Resident Short Review
Adenomyoepithelioma of the Breast
A Brief Diagnostic Review
Ji Yoon Yoon, MD; Dhananjay Chitale, MD
 Adenomyoepithelioma of the breast is an uncommon
tumor characterized by dual differentiation into luminal
cells and myoepithelial cells. A spectrum of histologic
patterns is observed among these tumors and even in
different areas of individual tumors. These lesions can be
diagnostically challenging, especially when a core needle
biopsy is performed, because of the heterogeneity of
adenomyoepitheliomas. Recognition of the biphasic cellu-
lar elements and the characteristic overall architecture of
the tumors in combination with immunohistochemistry are
essential to establish the correct diagnosis. Although most
tumors have a benign clinical course, local recurrences,
malignant transformations, and distant metastases have
been reported. All the reported malignant adenomyoepi-
theliomas with metastases have shown significant cytolog-
ic atypia and brisk mitotic rates. Therefore, adequate
sampling of the tumor to identify these features is
necessary. A complete excision with adequate margins
would lower the chance of local recurrence or potential
for metastasis.
(Arch Pathol Lab Med. 2013;137:725729; doi: 10.5858/
arpa.2011-0404-RS)
M yoepithelial cells are present in the normal mammary
duct system and are often prominent in benign
lesions, such as usual ductal hyperplasia, sclerosing adeno-
sis, and intraductal papilloma.1 Tumors largely or entirely
composed of myoepithelial cells have also been reported.2
Adenomyoepithelioma (AME), a biphasic neoplastic pro-
liferation of luminal and myoepithelial cells, was first
described by Hamperl1 in 1970. As Hamperl noted, this
tumor may display a heterogeneous pattern because of the
variable proliferation of epithelial and myoepithelial cells.
Papillary architecture is seen in most tumors, and therefore,
AME is considered to be a variant of intraductal papilloma.3
Striking morphologic heterogeneity, such as papillary con-
figuration or multinodularity, especially in a limited biopsy
sample,46 may not be appreciated, which may lead to
erroneous diagnoses of carcinoma.3 So far, other than case
Accepted for publication June 20, 2012.
From the Department of Pathology and Laboratory Medicine,
Henry Ford Hospital, Detroit, Michigan.
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Ji Yoon Yoon, MD, Department of Pathology and
Laboratory Medicine, Henry Ford Hospital, 2799 W Grand Blvd,
Detroit, MI 48202 (e-mail: jyoon1@hfhs.org).
Arch Pathol Lab MedVol 137, May 2013
reports, only 4 comprehensive series studies2,3,6,7 have been
reported. Although most AMEs have been benign, sporadic
malignant AMEs with distant metastases have also been
reported.2,79 Recognition of this entity, accurate diagnosis,
and knowledge of the expected behavior are important in
guiding the most appropriate patient management.
CLINICAL FEATURES
Patient age ranged from 22 to 92 years (mean age, 59
years) in one series of study.6 Nearly all of the affected
patients have been women, although rare cases have been
reported in men.10 Patients usually present with a solitary,
palpable nodule,6 and the duration of symptoms varies from
several weeks to several months.2 The tumors are usually
located in a peripheral portion of the breast,3 although the
lesions have been found centrally or near the areola.2,11
Tenderness and serous nipple discharge have been found
infrequently.2 On mammography, AME appears as a round
or lobulated, dense, mostly circumscribed mass, sometimes
with partially indistinct margins.12 Calcifications and cystic
appearance are not typical findings.13
GROSS PATHOLOGIC FEATURES
The size of AME ranges from 0.3 cm to 7 cm, with an
average size of 2.5 cm.2,6 The tumors have been described as
round to lobulated, well circumscribed or discrete, and
firm.2,3 Multinodular or papillary configurations and focal
cystic changes have also been described.6,14,15 The recurrent
tumors had irregular borders and ranged from 2 cm to 6
cm.7 The cut surface reveals pink-white to gray-tan tissue
with focal to diffuse translucency.2,7 Hemorrhage and focal
necrosis have also been reported.3,5,16
MICROSCOPIC PATHOLOGY
AND IMMUNOHISTOCHEMISTRY
The AME tumor has a biphasic nature, composed of
cuboidal to columnar, epithelial-lined tubules surrounded
by myoepithelial cells.6 A spectrum of histologic patterns,
however, has been observed among various examples of
these tumors and even in different areas of individual
tumors.3 These variations were based on the distribution of
proliferating glandular and myoepithelial cells, the extent of
spindle or polygonal configuration of myoepithelial cells,
the prominence of papillary component, and the degree of
fibrosis.3
Three variants of AMEs were described by Tavassoli.2 The
first variant is the tubular pattern, which is characterized by
a balanced proliferation of rounded tubules, as well as
Adenomyoepithelioma of the BreastYoon & Chitale 725
unusually prominent and hyperplastic myoepithelial cells.
The second variant is the spindle cell type, which is
composed of a predominantly spindled myoepithelial cell
proliferation admixed with a few columnar, epithelial-lined
tubules. Finally, the third variant exhibits a lobular pattern
composed of solid nests of myoepithelial cells proliferating
around compressed tubules; the solid nests of tumor are
then surrounded by fibrous connective tissue septa of
varying thicknesses.2
Most AMEs have papillary configuration and, therefore,
have been considered a variant of intraductal papilloma by
some authors or a morphologic evolution from intraductal
papilloma (Figure 1, A).3,7,17 Myoepithelial cells forming
nests or sheets frequently display a spindle to myoid
appearance at places with clear cytoplasm. This solid
proliferation may displace, compress, or obliterate the
epithelial gland, resulting in a zone nearly devoid of glands
(Figure 1, B and C).2,3,6 These areas, if pronounced, may lead
to a differential diagnosis of myoepithelioma. The myoid
areas may exhibit myoepithelial cells with pink to ampho-
philic cytoplasm or a plasmacytoid appearance with dense,
hyaline-like, glassy eosinophilic cytoplasm and eccentric
nuclei (Figure 1, D).2,12,17 Myxochondroid matrices produced
by the myoepithelial cells may also be noted, as seen in
pleomorphic adenomas (Figure 1, E).6,12 Dense, collagenous,
hyaline-like matrix materials can be seen in thick basement
membranes.18 Epithelial cells tend to have hyperchromatic
nuclei and dense eosinophilic to amphophilic cytoplasm,
when compared with myoepithelial cells.17 Apocrine meta-
plasia of epithelial cell component, as well as squamous and
sebaceous metaplasia may be variably present.2,17,19 Atypical
features, including increased mitotic activity, cytologic
atypia with nuclear pleomorphism, prominent nucleoli,
hyperchromasia, and necrosis, if observed, are usually
associated with cases that either recurred or had a malignant
clinical outcome (Figure 1, F).2,7,9
The interplay between epithelial and myoepithelial cell
elements is highlighted by immunohistochemical staining
with antibodies specific for these 2 components. The
cytoplasm of epithelial cells uniformly reacts with antibodies
to cytokeratins, such as cytokeratin AE1/3 (Figure 2, A and
B), CAM 5.2, or CK7.6,7 The luminal surfaces of the
glandular cells are positive for the epithelial membrane
antigen.17 Polygonal and spindle myoepithelial cells are not
reactive to epithelial membrane antigen and are often only
subtly reactive or weakly reactive to cytokeratin AE1/3.6,7
The myoepithelial component is highlighted by p63, smooth
muscle myosin heavy chains, CK5, CD10, calponin, actin,
and S100.6,7,17,20 McLaren et al6 reported that p63 produced
the best results with consistent, intense nuclear staining
(Figure 2, C), whereas some studies have reported
discontinuous staining patterns.20 The distribution and
intensity of staining for anti-actin antibodies is heteroge-
neous, more conspicuous in spindle cells than in clear
polygonal cells. However, no reactivity to actin is seen in
epithelial cells.17
Smooth muscle myosinheavy chain is the most sensitive
marker, which is easier to interpret than smooth muscle
actin and muscle-specific actin because of its low cross-
reactivity with myofibroblasts.17,20,21 Calponin is also highly
sensitive for detecting myoepithelial cells with cytoplasmic
staining (Figure 2, D), but calponin myofibroblasts can be
detected in up to 74% of breast proliferations by light,
patchy staining patterns.20 S100 was expressed in virtually
all of the myoepithelial cells, with variable intensity and
726 Arch Pathol Lab MedVol 137, May 2013
uniformity of reactivity.7,17,20 Most of the luminal epithelial
cells are S100, but some reports have noted strong
expression in the luminal epithelial cells. In these cases, its
diagnostic utility as a myoepithelial marker may be
limited.17,2224 The myoepithelial-specific antibodies display
various cross-reactivity patterns and variable protein ex-
pression, especially in the neoplastic myoepithelial cells
compared with their normal counterparts.17,20 Therefore, a
panel-based approach of 2 or more markers should be used
to minimize the chance of failure in detecting the
myoepithelial cells.17,20
Proliferative indices of Ki-67 immunostaining are present
in both compartments of the tumor but may be higher in the
myoepithelial cells than it is in the ductal cells.25 Immuno-
stain for estrogen is either negative or weakly positive in a
patchy pattern.12 Progesterone receptor and ERBB2 (for-
merly Her2/neu) have, however, been consistently reported
to be negative in all the published studies.3,12
DIFFERENTIAL DIAGNOSIS
Most AMEs appear to represent variants of intraductal
papilloma.3 The differentiation of papilloma with prominent
myoepithelial cells from AMEs can be made based on
architecture, pattern, and degree of myoepithelial prolifer-
ation.6 Those cases with only myoepithelial cells lining the
papillae and forming the basal layer below the epithelial
elements and without nests, nodules, or an increased
proportion of myoepithelial cells are categorized as papil-
lomas with prominent myoepithelial cells.6 Myoepithelial
cell markers highlight the presence of prominent myoepi-
thelial cells within the papillae and at the periphery.20 When
the stroma associated with papillary lesions are sclerotic or
exuberant, nuclear stains, such as p63 and maspin, should
be included in a myoepithelial marker panel to avoid cross-
reactivity with myofibroblasts within the sclerotic stroma.20
A diagnosis of AME is favored if myoepithelial proliferation
is extensive and involves the lesion diffusely.12 Nipple
adenoma may mimic AME, but the presence of florid ductal
hyperplasia and the pseudoinfiltrative pattern of stromal
sclerosis entrapping glandular epithelium without an
entrapped fibrous tissue or supporting fibrovascular cores
are useful features to help differentiate the former.6 Clear
cell carcinoma may also mimic AMEs, but that may be
differentiated by the presence of both epithelial and
myoepithelial cell types, and confirmed with immunohisto-
chemical stains, if necessary.6 Metaplastic tumors associated
with papilloma are also included in the differential
diagnoses.26 The rarest adenosis variant of AME has an
infiltrative growth pattern that resembles microglandular
adenosis. Microglandular adenosis is characterized by an
absence of myoepithelial layer and S100 positivity.17
When the tumor predominantly displays a spindle cell
component, it may morphologically be mistaken for a myoid
hamartoma or leiomyoma.2 Strong reactivity for S100 and
p63, and minimal staining for actin and cytokeratin in AME
are helpful in differentiating the 2 lesions.2,17 Myoid
hamartomas also strongly express CD34, unlike AME,
which is negative. Lesions composed exclusively of benign
myoepithelial cells suggest a diagnosis of myoepithelio-
ma.1,2,17 Thorough sampling of the tumor to identify the
luminal epithelial component would help separate AMEs
from myoepithelioma.
Some areas of an AME may resemble adenoid cystic
carcinoma of the breast, but that has infiltrative borders and
Adenomyoepithelioma of the BreastYoon & Chitale
Figure 1. A, Adenomyoepithelioma with intraductal papillary configuration. B, Myoepithelial cells with clear cytoplasm. C, Adenomyoepithelioma
with spindle cell features. D, Myoepithelial cells with plasmacytoid appearance. E, Myxochondroid background matrix. F, Atypical feature of
adenomyoepithelioma; increased mitotic activity (hematoxylin-eosin, original magnifications 3100 [A and F], 3400 [B through D], and 3200 [E]).

a characteristic cribriform architecture in most cases. The
myoepithelial cells of an adenoid cystic carcinoma tend to be
smaller, more hyperchromatic, and basaloid appearing and
have much less cytoplasm than do those of an AME.12 In
addition, adenoid cystic carcinoma may be excluded by the
Arch Pathol Lab MedVol 137, May 2013
absence of the 2 types of mucins and the presence of
apocrine epithelia.6 Pleomorphic adenomas have features
that overlap with AMEs, but a hyaline matrix with
chondroid areas and distinct encapsulation are more
prominent in pleomorphic adenoma.6,12,17
Adenomyoepithelioma of the BreastYoon & Chitale 727
Figure 2. A, Adenomyoepithelioma with corresponding cytokeratin AE1/AE3 immunostain (B) demonstrating strong staining of epithelial elements
and weak staining of myoepithelial cells. C, p63 immunostain, demonstrating nuclear staining of myoepithelial components. D, Calponin,
demonstrating cytoplasmic staining of myoepithelial components (hematoxylin-eosin, original magnification 3200 [A]; original magnification 3200
[B]; original magnifications 3400 [C] and D).

The diagnosis of AME on a needle core biopsy can be
challenging because of morphologic heterogeneity. In
limited biopsy material, the sampled tissue may even be
mistaken for invasive carcinoma, especially in tumors that
have compact glandular structures with clear cell epithelioid
myoepithelial proliferation.35,17 The presence of regularly
spaced, rounded or ovoid glands; unidirectional streaming
of the glands; and prominent clear cell or spindle cell
myoepithelium are some morphologic clues to the diagnosis
of AME.4 Immunostains for myoepithelial markers, espe-
cially p63, are useful for highlighting the abundant
myoepithelial components.4 Atypical features, such as
pronounced nuclear pleomorphism, mitotic activity, necro-
sis, invasive growth, and the overgrowth of 1 of the 2
components of the lesion may not be evident in the needle
core biopsy. Therefore, excisional biopsy is recommended to
rule out a carcinoma arising in an AME.4
BIOLOGIC BEHAVIOR AND TREATMENT
Most AMEs can be treated by local excision, but local
recurrences have occurred 8 months to 5 years after initial
728 Arch Pathol Lab MedVol 137, May 2013
excision.2,7,27 In the Tavossoli2 study, most tumors with
recurrence were of the tubular type of lesions, extending
into, and blending with, the adjacent normal ducts. The
recurrent lesions lacked an aggressive morphologic appear-
ance or noticeable mitotic activity.2 The recurrent tumor
with a lobulated variant displayed only cytologic atypia and
had an increased mitotic activity with 8/10 high-power fields
(as compared with 3/10 high-power fields in the original
tumor).2 Cytologic atypia and mitotic rates were found to be
variable in other studies.7 Peripheral intraductal extension,
incomplete excision, and variable cytologic atypia may be
linked to local recurrence.2,3,7
Although most AMEs are benign, malignant transforma-
tions of tumors have been reported in the literature.2,79,13,28
Because of the biphasic nature of the tumor, carcinomas may
arise from ductal epithelial cells, myoepithelial cells, or
both.9,29,30 A myoepithelial carcinoma arising in an adeno-
myoepithelioma with a high Ki-67 labeling index in
myoepithelial cells has been reported.30 Distant metastases
to lung, brain, and liver have also been reported.7,8,13,28 Loose
et al7 suggested using the term Malignant AME to identify
Adenomyoepithelioma of the BreastYoon & Chitale
tumors with metastatic potential for the lesions associated
with more-aggressive histologic features that include high
mitotic activity and marked cytologic atypia. Axillary lymph
node metastasis was reported in the Tavassoli2 study, but the
possibility of the direct extension of the tumor to the lymph
node was taken into consideration because of the proximity
of the node with the primary lesion.2
Complete excision with appropriate margins is recom-
mended to prevent local recurrence.2,7,17 If the lesion recurs,
a wider excision would be required.2 Mastectomy or breast-
conserving surgery with radiation and axillary dissection are
not necessary for benign AMEs but may be indicated for
carcinoma arising from AMEs.2,17
SUMMARY
The AME of the breast is a relatively rare, benign tumor
that has a spectrum of disordered epithelial-myoepithelial
proliferations. Because of the morphologic heterogeneity of
this tumor, misinterpretation on a needle biopsy may
occur.4,6 Recognition of biphasic cellular elements and the
overall architecture of the tumor in combination with
immunohistochemistry are important when diagnosing
AMEs. Although most tumors have been benign, local
recurrences, malignant transformations, and metastases
have been reported. Cases with significant cytologic atypia,
necrosis, and brisk mitotic rates raise the likelihood that the
lesion is malignant AME and carries the potential risk of
metastasis.7,8 Therefore, atypical features should be noted in
the pathology report, and complete excision with adequate
margins is recommended to decrease the potential for
recurrence and metastasis.
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