
Paediatr. 2011;100(6):814-818.
6. Friedman LS, Gayther SA, Kurosaki T, et al. Mutation analysis of BRCA1 and BRCA2
in a male breast cancer population. Am J Hum Genet. 1997;60(2):313-319.
7. Ottini L, Rizzolo P, Zanna I, et al. BRCA1/BRCA2 mutation status and clinical-patho-
logic features of 108 male breast cancer cases from Tuscany: a population-based study
in central Italy. Breast Cancer Res Treat. 2009;116(3):577-586.
8. Kwiatkowska E, Teresiak M, Filas V, Karczewska A, Breborowicz D, Mackiewicz A.
BRCA2 mutations and androgen receptor expression as independent predictors of out-
come of male breast cancer patients. Clin Cancer Res. 2003;9(12):4452-4459.
9. Hittmair AP, Lininger RA, Tavassoli FA. Ductal carcinoma in situ (DCIS) in the male
breast: a morphologic study of 84 cases of pure DCIS and 30 cases of DCIS associated
with invasive carcinoma—a preliminary report. Cancer. 1998;83(10):2139-2149.
10. Giordano SH, Cohen DS, Buzdar AU, Perkins G, Hortobagyi GN. Breast carcinoma in
men: a population-based study. Cancer. 2004;101(1):51-57.
11. Rayson D, Erlichman C, Suman VJ, et al. Molecular markers in male breast carcinoma.
Cancer. 1998;83(9):1947-1955.
12. Harlan LC, Zujewski JA, Goodman MT, Stevens JL. Breast cancer in men in the
United States: a population-based study of diagnosis, treatment, and survival. Cancer.
2010;116(15):3558-3568.
13. Fentiman IS, Fourquet A, Hortobagyi GN. Male breast cancer. Lancet.
2006;367(9510):595-604.
14. Goss PE, Reid C, Pintilie M, Lim R, Miller N. Male breast carcinoma: a review of 229
patients who presented to the Princess Margaret Hospital during 40 years: 1955-1996.
Cancer. 1999;85(3):629-639.
15. Heller KS, Rosen PP, Schottenfeld D, Ashikari R, Kinne DW. Male breast cancer: a
clinicopathologic study of 97 cases. Ann Surg. 1978;188(1):60-65.
16. Ge Y, Sneige N, Eltorky MA, et al. Immunohistochemical characterization of subtypes
of male breast carcinoma. Breast Cancer Res. 2009;11(3):R28.
17. Ciocca V, Bombonati A, Gatalica Z, et al. Cytokeratin profiles of male breast cancers.
18. Serour F, Birkenfeld S, Amsterdam E, Treshchan O, Krispin M. Paget’s disease of the
male breast. Cancer. 1988;62(3):601-605.
17
Breast Lesions in Children
and Adolescents
The prepubertal breast in both boys and girls consists primarily of

lactiferous ducts that exhibit some branching without evidence of pro-
gressive alveolar differentiation, although some rudimentary lobular
structures may be seen. The breast is maintained in this state until the
time of puberty. Extramedullary hematopoiesis in the stroma, a feature
seen in the fetal breast, may persist until 4 months of age (Fig. 17.1,
e-Fig. 17.1).1
At puberty in females, there is duct elongation, branching, and
development of a thickened epithelium, which is primarily due to the
influence of estrogen.2 This is accompanied by an increase in the density
of periductal connective tissue, which is also the result of relative estro-
gen dominance. Deposition of stromal adipose tissue also occurs, and it
is this adipose tissue that is largely responsible for the enlargement and
protrusion of the breast disc at this time. Cyclical exposure to proges-
terone following exposure to estrogen during ovulatory cycles promotes
lobulo-acinar growth as well as connective tissue growth. Although the
majority of lobulo-acinar development occurs during puberty, this process
continues into the third decade and terminal differentiation of the breast
is induced only by pregnancy.
The adolescent male breast is composed of fibroadipose tissue and
ducts lined by low cuboidal epithelial cells.
A number of breast lesions that occur in adults may be seen in chil-
dren and adolescents, including fibroadenomas, phyllodes tumors, and
intraductal papillomas. Gynecomastia may be seen in adolescent boys, as
discussed in Chapter 16. This chapter will focus on several lesions that are
primarily seen in children and adolescents.
462
Breast Lesions in Children and Adolescents ——— 463
B
FIGURE 17.1 A: Low-power view of breast tissue from a neonate showing ducts
embedded in a stroma composed of loose connective tissue and adipose tissue. The
stromal mononuclear cells are hematopoietic elements, which is indicative of persistent
extramedullary hematopoiesis. B: High-power view demonstrating hematopoietic cells in
the stroma (courtesy of Dr. Theonia K. Boyd).
Juvenile (Virginal) Hypertrophy

Rapid and distressing enlargement of one or frequently both breasts may
occasionally occur in adolescence. Careful clinical history and physical
examination are required, particularly in patients with unilateral enlarge-
ment, to prevent the interpretation of this lesion as a tumor which, in turn,
could result in inadvertent surgical removal of the developing breast disc.
Histologic examination shows features similar to those of gynecomastia,
with abundant connective tissue and duct proliferation, frequently with
epithelial hyperplasia, but with little or no lobule formation.3
Reduction mammaplasty is usually the treatment of choice.
Recurrences have been reported and may require a second mammaplasty
procedure or even mastectomy with reconstruction. Recurrences are more
common if hypertrophy developed early in puberty.4
Juvenile Fibroadenoma
Most fibroadenomas that occur in the adolescent female are histologically
similar to those presenting in older women. The term juvenile fibroad-
enoma refers to a distinct lesion characterized by a rapid growth phase
that more commonly occurs in postpubertal children and usually attains a
larger size than the fibroadenomas seen in adults. The histologic features
of this entity are discussed in Chapter 6.
Juvenile Papillomatosis
Juvenile papillomatosis, as the name implies, is a disorder that usually
occurs in young women, most often in those <30 years of age. Two-thirds
of the reported patients have been <25 years of age. However, the lesion
has been noted in patients as young as 12 and as old as 48 years.5
This lesion presents as a well-defined, firm mass often mistaken
clinically for a fibroadenoma. Gross examination shows cysts of varying
size, which impart a Swiss cheese–like appearance to the specimen on
cut section. Microscopically, juvenile papillomatosis is characterized by
a combination of cysts and ectatic ducts, which may contain inspissated
secretions and intraluminal foamy histiocytes, epithelial hyperplasia and
papillomatosis, and apocrine metaplasia. Fibroadenomatous change and
sclerosing adenosis may also be seen (Figs. 17.2–17.5, e-Figs. 17.2–17.4).
The epithelial hyperplasia most often has the features of usual ductal
hyperplasia; this may be quite florid and may even show foci of necrosis.
Atypical ductal hyperplasia (ADH) may be seen. None of the histologic
features seen in juvenile papillomatosis are unique to this lesion; it is the
constellation of the pathologic and clinical features in conjunction with
the age at presentation that merits the recognition of juvenile papilloma-
tosis as a distinct entity.
FIGURE 17.2 Juvenile papillomatosis. Numerous cysts and ectatic ducts are evident at
scanning magnification. These impart a Swiss cheese–like appearance to the tissue sections.
FIGURE 17.3 Juvenile papillomatosis. This low-power photomicrograph illustrates a

combination of cysts and ectatic ducts with inspissated secretions, usual ductal hyperplasia,
apocrine metaplasia, and sclerosing adenosis.
FIGURE 17.4 Juvenile papillomatosis. Cysts with inspissated secretions and intraluminal
foamy histiocytes.
FIGURE 17.5 Juvenile papillomatosis. Usual ductal hyperplasia and apocrine metaplasia.
A high proportion of patients with juvenile papillomatosis have

reported a family history of breast cancer, and both coincident and sub-
sequent carcinomas have been described in a few cases.5-7 However, the
risk of subsequent breast cancer related to this condition has not been
well-defined. Treatment should consist of excisional biopsy, and careful
TABLE 17.1 Key Features of Juvenile Papillomatosis
• Primarily occurs in young women (two-thirds of cases occur in women

<25 years of age)
• Many patients have a positive family history of breast cancer
• Presents as a discrete mass
• Gross examination reveals multiple cysts and dilated ducts (“Swiss cheese”
appearance)
• Histologic constellation of cysts and ectatic ducts with variable inspissation
of secretions and intraluminal histiocytes, florid epithelial hyperplasia and
papillomatosis, and apocrine metaplasia
clinical follow-up is recommended. The key features of juvenile papil-

lomatosis are summarized in Table 17.1.
Papillary Duct Hyperplasia

Papillary duct hyperplasia may occur in adolescent and young women
and is distinguished from juvenile papillomatosis by the presence of
papillary epithelial hyperplasia without prominent cyst formation, stasis
of secretions, and apocrine metaplasia.8,9 The histologic criteria for the
diagnosis of ADH in this setting are the same as those used elsewhere
in the breast. The risk of subsequent breast cancer associated with this
condition is not known.
Secretory Carcinoma
Carcinoma of the breast in children is rare. When it does occur, it is usu-
ally of secretory type,10 although other types commonly found in adults
have been reported in children and, conversely, secretory carcinomas can
occur in adults. This type of carcinoma has been reported in both females
and males.
Secretory carcinomas are typically well-circumscribed, mobile mass-
es with a predilection for a subareolar location in prepubertal girls and
in males. They may resemble fibroadenomas grossly. Histologically, the
tumor cells grow as glands and as more solid, circumscribed islands con-
taining variably sized acini, some forming microcystic structures. Many
of the lumens of the acini and microcysts contain eosinophilic, periodic
acid Schiff–positive, diastase-resistant material. The border of the lesion
histologically is most often circumscribed but may be infiltrative. The
tumor cells show minimal nuclear pleomorphism and few, if any, mitoses.
The cytoplasm is granular or vacuolated, pale staining, and usually plenti-
ful (Fig. 17.6, e-Fig. 17.5). Some tumors contain a component of ductal
carcinoma in situ. Given the circumscribed nature of many of the invasive
B
FIGURE 17.6 Secretory carcinoma. A: Low-power view demonstrates the circumscribed
border of this tumor, which was thought to be a fibroadenoma clinically and was “shelled
out.” Numerous acini and microcysts are evident, many of which contain eosinophilic
secretions. B: High-power view demonstrates the cytologic features. The cells have
abundant pale, granular, or vacuolated cytoplasm and uniform nuclei.
TABLE 17.2 Key Features of Secretory Carcinoma
• Occurs primarily in children and young adults, though persons of any age
may be affected
• Predilection for the subareolar location in prepubertal girls
• Grossly well-circumscribed
• Composed of glands and solid nests with microacini and cysts containing
eosinophilic, periodic acid Schiff–positive secretions
• Tumor cells have pale granular or vacuolated cytoplasm and low nuclear
grade and are estrogen receptor negative
• Favorable prognosis in children and adolescents; may recur locally or even
metastasize, particularly in older women
tumor cell nests, it may be difficult to determine the relative proportions

of invasive and in situ carcinoma.
Of the few cases in which estrogen receptor (ER) staining has
been evaluated by immunohistochemistry, the majority appear to be
ER-negative. Strong expression for alpha-lactalbumin, S100 protein, and
carcinoembryonic antigen has been reported. Gross cystic disease fluid
protein expression has not been observed. Secretory carcinomas exhibit
a balanced translocation, t(12:15), which creates an ETV6–NTRK3 gene
fusion encoding a chimeric tyrosine kinase protein.11 Furthermore, tumors
with this fusion gene have been shown to belong to the basal-like subtype
of breast carcinomas by gene expression profiling.12
Secretory carcinomas in children and young adults (<30 years)
are associated with a favorable prognosis. When they occur in older
patients, the prognosis may not be quite so good; late recurrences
(i.e., >20 years after diagnosis) have been reported.13-15 Treatment
recommendations vary, but more recent reports propose breast-con-
serving surgery with sentinel node biopsy but without radiation therapy
in children.16 The key features of secretory carcinoma are summarized
in Table 17.2.
Metastatic Tumors
In young patients, metastases to the breast are more common than are pri-
mary breast carcinomas. Most metastatic lesions in this population arise
from tumors that are more commonly found in children and young adults
such as lymphomas/leukemias, rhabdomyosarcoma, neuroblastoma, med-
ullary carcinoma of the thyroid, medulloblastoma, and primitive neuroec-
todermal tumor/Ewing sarcoma.17 Of these, alveolar rhabdomyosarcoma
seems to have a predilection for metastasizing to the breast, particularly
among postpubertal females.18,19 Primary alveolar rhabdomyosarcomas of
the breast have also been reported in children.
References
1. Anbazhagan R, Bartek J, Monaghan P, Gusterson BA. Growth and development of the

human infant breast. Am J Anat. 1991;192(4):407-417.
2. Monaghan P, Perusinghe NP, Cowen P, Gusterson BA. Peripubertal human breast
development. Anat Rec. 1990;226(4):501-508.
3. Oberman HA. Breast lesions in the adolescent female. In: Sommers SC, Rosen PP, eds.
Pathology Annual, Part 1. Norwalk, CT: Appleton-Century-Crofts; 1979:175-201.
4. Baker SB, Burkey BA, Thornton P, LaRossa D. Juvenile gigantomastia: presentation of
four cases and review of the literature. Ann Plast Surg. 2001;46(5):517-525; discussion
525-526.
5. Rosen PP, Cantrell B, Mullen DL, DePalo A. Juvenile papillomatosis (Swiss cheese dis-
ease) of the breast. Am J Surg Pathol. 1980;4(1):3-12.
6. Rosen PP, Holmes G, Lesser ML, Kinne DW, Beattie EJ. Juvenile papillomatosis and
breast carcinoma. Cancer. 1985;55(6):1345-1352.
7. Taffurelli M, Santini D, Martinelli G, et al. Juvenile papillomatosis of the breast. A mul-
tidisciplinary study. Pathol Annu. 1991;26(Pt 1):25-35.
8. Rosen PP. Papillary duct hyperplasia of the breast in children and young adults. Cancer.
1985;56(7):1611-1617.
9. Wilson M, Cranor ML, Rosen PP. Papillary duct hyperplasia of the breast in children
and young women. Mod Pathol. 1993;6(5):570-574.
10. McDivitt RW, Stewart FW. Breast carcinoma in children. JAMA. 1966;195(5):388-390.
11. Tognon C, Knezevich SR, Huntsman D, et al. Expression of the ETV6-NTRK3
gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell.
2002;2(5):367-376.
12. Lae M, Freneaux P, Sastre-Garau X, Chouchane O, Sigal-Zafrani B, Vincent-Salomon
A. Secretory breast carcinomas with ETV6-NTRK3 fusion gene belong to the basal-like
carcinoma spectrum. Mod Pathol. 2009;22(2):291-298.
13. Krausz T, Jenkins D, Grontoft O, Pollock DJ, Azzopardi JG. Secretory carcinoma
of the breast in adults: emphasis on late recurrence and metastasis. Histopathology.
1989;14(1):25-36.
14. Rosen PP, Cranor ML. Secretory carcinoma of the breast. Arch Pathol Lab Med.
1991;115(2):141-144.
15. Tavassoli FA, Norris HJ. Secretory carcinoma of the breast. Cancer. 1980;45(9):
2404-2413.
16. Vieni S, Cabibi D, Cipolla C, Fricano S, Graceffa G, Adelfio Latteri M. Secretory breast
carcinoma with metastatic sentinel lymph node. World J Surg Oncol. 2006;4(1):88.
17. Dehner LP, Hill DA, Deschryver K. Pathology of the breast in children, adolescents, and
young adults. Semin Diagn Pathol. 1999;16(3):235-247.
18. Hays DM, Donaldson SS, Shimada H, et al. Primary and metastatic rhabdomyosar-
coma in the breast: neoplasms of adolescent females, a report from the Intergroup
Rhabdomyosarcoma Study. Med Pediatr Oncol. 1997;29(3):181-189.
19. D’Angelo P, Carli M, Ferrari A, et al. Breast metastases in children and adolescents with
rhabdomyosarcoma: experience of the Italian Soft Tissue Sarcoma Committee. Pediatr
Blood Cancer. 2010;55(7):1306-1309.
18
Axillary Lymph Nodes
Axillary lymph nodes are removed for pathologic examination in patients

with breast cancer to determine the presence or absence of metastatic dis-
ease; this information is essential for the purpose of cancer staging. Axillary
lymph nodes may also be removed when they become enlarged due to
other neoplastic diseases or as the result of various reactive and inflamma-
tory processes. This chapter will focus on issues related to the assessment
of axillary lymph nodes for the presence of metastatic breast carcinoma and
other pathologic changes encountered in axillary lymph nodes.
Assessment of Lymph Nodes for Metastatic Carcinoma

Pathologic Staging
In current clinical practice, pathologists most frequently encounter axil-
lary lymph nodes as sentinel lymph node biopsies or in axillary dissection
specimens, the latter of which are most often preceded by a sentinel lymph
node biopsy. Recommendations for processing these specimens are pro-
vided in Chapter 20. The prognostic significance of axillary lymph node
metastases is discussed in Chapter 10.
The examination of axillary lymph nodes from breast cancer patients
requires not only assessment for the presence or absence of metastatic
carcinoma but also determination of the size of the metastatic foci, if pres-
ent, because this is considered in assigning the pathologic (p) N-stage.
The current American Joint Commission on Cancer staging system for
lymph nodes removed from patients with breast cancer is presented in
Table 18.1.1 Lymph node metastases are classified as macrometastases,
micrometastases, and isolated tumor cells (ITCs). Macrometastases are
defined as tumor deposits >2.0 mm in size. Micrometastases (pN1mi) are
deposits >0.2 mm in size and/or more than 200 cells but <2.0 mm in size.
ITCs (pN0i+) are currently defined as clusters of tumor cells not exceed-
ing 0.2 mm or nonconfluent clusters of cells not exceeding 200 cells in
a single histologic lymph node cross section, detected on H&E-stained
471
TABLE 18.1 American Joint Commission on Cancer System for

Pathologic Node (pN) Staging in Breast Cancer
pNX Regional lymph nodes cannot be assessed (e.g., previously

removed or not removed for pathologic study)
pN0 No regional lymph node metastasis histologically
Note: ITC clusters are defined as small clusters of cells not
greater than 0.2 mm, or single tumor cells, or a cluster of
fewer than 200 cells in a single histologic cross section.
ITCs may be detected by routine histology or by IHC
methods. Nodes containing only ITCs are excluded
from the total positive node count for the purpose of N
classification but should be included in the total number of
nodes evaluated
pN0(i–) No regional lymph node metastasis histologically, negative
IHC
pN0(i+) Malignant cells in regional lymph node(s) not greater than
0.2 mm (detected by H&E or IHC including ITC)
pN0(mol–) No regional lymph node metastases histologically, negative
molecular findings (RT-PCR)
pN0(mol+) Positive molecular findings (RT-PCR), but no regional lymph
node metastases detected by histology or IHC
pN1 Micrometastases or metastases in one to three axillary lymph
nodes and/or in internal mammary nodes with metastases
detected by sentinel lymph node biopsy but not clinically
detected
pN1mi Micrometastases (greater than 0.2 mm and/or more than 200
cells, but none >2.0 mm)
pN1a Metastases in one to three axillary lymph nodes; at least one
metastasis greater than 2.0 mm
pN1b Metastasis in internal mammary nodes with micrometastases
or macrometastases detected by sentinel lymph node
biopsy but not clinically detected
pN1c Metastases in one to three axillary lymph nodes and in
internal mammary lymph nodes with micrometastases or
macrometastases detected by sentinel lymph node biopsy
but not clinically detected
pN2 Metastases in four to nine axillary lymph nodes or in
clinically detected internal mammary lymph nodes in the
absence of axillary lymph node metastases
pN2a Metastases in four to nine axillary lymph nodes or in
clinically detected internal mammary lymph nodes in the
absence of axillary lymph node metastases
pN2b Metastases in clinically detected internal mammary lymph
nodes in the absence of axillary lymph node metastases
Axillary Lymph Nodes ——— 473
pN3 Metastases in 10 or more axillary lymph nodes; or in

infraclavicular (level III axillary) lymph nodes; or in
clinically detected ipsilateral internal mammary lymph
nodes in the presence of one or more positive level I/II
axillary lymph nodes; or in more than three axillary
lymph nodes and in internal mammary lymph nodes with
micrometastases or macrometastases detected by sentinel
lymph node biopsy; or in ipsilateral supraclavicular lymph
nodes
pN3a Metastases in 10 or more axillary lymph nodes (at least
one tumor deposit >2.0 mm) or metastases to the
infraclavicular (level III axillary) lymph nodes
pN3b Metastases in clinically detected ipsilateral internal
mammary lymph nodes in the presence of one or
more positive axillary lymph nodes or in more than
three axillary lymph nodes and in internal mammary
lymph nodes with micrometastases or macrometastases
detected by sentinel lymph node biopsy but not clinically
detected
pN3c Metastasis in ipsilateral supraclavicular lymph nodes
IHC, immunohistochemical; ITC, isolated tumor cell; RT-PCR, reverse transcriptase

polymerase chain reaction.
Adapted from AJCC Cancer Staging Manual Seventh Edition. New York, NY: Springer;
2010.
s ections or by cytokeratin immunohistochemistry (Figs. 18.1 and 18.2,

e-Figs. 18.1 and 18.2).1 Such deposits are usually associated with little or
no stromal reaction.
Unfortunately, in some cases, determining the size of a lymph node
metastasis, and in turn the pN-stage, is problematic and subject to consid-
erable interobserver variability.2-4 In particular, how to categorize lymph
nodes that contain multiple foci of ITC/small tumor cell clusters has been
a matter of debate. Some pathologists assign the pN-stage based on the
size of the single largest cell cluster; if it is ≤0.2 mm, the patient is staged
as pN0(i+) even if there are numerous aggregates in that size range. Others
measure the span of aggregates that are in close proximity to each other
and consider that to represent the size of the metastatic deposit (Fig. 18.3).
The current edition of the staging system1 recommends that when there
are multiple foci of tumor cells in a lymph node, the size of only the
largest contiguous tumor deposit is used to classify the node; the sum of
all the individual tumor deposits or the distance between non-contiguous
deposits should not be used. In the case of a lymph node that contains
dispersed ITC or small aggregates throughout the subcapsular and/or
medullary sinuses (as is commonly seen in invasive lobular carcinomas),
FIGURE 18.1 Isolated tumor cells in the subcapsular sinus of a sentinel lymph node,
detected by cytokeratin immunostain. If this were the only finding in the lymph nodes,
the pathologic node stage would be pN0(i+).
FIGURE 18.2 Isolated tumor cells in the subcapsular sinus of a sentinel lymph node
detected on an H&E-stained section. If this were the only finding in the lymph nodes, the
pathologic node stage would be pN0(i+).
FIGURE 18.3 Several isolated tumor cell clusters detected on a cytokeratin immunos-
tain. Some observers would consider this lymph node to be involved by isolated tumor
cells; others would measure the distance from one cluster to the other and use that size
to determine the category of lymph node stage. In current practice, a lymph node with
these features should be staged as pN0(i+).
some would consider the pathologic nodal stage pN0(i+). However, most
would consider the entire node to be involved and stage it as a macrome-
tastasis (pN1a) if the node itself was >2.0 mm in size (Fig. 18.4). The his-
tologic finding of extension of tumor cells beyond the lymph node capsule
into the perinodal soft tissue (extranodal or extracapsular extension) does
not change the pathologic N-stage, but should be commented on in the
surgical pathology report because it may represent a risk factor for tumor
recurrence (Fig. 18.5).
As indicated in Chapter 20, evaluation of sentinel lymph nodes by
frozen sections and/or cytologic preparations is performed at some insti-
tutions to determine the need for further axillary node dissection at the
time of sentinel lymph node biopsy.5 It should be noted that regardless of
the method used for intraoperative evaluation, the false-negative rate is
approximately 25% to 30%. Therefore, the final pathologic nodal stage
can only be determined after examination of permanent sections. Further,
as discussed in Chapter 20, results from the American College of Surgeons
Oncology Group (ACOSOG) Z0011 trial have called into question the
need for routine intraoperative evaluation of sentinel lymph nodes.6
Histologic Features of Lymph Node Metastases
Breast cancer metastases in axillary lymph nodes almost always have cyto-
architectural and immunophenotypic features similar to those of the pri-
mary tumor. Differences in the histologic appearance between the tumor
FIGURE 18.4 Sentinel lymph node from a patient with invasive lobular carcinoma, immu-
nostained for cytokeratin showing numerous cytokeratin-positive tumor cells throughout
the node. Although this could theoretically be staged as pN0(i+), it is better considered to
be pN1a (Courtesy of Dr. Susan Lester).
FIGURE 18.5 Metastatic lobular carcinoma in axillary lymph node with extracapsular
extension of tumor into perinodal adipose tissue.
FIGURE 18.6 Metastatic carcinoma in axillary lymph node. Some of the metastatic tumor
cell nests have a pattern that mimics ductal carcinoma in situ.
in the lymph nodes and that in the breast should raise the possibility of
another, undetected area of carcinoma in the breast. Occasionally, meta-
static carcinoma in a lymph node occurs in circumscribed nests, which
may show foci of necrosis creating an appearance reminiscent of ductal
carcinoma in situ (DCIS) (Fig. 18.6).
Macrometastases disrupt the nodal architecture and are readily recog-
nizable on low-power microscopic examination, if not grossly (Fig. 18.7).
However, recognition of smaller metastatic foci may be more problematic.
As is the case for carcinomas metastatic to lymph nodes in general, the
earliest breast cancer metastases in axillary lymph nodes usually appear in
the subcapsular sinus followed by the medullary sinuses; careful scrutiny
of these regions is essential in cases in which metastases are not imme-
diately evident. Further, tumor cells in the sinuses must be distinguished
from histiocytes. This may be especially difficult in patients with invasive
lobular carcinoma, the cells of which may appear deceptively bland (Fig.
18.8, e-Fig. 18.3). In cases in which the distinction between carcinoma
cells and histiocytes cannot be resolved on routine H&E-stained sections,
cytokeratin immunostains are a useful adjunct.
As discussed in Chapter 20, the results of two randomized trials
(NSABP B32 and ACOSOG Z0010)7,8 have raised questions about the
clinical significance of micrometastases and ITC. As a result, it has been
suggested that routine evaluation of sentinel lymph nodes with cytokeratin
immunostains be abandoned.9,10 Immunostaining for cytokeratin does
have a role in the evaluation of both sentinel and non-sentinel lymph
nodes when there are cells identified on H&E-stained sections that are
FIGURE 18.7 Axillary lymph node macrometastasis. The metastatic deposit in this case is
>2 mm in size and almost completely replaces the lymph node. Only a thin rim of normal
lymph node tissue is visible at the periphery.
A
FIGURE 18.8 Metastatic lobular carcinoma in an axillary lymph node. A: On medium-
power examination, tumor cells are seen in the subcapsular sinus. B: High-power view
emphasizes the relatively bland cytologic features of the tumor cells and the superficial
resemblance to histiocytes.
B
suspicious for but not diagnostic of tumor cells. If cytokeratin staining is

to be performed in this setting, it is important to recognize that other cell
types in lymph nodes, particularly interstitial reticulum cells, demonstrate
cytokeratin reactivity with some anti-cytokeratin antibodies (especially
antibody CAM 5.2) (Fig. 18.9)11,12; these cells much less frequently stain
FIGURE 18.9 Axillary lymph node immunostained with anti-cytokeratin antibody CAM
5.2. Numerous interstitial reticulum cells show cytokeratin immunoreactivity.
with anti-cytokeratin antibodies AE1/AE3.11,12 Therefore, AE1/AE3 is pref-

erable to CAM 5.2 for the confirmation of carcinoma cells in lymph nodes.
Displaced Epithelium
Mechanical displacement of benign and malignant breast epithelial cells
to axillary lymph nodes may occur as the result of a prior needling proce-
dure, such as fine-needle aspiration or core-needle biopsy.13-16 In addition,
there is evidence that breast massage in women undergoing sentinel lymph
node biopsy can result in epithelial cell displacement to lymph nodes.15,17
The displaced cells may be neoplastic cells derived from an invasive car-
cinoma or DCIS, or they may be benign cells derived from normal breast
glandular structures or benign epithelial proliferative lesions, such as
intraductal papillomas. They may be detected on H&E-stained sections or
on cytokeratin immunostains. Because they are typically found as isolated
cells or small cell clusters in the subcapsular sinus, their distinction from
metastatic tumor cells is not always possible.
Features that favor mechanical displacement over metastatic carcino-
ma include degenerative cytologic changes, associated hemosiderin-laden
macrophages, and damaged erythrocytes (Fig. 18.10).13 One study report-
ed a series of cases in which there were immunophenotypic differences
between the cells of the carcinoma in the breast and the epithelial cells in
FIGURE 18.10 Epithelial cells with degenerative changes in the subcapsular sinus of a
sentinel lymph node. The patient had a prior core-needle biopsy that demonstrated duc-
tal carcinoma in situ (DCIS). No invasive carcinoma was identified in either the core-needle
biopsy or in the subsequent excision. Given the degenerative features seen in these cells
and the absence of documented invasive carcinoma in the breast, they likely represent
displaced epithelial cells, possibly derived from the DCIS. However, the possibility of
metastasis cannot be entirely excluded.
the lymph node.16 This observation has been used as evidence to support
the view that in such cases, the cells in the lymph node were not due to
metastasis from the primary breast tumor and rather were benign epithelial
cells that were mechanically transported to the lymph nodes.
In practice, it may be impossible to determine on morphologic
grounds if epithelial cells in a lymph node detected on H&E sections or
cytokeratin immunostains arrived there via metastatic spread or as the
result of mechanical displacement. In patients with invasive breast can-
cer in which this problem arises, it is reasonable to provide in the final
diagnosis an explanatory note highlighting this uncertainty, but indicating
that the possibility of metastasis cannot be excluded. Similarly, in patients
with DCIS who undergo sentinel lymph node biopsy or axillary dissection
and in which this issue arises, an explanation of the uncertain nature and
uncertain clinical significance of the cells in the lymph node should be
provided in the surgical pathology report.
Nevus Cell Aggregates

Cellular aggregates that have the histologic, immunohistochemical, and
ultrastructural features of nevus cells can be identified in axillary lymph
nodes, albeit infrequently. In a study of 909 mastectomy specimens from
patients with breast cancer, axillary lymph node nevus cell aggregates
were identified in only 0.33% of cases and in only 0.017% of the lymph
nodes examined.18 However, they appear to be more frequent in axillary
lymph nodes in patients with malignant melanoma.
Nevus cell aggregates are virtually always incidental microscopic
findings; only a few cases with grossly evident lesions have been reported.
They are limited to the lymph node capsule and fibrous trabeculae. Rarely,
they appear to be in the parenchyma when the fibrous stroma of the asso-
ciated trabeculae is scant. However, they do not involve the subcapsular
or medullary sinuses.18
Most commonly, nevus cell aggregates are composed of oval, epi-
thelioid cells with pale to clear cytoplasm and indistinct cell borders
resembling the cells seen in dermal nevi. Cytoplasmic melanin pigment
is only infrequently present. The cells appear as one or more clusters of
varying size within the lymph node capsule and/or fibrous trabeculae
(Figs. 18.11 and 18.12, e-Fig. 18.4). In rare cases, the cells have a spindle
configuration and prominent melanin pigmentation resembling the cells
of blue nevi.19
The main importance of nevus cell aggregates is that they must
be distinguished from foci of metastatic carcinoma, particularly lobu-
lar carcinoma. Features that distinguish nevus cell aggregates are their
capsular location, absence of mucin production, and melanin pigment
(when present). In problematic cases, immunostains for cytokeratin and
S-100 protein in combination will resolve the issue, because nevus cells
are S-100 positive and cytokeratin negative (Fig. 18.13). Stains for S-100
B
FIGURE 18.11 Nevus cell aggregate. A: At low power, a collection of epithelioid cells
is present in the capsule of this axillary lymph node. B: High-power view illustrates the
indistinct borders, pale cytoplasm, and uniform nuclei of the cells. No melanin pigment is
present.
protein should not be used alone in this context, because some breast
cancer cells show S-100 expression; this could result in the erroneous
categorization of a focus of metastatic carcinoma as a nevus cell aggre-
gate. Two caveats merit comment. First, foci of metastatic carcinoma can
occur within the lymph node capsule (either within the connective tissue
FIGURE 18.12 Nevus cell aggregate in axillary lymph node capsule with prominent
melanin pigment.
FIGURE 18.13 Nevus cell aggregate, immunostain for S-100 protein. The nevus cells
show strong nuclear and cytoplasmic reactivity.
itself or in capsular lymphatic spaces). Therefore, a capsular location

alone is not definitive proof that the cells of concern are nevus cells
rather than carcinoma. Second, the presence of nevus cell aggregates
and metastatic carcinoma is not mutually exclusive; both can occur in the
same lymph node.
Silicone Lymphadenopathy
In patients who have had silicone injections in the breast or silicone leak-
age from intact or ruptured breast implants, silicone may be transported to
the axillary lymph nodes and evoke a distinctive reaction pattern.20,21 These
lymph nodes may be grossly unremarkable or may be firmer than normal.
The most characteristic histologic feature of silicone lymphadenopathy is the
presence within the lymph node of histiocytes and foreign body–type giant
cells with cytoplasmic vacuoles of varying size. Pale to clear, refractile but
non-polarizable material may be evident in the cytoplasmic vacuoles, particu-
larly when the illumination is reduced by partially closing the microscope’s
iris diaphragm or lowering the microscope condenser (Fig. 18.14, e-Fig. 18.5).
B
FIGURE 18.14 Silicone lymphadenopathy. A: At low power, the lymph node is extensively
infiltrated by cells with cytoplasmic vacuoles. B: At higher power, vacuolated histiocytes
and giant cells are evident. C: Silicone is seen as a refractile, nonpolarizable material.
C
Benign epithelial Inclusions

A variety of benign epithelial inclusions may be encountered in axillary
lymph nodes, although all of these are extremely rare. Based on their
histologic features, these inclusions have been classified into three main
groups: those composed exclusively of glandular structures, those com-
posed exclusively of squamous epithelial-lined cysts, and those composed
of both glandular and squamous components.22 Glandular-type inclusions
can be further categorized as those composed of mammary-type epithe-
lium and those composed of Müllerian-type epithelium and resembling
endosalpingiosis.22,23 Benign epithelial inclusions are most often present
in the lymph node capsule or septae but may also be seen in the subcap-
sular area or even in the parenchyma (Fig. 18.15). Those composed of
mammary-type epithelium can show a variety of alterations including cys-
tic change, apocrine metaplasia, sebaceous metaplasia, and proliferative
changes including usual ductal hyperplasia and papilloma formation.22-26
Myoepithelial cells are typically identified in association with these inclu-
sions but may require immunostains for their demonstration (Fig. 18.15).
Müllerian-type inclusions are characterized by small, simple glands lined
by a single layer of cuboidal to columnar epithelial cells, some of which
demonstrate cilia. Cytologic atypia is not present. “Peg cells” with clear
cytoplasm may be seen wedged between the columnar epithelial cells.
These glands lack a surrounding myoepithelial cell layer.23 Associated
psammomatous calcifications may be present. The epithelial cells show
immunostaining for WT-1 and PAX8, supporting a Müllerian pheno-
type.22,23 Squamous-type inclusions are characterized by cystic structures
lined by benign squamous epithelium that may exhibit keratinization.
These are usually located more centrally in the lymph nodes than are
B
FIGURE 18.15 Axillary lymph node with benign glandular inclusion. A: Low-power
examination reveals a single, cystically dilated gland confined to the nodal capsule.
B: At high power, two cell layers are apparent: an inner columnar epithelial layer with
apical cytoplasmic snouts and an outer layer of myoepithelial cells. C: p63 immunostain
confirming the presence of myoepithelial cells around the gland and supporting its
benign nature.
C
g landular inclusions (Fig. 18.16). Mixed glandular and squamous inclu-

sions exhibit a combination of the features described above.
Benign epithelial inclusions in axillary lymph nodes must be dis-
tinguished from metastatic carcinoma. Features favoring a diagnosis of
benign inclusions include location in the nodal capsule or trabeculae,
A
FIGURE 18.16 Axillary lymph node with benign squamous epithelial inclusion. A: Low-
power view demonstrates a squamous epithelial-lined cyst with abundant keratin within
the cyst lumen. B: High-power view demonstrating the benign, keratinizing squamous
epithelial lining and keratinaceous debris.
B
lack of cytologic atypia, cystically dilated glandular-squamous struc-

tures in the nodal parenchyma without associated stromal desmoplasia,
presence of ciliated cells and peg cells, and histologic differences from
the primary tumor in the breast. The presence of myoepithelial cells in
association with glandular structures further supports a benign diag-
nosis; however, myoepithelial cells are not present in association with
Müllerian-type glandular inclusions. As noted above, immunoreactiv-
ity of glandular epithelium for WT-1 and PAX8 supports a Müllerian
phenotype.
It should be emphasized that epithelial elements in an axillary lymph
node of a patient with breast cancer are far more likely to represent meta-
static disease than benign inclusions (Fig. 18.17). Therefore, the diagnosis
of benign epithelial inclusions should be considered a diagnosis of exclu-
sion; the burden of proof is on the pathologist to demonstrate that such
foci do not represent metastatic carcinoma.
Other Conditions
Although any condition that affects lymph nodes can be identified in
axillary lymph nodes, a few merit specific comment. Megakaryocytes
may rarely be identified in lymph nodes in otherwise healthy individu-
als and may be numerous in patients with extramedullary hematopoiesis
(Fig. 18.18). Their large size and large, irregular nuclei could cause them
to be mistaken for malignant cells.27 Vascular lesions can occur in axillary
lymph nodes; hemangiomas are the most common of these (Fig. 18.19),
but vascular transformation of the lymph node sinuses and other
B
FIGURE 18.17 Metastatic low-grade breast carcinoma in a lymph node. A: Two simple
glands are present in the lymph node capsule. The capsular location and bland cytologic
features raise the possibility that these represent benign glandular inclusions. B: Primary
breast carcinoma from the same case. The tumor is a low-grade, invasive ductal carci-
noma with perineural invasion. The glands in the lymph node capsule are histologically
similar to those comprising the primary breast tumor confirming their metastatic nature.
ascular lesions may also occur.28,29 Finally, granulomatous inflamma-

v
tion in axillary lymph nodes may be seen as a manifestation of a systemic
granulomatous disorder (such as sarcoidosis), as an infection, or as a reac-
tion to a carcinoma in the breast.
B
FIGURE 18.18 Megakaryocytes in axillary lymph node in a patient with myelofibrosis and
myeloid metaplasia. A: Low-power view illustrates several large cells with large, hyperchro-
matic nuclei. B: High-power view demonstrates the typical cytologic features of mega-
karyocytes. These cells should not be mistaken for metastatic carcinoma.
FIGURE 18.19 Axillary lymph node with hemangioma.
References
1. AJCC Cancer Staging Manual Seventh Edition. New York, NY: Springer; 2010.
2. Roberts CA, Beitsch PD, Litz CE, et al. Interpretive disparity among pathologists in
breast sentinel lymph node evaluation. Am J Surg. 2003;186(4):324-329.
3. Cserni G, Bianchi S, Boecker W, et al. Improving the reproducibility of diagnosing
micrometastases and isolated tumor cells. Cancer. 2005;103(2):358-367.
4. Turner RR, Weaver DL, Cserni G, et al. Nodal stage classification for breast carcinoma:
improving interobserver reproducibility through standardized histologic criteria and
image-based training. J Clin Oncol. 2008;26(2):258-263.
5. Weaver DL. Pathology evaluation of sentinel lymph nodes in breast cancer: protocol
recommendations and rationale. Mod Pathol. 2010;23 (suppl 2):S26-S32.
6. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in
women with invasive breast cancer and sentinel node metastasis: a randomized clinical
trial. JAMA. 2011;305(6):569-575.
2011;22(2):115-117.
nodes? Breast Dis. 2011;22(1):20-21.
11. Xu X, Roberts SA, Pasha TL, Zhang PJ. Undesirable cytokeratin immunoreactivity of
native nonepithelial cells in sentinel lymph nodes from patients with breast carcinoma.
Arch Pathol Lab Med. 2000;124(9):1310-1313.
12. Linden MD, Zarbo RJ. Cytokeratin immunostaining patterns of benign, reactive
lymph nodes: applications for the evaluation of sentinel lymph node specimen. Appl
Immunohistochem Mol Morphol. 2001;9(4):297-301.
13. Carter BA, Jensen RA, Simpson JF, Page DL. Benign transport of breast epithelium into
axillary lymph nodes after biopsy. Am J Clin Pathol. 2000;113(2):259-265.
14. Moore KH, Thaler HT, Tan LK, Borgen PI, Cody HS 3rd. Immunohistochemically
detected tumor cells in the sentinel lymph nodes of patients with breast carcinoma:
biologic metastasis or procedural artifact? Cancer. 2004;100(5):929-934.
15. Diaz NM, Vrcel V, Centeno BA, Muro-Cacho C. Modes of benign mechanical transport
of breast epithelial cells to axillary lymph nodes. Adv Anat Pathol. 2005;12(1):7-9.
16. Bleiweiss IJ, Nagi CS, Jaffer S. Axillary sentinel lymph nodes can be falsely positive due
to iatrogenic displacement and transport of benign epithelial cells in patients with breast
carcinoma. J Clin Oncol. 2006;24(13):2013-2018.
17. Diaz NM, Cox CE, Ebert M, et al. Benign mechanical transport of breast epithelial cells
to sentinel lymph nodes. Am J Surg Pathol. 2004;28(12):1641-1645.
18. Ridolfi RL, Rosen PP, Thaler H. Nevus cell aggregates associated with lymph nodes:
estimated frequency and clinical significance. Cancer. 1977;39(1):164-171.
19. Epstein JI, Erlandson RA, Rosen PP. Nodal blue nevi. A study of three cases. Am J Surg
Pathol. 1984;8(12):907-915.
20. Truong LD, Cartwright J Jr, Goodman MD, Woznicki D. Silicone lymphadenopathy
associated with augmentation mammaplasty. Morphologic features of nine cases. Am J
Surg Pathol. 1988;12(6):484-491.
21. van Diest PJ, Beekman WH, Hage JJ. Pathology of silicone leakage from breast implants.
J Clin Pathol. 1998;51(7):493-497.
22. Fellegara G, Carcangiu ML, Rosai J. Benign epithelial inclusions in axillary lymph nodes:
report of 18 cases and review of the literature. Am J Surg Pathol. 2011;35(8):1123-1133.
23. Corben AD, Nehhozina T, Garg K, Vallejo CE, Brogi E. Endosalpingiosis in axillary
lymph nodes: a possible pitfall in the staging of patients with breast carcinoma. Am J
Surg Pathol. 2010;34(8):1211-1216.
24. Turner DR, Millis RR. Breast tissue inclusions in axillary lymph nodes. Histopathology.
1980;4(6):631-636.
25. Layfield LJ, Mooney E. Heterotopic epithelium in an intramammary lymph node. Breast
J. 2000;6(1):63-67.
26. Fisher CJ, Hill S, Millis RR. Benign lymph node inclusions mimicking metastatic carci-
noma. J Clin Pathol. 1994;47(3):245-247.
27. Hoda SA, Resetkova E, Yusuf Y, Cahan A, Rosen PP. Megakaryocytes mimicking meta-
static breast carcinoma. Arch Pathol Lab Med. 2002;126(5):618-620.
28. Chan JK, Frizzera G, Fletcher CD, Rosai J. Primary vascular tumors of lymph nodes
other than Kaposi’s sarcoma. Analysis of 39 cases and delineation of two new entities.
Am J Surg Pathol. 1992;16(4):335-350.
29. Chan JK, Warnke RA, Dorfman R. Vascular transformation of sinuses in lymph nodes. A
study of its morphological spectrum and distinction from Kaposi’s sarcoma. Am J Surg
Pathol. 1991;15(8):732-743.
19
Treatment Effects
The combination of breast-conserving surgery and radiation therapy is

now the local treatment method of choice for most patients with inva-
sive breast cancer and ductal carcinoma in situ (DCIS).1,2 Some patients
treated in this manner require subsequent biopsy of the irradiated breast
because of the development of a new abnormality on physical examina-
tion or mammography. Therefore, the surgical pathologist must be famil-
iar with the effects of radiation on the breast.
In addition, neoadjuvant (preoperative) chemotherapy is being used
increasingly to treat patients with invasive breast cancer.3-6 In this treat-
ment approach, a core-needle biopsy of the breast tumor is performed
to obtain tissue for diagnosis and to assess hormone receptor and HER2
status. Systemic therapy (i.e., chemotherapy, hormonal therapy, HER2-
targeted therapy) is then administered before definitive surgery (i.e., exci-
sion or mastectomy). Although the use of neoadjuvant chemotherapy
does not improve survival when compared with adjuvant (postoperative)
chemotherapy, it reduces the tumor size sufficiently to permit breast-
conserving surgery in some patients who would otherwise require a mas-
tectomy.7-9 In addition, neoadjuvant treatment provides the opportunity to
obtain early information about tumor responsiveness to a given systemic
therapy regimen.6 Thus, the potential to tailor drug combinations earlier
in the course of treatment is an added benefit of this approach. Given
the increasing use of neoadjuvant treatments, pathologists must become
familiar with chemotherapy-related alterations in both breast cancers
and non-neoplastic breast tissue. Furthermore, it is necessary to have
an understanding of how to evaluate breast specimens obtained after
neoadjuvant chemotherapy in order to properly assess the response to
chemotherapy.
493
Radiation Effects
Radiation-induced changes in the skin of the breast are identical to those
described in irradiated skin from other sites and include epidermal atro-
phy and telangiectasia.10 The nature of these changes is, in part, dependent
upon the interval between irradiation and histological examination.
Patients with invasive cancer and DCIS treated by breast-conserving
surgery and radiation therapy occasionally develop areas of fat necrosis
in the vicinity of the primary tumor site. These lesions may clinically,
mammographically, and macroscopically resemble carcinoma.11 Although
the diagnosis of fat necrosis can be readily made on core-needle biopsy,
whether the changes in the needle biopsy samples are fully representative
of the lesion in the breast may be a matter of concern. In such cases, care-
ful pathologic-radiologic-clinical correlation is essential in order to avoid
the underdiagnosis of breast cancer recurrence. If there is doubt about
whether or not the core-needle biopsy samples are representative, a surgi-
cal excision should be performed.
A characteristic constellation of histological changes is observed in
non-neoplastic breast tissue in patients treated by breast-conserving sur-
gery and radiation therapy.12 The most frequent finding is that of scattered
atypical epithelial cells in the terminal duct lobular unit (TDLU), usually
associated with variable degrees of lobular sclerosis and atrophy. These
atypical cells are large, with enlarged, diffusely hyperchromatic nuclei, gen-
erally small or inconspicuous nucleoli, and finely vacuolated eosinophilic
cytoplasm. The cells often protrude into the lumen of the involved duct or
acinus but do not show evidence of proliferation such as cellular stratifica-
tion, loss of polarity, or mitotic activity (Fig. 19.1, e-Figs. 19.1–19.3).
Radiation effects in the TDLU must be distinguished from carcinoma
to prevent an incorrect diagnosis of tumor recurrence. The distinction
between radiation change and lobular carcinoma in situ is not difficult
because of the characteristic histologic appearance of the latter (i.e., a
monotonous population of relatively small cells that fill and distend small
ducts and acini). The differentiation of radiation-induced changes from
DCIS involving the TDLU (cancerization of lobules) may be more diffi-
cult. However, when DCIS involves the TDLU, there is generally evidence
of cellular proliferation as characterized by cellular stratification, loss of
polarity, and distension of the involved ducts and acini. In addition, the
nuclei in carcinoma cells tend to show irregularly dispersed chromatin
and variably prominent nucleoli. Finally, necrosis of varying degrees may
be seen with DCIS, and mitoses may be apparent. Conversely, the epithe-
lial cells in areas of radiation change generally show maintenance of cel-
lular polarity and cohesion, lack of stratification, a diffuse homogeneous
increase in chromatin, usually small or inconspicuous nucleoli, and no
evidence of necrosis or mitotic activity. In some instances of radiation
change, there may be extensive lobular fibrosis and atrophy with distor-
tion of the lobular architecture. Entrapment of acini containing atypical
Treatment Effects ——— 495
Figure 19.1 Radiation effects in terminal duct lobular unit (TDLU). A: This TDLU shows
minimal sclerosis. Scattered enlarged epithelial cells with large, hyperchromatic nuclei are
present in the acini. B: This TDLU shows more sclerosis of the acini; again scattered atypi-
cal cells are present. C: In this TDLU, lobular sclerosis is more pronounced; the residual
acini containing atypical epithelial cells are compressed and distorted.
Table 19.1 Key Features of Radiation Effects in Non-neoplastic

Breast Tissue
• Scattered atypical epithelial cells in terminal duct lobular units

• Cells often enlarged
• Enlarged, diffusely hyperchromatic nuclei
• Usually small or inconspicuous nucleoli
• Finely vacuolated eosinophilic cytoplasm
• Atypical cells often protrude into the lumen of the involved duct or acinus
• Variable degrees of lobular sclerosis and atrophy
• No evidence of cellular proliferation, such as cellular stratification, loss of
polarity, or mitotic activity
epithelial cells may result in a pseudoinfiltrative pattern, thereby simulat-

ing invasive carcinoma. However, the lobulocentric configuration of such
areas is usually apparent on low-power examination.
Additional pathological changes that may be observed in non-
neoplastic irradiated breast tissue include epithelial atypia in large
(extralobular) ducts, atypical fibroblasts in the stroma, and vascular
changes, such as myointimal hyperplasia in small arteries and prominent
capillary endothelial cells.12 However, these changes tend to be most
pronounced in cases in which the alterations in the TDLU are marked.
It is important to note that stromal fibrosis, a well-recognized feature of
radiation effect in other organs, is so variable in both irradiated and non-
irradiated breasts that it cannot by itself be considered a constant and
reliable histological indicator of prior irradiation in the breast.
The key features of radiation changes in non-neoplastic breast tissue
are summarized in Table 19.1.
Chemotherapy Effects
Histopathologic alterations attributable to chemotherapy may be seen in
both non-neoplastic breast tissue and breast cancers.
Changes in Non-neoplastic Breast Tissue
Non-neoplastic breast tissue shows atrophic changes and a consider-
able reduction in the volume of lobular tissue compared with tissue from
untreated women of similar age. Lobular sclerosis is often present as
well as attenuation of the epithelium lining the ducts and lobules; this
results in the appearance of a prominent myoepithelial cell layer.13-15
Nuclear atypia in the non-neoplastic epithelium similar to that described
earlier after radiation treatment is seen in some patients treated with
chemotherapy .13,14,16
Changes in Breast Cancers

The pathologist has a critical role in assessing the tumor response in
breast cancer patients treated with neoadjuvant chemotherapy because
clinical examination and imaging studies are associated with both high
false-positive and high false-negative rates. Oriented excision specimens
should be inked in multiple colors as described in Chapter 20. Specimen
radiographs are helpful for locating the site of the tumor bed, which at
most institutions is marked with a radiopaque clip at the time of the pre-
treatment diagnostic core-needle biopsy.16,17
Gross examination may reveal a fibrotic area that corresponds to
the tumor bed. Within this area, foci of residual tumor may be detectable
as fleshy tan nodules. However, there may be occasions when the tumor
bed cannot be recognized grossly; correlation with the specimen radio-
graph to guide sampling is helpful in such situations. It is important to
remember that to accurately evaluate tumor response after neoadjuvant
chemotherapy, the tumor bed must be identified and sampled for histo-
logic examination. There are no universally accepted guidelines regarding
the extent to which the tumor bed should be sampled in the absence of
grossly evident residual tumor.16 Submitting one to two tissue blocks per
centimeter of pretreatment tumor size is an appropriate first step; however,
more extensive sampling is required if no residual tumor is found in slides
from the initially submitted blocks.16,17
Microscopically, the tumor bed is recognizable as an area of fibrous or
fibromyxoid stroma, with variable numbers of histiocytes, lymphocytes, and
foreign body–type giant cells, hemosiderin deposition, and absence of nor-
mal mammary glandular elements (Fig. 19.2, e-Figs. 19.4 and 19.5). Having
identified the tumor bed, it is incumbent on the pathologist to make every
effort to identify residual tumor before a diagnosis of complete pathologic
response is rendered. Residual carcinoma may be seen as widely dispersed
single cells, cords, or nests of tumor cells within a fibrotic stroma (Fig. 19.3)
or as a larger mass that has shrunk in size circumferentially, sometimes
with a peripheral rim of fibrotic tissue. Cytologic changes that may be seen
in tumor cells secondary to chemotherapy effect include hypereosinophilic
cytoplasm with vacuolization, nuclear enlargement, multinucleation, and
vesicular chromatin (Fig. 19.4; e-Figs. 19.6 and 19.7).13,15,18,19 In some
cases, it may be difficult to distinguish residual tumor cells from histiocytes
(Fig. 19.5, e-Fig. 19.8); immunostains for cytokeratin and CD68 may be
required in such cases to determine the presence and extent of residual
carcinoma.14,16,19 Prominence of the myoepithelial cell layer surrounding
foci of residual DCIS has been reported.15 The epithelial cells comprising
the residual DCIS may show cytologic changes identical to those described
earlier for invasive carcinoma cells (Fig. 19.6, e-Fig. 19.9).
The size or extent of residual tumor may be reported as the largest
contiguous focus of residual carcinoma or as the number of foci of residual
tumor over the extent of the tumor bed. The histologic type and grade do
not usually change after chemotherapy, though on occasion the nuclei may
B
Figure 19.2 Tumor bed following neoadjuvant chemotherapy. A: Low-power view
illustrating a fibrous stroma containing numerous foamy histiocytes, patchy lympho-
cytic infiltrates, and hemosiderin deposition. No mammary ductal–lobular structures are
present. B: Higher power view demonstrates foamy histiocytes and lymphocytes. No
tumor cells were identified on multiple sections; therefore, this is a complete pathologic
response.
Figure 19.3 Tumor bed following neoadjuvant chemotherapy. In addition to histiocytes

and lymphocytes, a few nests of carcinoma cells are present. This case is an example of a
partial pathologic response.
Figure 19.4 Invasive breast carcinoma with cytologic alterations secondary to neoadjuvant
chemotherapy. The tumor cells show cytoplasmic hypereosinophilia and vacuolization. The
nuclei are enlarged and pleomorphic.
Figure 19.5 Invasive breast carcinoma with chemotherapy effects. Some of the tumor
cells have abundant, finely vacuolated, eosinophilic cytoplasm and relatively small nuclei;
these cells could be mistaken for histiocytes.
appear more pleomorphic, giving the impression of a higher grade lesion.

Margin evaluation of excision specimens may be challenging.16 However,
an effort should be made to accurately report the presence of invasive car-
cinoma, DCIS, and the tumor bed at the specimen margins. Occasionally,
the only residual carcinoma seen is within lymphovascular spaces. Care
Figure 19.6 DCIS with chemotherapy effects. Many of the cells are enlarged and have
abundant eosinophilic cytoplasm and enlarged, bizarre nuclei.
should be taken to distinguish true lymphovascular invasion from invasive

tumor cell nests with stromal retraction artifact since the latter is often seen
after chemotherapy.20 In cases in which no residual carcinoma is identified,
there must be certainty that the tumor bed has been identified and exten-
sively sampled before concluding that there was a complete pathologic
response. Cases in which the post-treatment specimen contains mucin
pools with no tumor cells should be classified as having no evidence of
residual disease. Hormone receptor and HER2 assays should be repeated
on the post-treatment specimen if there is residual tumor present.17
Following neoadjuvant chemotherapy, axillary lymph nodes are usu-
ally small and atrophic. Any lymph nodes identified grossly should be
submitted in their entirety; surrounding tissue should also be included so
that it can be evaluated for the presence of extranodal tumor extension.13
Histologic evaluation of the lymph nodes may reveal pronounced lympho-
cyte depletion. Replacement of a lymph node by fibrosis with or without
associated histiocytes is indicative of a metastasis that has responded com-
pletely to chemotherapy (Fig. 19.7).16,20 However, lymph nodes with these
features should not be considered positive after treatment in the absence
of identifiable tumor cells. In addition to reporting the number of lymph
nodes with histologically evident metastases, in patients treated with
neoadjuvant chemotherapy, the number of lymph nodes with evidence of
treatment response (i.e., fibrosis) with and without tumor cells should also
be documented (Fig. 19.8).
The key features of breast cancer specimens after neoadjuvant che-
motherapy are summarized in Table 19.2.
A
Figure 19.7 Axillary lymph node following neoadjuvant chemotherapy. A: Low-power
view illustrates lymphocyte depletion and stromal fibrosis. B: High-power view illustrates
absence of tumor cells in this fibrotic lymph node. In the absence of tumor cells, this
lymph node should not be considered “positive”; however, these changes are consistent
with a lymph node metastasis with a complete pathologic response.
B
A
Figure 19.8 Axillary lymph node following neoadjuvant chemotherapy. A: Low-power
view illustrates lymphocyte depletion, stromal fibrosis, and metastatic carcinoma. B: High-
power view illustrates residual tumor cells in this fibrotic lymph node. This lymph node
should be classified as positive.
B
Table 19.2 Key Features of Breast Cancer Specimens After

Neoadjuvant Chemotherapy
• Fibrotic area corresponding to the tumor bed may or may not be seen grossly
• Residual tumor may be detectable grossly as fleshy nodules
• Microscopically, the tumor bed consists of an area of fibrous or fibromyxoid
stroma with variable numbers of histiocytes, lymphocytes, and/or foreign
body–type giant cells, as well as hemosiderin deposition and absence of
mammary ductal–lobular structures
• Residual carcinoma may be seen as widely dispersed single cells, cords, or
nests of tumor cells within a fibrotic stroma or as a larger, contiguous mass
of neoplastic cells
• Cytologic changes in tumor cells include hypereosinophilic cytoplasm with
vacuolization, nuclear enlargement, multinucleation, and vesicular chromatin;
tumor cells may be difficult to distinguish from histiocytes in some cases
• Normal terminal duct lobular units show sclerosis and may show cytologic
atypia of epithelial cells
Grading Chemotherapy Response

The pathologic response to neoadjuvant chemotherapy must be accurately
categorized, because this is an important prognostic indicator. Patients
with a complete pathologic response have the most favorable outcome
and those with no pathologic response have the poorest outcome.
A number of different systems have been used for grading the patho-
logic response following neoadjuvant chemotherapy.13,21-26 The two that
will be mentioned here are the Miller-Payne grading system22 and the
Residual Cancer Burden (RCB) system.24
The Miller-Payne system is a five-tiered grading scheme based on the
reduction in the proportion of tumor cellularity when compared with that
of the pretreatment specimen (Table 19.3).22 While this is probably the
most widely used system, it does not include an evaluation of the lymph
node response to treatment. This is of concern because the presence of
residual tumor in lymph nodes appears to be a more important prognostic
factor than the presence of residual disease in the breast.
The RCB system developed by investigators at the MD Anderson
Cancer Center incorporates tumor size in two dimensions, tumor cel-
lularity, percentage of in situ carcinoma, the number of lymph nodes
with metastases, and the size of the largest nodal metastasis.24 These fac-
tors are combined mathematically using a website calculator to produce
a continuous variable, which is used to define four categories of RCB
(www.mdanderson.org/breastcancer_RCB) (Table 19.4). The RCB score
has been shown to correlate with patient outcome.24
Table 19.3 Miller-Payne System for Classification of Neoadjuvant

Chemotherapy–Treated Breast Cancers
The Miller-Payne grade is determined by comparing the histologic features

of the specimen after neoadjuvant chemotherapy with those of the
pretreatment specimen:
Grade 1: No change or some alteration to individual malignant cells, but no
reduction in overall cellularity
Grade 2: A minor loss of tumor cells, but overall cellularity still high; up to
30% loss
Grade 3: Between an estimated 30% and 90% reduction in tumor cells
Grade 4: A marked disappearance of tumor cells such that only small clusters of
widely dispersed individual cells remain; more than 90% loss of tumor
cells
Grade 5: No malignant cells identifiable in sections from the site of the
tumor. Only vascular fibroelastotic stroma remains often containing
macrophages; however, DCIS may be present
Adapted from Ogston KN, Miller ID, Payne S, et al. A new histological grading system to
assess response of breast cancers to primary chemotherapy: prognostic significance and
survival. Breast. 2003;12(5):320-327.
Table 19.4 Residual Cancer Burden System for Classification

of Neoadjuvant Chemotherapy–Treated Breast Cancers
RCB 0: No carcinoma in breast or lymph nodes

RCB I: Partial response, minimal residual disease
RCB II: Partial response, moderate residual disease
RCB III: Chemoresistant, extensive residual disease
Adapted from Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual

breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol.
2007;25(28):4414-4422.
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2303-2312.
10. Fajardo LJ. Pathology of Radiation Injury. New York: Masson Publishing; 1982.
11. Clarke D, Curtis JL, Martinez A, Fajardo L, Goffinet D. Fat necrosis of the breast simu-
lating recurrent carcinoma after primary radiotherapy in the management of early stage
breast carcinoma. Cancer. 1983;52(3):442-445.
12. Schnitt SJ, Connolly JL, Harris JR, Cohen RB. Radiation-induced changes in the breast.
Hum Pathol. 1984;15(6):545-550.
13. Fisher ER, Wang J, Bryant J, Fisher B, Mamounas E, Wolmark N. Pathobiology of pre-
operative chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel
(NSABP) protocol B-18. Cancer. 2002;95(4):681-695.
14. Kennedy S, Merino MJ, Swain SM, Lippman ME. The effects of hormonal and chemo-
therapy on tumoral and nonneoplastic breast tissue. Hum Pathol. 1990;21(2):192-198.
15. Sharkey FE, Addington SL, Fowler LJ, Page CP, Cruz AB. Effects of preoperative che-
motherapy on the morphology of resectable breast carcinoma [see comments]. Mod
Pathol. 1996;9(9):893-900.
16. Pinder SE, Provenzano E, Earl H, Ellis IO. Laboratory handling and histology report-
ing of breast specimens from patients who have received neoadjuvant chemotherapy.
17. Santinelli A, De Nictolis M, Mambelli V, et al. Breast cancer and primary systemic
therapy. Results of the consensus meeting on the recommendations for pathological
examination and histological report of breast cancer specimens in the Marche region.
Pathologica. 2011;103(5):294-298.
18. Honkoop AH, Pinedo HM, De Jong JS, et al. Effects of chemotherapy on patho-
logic and biologic characteristics of locally advanced breast cancer. Am J Clin Pathol.
1997;107(2):211-218.
19. Sneige N, Page D. Diagnostic approaches to the pathology of primary breast cancer
before and after neoadjuvant chemotherapy. Semin Breast Dis. 2004;7:79-83.
20. Sunati S, Lester S. Pathology considerations in patients treated with neoadjuvant che-
motherapy. In: Shin S, Schnitt S, eds. Surgical Pathology Clinics. Philadelphia, PA:
W.B. Saunders Company (in press).
21. Chevallier B, Roche H, Olivier JP, Chollet P, Hurteloup P. Inflammatory breast cancer.
Pilot study of intensive induction chemotherapy (FEC-HD) results in a high histologic
response rate. Am J Clin Oncol. 1993;16(3):223-228.
22. Ogston KN, Miller ID, Payne S, et al. A new histological grading system to assess
response of breast cancers to primary chemotherapy: prognostic significance and sur-
vival. Breast. 2003;12(5):320-327.
23. Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z. Pathologic
response to induction chemotherapy in locally advanced carcinoma of the breast: a
determinant of outcome. J Am Coll Surg. 1995;180(3):297-306.
24. Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual breast cancer
burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007;25(28):
4414-4422.
25. Mittendorf EA, Jeruss JS, Tucker SL, et al. Validation of a novel staging system for
disease-specific survival in patients with breast cancer treated with neoadjuvant chemo-
therapy. J Clin Oncol. 2011;29(15):1956-1962.
26. Rodenhuis S, Mandjes IA, Wesseling J, et al. A simple system for grading the response of
breast cancer to neoadjuvant chemotherapy. Ann Oncol. 2010;21(3):481-487.
20
Specimen Processing,
Evaluation, and Reporting
A variety of breast specimen types are encountered by the surgical pathol-

ogist in daily practice. Appropriate processing and evaluation of these
specimens is necessary in order to obtain the maximum clinically relevant
information.
Core-Needle Biopsies
Core-needle biopsy (CNB) using image-directed guidance methods,
such as stereotactic mammography, ultrasound, and magnetic resonance
imaging, has become the method of choice for the initial evaluation
of non-palpable lesions at many institutions.1-3 CNB, sometimes with
ultrasound guidance, may also be used to sample palpable lesions. Some
CNB devices are spring-loaded and fire a cutting needle into the breast
tissue. Others employ vacuum assistance following needle insertion to
draw tissue into the cutting chamber and to facilitate sample collection.
For any given needle size, the use of vacuum-assisted devices results
in substantially larger specimens than spring-loaded devices. Another
advantage of vacuum-assisted devices is that they permit the collection of
numerous, contiguous samples with a single needle insertion in contrast
to the multiple insertions required to obtain samples using spring-loaded
devices. At many institutions, vacuum-assisted devices are used to sample
microcalcifications, whereas spring-loaded devices are used to sample
mass lesions.
A newer, percutaneous approach utilizes a 15- or 20-mm vacuum-
and radiofrequency-assisted device that removes a mammographically
targeted lesion in a single, intact specimen. In contrast to the fragmented
specimens obtained by CNB, this method permits evaluation of the entire
lesion intact and enables assessment of excision margins.4 However, the
role of this technique in clinical practice remains to be determined.
507
If the indication for CNB is mammographic microcalcifications, a

specimen radiograph should be obtained by the radiologist and the core-
needle samples with the calcifications submitted separately from those
without calcifications in order to identify for the pathologist the cores of
greatest concern. The pathology requisition that accompanies the speci-
men should indicate at a minimum the laterality and location in the breast
from where the CNB specimens were obtained, the indication for biopsy
(i.e., mass, microcalcifications, architectural distortion), the image guid-
ance method, and the size of the needle used.
CNB specimens should be submitted in their entirety for microscopic
evaluation. While there is no universal agreement about the number of
levels that should be cut from blocks of CNB specimens, a sufficient
number of levels should be cut to permit as complete a pathologic–radio-
graphic correlation as possible in every case. We routinely cut three levels
from each block for initial evaluation. If the findings on the initial histo-
logic sections do not account for the findings on the imaging studies, every
attempt should be made to resolve the discrepancy. Examples of com-
mon discrepancies and their possible resolutions are listed in Table 20.1.
However, not all discrepancies can be resolved by further pathologic
evaluation of the CNB specimen and if this occurs, it should be noted
in the final pathology report. For example, if the indication for CNB is a
mass lesion and the CNB samples reveal only unremarkable breast tissue
after multiple levels are examined, the final report should indicate that
histologic findings of a mass-forming lesion are not identified and that
clinical and radiographic correlation are advised. Regularly scheduled
radiology–pathology correlation conferences are of great value to discuss
cases with radiologic–pathologic discordance and to formulate a plan to
resolve such discrepancies.
TABLE 20.1 Common Pathologic–Radiologic Discrepancies in

Core-Needle Biopsies and Their Possible Resolutions
Discrepancy Possible Resolution(s)
Mass on imaging studies, but no • Obtain additional levels

histologic evidence of mass lesion
on core-needle biopsy
Microcalcifications on imaging • Polarize slides to look for calcium
studies; no calcifications on oxalate
histologic sections • Obtain additional levels
• Radiograph paraffin blocks
Suspicious microcalcifications on • Obtain additional levels
imaging studies; rare scattered • Radiograph paraffin blocks
calcifications on histologic sections
Specimen Processing, Evaluation, and Reporting ——— 509
Immunohistochemical evaluation for hormone receptors, HER2, and

other biomarkers can be performed on CNB specimens, and the results
generally correlate well with those on subsequent excision specimens.5-8
In fact, the results of one study suggested that estrogen receptor (ER) and
progesterone receptor (PR) assays are more reliable on CNB specimens
than on excision specimens.7 Assessing these biomarkers on CNB samples
is particularly important for clinical decision making in patients with
breast cancer who will be treated with neoadjuvant chemotherapy. We
routinely perform ER, PR, and HER2 assays on CNB specimens contain-
ing invasive breast cancers and ER on those that show ductal carcinoma
in situ (DCIS).9
Incisional Biopsies
Incisional biopsies of breast masses are rarely performed in current clini-
cal practice, but if received, these should be submitted completely for his-
topathologic examination. As for CNB specimens, these specimens are
suitable for the evaluation of hormone receptor status, HER2, and other
biomarkers.
Excisional Biopsy (Lumpectomy, Partial Mastectomy)

Performed for a Palpable Mass
Careful macroscopic examination of excisional biopsy specimens is an
essential component of their evaluation. Every breast excision should
be measured in three dimensions. The palpable lesion should also be
measured in three dimensions and its relationship to the overlying skin
or underlying fascia or skeletal muscle, if present, should be noted. The
distance between any macroscopically evident tumor and the margins of
excision should also be recorded.
If the specimen has been oriented by the surgeon, the margins
should be inked in six colors prior to sectioning to retain orientation
and to permit the identification of specific margins (superficial/anterior,
deep/posterior, medial, lateral, superior, and inferior) on histopathologic
examination (Fig. 20.1). Unoriented specimens should be inked in a single
color (Fig. 20.2). Following inking, the specimen should be sectioned
through the equatorial plane (“breadloafed”). Unfortunately, even with
careful attention to technical details, ink commonly seeps into the speci-
men and this in turn may create difficulties in the histologic evaluation of
the margins (Fig. 20.3). The seepage of ink can be minimized by blotting
the specimen surface before and after application of ink and then immers-
ing the specimen briefly in Bouin solution, which serves to mordant the
ink. When this method of margin evaluation is used for cases with DCIS
or invasive cancer, a margin is considered positive when the lesion of con-
cern is present at the inked tissue edge (Fig. 20.4, e-Fig. 20.1). There is no
universal agreement among pathologists or clinicians as to what distance
FIGURE 20.1 This specimen was oriented by the surgeon with a long suture on the lateral
margin and a short suture on the superior margin. The specimen was then inked in six
different colors to permit the identification of anterior, posterior, superior, inferior, medial,
and lateral margins on histologic examination (not all colors can be seen in this picture).
FIGURE 20.2 Unoriented breast specimen inked in a single color.

FIGURE 20.3 Ink commonly tracks into the substance of the specimen. In some cases,
this makes it difficult to identify the true margin of excision on histologic evaluation.
between the inked tissue edge and the tumor cells constitutes an adequate
negative margin.10-12 Further, the optimal margin width varies with the
clinical situation. For example, a wider margin is more desirable for a
patient with DCIS who will be treated by excision alone than for a patient
with invasive breast cancer who will be treated by excision, radiation
therapy, and systemic therapy. Therefore, subjective, judgmental terms
such as “close” and “negative” should be avoided in pathology reports.
In our practice, if the lesion is not at the inked tissue edge, we report the
FIGURE 20.4 Invasive carcinoma extending to inked margin of excision.

FIGURE 20.5 Invasive carcinoma extending to within <1 mm of the inked margin
of excision. In cases in which the tumor does not extend to the inked tissue edge,
the distance between the tumor and the margin in millimeters or fractions thereof
is reported; margins such as this are not reported as “negative,” because there is no
universal agreement as to what constitutes a “negative” margin.
closest distance of the lesion to the nearest inked margin(s) in millimeters

or fractions thereof (Fig. 20.5).
An alternative method of margin evaluation consists of shaving off
some or all of the surface of the specimen and submitting these tangen-
tially obtained (en face) sections for histological examination. Although
this method affords sampling of a greater surface area of the specimen, the
shaved margin method may result in patients categorized as having posi-
tive margins when, in fact, there is no cancer at the inked surface of the
specimen (false positives), and this in turn may result in unnecessary fur-
ther surgery or even mastectomy in a patient who may be a suitable can-
didate for breast-conserving treatment.13 In some instances, the surgeon
may remove arcs of additional tissue from the walls of the biopsy cavity
immediately after the lumpectomy specimen has been excised and submit
these specimens to the pathologist individually as separate margins.14
The surgeon should ideally mark with a suture the side of the specimen
that represents the final margin so that surface can be inked and assessed
microscopically.
Arguably the most accurate way to evaluate margins of breast exci-
sion specimens is with whole mount or large format sections with or with-
out three-dimensional reconstruction.15 However, the prolonged process-
ing time and special equipment, supplies, and slide storage requirements
for whole mount sections make this approach impractical at most centers.
Some authors have advocated the use of frozen sections or touch
imprints for the intraoperative evaluation of breast excision margins.16,17
The theoretical advantage of this approach is that it could reduce the need
for a second surgical procedure in patients with positive margins in the

initial excision specimen. However, cutting and interpretation of frozen
sections of breast specimen margins are often problematic. In addition,
when intraoperative margin evaluation is used, the decision to perform
additional breast surgery is unifactorial and depends solely on the status
of the margins determined intraoperatively. In clinical practice, at most
institutions, the need for further surgery is based on consideration of
multiple factors in addition to the status of the margins, including the
specific margin involved, the extent of margin involvement, the presence
of an extensive intraductal component, the status of the axillary lymph
nodes, the use of systemic therapy, the competing risk of distant recur-
rence, tumor size relative to breast size, and the patient’s desire for breast
conservation. Further, even with the use of intraoperative margin evalua-
tion, positive final margins are seen in 20% to 25% of cases.16 Therefore,
the rationale for routinely performing intraoperative margin assessment
can be questioned.18
Needle (WIRE) Localization Excisions for Non-palpable

Lesions
The needle or wire localization technique is used to guide the surgeon
to the area of mammographic abnormality or to the site of a prior CNB
for non-palpable lesions. The most frequent mammographic abnormali-
ties prompting biopsy are microcalcifications, a soft tissue density, or a
combination of the two. Specimen radiography is crucial in the evalua-
tion of these specimens in order to document the presence of the lesion
detected by mammography and/or the radiopaque clip or marker placed
at the site of a prior CNB and to localize the targeted area for histologic
examination (Fig. 20.6). Although the specimen radiograph may also be
of some value in assessing the adequacy of excision of carcinomas, the
overall accuracy of this procedure is fairly low when single-view specimen
radiographs are used.19
After radiography of the intact specimen has demonstrated that the
targeted area is present, this area must be identified by the pathologist.
Some specimens will contain a grossly palpable tumor, in which case fur-
ther efforts to demonstrate the lesion will not be necessary. If, however,
there is no grossly evident lesion, a number of methods can be used to
identify the targeted area within the specimen. One simple method con-
sists of comparing the gross specimen with the specimen radiograph and
placing a pin or needle into the specimen at the site of the mammographic
lesion or clip to permit the identification of its location by the prosector.
Another method consists of performing the initial specimen radiograph
after placing the tissue in a specimen holder that incorporates a grid that
is visible on the radiograph. The holder containing the specimen and the
specimen radiograph are then compared to precisely locate the target
lesion using the X and Y coordinates of the grid. A third method involves
B
FIGURE 20.6 Specimen radiography is a crucial part of the evaluation of needle localization
excision specimens. A: Specimen radiograph showing linear, branching microcalcifications
without an associated mass. Histologic examination of this specimen showed high-grade
ductal carcinoma in situ. B: Specimen radiograph showing a mass lesion with irregular
borders. On histologic examination, this was found to be an invasive ductal carcinoma.
slicing the specimen at 3-mm intervals and obtaining a radiograph of

the sliced specimen.20 The slices on the radiograph can then be labeled
and the tissue slices placed in correspondingly labeled tissue cassettes
to permit one-to-one correlation between the histologic sections and the
radiograph of the sliced specimen (Figs. 20.7 and 20.8). As for excisions
A B C D E F G H
A B C D E F G H
B
FIGURE 20.7 Schematic representation of one method used to process needle
localization breast excision specimens. A: The specimen is inked. Then the inked speci-
men is sliced (“breadloafed”), and the slices are laid out sequentially. B: The slices are then
radiographed. Each slice on the radiograph is labeled and placed in a correspondingly
labeled tissue cassette. The slices with the microcalcifications (D and E) and the adjacent
slices (C and F) are submitted for histologic examination. The remaining tissue is submit-
ted only if sections from the initial slices show atypia or carcinoma.
FIGURE 20.8 Radiograph of sliced specimen. Slices B and C contain the targeted
mammographic microcalcifications.
of palpable lesions, the specimen should be inked prior to sectioning, in

six colors if the specimen is oriented.
Beyond submitting the breast tissue containing the mammographi-
cally targeted area, the extent to which the remaining breast tissue is
sampled for microscopic evaluation varies among different institutions,
particularly in cases with no grossly apparent abnormality. In current
practice, most patients come to needle localization excision following a
CNB, and the extent of sampling of the excision specimen should be guid-
ed by the findings on the CNB and the size of the specimen. For example,
total sequential embedding is ideal for specimens containing CNB-proven
DCIS,21 particularly if the specimen can be entirely submitted in a reason-
able number of cassettes. However, this detailed an examination is prob-
ably not necessary for a CNB-proven intraductal papilloma where initially
submitting only the mammographically targeted area and the immediately
surrounding tissue is sufficient.
In some cases, the initial histologic sections of breast specimens
containing radiographic calcifications fail to reveal microscopic calcifica-
tions, even when the specimen radiograph clearly indicated that the cal-
cifications are contained within the specimen. A similar situation may be
encountered in CNBs performed for microcalcifications. There are several
possible explanations for this. First, the calcifications may be composed
of calcium oxalate rather than the more common calcium phosphate.22,23
Both types of calcium deposits produce the mammographic appearance
of microcalcifications but appear different histologically. The basophilic
nature of calcium phosphate deposits is well known and is easily recog-
nized by pathologists (Fig. 20.9). In contrast, calcium oxalate deposits, on
hematoxylin and eosin (H&E) sections, are pale and refractile and may be
difficult to identify using routine microscopy. Examination of such speci-
mens under polarized light, however, readily demonstrates this type of
FIGURE 20.9 Calcium phosphate–type calcifications in normal lobules.
calcification. Calcium oxalate crystals are most often seen in association

with apocrine cysts (Fig. 20.10, e-Fig. 20.2). If, after examination under
polarized light, there is still no microscopic evidence of calcifications,
other possibilities must be considered. For example, the paraffin blocks
may not have been cut deeply enough to provide histologic sections that
demonstrate the calcifications. To investigate this possibility, the blocks
may themselves be radiographed (e-Fig. 20.3); any block containing radio-
graphic calcifications should be cut more deeply until the calcifications
are microscopically identified. In some cases, larger calcifications may be
displaced out of the block during sectioning and will, therefore, not be
demonstrable on histologic sections. A helpful clue that this has occurred
is the identification of a linear tear in the tissue, representing the area
where a calcium deposit was dragged through the tissue by the microtome
blade. Finally, some calcifications may dissolve when the tissue is placed
into certain fixatives.
It is incumbent on the pathologist to make every effort to identify
histologically the lesion for which the surgical excision was performed
and/or the site of the prior CNB. It should be noted that calcifica-
tions are commonly identified in histologic sections of breast tissue,
even in breast biopsies performed for indications other than mam-
mographic microcalcifications. Therefore, in order to ensure accurate
mammographic–pathologic correlation, the calcifications identified
histologically should correspond to the mammographic calcifications.
For example, the histologic identification of a few small calcifications
B
FIGURE 20.10 Calcium oxalate–type calcifications in an apocrine cyst viewed under
standard transmitted light (A) and polarized light (B).
in normal lobules is not sufficient to explain the presence of linear,

branching microcalcifications detected mammographically. In such
a case, additional effort should be made to identify microscopically
calcifications that more closely correspond to those seen on the mam-
mogram (Fig. 20.11).
B
FIGURE 20.11 A needle localization breast biopsy was performed because of suspicious
(linear, branching) microcalcifications identified on a screening mammogram. Initial
histologic sections showed calcifications present only in lobules (A). However, these
calcifications did not account for the pattern of microcalcifications seen on the patient’s
mammogram. Deeper sections were cut from the paraffin block and these showed
high-grade ductal carcinoma in situ with comedo necrosis and calcifications (B).
Re-excision Specimens
Many patients with DCIS and invasive breast cancer who are considered
candidates for breast-conserving treatment undergo re-excision of the ini-
tial tumor site because of the presence of positive or close margins on the
initial excision specimen. Re-excision specimens should be inked before
sectioning as described previously for excision specimens. In many cases,
hemorrhage, fat necrosis, and fibrosis in the vicinity of the tumor site ren-
der accurate gross evaluation for the presence or absence of residual neo-
plasm extremely difficult if not impossible. This judgment is best deferred
to the permanent sections. There are only limited data addressing the most
cost-effective method to sample re-excision specimens, which are often
large. One study suggested that for grossly benign re-excisions submitting
two tissue blocks for each centimeter of the largest specimen diameter is
sufficient for providing the clinically essential information needed from
these specimens in most cases.24 Adequate representation of the excision
margins is particularly important.
Mastectomy Specimens
Mastectomy specimens should be oriented for the pathologist by the
surgeon, particularly for those that do not have a contiguous axillary tail.
The following features should be recorded before any mastectomy speci-
men is incised: specimen weight; overall dimensions; descriptions and
measurements of the skin, areola, nipple, and any incisions or scars; com-
position of the deep margin (i.e., presence of fascia or muscle); descrip-
tion of the axillary tail (if present); and location and size of any palpable
tumor, with careful attention paid to its relationship to the overlying skin
and deep margin.
Prior to incising the specimen, the deep margin should be inked to
facilitate its identification on histologic sections.
Further examination of the specimen is best performed by plac-
ing the specimen skin side down and making multiple parallel incisions
through the deep aspect 0.5 to 1 cm apart leaving the skin intact. The cut
surfaces of each slice should be examined carefully for the presence of
grossly evident tumor and/or biopsy site/clip.
Sampling for histologic examination should include sections of any
grossly apparent tumor and/or biopsy site, the deep margin, the overly-
ing skin (including scars), the nipple, and random sections of the grossly
unremarkable quadrants of breast tissue. In nipple-sparing mastectomy
specimens, the margin closest to the nipple-areolar complex (retroareloar
margin) should be examined histologically.25 At some institutions, this
is submitted as a separate, designated specimen in addition to the mas-
tectomy specimen. Whether or not a positive superficial margin in skin-
sparing mastectomy specimens is associated with an increased risk of local
recurrence is an unresolved issue.26 Therefore, at this time, the need for
routine inking and evaluation of the superficial margin of such specimens

is unclear and should probably not be done outside the setting of a study.
In a number of situations, more extensive examination of a mas-
tectomy specimen may be required. In patients with DCIS, particularly
those with larger lesions, many sections may be required to exclude the
presence of stromal invasion, a finding of clinical importance. Similarly,
extensive sampling may be required to identify a carcinoma in the breast
in patients with Paget disease of the nipple and in patients who present
with metastatic carcinoma in an axillary lymph node and an “occult” pri-
mary tumor. In these situations, radiography of the mastectomy specimen
(either intact or after it has been sectioned) may be of value in directing
histologic sampling. Finally, mastectomy specimens from patients treated
with neoadjuvant chemotherapy often require more extensive examina-
tion (see Chapter 19).
Reduction MammAplasty Specimens

Reduction mammaplasty specimens typically consist of hundreds to thou-
sands of grams of grossly unremarkable fibrofatty breast tissue. Although
clinically important lesions may be encountered during histologic exami-
nation of such specimens, this is very infrequent. In a recent literature
review that included over 5,300 patients from nine studies, invasive carci-
noma was reported in 0% to 0.6% of patients who underwent reduction
mammaplasty and DCIS or lobular carcinoma in situ was identified in 0%
to 3.5%.27 Atypical hyperplasias (atypical ductal hyperplasia and atypical
lobular hyperplasia) have been reported in 1.4% to 4.4% of mammary
reduction specimens.27
There are no guidelines regarding the extent to which reduction
mammaplasty specimens should be examined histologically. A few stud-
ies have suggested that more extensive sampling should be performed
in women >40 years of age and in those with a prior history of breast
cancer,27-29 but these studies have not provided recommendations for a
specific number of sections that should be submitted.
At our institution, if careful gross examination of a reduction mam-
maplasty specimen reveals no abnormalities, two blocks of fibrous paren-
chyma per breast are routinely submitted for histologic examination. If
histologic examination reveals a clinically important lesion, 20 additional
sections are then submitted from that side. Unfortunately, if DCIS or inva-
sive carcinoma is identified in such a specimen, neither the location in the
breast nor the adequacy of excision can be determined.
Axillary Lymph Node Dissection/Sampling

Axillary lymph nodes may be submitted to the pathologist either as an
axillary dissection specimen or as part of mastectomy. In either case, initial
pathologic examination should include gross inspection and palpation for
lymph nodes. The number, size range, and gross appearance of the identi-
fied nodes should be recorded. Lymph nodes should be sectioned at ≤2
mm intervals. Although lymph nodes with macroscopically evident meta-
static carcinoma may be sampled, grossly uninvolved lymph nodes should
be submitted in their entirety for histologic evaluation. At most institu-
tions, only a single H&E-stained section is examined for each lymph node
block of non-sentinel nodes.
Sentinel Lymph Node Biopsy

Sentinel lymph node biopsy is the procedure of choice for the initial
evaluation of the axillary lymph nodes in patients with invasive breast
cancer as well as for those with extensive DCIS.30,31 While the evaluation
of sentinel lymph node biopsies is now part of routine pathology practice,
the results of recent clinical trials have called into question the manner in
which these lymph nodes should be evaluated.
Results from the ACOSOG Z0011 trial indicated that a completion
axillary dissection is unnecessary in many women with T1 and T2 breast
cancer who have one or two positive sentinel lymph nodes.32 The impli-
cation of this finding is that there is no need to perform intraoperative
evaluation of sentinel lymph nodes in women who fulfill the criteria that
would have permitted entry into that trial.33
Further, results from the NSABP B3234 and ACOSOG Z001035 tri-
als have suggested that the identification of micrometastases and isolated
tumor cells in sentinel lymph nodes has little or no prognostic significance
in current clinical practice where most patients receive some type of
systemic therapy. These results support the view that there is no need to
perform adjunctive studies, such as immunohistochemistry for cytokeratin
or molecular studies to detect expression of epithelial-related genes, to
identify these small tumor deposits.33,36
Given the foregoing, sentinel lymph nodes should be sectioned at
intervals of ≤2 mm and submitted in their entirety for permanent sec-
tions, as discussed previously for non-sentinel lymph nodes. There should
theoretically be no need to obtain multiple levels on sentinel lymph node
blocks if the submitted tissue slices are ≤2 mm in thickness, since the main
goal in examination of these lymph nodes in current clinical practice is the
identification of macrometastases.30 However, at some institutions, there
may be considerable variability in the thickness of the submitted sections
such that obtaining multiple levels remains a prudent approach. At our
institution, we currently obtain three H&E-stained levels from each sen-
tinel lymph node block. Immunostains for cytokeratin are used only to
characterize foci that are suspicious for, but not unequivocally diagnostic
of, malignancy on H&E-stained sections. They are not performed as a
matter of routine.
Surgical Pathology Reporting

Core-Needle Biopsies
The final pathology report for CNB specimens should provide sufficient
information for further clinical decision making, but overdiagnosis should
be avoided. In particular, diagnoses such as microinvasion and lympho-
vascular invasion should not be rendered in the absence of unequivocal
findings, and borderline intraductal proliferative lesions should not be
overinterpreted as DCIS. For CNB specimens that demonstrate invasive
breast cancer, in addition to reporting the histologic type, a minimum size
should be reported (based on microscopic measurement of the single larg-
est length of invasive breast cancer on any single core) and a provisional
histologic grade provided (although this may not always accurately reflect
the histologic grade as determined on subsequent excision specimens).37,38
In CNB specimens with DCIS, nuclear grade, architectural patterns and
the presence of comedo necrosis should be noted. When CNB is per-
formed for mammographic microcalcifications, the report should indicate
the location of the calcifications identified histologically.
Biopsies with Benign Changes
Terms such as fibrocystic disease and fibrocystic change are not clinically
meaningful because they encompass a heterogeneous group of processes,
some physiologic and some pathologic, with widely varying cancer risks.
Therefore, their use in surgical pathology reports of benign breast biop-
sies is strongly discouraged. In our practice, for both CNB and excisional
biopsies that show benign changes without a discrete lesion, such as a
fibroadenoma or a papilloma, the benign lesions present are listed in
descending order of importance with regard to their level of breast cancer
risk. If the indication for biopsy was mammographic microcalcifications,
the specific lesion(s) or normal histologic structures with which calcifica-
tions are associated are noted.
Ductal Carcinoma In Situ
The surgical pathology report for excision specimens containing DCIS
should include, in addition to the diagnosis, information needed for thera-
peutic decision making. This includes nuclear grade (low, intermediate,
or high), the presence of necrosis (comedo or punctate), and architectural
pattern(s).39,40 The specimen size, a measurement or estimate of the lesion
size/extent, the location of calcifications (DCIS only, normal/benign
breast tissue only, or both), and the status of the surgical margins should
also be documented.39,40 If ancillary studies are in progress (e.g., hormone
receptor assays), this should also be documented in the final report. The
use of a checklist or synoptic report increases the likelihood that all clini-
cally relevant information will be included and facilitates transmission of
information to the clinicians.39,40 A protocol and checklist for the evalu-

ation of specimens with DCIS is available from the College of American
Pathologists (www.cap.org).
Invasive Breast Cancer
As for DCIS, the surgical pathology report for excision specimens contain-
ing invasive breast cancer should include, in addition to the diagnosis,
information needed for staging and therapeutic decision making. At a min-
imum, every surgical pathology report for specimens containing an inva-
sive breast cancer should include the specimen size, tumor size, histologic
type, histologic grade, presence and extent of coexistent DCIS, presence
or absence of lymphovascular invasion, the status of the microscopic mar-
gins, and lymph node status (if applicable).41,42 In addition, for specimens
removed because of the presence of mammographically detected micro-
calcifications, it is important to note the location of the calcifications. If
ancillary studies are in progress (e.g., hormone receptor assays, HER2,
other biomarkers), this should also be documented in the final report. As
for DCIS, the use of a checklist or synoptic report is encouraged to facili-
tate clear communication of clinically relevant information. A protocol
and checklist for the evaluation of specimens with invasive breast cancer
is available from the College of American Pathologists (www.cap.org).
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Index
Note: Locators following ‘f’ and ‘t’ refer to figures and tables respectively.
A secretory, 220–221, 220f–221f

Acini, 2, 3f tubular, 219–220, 219f–220f
Adenoid cystic carcinoma, 321–325 ADH. See Atypical ductal hyperplasia
biomarkers/molecular pathology, 324 (ADH)
clinical course of, 324–325 Adolescent breast lesions. See Children/
clinical presentation, 321 adolescent breast lesions
differential diagnosis, 325 ALCL. See Anaplastic large cell
gross pathology, 321 lymphomas (ALCLs)
histopathology, 321–324 Aldehyde dehydrogenase (ALDH1), 9
basaloid features, 323, 323f–324f American College of Surgeons Oncology
cribriform/trabecular pattern, Group (ACOSOG) Z0011
321, 322f trial, 475
prognosis for, 324–325 American Joint Commission on Cancer
Adenolipomas, 410 pathologic lymph node staging, 471,
Adenomas, 182–185 472t–473t, 473
apocrine, 185 tumor staging, 336, 337t
ductal/pleomorphic, 185 American Society of Clinical Oncology
lactating, 183–184, 183f, 184f (ASCO), 342
tubular, 182, 183f Amyloid tumor, 419
Adenomyoepithelioma, 259, 260f, Amyloidosis, 52
261–262, 261f Anatomy. See Breast anatomy/histology
Adenosis Anaplastic large cell lymphomas
apocrine, 211–212, 211f (ALCLs), 420
atypical apocrine, 211–212, 212f Angiolipomas, 408, 409f
blunt duct, 221 cellular, 408, 410f
microglandular, 212–218, 213f, 214f, Angiomatosis, 391–392, 391f
215f Angiosarcoma, 392–400, 392f
atypical, 216, 216f histologic features, 393, 393t, 394f,
differential diagnosis, 218 395f, 396f–397f
features of, 218t MYC amplification, 398
invasive carcinomas, 217, 217f–218f post-irradiation cutaneous, 398, 399f
treatment, 218 post-radiation angiosarcomas, 395, 398
sclerosing, 202–210, 203f, 204f, Apocrine adenoma, 185
206f–207f Apocrine adenosis, 211–212, 211f
calcifications, 205f Apocrine differentiation, carcinomas
DCIS/LCIS in, 208, 208f–209f, with, 328–330
209f–210f biomarkers/molecular pathology, 328
features of, 209, 210t clinical course of, 329
nodular adenosis and adenosis clinical presentation, 328
tumor, 205, 207f–208f differential diagnosis, 330
527
528 –––––– Index
Apocrine differentiation (continued) Biopsy site changes, 25–35

gross pathology, 328 core-needle biopsy (CNB), 28–35, 29f,
histopathology, 328, 329f 30f, 31f
prognosis for, 329 ductal carcinoma in situ (DCIS),
Apocrine metaplasia, 55, 55f, 56f 30–35, 31f, 32f, 33f–34f, 35f
Atypical apocrine adenosis, 211–212, papillary lesions, 28, 28f
212f post-biopsy changes, 25, 26f
Atypical ductal hyperplasia (ADH), reactive spindle cell nodules (RSCNs),
70–79, 464 25–27
with calcification, 73f squamous metaplasia, 27, 27f
clinical course of, 79 Blunt duct adenosis, 221
vs. DCIS, 73–74, 76f, 77–78, 100, 101t Bowen disease (squamous cell carcinoma
differential diagnosis, 100, 101t in situ), 444–445
features of, 71f, 72f, 74f, 75f, 77f, 78t BRCA1
immunophenotype/genetics, 78–79, 78f breast cancers from mutations in, 309
prognosis for, 79 gene expression profiling with, 348t
Atypical lobular hyperplasia (ALH), 123, medullary carcinoma from mutations
164–168 in, 309
clinical course of, 166, 168 BRCA2, 333, 457t
clinical presentation, 164 male breast cancer risk with mutations
differential diagnosis, 168 in, 456, 457t
histopathology, 164–165, 165f, Breast anatomy/histology, 1–21
166f, 167f arterial supply in, 1
prognosis for, 166, 168 basal lamina in, 9, 10f
Atypical medullary carcinomas. See ductal-lobular system in, 2–3, 6f
Medullary carcinoma estrogen receptor (ERα, ERβ), 13,
Atypical vascular lesions, 400–402, 15–16, 15f
401f, 402t gross anatomy of, 1, 3f
Axillary lymph nodes. See Lymph nodes, intralobular/interlobular stroma, 10,
axillary 11f, 12f
lobule types, 11–13
B lymphatic drainage in, 1
Basal-like carcinoma, 217, 347 mammary ductal-lobular system, 5, 6f
Benign mixed tumors. See Pleomorphic menopause in, 14f, 19
adenoma menstrual cycle, morphological
Biomarkers changes, 13, 14t
for adenoid cystic carcinoma, 324 multinucleated giant cells in, 10, 12f
with apocrine differentiation, 328 myoepithelial cell layer, 5–9, 7f, 8f, 9f
with ductal carcinoma in situ (DCIS), nipple-areolar complex, 16–18, 16f, 17f
94–98, 97f pregnancy/lactation in, 18–19
for invasive cribriform carcinoma, 302 progesterone receptor expression in, 9
for invasive ductal carcinoma, 285–286 segments in, 3–4
for invasive lobular carcinoma, stroma in, 2, 4f
293–294 terminal duct lobular unit (TDLU),
for invasive micropapillary 10, 10f
carcinoma, 314 terminal ductules in, 2, 3f
for medullary carcinoma, 309–311 tubercles of Montgomery in, 16,
for metaplastic carcinoma, 320 18, 18f
for microinvasive carcinoma, 276, 276f type IV collagen and laminin, 9, 10f
for mucinous carcinoma, 305 Breast-conserving therapy, 98
with neuroendocrine features, 326 Breast infarction, 52
for tubular carcinoma, 298 Burkitt lymphoma, 420
Index ——— 529
C Children/adolescents, breast lesions in,

Capsular synovial hyperplasia, 37 462–469
Carcinoma, clinging, 115 juvenile fibroadenoma, 464
Carcinomas juvenile papillomatosis, 464, 465f,
with apocrine differentiation, 328–330 466–467, 466f, 467t
biomarkers/molecular juvenile (virginal) hypertrophy, 464
pathology, 328 metastatic tumors, 469
clinical course of, 329 papillary duct hyperplasia, 467
clinical presentation, 328 secretory carcinoma, 467–469
differential diagnosis, 330 Chondrolipomas, 186
gross pathology, 328 Chondro-osseous tumors, 413
histopathology, 328, 329f Chronic lymphocytic leukemia (CLL),
prognosis for, 329 423, 423f, 424f
with medullary features, 307–311 Churg-Strauss syndrome, 50
biomarkers/molecular pathology, CLL. See Chronic lymphocytic
309–311 leukemia (CLL)
clinical course of, 311 CNB. See Core-needle biopsy (CNB)
clinical presentation, 309 Collagenous spherulosis, 262–263, 263f
differential diagnosis, 310f, 311 College of American Pathologists
gross pathology, 309 (CAP), 342
histopathology, 309 Colloid carcinoma. See Mucinous
prognosis for, 311 carcinoma
with neuroendocrine features, 325–328 Columnar cell change
biomarkers/molecular pathology, 326 classification/histologic features, 107,
clinical course of, 326–327 108f, 117t
clinical presentation, 325 clinical course of, 123, 125f–126f
differential diagnosis, 327–328 core-needle biopsy (CNB), 130–131, 131t
gross pathology, 326 differential diagnosis, 128–130
histopathology, 326, 327f excisional biopsy, 131–132
prognosis for, 326–327 immunophenotype/genetics, 118–121,
WHO classification, 326 119f, 120f
Carney syndrome, 172, 175 prognosis for, 123, 125f–126f
CD117 (c-kit), expression of, 324 Columnar cell hyperplasia
Cellular fibroadenoma, 175, 178f classification/histologic features,
CGH. See Comparative genomic 107–108, 109f–110f, 110,
hybridization (CGH) 111f, 117t
Chemotherapy effects core-needle biopsy (CNB),
breast cancer changes with, 497–503 130–131, 131t
DCIS, 497, 500, 500f differential diagnosis, 128–130
gross examination, 497 excisional biopsy, 131–132
invasive breast carcinoma with immunophenotype/genetics, 118–121
cytologic alterations, 499f, 500f Comparative genomic hybridization
neoadjuvant chemotherapy, 497, (CGH), 150
498f, 499f, 501, 501f–502f, Complex fibroadenoma, 180, 180f
502f–503f, 503t Core-needle biopsy (CNB), 28–35, 29f,
grading response, 504–505 30f, 31f, 507–509
Miller-Payne grading system, 504, atypical ductal hyperplasia, 73–74,
504t 77, 79
Residual Cancer Burden (RCB) axillary lymph nodes, 480
system, 504, 505t columnar cell change, 130–131, 131t
non-neoplastic breast tissue changes columnar cell hyperplasia,
with, 496 130–131, 131t
530 –––––– Index
Core-needle biopsy (CNB) (continued) low-grade, 83–86, 83f–84f, 85f, 86t

ductal carcinoma in situ (DCIS), lymphovascular invasion vs., 102–103
30–35, 31f, 32f, 33f–34f, 35f of male breast, 456
fibroepithelial lesions, 199 papillary, 243–247, 244f, 245f
fibromatosis, 373, 374f–375f with dimorphic cell population,
flat epithelial atypia (FEA), 245, 246f
130–131, 131t features of, 247t
immunohistochemical evaluation, 509 from intraductal papilloma,
lobular neoplasia, 151–152 distinguishing features, 243t
mammographic microcalcifications, 508 papilloma with, 239–243,
papillary lesions, 255–257 240f–241f, 242f
with intraductal papilloma, 255, 256f pathology, 80
with micropapilloma, 255, 256f–257f prognosis for, 98–99, 99t
pathologic-radiologic discrepancies/ unusual types, 93–94, 95f, 96f
resolutions, 508, 508t usual ductal hyperplasia (UDH)
use of vacuum-assisted devices, 507 vs., 100
Cowden syndrome, 335, 457t Ductal-lobular system, 2–3, 6f
Cutaneous appendageal and salivary Ductogram (galactogram), 2, 5f
gland-type tumors, 425–426
Cystic hypersecretory hyperplasia, 93 E
E-cadherin
D invasive ductal carcinomas with, 283
DCIS. See Ductal carcinoma in situ invasive lobular carcinomas with, 286,
(DCIS) 287f, 288, 289, 295
Dirofilarial infection, 52 LCIS with, 101, 136, 137f, 138, 138f,
Ductal adenoma, 185, 257, 258f 139–142, 153t, 154f, 146f,
Ductal carcinoma in situ (DCIS), 30–35, 158, 160
31f, 32f, 33f–34f, 35f, 79–99 DCIS distinguished from, 101, 263
apocrine, 92–93, 92f Encapsulated papillary carcinoma,
atypical ductal hyperplasia (ADH) in, 247–250, 248f
73–74, 76f, 77–78, 100, 101t features of, 250t
biomarkers/genetics with, 94–98, 97f intracystic or encysted papillary
classification, 80–83, 80f–81f, 82f carcinoma, 247
architectural patterns of DCIS, 80, with invasive ductal carcinoma,
80f–81f 249, 249f
nuclear grading of DCIS, 80, 82f Endocrine DCIS, 93
clinical course of, 98–99, 99t Eosinophilic mastitis, 50–51, 51f
clinical presentation, 79 ERα. See Estrogen receptor (ERα)
core-needle biopsy (CNB), 30–35, 31f, ERβ. See Estrogen receptor (ERβ)
32f, 33f–34f, 35f Erosive adenomatosis. See Nipple
cystic hypersecretory, 93, 94f adenoma
differential diagnosis, 100–103, 102f Estrogen receptor (ERα), 13, 15f, 16
endocrine, 93 cells of myofibroblastoma, 381, 381f
flat epithelial atypia (FEA), 123, 124f columnar cell lesions with, 120f
high-grade, 86–89, 86f, 87f, 88f, 89f DCIS with, 85, 97f
intermediate-grade, 89–90, 90f, 91f immunostains for in male breast
intraductal proliferative lesions, 79–99 cancer with, 458f, 459t
intraductal proliferative lesions vs., invasive breast cancer prognosis from,
100–101 341–342, 343f, 456
invasive carcinoma vs., 102 LCIS with, 148
LCIS vs., 101, 102f, 155–164, 156f, Estrogen receptor (ERβ), 13, 15–16
157f, 158f–159f, 160t fibroadenoma with, 175
Index ——— 531
Excisional biopsy, 509–513 Fibromatosis, 373–376, 373f–374f

columnar cell lesions with, core-needle biopsy, 373, 374f–375f
131t, 131 expression of b catenin, 375, 375f
flat epithelial atypia with, 131t, features of, 376t
131–132 Fine-needle aspiration
margin evaluation in, 509, 510f, displaced epithelium, 480
511f, 512f fibroepithelial lesions following, 28
shaved margin method, 512 papillary lesions following, 236
specimen processing for palpable mass Flat epithelial atypia (FEA)
with, 509–513, 510f–512f and ADH, 122, 122f–123f
unoriented breast specimen in single classification/histologic features, 110,
color, 509, 510f 111f–112f, 112–116, 113f, 114f,
use of frozen sections or touch 115f, 116t, 117t
imprints, 512–513 clinical course of, 122–123, 122f–123f,
whole mount or large format 124f, 125f, 127, 127f, 128t
sections, 512 core-needle biopsy (CNB),
Extralobular ducts, 2, 3f 130–131, 131t
Extramedullary hematopoiesis, 425, and DCIS, 123, 124f
425f–426f, 462, 463f differential diagnosis, 128–130
excisional biopsy, 131–132
F immunophenotype/genetics, 118–121,
Familial adenomatous polyposis, 373 118f, 119f, 120f, 121f
Fascicular PASH, 404 and lobular carcinoma,
Fat necrosis, 35–36, 36f 125f–126f, 127f
Fibroadenoma, 171–179 and tubular carcinoma, 125f, 127f
cellular fibroadenoma, 175, 178f prognosis for, 122–123, 122f–123f,
features of, 179t 124f, 125f, 127, 127f, 128t
intracanalicular pattern, 171, 173f Florid adenomatosis. See Nipple
multinucleated giant cells, 175, adenoma
178f–179f Florid LCIS, 150
myxoid fibroadenomas, 172, Florid papillomatosis of nipple. See
175, 177f Nipple adenoma
pericanalicular pattern, 171, 174f Fluorescence in situ hybridization
prominent intracanalicular pattern, (FISH), 343
171–172, 175f Foreign body-type granulomatous
in situ carcinomas, 172, 176f inflammation, 36–38
Fibroadenomatoid hyperplasia, mammary implant capsule, 36–37,
182, 182f 37f, 38f
Fibroadenomatous change, 182, 182f silicone gel implants, 37
Fibroadenoma variants, 180–182
complex fibroadenoma, 180, 180f G
fibroadenomatous change, 182, 182f Galactocele, 51–52
juvenile fibroadenoma, 180, 181f Gardner syndrome, 373
Fibroepithelial lesions, 171–199 Gestational macromastia, 52
adenomas, 182–185 Giant cells
on core-needle biopsy, 199 foreign body-type, 29, 29f, 36–37, 37f,
fibroadenoma, 171–179 376, 432f, 484, 497
fibroadenoma variants, 180–182 multinucleated, 10, 12f, 175, 403
mammary hamartoma, 185–186, osteoclast-like, 331–332, 332f
185f–186f stromal, 178f, 187
phyllodes tumor, 186–199, 187f, 188f, Giant fibroadenoma, 180
189f, 190t Granular cell tumor, 411–412, 411f–412f
532 –––––– Index
Granulomatous inflammation, 489 Inflammatory carcinoma, 330–331

Granulomatous lesions, 46–49 dermal lymphatic spaces, 330f
idiopathic/lobular granulomatous secondary inflammatory
mastitis, 47–48, 48f, 49t carcinoma, 331
sarcoidosis, 46–47, 47f Inflammatory lesions
tuberculous mastitis, 46, 46f acute mastitis, 52
Gynecomastia, 451–455 apocrine metaplasia, 55, 55f, 56f
abortive lobule formation, biopsy site changes, 25–35
453–454, 455f breast infarction, 52
atypical ductal hyperplasia, 455, 456f diabetic mastopathy, 44–46, 45f, 46t
histologic features, 451, 452f, 454t dirofilarial infection, 52
periductal fibrosis, 453, 453f eosinophilic mastitis, 50–51, 51f
pseudoangiomatous stromal fat necrosis, 35–36
hyperplasia, 453, 454f foreign body-type granulomatous
inflammation, 36–37
H mammary implant capsule, 36–37,
Hemangiomas, 388–390, 389f 37f, 38f
perilobular, 387–388, 388f silicone gel implants, 37
venous, 390–391 galactocele, 51–52
Hematopoietic tumors. See Lymphoid/ gestational macromastia, 52
hematopoietic tumors granulomatous lesions, 46–49
HER2 protein idiopathic granulomatous mastitis,
breast cancer prognosis with, 47–48, 48f, 49t
342–345, 344f IgG4-related sclerosing mastitis, 49–50,
high-grade DCIS lesions, 97, 49f–50f
97f, 276f juvenile (virginal) hypertrophy, 52
Paget cells, 442, 443f, 445t lobular granulomatous mastitis, 47–48,
pleomorphic LCIS, 149, 149f, 294 48f, 49t
Hereditary breast cancer, 333–335 lymphocytic mastopathy, 44–46,
BRCA1/BRCA2 genes, 333, 45f, 46t
334f, 335 mammary duct ectasia, 39–44, 39f, 40f,
Hereditary desmoid syndrome, 373 41f, 42f, 43f, 44t
High-molecular-weight cytokeratins Mondor disease, 52
(HMW-CKs), 118 Inflammatory myofibroblastic
Histologic grade tumor, 413
invasive breast cancer, 524 Intracystic or encysted papillary
invasive ductal carcinoma, 284, 284f carcinoma, 247
Nottingham system for determining, Intraductal papilloma, 229–238, 231f,
338, 338t 232f
use of, 338–339 apocrine metaplasia in, 232, 233f
Hodgkin disease, 420 central/peripheral papillomas, 229,
Hypereosinophilic syndrome, 50 229f–230f
Hyperestrogenemia, 456 with collagenous spherulosis, 232,
Hyperplasia of usual type. See Usual 235f
ductal hyperplasia (UDH) features of, 238t
with infarction, 236, 237f–238f
I myoepithelial cell hyperplasia in, 232,
Idiopathic granulomatous mastitis, 234f
47–48, 48f, 49t from papillary DCIS, distinguishing
IgG4-related sclerosing mastitis, 49–50, features, 243t
49f–50f with sclerosis (sclerosing papilloma),
Incisional biopsies, 509 236, 236f–237f
Index ——— 533
with usual ductal hyperplasia (UDH), lymphovascular invasion, 339–341,

232, 233f 339f, 340f, 341f, 341t, 342f
variants of, 257–263 molecular prognostic and predictive
adenomyoepithelioma, 259, 260f, tests, 346–347
261–262, 261f PR status, 341–342, 343f
collagenous spherulosis, tumor size, 336
262–263, 263f secretory carcinoma, 331
ductal adenoma, 257, 258f tubular carcinoma, 297–300
pleomorphic adenoma, 257, 259, tubulolobular carcinoma, 297, 297f
259f, 260f Invasive carcinomas with medullary
Intraductal proliferative lesions, 58–102 features. See Medullary carcinoma
atypical ductal hyperplasia (ADH), Invasive cribriform carcinoma, 300–302
70–79 biomarkers/molecular pathology, 302
ductal carcinoma in situ (DCIS), 79–99 clinical course of, 302
usual ductal hyperplasia (UDH), 58–70 clinical presentation, 300
Invasive breast cancer, 282–351 differential diagnosis, 302
adenoid cystic carcinoma, 321–325 histopathology, 300–302, 301f
apocrine differentiation in carcinomas, prognosis for, 302
328–330 Invasive ductal carcinoma, 283–286
choriocarcinomatous features, 333 biomarkers/molecular pathology,
extramammary metastatic, 349–351 285–286
hereditary, pathologic features, clinical course of, 286
333–335 clinical presentation, 283
inflammatory carcinoma, 330–331 differential diagnosis, 286
invasive carcinomas with ductal/ gross pathology, 283, 283f
lobular features, 295–297 histopathology, 284–285, 284f–285f
invasive cribriform carcinoma, with medullary features. See Medullary
300–302 carcinoma
invasive ductal carcinoma, 283–286 prognosis for, 286
invasive lobular carcinoma, 286–295 Invasive lobular carcinoma, 286–295
invasive micropapillary carcinoma, biomarkers/molecular pathology,
311–314 293–294
invasive papillary carcinoma, 330 clinical course of, 294–295
lipid-rich and glycogen-rich clinical presentation, 286–287
carcinomas, 332 differential diagnosis, 295
medullary carcinoma, 307–311 gross pathology, 287
metaplastic carcinoma, 315–321 histopathology, 287–293, 287f–288f,
molecular classification of, 347–349 289f, 290f–291f
mucinous carcinoma, 303–307 alveolar variant, 291, 292f
mucinous cystadenocarcinoma, 333 histiocytoid variant, 291, 294f
neuroendocrine features in pleomorphic variant, 291, 293f
carcinomas, 325–328 solid variant, 291, 292f
osteoclast-like giant cells with, prognosis for, 294–295
331–332 Invasive micropapillary carcinoma,
pleomorphic carcinoma, 332–333 311–314
prognostic/predictive factors, 335–347 biomarkers/molecular pathology, 314
axillary lymph node status, 335–336 clinical course of, 314
combining prognostic factors, 346 clinical presentation, 312
ER status, 341–342, 343f differential diagnosis, 314
HER2 status, 342–345, 344f gross pathology, 312
histologic grade, 338–339 histopathology, 312–314, 312f–313f
histologic type, 337 prognosis for, 314
534 –––––– Index
Invasive papillary carcinoma, 254–255, features of, 139–142, 140f, 141f,

254f–255f, 330 142f, 145, 145f, 146f, 147f–148f
Isolated tumor cells (ITCs), 335, 471 mixture of type A/B cells, 139, 139f
ITC. See Isolated tumor cells (ITCs) pleomorphic LCIS, 143–144, 143f,
144f–145f
J type A cells, 137–138, 137f–138f
Juvenile fibroadenoma, 180, 181f, 464 type B cells, 138–139, 138f–139f
Juvenile papillomatosis, 464, 465f, immunophenotype/genetics, 148–150,
466–467, 466f, 467t 149f, 150f
Juvenile (virginal) hypertrophy, 52, 464 prognosis for, 151–152, 153f
sclerosing adenosis, 208, 208f–209f,
K 209f–210f
Klinefelter syndrome, 451, 456, 457t Lobular granulomatous mastitis, 47–48,
48f, 49t
L Lobular neoplasia, 136, 151
Lactating adenoma, 183–184, Lobules, 2, 3f
183f, 184f Low-grade adenosquamous carcinoma,
Lapatinib (Tykerb), 342 318–320, 319f
LCIS. See Lobular carcinoma in situ Luminal A, 98, 282, 314, 348t, 349t
(LCIS) Luminal B, 98, 282, 314, 348t, 349t
Li-Fraumeni syndrome, 335 Lumpectomy, specimen processing for,
Lipid-rich and glycogen-rich 509–513, 510f–512f
carcinomas, 332 Lymph nodes, axillary, 471–491
Lipoma, 408–410 benign epithelial inclusions, 485–488
adenolipomas, 410 glandular-type inclusions, 485,
angiolipomas, 408, 409f 486f–487f
cellular angiolipoma, 408, 410f metastatic low-grade breast
Lobular carcinoma in situ (LCIS), carcinoma, 488, 489f
136–164 Müllerian-type inclusions, 485
clinical course, 151–152, 153f squamous-type inclusions, 485,
clinical presentation, 137 487f–488f
DCIS vs., 155–164, 156f, 157f, displaced epithelium, 480–481
158f–159f, 160t fine-needle aspiration or core-needle
collagenous spherulosis vs. biopsy, 480
cribriform pattern in, 161, dissection/sampling, 521–522
162f, 163 granulomatous inflammation, 489
comedo necrosis vs., 147f–148f, 161 hemangiomas, 488, 491f
pagetoid LCIS vs. pagetoid, 163, megakaryocytes, 488, 490f
163f–164f for metastatic carcinoma, assessment
pleomorphic LCIS vs. high-grade, ACOSOG Z0011 trial, 475
158f–159f, 161 cytokeratin staining, 477, 479–480
small cell, solid DCIS in, 160, histologic features of lymph node
160f–161f, 160t metastases, 475–480, 476f–479f
differential diagnosis isolated tumor cells, 473, 474f, 475f
ALH in, 155 macrometastases, 477, 478f
artifactual dyshesion in, 152 pathologic staging, 471–475
benign cells in, 152–153 pN staging, 471, 472t–473t
classical vs. pleomorphic LCIS, sentinel lymph node, 475, 476f
153–154 nevus cell aggregates, 481–483, 482f,
invasive carcinoma in, 155 483f
florid, 150 silicone lymphadenopathy, 484–485,
histopathology, 137–148 484f–485f
Index ——— 535
Lymphoblastic lymphomas, 420 histologic features of, 44t

Lymphocytic mastopathy/diabetic ochrocytes with, 40, 43f
mastopathy, 44–46, 45f, 46t periductal fibrosis with, 41, 43f
Lymphoid/hematopoietic tumors Mammary hamartoma, 185–186,
chronic lymphocytic leukemia (CLL), 185f–186f
423, 423f, 424f Mammary not otherwise specified-type
extramedullary hematopoiesis, 425, sarcoma, 417
425f–426f Mammography, 39
lymphoma, 420–422 Marking devices, 28, 29f, 30
implant-associated ALCL, 420–421 collagen plug, 28, 29f
large cell lymphomas, 420 core-needle biopsy using, 28
primary breast lymphomas, 420, Mastectomy
421f, 422t partial, for palpable mass, 509–513,
plasma cell dyscrasias, 422 510f–512f
pseudolymphoma, 425 specimen processing for, 520–521
Rosai-Dorfman disease, 422 Mastitis, acute, 52
small lymphocytic lymphoma (SLL), Medullary carcinoma, 307–311
423, 424f biomarkers/molecular pathology,
Lymphoma, 420–422 309–311
implant-associated ALCL, 420–421 clinical course of, 311
large cell lymphomas, 420 clinical presentation, 309
primary breast lymphomas, 420, differential diagnosis, 310f, 311
421f, 422t gross pathology, 309
histopathology, 309
M prognosis for, 311
Macrometastases, 471 Megakaryocytes, 488, 490f
Male breast lesions, 451–461 Melanocytic lesions, 426
carcinoma of male breast, 456–459 Membranous fat necrosis, 36
BRCA2 germline mutations, 456 Menopause, 19, 21f
DCIS, 456 Menstrual cycle, changes in lobules
features of, 459t during, 10–13, 14t
invasive ductal carcinoma, 457f Mesenchymal lesions
papillary carcinoma, 458 benign, 408–415
risk factors, 457t granular cell tumor, 411–412,
gynecomastia, 451–455 411f–412f
abortive lobule formation, inflammatory myofibroblastic
453–454, 455f tumor, 413
atypical ductal hyperplasia, 455, 456f lipoma, 408–410, 409f, 410f
histologic features, 451, 452f, 454t myxoma, 413, 414f
periductal fibrosis, 453, 453f neural lesions, 413
pseudoangiomatous stromal periductal stromal sarcoma,
hyperplasia, 453, 454f 413–415, 415f
histology, 451 malignant, 416–417
metastasis to, 459–460, 459f, 460f osteosarcoma of breast, 416,
MALT lymphomas, 420 416f–417f
Mammaplasty, specimen processing for, Metaplastic carcinoma, 315–321
521–461 biomarkers/molecular pathology, 320
MammaPrint, 346 clinical course of, 320–321
Mammary duct ectasia, 39–44, 44t clinical presentation, 315
cysts vs., 41 differential diagnosis, 321
foamy histiocytes with, 40, 41f gross pathology, 315
garland pattern with, 41, 43f histopathology, 315–320
536 –––––– Index
Metaplastic carcinoma (continued) collagenized variant, 377, 378f–379f

low-grade adenosquamous differential diagnosis, 382, 382t
carcinoma, 318–320, 319f epithelioid variant, 377, 380f
with mesenchymal differentiation, estrogen receptor immunostain,
316–318, 317f, 318f 381, 381f
squamous cell carcinoma, 316, 316f features of, 382t
prognosis for, 320–321 pseudoangiomatous stromal
Metastatic tumors, 469 hyperplasia (PASH), 383
Microglandular adenosis (MGA), Myoid hamartomas, 186
212–218, 213f, 214f, 215f Myxoid fibroadenomas, 172, 175, 177f
atypical, 216, 216f Myxoma, 413, 414f
differential diagnosis, 218
features of, 218t N
invasive carcinomas, 217, 217f–218f Necrosis
treatment, 218 DCIS with
Microinvasive carcinoma, 267–280 high-grade, 78, 130f
biomarkers, 276, 276f intermediate-grade, 89, 90f
clinical course of, 276–277 low-grade, 78t, 83, 83f, 150
clinical presentation, 267 fat, 35–37, 36f
differential diagnosis, DCIS, 277–280, invasive breast cancer tumor, 314
279f, 280f LCIS with, 136, 137f, 144
duct branching, 277, 278f usual ductal hyperplasia with, 59f
lobules, 277, 277f Needle (wire) localization excisions,
sclerosing adenosis, 278, 279, 513–519
279f–280f calcium oxalate-type calcifications,
stromal fibrosis, 277, 278f 517, 518f
gross pathology, 267 calcium phosphate-type calcifications,
with high-grade DCIS, 267, 271f 516, 517f
histopathology, 267, 269f, 270f, 271f, microcalcifications, 518, 519f
272f, 273f, 275f, 275t specimen radiography, 513
prognosis for, 276–277 specimen targeted area, 513–514, 514f,
Micrometastases, 471 515f, 516, 516f
Miller-Payne grading system, 504, 504t total sequential embedding, 516
MINDACT trial, 347 Neoadjuvant chemotherapy
Molecular markers, 19 effects, 493, 497, 497f– 498f, 501, 501f,
Mondor disease, 52 503t, 504t
Montgomery areolar tubercle, 16, 18f extramedullary hematopoiesis, 425
Mucinous carcinoma, 303–307 histologic grade, 338
biomarkers/molecular pathology, 305 inflammatory carcinoma with, 331
clinical course of, 305–306 features of breast specimens after, 503t
clinical presentation, 303 Miller-Payne system for classification
differential diagnosis, 306–307, 306f of, 503t
gross pathology, 303 Residual Cancer Burden System for
histopathology, 303–305, 304f, 305f classification of, 505t
mucocele-like lesions, 306, 306f, 307f, Neural lesions, 413
308f Neuroendocrine features, carcinomas
prognosis for, 305–306 with, 325–328
Mucinous cystadenocarcinoma, 333 biomarkers/molecular pathology, 326
MYB-NFIB fusion gene, 324 clinical course of, 326 –327
Myofibroblastoma, 376–383, 377f–378f clinical presentation, 325
CD34 immunostain, 381, 381f differential diagnosis, 327–328
cellular variant, 377, 379f gross pathology, 326
Index ——— 537
histopathology, 326, 327f distribution of myoepithelial cells, 229t

WHO classification, 326 encapsulated papillary carcinoma,
prognosis for, 326–327 247–250, 248f
Neurofibromas and neurilemomas features of, 250t
(Schwannomas), 413 intracystic or encysted papillary
Nipple adenoma, 433–438 carcinoma, 247
features of, 433, 434f, 435f, 437f, 438t with invasive ductal carcinoma,
gynecomastoid hyperplasia, 433, 249, 249f
436f–437f intraductal papilloma, 229–238,
with prominent papillary hyperplasia, 231f, 232f
433, 436f invasive papillary carcinoma, 254–255,
Nipple disorders, 429–449 254f–255f
nipple adenoma, 433–438 papillary DCIS, 243–247, 244f, 245f
Paget disease, 441–449 papilloma with atypia (atypical
squamous metaplasia of lactiferous papilloma), 239–243, 239f–240f
ducts (SMOLD), 429–433 papilloma with DCIS, 239–243,
syringomatous adenoma, 438–440, 240f–241f, 242f
439f, 440f, 440t solid papillary carcinoma, 250–254,
Nodular fasciitis, 383–384, 384f, 384t 251f, 252f, 253f–254f
Nodular lactational hyperplasia. See variants of intraductal papilloma,
Lactating adenoma 257–263
Nonproliferative lesions, 52–56 adenomyoepithelioma, 259, 260f,
cysts, 52–53, 53f, 54f 261–262, 261f
metaplastic change, 55–56, 55f, 56f collagenous spherulosis,
262–263, 263f
O ductal adenoma, 257, 258f
OncotypeDX, 346 pleomorphic adenoma, 257, 259,
Osteosarcoma of breast, 416, 259f, 260f
416f–417f Papillary synovial hyperplasia, 37
Papilloma with atypia (atypical
P papilloma), 239–243, 239f–240f
Paget disease, 441–449 Papilloma with DCIS, 239–243,
expression of cytokeratins, 442, 240f–241f, 242f
443f–444f PASH. See Pseudoangiomatous stromal
malignant cells, 441–442, 441f, 442f hyperplasia (PASH)
squamous cell carcinoma in situ, Perilobular hemangiomas, 387–388, 388f
444–445, 445f, 446f–447f Periductal mastitis. See Mammary
Toker cell hyperplasia, 445, 446f–447f, duct ectasia
448f, 449 Periductal stromal sarcoma,
Papillary DCIS, 243–247, 244f, 245f 413–415, 415f
with dimorphic cell population, 245, Peripheral eosinophilia, 50
246f Phyllodes tumor, 186–199, 187f, 188f,
features of, 247t 189f, 190t
from intraductal papilloma, benign, 190, 191f–192f, 192
distinguishing features, 243t borderline, 193, 196f, 197f, 198f
Papillary duct hyperplasia, 467 malignant, 192–193, 193f, 194f–195f,
Papillary endothelial hyperplasia, 195f–196f
389–390, 390f Plasma cell dyscrasias, 422
Papillary lesions, 228–263 Pleomorphic adenoma, 185, 257, 259,
on core-needle biopsy, 255–257 259f, 260f
with intraductal papilloma, 255, 256f Pleomorphic carcinoma, 332–333
with micropapilloma, 255, 256f–257f P53 protein, 97, 149
538 –––––– Index
Pregnancy and lactation, 18–19, 20f gestational macromastia, 52

Prepubertal breast, 462 granulomatous lesions, 46–49
Progesterone receptor (PR), 9, 349t, 449t idiopathic granulomatous mastitis,
DCIS with, 94 47–48, 48f, 49t
immunostains for microinvasive IgG4-related sclerosing mastitis, 49–50,
carcinoma with, 276 49f–50f
invasive breast cancer prognosis from, juvenile (virginal) hypertrophy, 52
341–342 lobular granulomatous mastitis, 47– 48,
Prognostic factors, 335–347 48f, 49t
axillary lymph node status, 335–336 lymphocytic mastopathy, 44– 46,
combining, 346 45f, 46t
ER status, 341–342, 343f mammary duct ectasia, 39– 44, 39f,
HER2 status, 342–345, 344f 40f, 41f, 42f, 43f, 44t
histologic grade, 338–339 Mondor disease, 52
histologic type, 337 Reactive spindle cell nodules (RSCNs),
lymphovascular invasion, 339–341, 25–27
339f, 340f, 341f, 341t, 342f Recurrent subareolar abscess. See
molecular prognostic and predictive Squamous metaplasia of
tests, 346–347 lactiferous ducts (SMOLD)
PR status, 341–342, 343f Reduction mammaplasty, 464, 521
tumor size, 336 Re-excision specimens, 520
Pseudoangiomatous stromal hyperplasia Residual Cancer Burden (RCB) system,
(PASH), 383, 402–406 504, 505t
with cellular foci, 404, 405f Reverse transcriptase polymerase chain
fascicular, 404 reaction-based assay, 99, 346
with multinucleated myofibroblasts, Rosai-Dorfman disease, 422
404, 404f RSCN. See Reactive spindle cell nodules
Pseudoepithelialization, 37 (RSCNs)
Pseudolymphoma, 425
S
R Sclerosing adenosis, 202–210, 203f, 204f,
Radiation effects 206f–207f
in non-neoplastic breast tissue, 494, calcifications, 205f
496, 496t DCIS/LCIS in, 208, 208f–209f,
in terminal duct lobular unit (TDLU), 209f–210f
494, 495f features of, 209, 210t
Reactive lesions nodular adenosis and adenosis tumor,
acute mastitis, 52 205, 207f–208f
apocrine metaplasia, 55, 55f, 56f Sclerosing lesions
biopsy site changes, 25–35 complex, 223–225, 224f, 225t
breast infarction, 52 radial scars, 221, 222f–223f, 225, 225t
diabetic mastopathy with, 44–46, Secretory adenosis, 220–221, 220f–221f
45f, 46t Secretory carcinoma, 331, 467– 469
dirofilarial infection, 52 Sentinel lymph node biopsy, 522
eosinophilic mastitis, 50–51, 51f ACOSOG Z0011 trial, 522
fat necrosis, 35–36 NSABP B32, 522
foreign body-type granulomatous “Sick lobe” hypothesis, 3
inflammation, 36–37 Silicone, 36
mammary implant capsule, 36–37, Silicone lymphadenopathy, 484–485,
37f, 38f 484f–485f
silicone gel implants, 37 Small lymphocytic lymphoma (SLL),
galactocele, 51–52 423, 424f
Index ——— 539
SMOLD. See Squamous metaplasia of Toker cells, 16, 16f

lactiferous ducts (SMOLD) Trastuzumab (Herceptin), 342
Solid papillary carcinoma, 250–254, 251f, Treatment effects, 493–505
252f, 253f–254f chemotherapy
Spindle cell carcinoma, 363–372, breast cancers changes with,
365f, 366f 497–503
cytokeratin expression, 368f, 372, 372f grading response, 504–505
features of, 372t non-neoplastic breast tissue changes
fibromatosis-like metaplastic with, 496
carcinoma, 370, 371f radiation
gene expression profiling studies, 367 in non-neoplastic breast tissue, 494,
with glandular differentiation, 496, 496t
366, 369f in terminal duct lobular unit
with overt epithelial differentiation, (TDLU), 494, 495f
364, 367f Tubular adenoma, 182, 183f
with pseudovascular spaces, 364, 366f Tubular adenosis, 219–220, 219f–220f
with squamous differentiation, Tubular carcinoma, 297–300
364, 367f biomarkers/molecular pathology, 298
Spindle cell lesions, 363–385, 363t clinical course of, 298–300
fibromatosis, 373–376, 373f–374f clinical presentation, 298
myofibroblastoma, 376–383, 377f–378f differential diagnosis, 300
nodular fasciitis, 383–384, 384f, 384t gross pathology, 298
spindle cell carcinoma, 363–372, histopathology, 298, 299f
365f, 366f prognosis for, 298–300
spindle cell sarcomas, 385
Spindle cell sarcomas, 385 U
Squamous metaplasia, 27f, 55 UDH. See Usual ductal hyperplasia
Squamous metaplasia of lactiferous ducts (UDH)
(SMOLD), 429–433 USC-VNPI (University of Southern
features of, 431f, 432f, 433t California-Van Nuys Prognostic
keratinizing squamous epithelium, Index, USC-VNPI), 99
429, 430f Usual ductal hyperplasia (UDH), 58–70
Stereotactic mammography, 507 vs. ADH, 100
Stewart-Treves syndrome, 392 with apocrine metaplasia, 65f, 66f
Stroma, 2, 4f architectural/cytologic features of, 59f,
Subareolar duct papillomatosis. See 60f, 61f, 62f, 63f, 64f, 65f, 68t
Nipple adenoma with calcification, 67f
Surgical pathology reporting clinical course of, 69–70
biopsies with benign changes, 523 vs. DCIS, 100
core-needle biopsies, 523 differential diagnosis, 100
ductal carcinoma in situ, 523–524 with foamy histiocytes, 66f
invasive breast cancer, 524 immunophenotype/genetics, 67–68,
Synovial metaplasia, 37 68f, 69f, 70f
Syringomatous adenoma, 438–440, 439f, prognosis for, 69–70
440f, 440t
V
T Vacuum-assisted devices, use of, 507
TAILORx trial, 347 Vascular lesions, 387–406
T-cell lymphomas, 420 angiosarcoma, 392–400, 392f
Terminal duct lobular units (TDLUs), histologic features, 393, 393t, 394f,
107, 136 395f, 396f–397f
Terminal ducts (TD), 2, 3f post-irradiation cutaneous, 398, 399f
540 –––––– Index
Vascular lesions (continued) with cellular foci, 404, 405f

post-radiation angiosarcomas, fascicular, 404
395, 398 with multinucleated myofibroblasts,
atypical, 400–402, 401f, 402t 404, 404f
benign, 387–392 Venous hemangiomas, 390–391
angiomatosis, 391–392, 391f
hemangiomas, 388–390, 389f W
perilobular hemangiomas, Wegener granulomatosis, 419–420
387–388, 388f
venous hemangiomas, 390–391 Z
pseudoangiomatous stromal Zuska disease. See Squamous metaplasia
hyperplasia (PASH), 402–406 of lactiferous ducts (SMOLD)

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BIOPSY INTERPRETATION SERIES

Series Editor: Jonathan I. Epstein, M.D.

Biopsy Interpretation of the Gastrointestinal Tract Mucosa: Neoplastic,

© 2013 by LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER business

Printed in the People’s Republic of China

Library of Congress Cataloging-in-Publication Data

There have been important advances in our understanding of the molecu-

Preface to the First Edition...........................................................................v

1 Normal Anatomy and Histology�������������������������������������������������������� 1

particularly ductal carcinoma in situ, is now widely appreciated. This rec-

FIGURE 1.4 Ductogram (galactogram), performed by injecting contrast material into an

The issue of anastomoses between ductal systems is also unresolved.

express high-molecular-weight cytokeratins 5/6, 14, and 17 (Fig. 1.9), but

absence of expression of markers of differentiated luminal epithelial cells

mature structures (type 2 and type 3 lobules) through the development of

Of interest, Russo et al.26 have reported that type 1 l­obules ­predominate in

FIGURE 1.13 Lobule with clear cell change in epithelial cells.

l­evels of ERβ relative to ERα are protective against neoplastic progression

The proximal ramifications of the mammary ductal system that are

FIGURE 1.17 High-power view of nipple dermis/stroma demonstrating prominent

Pregnancy and Lactation

Some reactive, inflammatory, and nonproliferative lesions of the breast

Biopsy Site Changes

which are hemosiderin-laden. The spindle cells show mild to moderate

Partial or total infarction of lesions, especially papillary lesions

e­ osinophils, and occasionally neutrophils, initially at the periphery of the

collagen.2 A third type of marking device is composed of a ­biodegradable

diagnosis of lymphovascular invasion. In some cases, particularly fol-

presence of ­myoepithelial cells around the epithelial nests, a feature indi-

Epithelial displacement into lymphovascular spaces can be even

Reactions to Foreign Material

and the surrounding capsule. Histological examination of the capsular tis-

Mammary Duct Ectasia (Periductal Mastitis)

periductal inflammation. Plasma cells may be a prominent component

are present. Less frequently, the periductal inflammatory infiltrate may be

TABLE 2.1 Key Histologic Features of Mammary Duct Ectasia

• Inspissation of lipid-rich secretions within duct lumens

Lymphocytic mastopathy/Diabetic mastopathy

TABLE 2.2 Key Histologic Features of Lymphocytic Mastopathy/

FIGURE 2.21 Tuberculous mastitis. The breast stroma shows granulomatous

FIGURE 2.22 Sarcoidosis involving the breast, characterized by nonnecrotizing

of ­nonnecrotizing granulomas, with varying numbers of giant cells

There is some evidence to suggest that patients with this condition

TABLE 2.3 Key Histologic Features Distinguishing Granulomatous

Granulomatous Lesion Key Features

Mycobacterial, fungal, Granulomas resemble those seen in

IgG4-related Sclerosing Mastitis

lobular epithelium in the areas of inflammatory infiltration may exhibit

Miscellaneous reactive and inflammatory lesions

epithelial-lined channels. The luminal epithelium may show secretory

FIGURE 2.26 Cyst. This cyst is lined by an attenuated epithelial layer.

Intraductal proliferative lesions are a diverse group of epithelial prolifera-

Usual Ductal Hyperplasia

FIGURE 3.7 Usual ductal hyperplasia with micropapillary (gynecomastoid) features.

FIGURE 3.10 Usual ductal hyperplasia with foci of apocrine metaplasia.

FIGURE 3.12 Usual ductal hyperplasia with foamy histiocytes.

FIGURE 3.13 Usual ductal hyperplasia with calcification.

Immunophenotype and Genetics

TABLE 3.1 Key Features of Usual Ductal Hyperplasia

The use of immunostain cocktails composed of antibodies to both low-

Clinical Course and Prognosis

FIGURE 3.17 Usual ductal hyperplasia immunostained with a cocktail of antibodies to

family history of breast cancer in a first-degree relative.8,9 There are at

Atypical Ductal Hyperplasia

1 Normal Anatomy and Histology�� 1

Of interest, Russo et al.26 have reported that type 1 lobules predominate in

levels of ERβ relative to ERα are protective against neoplastic progression

e osinophils, and occasionally neutrophils, initially at the periphery of the

collagen.2 A third type of marking device is composed of a biodegradable

presence of myoepithelial cells around the epithelial nests, a feature indi-

of nonnecrotizing granulomas, with varying numbers of giant cells

nuclear size, shape, and placement. There may be chromatin clumping

f eatures with the cells comprising these other lesions.8-10,36 A number of

the columnar nature of the lining epithelial cells, distinguishing these