New Frontiers in Breast Pathology
Moderator: Dr. Sunil Lakhani
Section 5 -
Comparative Molecular Pathology of Myoepithelial Lesions
Jorge S Reis-Filho & Sunil R Lakhani
The Breakthrough Breast Cancer Research Centre
Institute of Cancer Research, London, UK
& Cellular Pathology, Mayne Medical School
University of Queensland
Queensland Institute of Medical Research and Royal Brisbane and Women's Hospital
Myoepithelial cells are ectordermally-derived, contractile cells which lie in between luminal
epithelial cells and the basal membrane of acini and ducts, forming a network of slender processes that
invest the overlying luminal cells in a discontinuous net like pattern
These cells are
found in breast, salivary, sweat and lachrymal glands
Myoepithelial cells are multifaceted and posses a dual basal epithelial-myoid nature
The basal epithelial features are best exemplified by the presence of tonofilaments, desmosomes and
expression of basal cytokeratins (i.e., cytokeratin 5 and 14), whereas the smooth muscle characteristics
is best appreciated by ultrastructural analysis in the form of actin microfilaments with dense bodies,
and by the expression of smooth muscle actin, smooth muscle myosin heavy chain and calponin
The seminal studies by Dardick et al.
paved the way for a proper identification of
myoepithelial tumours. By recognising the remarkable morphological plasticity of neoplastic
myoepithelial cells, which may assume epithelioid, plasmacytoid (hyaline), spindle, clear and even
oncocytic cytomorphology, it has become possible to identify tumours composed of cells with myoepithelial
The morphological plasticity of myoepithelial cells is also reflected at
the immunohistochemical level, hence it is not surprising that not all myoid markers are expressed in
With the advent of novel myoepithelial markers that are neither
directly related to the epithelial features nor to the smooth muscle apparatus of myoepithelial cells,
including p63 ,
nerve growth factor receptor (NGFR) 
and caveolin 1
it has become possible to define the spectrum of lesions with myoepithelial differentiation or
myoepithelial cell participation.
In salivary glands, tumours with myoepithelial differentiation and/or participation have been
thoroughly characterised . More recently, a new group of benign and malignant soft tissue
tumours with myoepithelial differentiation has also been described
some of these
lesions bear remarkable histological and immunohistochemical similarities with chondroid syringomas.
For a long time, it was believed that breast neoplasms with myoepithelial differentiation would be
remarkably rare and the spectrum of lesions would encompass only adenoid cystic carcinomas, low-grade
adenosquamous carcinomas, adenomyoepitheliomas, poorly-differentiated myoepithelial rich carcinomas and
malignant myoepitheliomas . However, with comprehensive characterisation of myoepithelial
cells at the morphological, ultrastructural, transcriptomic  and proteomic 
levels, the spectrum of breast neoplasms with myoepithelial differentiation has significantly expanded.
Currently, apart from the above lesions, it is known that the vast majority of metaplastic breast
carcinomas and approx 15% of invasive breast carcinomas show features of myoepithelial differentiation .
The morphological and immunohistochemical features of breast tumours with myoepithelial
differentiation and how they compare with their respective salivary gland counterparts have been
comprehensively reviewed elsewhere
In this hand-out, the molecular genetic features
of breast tumours with myoepithelial differentiation are reviewed and compared with those of salivary
gland and soft tissue myoepithelial tumours.
Few examples of benign myoepithelioma of the breast have been reported mostly as case reports or small
series. These tumours frequently affect female patients and are show a modal distribution in the
decades . The histopathological features and
immunohistochemical profiles of myoepitheliomas of the salivary glands and have been comprehensively
Pure myoepithelial tumours have a wide spectrum of morphological
appearances, being composed of varying amounts of spindle cells, basaloid cells, plamacytoid/ hyaline
cells and clear cells
Interestingly, the majority of myoepitheliomas of the
salivary glands and the soft tissues are composed of cells of two or more types, whereas in the breast,
most pure myoepitheliomas consist of cells with spindle cytomorphology
with chrondroid, squamous and sebaceous metaplasia are not uncommon. In salivary glands, it is currently
accepted that basal cell adenomas, pleomorphic adenomas and myoepitheliomas are part of a continuum of
lesions harbouring varying degrees of myoepithelial cell participation
immunohistochemical level, myoepitheliomas of all sites express different combinations of basal Cks,
myoid markers, p63, glial fibrillary acidic protein (GFAP) and NGFR
The molecular genetic features of benign myoepitheliomas of the breast are poorly characterised. Gain
of 8q appears to be the most frequent unbalanced chromosomal change . Few myoepitheliomas
have been subjected to molecular analysis. Karyotypic information is available only for salivary gland
myoepitheliomas: whilst one showed either no changes  other case harboured a fairly complex
karyotype 46,XY,t(1;12)(q25;q12),del(9)(q22.1q22.3),del(13)(q12q22) .With the scant data
available in the literature, it seems that breast, salivary gland and soft tissue myoepitheliomas harbour
few unbalanced chromosomal changes as defined by CGH, with the recurrent rearrangements mapping to
chromosomes 6, 9 and 12.
Pleomorphic Adenoma (PA) (aka, Benign Mixed Tumour)
PA the most frequent tumour in salivary glands and is not uncommon in cutaneous tissues, where it is
known as chondroid syringoma. On the other hand, breast PA is exceedingly rare, with <80 cases
reported to date
These tumours have been found in patients ranging in age from 19
to 85 years and usually affects female patients (>15F:1M), with only four cases reported in men
Breast PA is more frequently located in the subareolar region, and cases showing
intraductal growth are on record. An association with intraductal papillomas has been described. Breast
PA is histologically similar to its salivary gland and cutaneous counterparts . Although
the vast majority of breast PAs have a benign course, Hayes et al.  have recently described
three cases of malignant transformation in breast PAs, two in the form of grade-3 invasive ductal
carcinoma NOS and areas of high-grade metaplastic carcinoma with chondroid matrix and one in the form of
matrix producing metaplastic carcinoma .
The dual epithelial-myoepithelial nature of the neoplastic cells of breast PA is easily appreciated at
the ultrastructural and immunohistochemical level. Epithelial cells lining lumina of the neoplastic
glandular structures are reactive to antibodies against LMW cytokeratins, epithelial membrane antigen
(EMA), and CEA
Antibodies against SMA, p63, S-100 protein and CD10 may highlight the
outer rim of myoepithelial cells. In addition, myoepithelial markers, SMA, S-100 protein, calponin, CD10
and Ck14 are positive in the spindle cells found in the myxoid and cartilaginous areas
Salivary gland PAs harbour frequent rearrangements involving 8q12 and 12q15, which are seen in 40% and
8% of the tumours, respectively
The target gene of 8q12 rearrangements is the
pleomorphic adenoma gene 1 (PLAG1), which encodes a developmentally
regulated zinc finger protein, whereas rearrangements of 12q15 affect HMGA2,
a gene that encodes one of the high mobility group (HMG) proteins
Even in pleomorphic
adenomas with normal karyotypes, cryptic rearrangements of one of these genes may be identified. In
approximately 25% of PAs, gross chromosomal abnormalities and translocations involving other genetic loci
have been described. Only one case of breast PA has been subjected to interphase FISH to evaluate the
presence of rearrangements involving 6p21 and 12q15 . Although the myoepithelial component
of that tumour showed immunohistochemical positivity for both HMGA2 and
HMGIY, no rearrangements were found .
We have recently studied one case of salivary gland pleomorphic adenoma and observed a high level gain
of 12q13.3-q21.1, which was shown to be present in both epithelioid, spindle and oncocytic cells, giving
support to the common origin of different components of pleomorphic adenomas . Similar high
level gains have been found in carcinomas ex-PAs  and malignant mixed tumours
It has been suggested that gains of 12q14-q15 contribute to malignant transformation of
pleomorphic adenomas .
In the breast, perhaps the best characterised lesion with myoepithelial differentiation is
adenomyoepithelioma, which was first described by Hamperl in 1970  and the concept expanded
by Kiaer et al. ,
Eusebi et al. 
and Tavassoli et al . The
similarities between adenomyoepitheliomas and epithelial-myoepithelial carcinomas of the salivary glands,
lung and skin at the histological and immunohistochemical levels are striking. Although
epithelial-myoepithelial carcinoma is considered a low-grade malignant neoplasm
clinical behaviour of adenomyoepitheliomas has been a matter of debate
whilst some believe that these lesions are best considered borderline/ low malignant potential tumours,
with potential for local recurrences and a rather low proclivity for distant metastasis, others claim
that when strict criteria are applied, all adenomyoepitheliomas behave in a benign fashion .
Histologically, adenomyoepitheliomas show distinctive growth patterns, including tubular, papillary or
solid; however tumours often show a combination of these. Regardless of the predominant growth pattern,
the basic morphological structure of adenomyoepitheliomas (and epithelial-myoepithelial carcinomas of
other sites) is a round glandular lumen lined by an inner layer of cuboidal, eosinophilic luminal
epithelial cells and an outer layer of spindle, often clear myoepithelial cells lying on a basement
When solid areas are present, they are predominantly composed of
When tumours are solely composed of spindle shaped,
myoepithelial cells, they are best classified as pure myoepitheliomas. At the ultrastructural and
immunohistochemical levels, the inner cell population shows unequivocal features of luminal epithelial
cells, including short microvilli at the luminal surface and positivity for luminal Cks, whereas the
abluminal population shows definite features of myoepithelial cells, including positivity for basal Cks,
myoid markers, p63 and NGFR
In adenomyoepitheliomas and epithelial-myoepithelial carcinomas, the proliferation rates found in
myoepithelial cells are greater than those seen in the epithelial compartment
suggesting that the epithelial component is terminally differentiated. There is a paucity of data on the
molecular genetic profiles of lung and salivary gland epithelial-myoepithelial carcinomas
It has been reported that up to 20% of these lesions are aneuploid
there are no data on the chromosomal aberrations found in these lesions. Breast adenomyoepitheliomas
have been analysed by means of comparative genomic hybridisation
Using an arbitrary
histological definition for benign, borderline and malignant adenomyoepithelial tumours, Hungermann et
al.  demonstrated a stepwise increase in the number of unbalanced chromosomal changes from
benign to malignant lesions. The most frequent recurrent chromosomal aberrations were gains of 8q (26%),
13q (18%), 6p and 12p (both, 15%). and deletions of 17p (41%), 12q and 14q (both, 15%) .
Interestingly, both Hungermann et al. 
and Jones et al.  demonstrated an
increased complexity of the genomic changes when comparing recurrent/ metastatic adenomyoepitheliomas
with their respective index cases. In addition, a reciprocal chromosomal translocation t(8;16)(p23;q21)
has been described in a case of adenomyoepithelioma by cytogenetic and fluorescent in situ hybridisation analysis .
Adenoid Cystic Carcinoma (AdCC)
Adenoid cystic carcinoma is a tumour composed of epithelial and myoepithelial cells and has been
reported in several anatomical sites, including salivary gland, breast, lung and prostate. In the
breast, AdCCs are rare, accounting for <1% of all breast carcinomas
In contrast to
similar tumours in other organs, breast AdCC shows a less aggressive clinical behaviour
Histologically, breast AdCC shows three different architectural patterns as the salivary analogue:
trabecular-tubular, cribriform, solid
AdCC of any anatomical site is
characterised by two types of spaces: true glandular lumina which contain a granular secretion of PASD
positive neutral mucosubstances and the myxoid 'cylinders' composed of basement membrane material or
basophilic mucin. These spaces are lined by two types of cells: the basaloid type, which lines the
spaces containing stroma and basement membrane-like material; and a population of cells with abundant,
bright eosinophilic cytoplasm, which surround true glandular lumina containing mucinous material.
Recently, a variant of breast AdCCs entirely composed of basal cells has been described and the term
basaloid adenoid cystic carcinoma of the breast has been coined to refer to these lesions
Squamous and sebaceous metaplasia in AdCC of different anatomical sites are not uncommon.
AdCC of the breast has been described in association with adenomyoepithelioma and with low grade
syringomatous (adenosquamous) carcinoma, giving further support to the concept of a spectrum of
epithelial–myoepithelial neoplasms . More intriguingly, it has been suggested that
microglandular adenosis may be a precursor of breast AdCC and that atypical microglandular adenosis
should be considered AdCC in situ.
Immunohistochemical analyses have demonstrated that basaloid cells are positive for vimentin and CK14
and focally for myoepithelial markers, including SMA, calponin, p63 and maspin
Ultrastructurally, basaloid cells show features of myoepithelial differentiation, such as thin
cytoplasmic filaments and well developed desmosomes; nevertheless, most frequently they present
nondescript features with rare cytoplasmic organelles. The glandular cell type is usually positive for
CK7 and shows short microvilli along the luminal surface
Positivity for oestrogen
receptor is rarely seen
It has recently been described that AdCC of the salivary glands, breast and lungs consistently show
however in most of these studies, heat-induced antigen
retrieval was used. Although immunohistochemical positivity for c-kit may help differentiate adenoid
cystic carcinomas from their mimics , its biological and therapeutic significance remains
unclear, as no activating KIT mutations have been found in AdCCs
Furthermore, there are anecdotal cases of c-kit positive but mutation negative metastatic AdCC
treated with imatinib mesylate, a small molecule inhibitor of c-kit and other related protein tyrosine
kinase, that have rapidly progressed , suggesting that c-kit tyrosine kinase inhibitors may
have a limited role in the treatment of these lesions
TP53 gene mutations have been demonstrated in salivary gland adenoid cystic carcinomas ;
however, there are no data for breast lesions.
A comparative analysis between a primary salivary gland AdCC cell line and normal salivary gland
tissue by 2-D-DIGE and MALDI-TOF mass spectrometric analysis revealed upregulation of stathmin, maspin,
fibrin beta and sialic acid binding immunoglobulin-like lectin 8, and downregulation of enoyl coenzyme A
hydratase short chain 1 (ECHS 1), serin proteinase inhibitor B 1 (SERPIN B1), superoxide dismutase 2 (SOD
2), aminolevulinate delta-dehydratase (ALAD) and pro-apolipoprotein . Although these
results are interesting, it is not clear whether these genes are truly differentially expressed in AdCC
or merely reflect the enrichment of cells with myoepithelial phenotype in the AdCC sample.
The genetic profiles of salivary gland AdCC have been extensively characterised. The most frequent
changes are deletions of 6q, 12q and 13q and gains of chromosome 19. In addition, rearrangements
involving chromosomes 6q and 9p have also been reported. On the other hand, data on the genetic profile
of breast AdCC are scant; the karyotypes of two tumours have been described: 46,XX,inv(9) 
and 46,XX,t(4;4)(q21;q35),t(5;11)(q13;q21)/46,XX,+1,der(1;16)(q10;p10) .
Malignant Myoepithelioma/ Myoepithelial Carcinoma
Myoepithelial carcinoma of the breast and salivary glands is an entity that has received great
attention in the literature in the last few years . In a way akin to benign
myoepitheliomas, the neoplastic cells that compose this lesion may have a plethora of morphological
appearances; however, they often show nuclear atypia and increased mitotic activity. Both breast and
salivary glands malignant myoepitheliomas appear to frequently arise from an underlying benign tumour;
whilst in the salivary glands, pleomorphic adenomas and benign myoepitheliomas are frequently found in
association with myoepithelial carcinomas; there are several examples of breast myoepithelial carcinomas
associated with adenomyoepitheliomas.
In the latest World Health Organisation Classification of Tumours , malignant
myoepithelioma of the breast was defined as an infiltrating tumour composed purely of myoepithelial
cells, however it is not clear whether this evidence should be gathered at the histological,
immunohistochemical or ultrastructural level. This definition is further complicated by the fact that
bona fide myoepithelial carcinomas frequently harbour an abortive myoepithelial phenotype, lacking
expression of α-smooth muscle actin and Ck14 in 50% and 47% of the cases, respectively . In
addition, aberrant expression of low molecular weight cytokeratins (eg, Ck 7) and other markers not
usually seen in normal myoepithelial cells (eg, epithelial membrane antigen) may be observed
Given the plasticity of neoplastic myoepithelial cells
myoepithelial carcinomas of all
sites may show a multitude of cytomorphological components. However, when arising in the salivary
glands, these lesions have a typical low power appearance characterised by multinodularity and the
presence of tongue-like processes infiltrating the adjacent tissues . On the other hand,
breast myoepithelial carcinomas do not necessarily show the same histological features, lesions with
predominantly intraductal or intralobular growth patterns have been reported . Although
most of breast myoepithelial carcinomas are reported to be composed of a solid proliferation of spindle
cells, with eosinophilic cytoplasm and very atypical nuclei, some may be deceptively bland. In addition,
squamous elements and chondroid and osseous metaplasia admixed with the spindle cell proliferation may be
The criteria for malignancy in myoepithelial tumours are contentious; however invasion of adjacent
tissues should be considered the minimum requirement for myoepithelial carcinoma. Although this is a
valid criteria for salivary gland lesions, it is insufficient for soft tissue lesions, as 48.3% of all
myoepithelial tumours in one series showed invasive borders and yet were not associated with recurrence
or metastasis . Cytologic atypia, although a helpful diagnostic feature, is not present in
all cases. High mitotic activity and proliferation index have also been reported to be important
characteristics of myoepithelial carcinomas .
Nagao et al.  have suggested
that myoepithelial tumours of the salivary glands with > 7 mitotic figures/ 10 HPF or a Ki-67
proliferation index > 10% would be best classified as myoepithelial carcinomas. However,
myoepithelial carcinomas with fewer than 7 mitotic figure/10 HPF are on record  and some
have argued that further validation of these thresholds is still required before it is used in diagnostic
Myoepithelial carcinomas of the breast appear to have an immunohistochemical profile  and
a clinical behaviour similar to that described for basal-like breast carcinomas: the majority show an
aggressive clinical course, high frequency of haematogenous spread and a peculiar proclivity to
disseminate to the brain and lungs. There is some evidence that pure spindle cell breast carcinomas and
myoepithelial carcinomas are the same entity
and some have suggested that calling these
lesions monophasic spindle cell metaplastic carcinomas or myoepithelial carcinomas is only a matter of
preference . Furthermore, some examples of matrix producing breast carcinomas are
morphologically and immunohistochemically indistinguishable from some types of myoepithelial carcinomas
found in the salivary glands.
Myoepithelial carcinomas express markers of epithelial and myoid differentiation. Kermix
high molecular weight cytokeratins (clone 34 bE12) 
are useful markers to determine whether a pure spindle cell lesion shows epithelial
differentiation. Recently, we have demonstrated that up to 70% of metaplastic breast carcinomas show
EGFR overexpression and that EGFR gene amplification is the underlying
genetic mechanism in one third of the cases
Array CGH analysis of these tumours
revealed that the SRO in cases with EGFR gene amplification mapped only to
SEC61G, LANCL2 and EGFR
Comparative genomic hybridisation has been used to define the molecular genetic profiles of
myoepithelial carcinomas of the breast and salivary glands. In both studies, a relative paucity of
unbalanced chromosomal changes was seen
However, the regions recurrently affected
appear to be distinct: whilst Jones et al.  reported recurrent losses of 16q and 17p in
30% of breast myoepithelial carcinomas, Hungermann et al.  identified gains of 8q (29%), 1q
and chromosome 5 (both, 23%) as the most frequent changes in salivary gland myoepithelial carcinomas. In
addition, some of the cases described by Hungermann et al.  under the term of breast
'monophasic adenomyoepithelial carcinoma, spindle cell type' could also have been classified as examples
of myoepithelial carcinomas. In those tumours, deletions of 17p and 14q and gains of 8q and 7q were the
most frequent changes. We have subjected two cases of salivary gland myoepithelial carcinomas to array
CGH analysis; both tumours showed recurrent deletions of 5q12.1-qter, 8p23.3-p12, gains of 1q21.1-q25.3,
8p12-qter and 18q11.21-q12.1 and amplification of 12q13.3-q14.1. The latter region has been implicated
in the progression of salivary gland PAs and encompasses several oncogene candidates, including cyclin
dependent kinase 4 (CDK4), sarcoma amplified sequence (SAS, aka tetraspanin 31 – TSPAN31) and
glioma-associated oncogene homolog (GLI).
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