Spindle cell lesions of the breast diagnostic issues 2019 (1)

Spindle cell lesions of the
breast: diagnostic issues
Joshua JX Li
Gary M Tse
Abstract
Spindle cell lesions of the breast encompass a broad spectrum of en-
tities. In addition to breast-specific spindle cell lesions, soft tissue and
cutaneous spindle cell lesions can also present in the breast. The
prognosis and proper management of each entity varies considerably
and thus calls for a systemic approach in diagnosis. A simple two-step
approach is described in this review, where spindle cell lesions are
classified into biphasic (with both spindle and epithelial components)
and monophasic (spindle cell only) types, followed by histologic
grading. This diagnostic algorithm is easy to use and adequately re-
flects the pathogenesis and clinical behavior of the entities. When sup-
plemented by careful histologic examination and judicious use of
immunostains, this algorithm will aid in the correct labeling of most
spindle cell lesions of the breast.
Keywords carcinoma; inflammation; metaplastic carcinoma; phyl-
lodes tumor; spindle cell
Introduction
Spindle cell lesions of the breast are uncommon, but encompass
a broad spectrum of entities. In addition to breast-specific spindle
cell lesions, soft tissue and cutaneous spindle cell lesions can also
present in the breast. As the prognosis and proper management
of each entity varies considerably, accurate diagnosis is essential.
The wide spectrum of differentials of spindle cell lesions calls for
a systemic approach in diagnosis. In this review, a stepwise
approach to diagnosis of spindle cell lesions is described,
together with the clinical, radiologic, histologic, immunohisto-
chemical (IHC) and molecular features of some entities.
Classification and approach
Spindle cell lesions of the breast may originate from breast-
specific tissues, such as ductal epithelium, myoepithelium and
stromal cells, or non-breast-specific tissue like skin and associ-
ated soft tissue. Morphologically, they can be divided into bland
looking, low-grade lesions and high-grade malignant lesions, and
these correlate mostly with indolent and aggressive clinical
behaviors.1,2
While binary or categorical classifications have been pro-
posed,1e5
a simple two-step approach is used in this review,
where spindle cell lesions are classified into biphasic (with both
spindle and epithelial components) or monophasic (spindle cells
only) types, followed by histologic grading; this approach can
adequately reflect the pathogenesis and clinical behavior of the
entities from a diagnostic point of view. This diagnostic algo-
rithm is detailed in Figure 1.
Biphasic spindle cell lesions
Biphasic spindle cell lesions include fibroadenoma, phyllodes
tumor, pseudoangiomatous stromal hyperplasia (PASH),
hamartoma, adenomyoepithelioma and some spindle cell meta-
plastic carcinoma (Tables 1 and 2). In general, biphasic spindle
cell lesions more commonly originate from breast tissue. The
stromal component of fibroepithelial lesions are interdependent
with its epithelial component,6
metaplastic carcinoma often re-
tains histologic or IHC evidence of epithelial origin7, PASH,
hamartomas and adenomyoepitheliomas possess both spindle
and epithelial components.
The first step in approaching spindle cell lesions of the breast
is identifying whether an epithelial component is present.
Adequate sampling of excision specimens is essential. In limited
biopsies or lesions with a predominantly stromal component, the
epithelial component may not be apparent. In such situations,
IHC markers such as cytokeratin and p63 can be useful in
highlighting any scant epithelial component.8,9
Biphasic lesions
are then further graded into those with bland (benign to low
grade malignant) spindle cells or pleomorphic (high-grade)
spindle cells.
Biphasic spindle cell lesions with bland spindle cells
Fibroadenoma
Fibroadenoma is the most common biphasic lesion with bland
stromal cells. In fibroadenoma, the epithelium is arranged in
intracanalicular and pericanalicular patterns.10
Many secondary
changes may occur and some may be prognostically significant.
Usual hyperplasia may be found in up to 43.6% of the fibroa-
denomas, whereas the frequencies of ductal carcinoma-in-situ
(Figures 2a, 2b), lobular carcinoma-in-situ (Figures 2c, 2d) and
atypical ductal hyperplasia superimposed on fibroadenomas
were reported at 1.3%, 0.8% and 0.3% respectively.11
Other
changes include squamous metaplasia, PASH change and stro-
mal smooth muscle metaplasia.11
It is important to recognize
atypical and premalignant changes in fibroadenoma, as they
dictate the prognosis. If the atypical focus is totally within a
fibroadenoma and not in the adjacent tissue, it does not confer
additional cancer risk for the patient when completely excised.12
A fibroadenoma is complex if it contains cysts 3 mm, sclerosing
adenosis, epithelial calcifications, and/or papillary apocrine
metaplasia; these changes have been reported in 0.3e28% of
fibroadenomas.11
Some but not all considered complex fibroa-
denoma to be associated with an increased risk of breast can-
cer.13,14
The stromal spindle cells of fibroadenoma are positive
for CD34 and bcl-2.15
Somatic mutations of MED12 (mediator
complex subunit 12) and RARA have been described in fibroa-
denoma.16,17
Use of cyclosporin A is observed in patients mul-
tiple bilateral fibroadenomas, implicating its direct etiologic role
and associated secondary hormonal changes.18
Joshua JX Li MBChB, Department of Anatomical and Cellular
Pathology, Prince of Wales Hospital, The Chinese University of Hong
Kong, Hong Kong. Conflicts of interest: none declared.
Gary M Tse FRCPC, Department of Anatomical and Cellular
Pathology, Prince of Wales Hospital, The Chinese University of Hong
Kong, Hong Kong. Conflicts of interest: none declared.
MINI-SYMPOSIUM: BREAST PATHOLOGY
DIAGNOSTIC HISTOPATHOLOGY 26:2 76 Ó 2019 Elsevier Ltd. All rights reserved.
Descargado para DellysAdriana Alvarez (dellysadrianaalvarez@gmail.com) en University of Antioquia de ClinicalKey.es por Elsevier en abril 05, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.

Phyllodes tumor (benign)
Phyllodes tumor is rare, constituting less than 3% of mammary
fibroepithelial lesions.19
Most phyllodes tumors are histologically
benign and present as palpable painless masses running a benign
clinical course.20
Mammographically, phyllodes tumor may
present as a large, well-defined rounded or lobulated mass with
high density.21
Phyllodes tumor is diagnosed and graded by a
combination of histologic parameters, including stromal cellu-
larity, atypia, mitotic rate, tumor border, stromal overgrowth
(defined as presence of stroma without epithelium occupying at
least one low-power field) and presence of heterologous com-
ponents.22
Benign phyllodes tumor demonstrates uniform and
scant stromal cellularity, mild or absence of stromal atypia, mi-
toses of 4/10 high-power fields (HPFs), well-defined borders,
and absence of stromal overgrowth.
While phyllodes tumor is traditionally distinguished from
fibroadenoma by increased stromal cellularity (condensation)
adjacent to the epithelium, stromal cellularity in fibroadenoma
can be variable and may be focally high. It is particularly
problematic in biopsies for this differentiation. Stromal features
including higher cellularity and stromal cell pleomorphism are
biopsy features favoring phyllodes tumor over fibroadenoma.23
Other suggestive features include fragmentation, intra-
canalicular growth pattern (Figure 3a), and presence of multi-
nucleated stromal giant cells (Figure 3b).24
In benign phyllodes tumor, the stromal spindle cells are
positive for CD34 and bcl-215
but are negative for p40 and p63.25
Only in a small percentage of cases the spindle cells express
cytokeratins,26
but the expression is usually focal and weak, and
limited to malignant phyllodes tumor.
Beta-catenin can be positive in the spindle cells in phyllodes
tumor, more commonly in benign than malignant ones.27
Beta-
catenin positivity may cause diagnostic confusion with desmoid
fibromatosis, but a biphasic pattern favors phyllodes tumor over
desmoid fibromatosis, which is monophasic. MED12 mutations in
benign phyllodes tumor are described at a similar rate to those of
fibroadenoma,19
FLNA, SETD2, KMT2D, BCOR and MAP3K1 are
observed in all grades of phyllodes tumor but not fibroadenoma.17
Figure 1 Histologic features of benign and borderline/malignant phyllodes tumor.

Pseudoangiomatous stromal hyperplasia (PASH)
PASH is a benign lesion composing of proliferation of stromal
myofibroblasts. PASH may present as a palpable mass (nodular
PASH) or be detected on imaging. It is seen in mostly women
who are premenopausal or with a history of hormone exposure
(oral contraceptive pills or hormone replacement therapy).28
The
Comparison of biphasic lesions with bland spindle cells
Fibroadenoma Phyllodes tumor (benign) Pseudoangiomatous
stromal hyperplasia
Hamartoma Adenomyoepithelioma
Clinical
features
Benign firm palpable
mass in young women
Variable behavior
according to histological
grade
Benign palpable mass,
associated with
circulating hormones
Discreet mass with
variable texture
Solitary palpable mass,
rare malignant
transformation reported
Radiological
features
Well circumscribed
hypoechoic lesion
Well defined lobulated
high-density mass
Mass with irregular
margin, can be ill-defined
or spiculated
Breast within a breast Round or lobulated dense
circumscribed mass
Histological
features
Epithelium in
intracanicular and
pericanalicular patterns,
secondary epithelial
changes common
Subepithelial stromal
condensation, leaf-like
pattern
Interanastomosing
channels resembling
vascular spaces
Distinct nodule containing
adipose tissue, lobules,
ducts and fibrous tissue
Unremarkable ducts and
myoepithelium with
variable cytology and
patterns
IHC profile
(spindle
cells)
CD34 þ
Bcl-2 þ
CD34 þ
Bcl-2 þ
Beta-catenin (nuclear) þ
CD34þ
Bcl-2 þ
SMAþ
ER þ PRþ
Vimentin þ
CD34þ
Desmin þ
SMAþ
ER þ PRþ
Vimentin þ
SMAþ
Calponin þ
S-100þ
AE1/3 þ
CK14 þ
p63þ
Molecular
features
MED12, RARA somatic
mutation
MED12, RARA, FLNA,
SETD2, KMT2D, BCOR and
MAP3K1 somatic
mutation
PTEN germline mutation
(Cowden syndrome)
Table 1
Comparison of biphasic lesions with high grade spindle cells
Phyllodes tumor (borderline/malignant) Spindle cell metaplastic carcinoma
Clinical features Rapidly growing mass, risk of local recurrence
and distant metastasis
Malignant, favoring hematogenous spread to
solid organs
Radiological features Overlaps with benign phyllodes tumor Variable, may show features suggestive of
benign lesions
Histological features High stromal cellularity, nuclear
pleomorphism, cell mitotic rate and
overgrowth, presence of and heterologous
components
Spindle cells in variable arrangements with
severe atypia and pleomorphism; epithelial
component most commonly glandular, less
commonly squamous or carcinoma-in-situ
IHC profile
(spindle cells)
CD117þ
p53þ
p63þ
p40þ
Cytokeratinþ
CD34 e (loss versus benign)
p63þ
p40þ
Cytokeratinþ
SMAþ (subset)
S-100þ (subset)
ER- PR-
HER2-
Molecular features PIK3CA, PTEN, BRAF, EGFR NF1, RB1 and TP53
mutations; high stromal TERT expression;
increased incidence of RARA and lower MED12
mutations
Table 2

clinical associations and IHC profile (see below) of PASH suggest
a hormone-related etiology.29
Despite its benign nature, radio-
logically PASH appears as lesion with irregular or spiculated
margins.28,30
Histologically PASH consists of complex inter-anastomosing
channels resembling vascular spaces lined by bland spindle
cells in a paucicellular or fibrotic background (Figures 4a, 4b).31
Fascicular areas with obliteration of pseudoangiomatous spaces
Figure 2 Fibroadenoma involved by ductal and lobular carcinoma-in-situ. (a) Fibroadenoma involved by low-grade ductal carcinoma-in-situ, 20x
magnification; (b) fibroadenoma involved by low-grade ductal carcinoma-in-situ, 100x magnification; (c) fibroadenoma involved by lobular
carcinoma-in-situ, 10x magnification; (d) fibroadenoma involved by lobular carcinoma-in-situ, 100x magnification.
Figure 3 Benign phyllodes tumor. (a) Benign phyllodes tumor showing characteristic “leaf-like” intracanalicular pattern, 40x magnification. (b)
Stromal giant cells in benign phyllodes tumor, 400x magnification.

is a common finding, and if extensive, it may be termed fascic-
ular variant.28
PASH can occur alone or in association with
hamartoma, fibroadenoma, or phyllodes tumor,.32e34
The spin-
dle cells in PASH express CD34 and bcl-2. Its positivity to es-
trogen receptor (ER) and progesterone receptor (PR) supports
hormone dependency29
and positivity to smooth muscle actin
(SMA) and vimentin confirms its myofibroblastic nature.32
Hamartoma
Hamartoma usually presents as a discreet breast mass with vari-
able consistency. With a benign clinical course and variable
physical examination findings, it is probably under-detected.33,35
A
characteristic “breast within a breast” appearance is seen on
mammography,36
which is the result of a well circumscribed lesion
of soft tissue and fat displacing normal breast parenchyma.36
Hamartoma is classically defined as nodule containing variable
amounts of adipose tissue, lobules, ducts and fibrous tissue.37
Histologically, interlobular fibrosis, encapsulated fat and presence
of PASH-like changes are helpful clues.33,35
Cases with co-existing
carcinoma-in-situ and invasive carcinomas have been re-
ported.33,38
The stromal cells in hamartoma resemble that of normal
breast stroma, and are positive to hormone receptors and smooth
muscle markers.38
Hamartomas occurring in the setting of Cowden
syndrome harbors PTEN germline mutation39
and may be associ-
ated with concomitant pre-malignant or invasive carcinomas.40
Adenomyoepithelioma
Adenomyoepithelioma usually presents as a solitary palpable
mass.41
Mammographically, adenomyoepithelioma is dense and
circumscribed, and can be round or lobulated.42
Adenomyoepi-
thelioma is histologically and clinically benign, composing of
bland ductal epithelial cells embedded within hyperplastic
myoepithelial cells, and this histologic appearance is retained at
local recurrence.43
Aggressive adenomyoepithelioma is rare and
shows characteristic malignant histologic features (see below).44
e46
The ductal component of adenomyoepithelioma resembles
normal mammary ducts. The myoepithelium is basaloid, plas-
macytoid or spindled with clear to eosinophilic cytoplasm and
comprise the main bulk of the lesion.43
In malignant
adenomyoepithelioma, the myoepithelial component shows se-
vere cytologic atypia, increased mitotic rate and invasion.45
Heterologous components including chondrosarcoma and oste-
osarcoma have also been reported.46
The lesional cells in ade-
nomyoepithelioma express myoepithelial markers (SMA,
calponin, S100), basal markers (p63) and cytokeratins (AE1/3,
CK14), and this profile helps to differentiate adenomyoepithe-
lioma from other biphasic spindle cell lesions.41
Biphasic spindle cell lesions with high grade spindle cells
Phyllodes tumor (borderline, malignant)
Malignant, and less commonly borderline phyllodes tumors
show predilection for distant metastasis and thus disease-related
mortality.47
Mammography is unreliable in grading phyllodes
tumors.19
Histologically, malignant phyllodes tumor are distin-
guished from their benign counterparts by a markedly and
diffusely increased stromal cellularity, marked stromal atypia, a
high (10/10HPFs) mitotic rate, presence of stromal overgrowth
and permeative borders (Figures 5a, 5b). Presence of high grade
heterologous components upgrades a phyllodes tumor into the
malignant category in most cases. Borderline phyllodes tumor
shows moderate stromal cellularity and atypia, a mitotic rate of 5
e9/10HPFs and may only demonstrate focal stromal overgrowth
and permeative border.48
The diagnosis of malignant phyllodes
tumor relies on the recognition of a phyllodal epithelial pattern
within the malignant sarcomatous and overgrown stroma. In
malignant and borderline phyllodes tumors, the stromal cells can
occasionally express p40, p63 and cytokeratins, thus may
potentially be mistaken for metaplastic carcinomas.25,26
However
the staining is usually focal, and more likely seen in the areas of
sub-epithelial stromal condensation. Malignant phyllodes tumors
may harbor p53 (TP53), retinoblastoma (RB1), neurofibromin 1
(NF1), PIK3CA, PTEN, BRAF and EGFR mutations,17,49,50
and
have been recently shown to have a high stromal telomerase
reverse transcriptase (TERT ) expression.51
Compared to benign
phyllodes tumor, malignant phyllodes tumor shows reduced
CD34 positivity52
and higher CD117, p53 and CD10 expression.53
e55
A lower incidence of MED12 and increased RARA mutation is
also reported.17
Figure 4 Pseudoangiomatous stromal hyperplasia (PASH). (a) PASH as a nodular lesion with irregular borders, 20x magnification. (b) PASH as a
bland spindle cell proliferation in a fibrotic background, 100x magnification.

Biphasic/carcinomatous metaplastic carcinoma
Metaplastic carcinomas are a group of histologically diverse
malignant neoplasms, defined by differentiation of neoplastic
epithelium into squamous cells and/or mesenchymal-looking
elements.48
Traditionally, they are classified into matrix producing, spindle
cell, carcinosarcoma, squamous cell and metaplastic carcinoma
with osteoclastic giant cells basing on morphologic characteris-
tics.56e60
For simplicity, metaplastic carcinomas with a spindle
cell component can be divided into monophasic (morphologic
sarcomatous component only) or biphasic (morphologic sarco-
matous and carcinomatous components), with or without heter-
ologous elements. Generally speaking, metaplastic carcinoma is
aggressive with a propensity for metastasis.7
Presence of heter-
ologous elements does not affect the overall prognosis.61
A low-
grade fibromatosis-like variant with better clinical outcome has
been described62,63
and is discussed under monophasic spindle
cell lesions. Radiologic appearance can be deceptive as meta-
plastic carcinoma, compared to invasive ductal carcinoma, can
show relatively circumscribed margin64.
The sarcomatous component of most metaplastic carcinomas
is composed of spindle cells with severe atypia and pleomor-
phism in variable arrangements ranging from long fascicles in a
herringbone pattern to short fascicles in a storiform pattern. In
biphasic metaplastic carcinomas, the defining carcinomatous
component is most commonly glandular (infiltrating duct carci-
noma) (Figures 6a, 6b) but can also be squamous or carcinoma-
in-situ.65
The sarcomatous component usually retains at least
focal immunohistochemical evidence of epithelial origin, which
can be demonstrated by cytokeratin cocktails and p63.66
Posi-
tivity to myoepithelial markers (SMA, S-100) can also be seen in
some metaplastic carcinomas.65
Metaplastic carcinomas are
mostly triple negative.67
Monophasic spindle cell lesions
Monophasic spindle cell lesions of the breast can be divided
morphologically into inflammatory/reactive (fibrous scar, des-
moid fibromatosis and nodular fasciitis), low-grade (myofibro-
blastoma, fibromatosis-like metaplastic carcinoma, neural and
lipomatous tumors), and high-grade (monophasic spindle cell
metaplastic carcinoma, metaplastic carcinoma with heterologous
components, sarcomas and metastatic neoplasms). Most mono-
phasic spindle cell lesions (with the exception of metaplastic
carcinomas) may also occur in extramammary sites.
Not uncommonly, biphasic lesions can be misrepresented as
monophasic lesions if epithelial components are not adequately
sampled, especially in a needle core biopsy. Entrapment of
normal epithelial structures in monophasic lesions may also lead
to erroneous classification as a biphasic lesion. Entrapment
usually occurs at the edge of the lesion, and sometimes a vague
ductal lobular architecture may be discerned. Correlation with
clinical and radiologic information, careful consideration of dif-
ferential diagnoses and use of ancillary methods are of para-
mount importance in making a correct diagnosis.
Monophasic spindle cell lesions e inflammatory/reactive
Fibrous scar/Reactive spindle cell nodule
Fibrous scar, or post-operative reactive spindle cell nodule,
usually occur within a month following fine-needle aspiration,
biopsy, surgical operations or physical trauma.68
Histologically
this is usually represented by a vague nodular proliferation of
spindle cells with mild to moderate degree of nuclear pleomor-
phism with prominent nucleoli and sometimes visible mitotic
activity (Figure 7), even though the lesion is reactive and non-
neoplastic in nature, and thus runs a benign clinical course.69
Accurate diagnosis requires clinical history of trauma or pro-
cedure and recognition of microscopic clues, including back-
ground mononuclear inflammatory cells, foreign body-type giant
cells, foamy macrophages, hemosiderin deposition and a
granulation-tissue like small vessel network. Reactive spindle
cell nodule displays a low mitotic count (up to 1 per 10 high-
power fields)17
and proliferative index (Ki-67 1%).68
The
spindle cells are myofibroblastic, and immunoreactive to SMA,
muscle-specific actin and vimentin69.
Nodular fasciitis
Nodular fasciitis is a reactive proliferation triggered by local
trauma or injury.70
It initially presents as a rapidly growing,
Figure 5 Borderline phyllodes tumor. (a) Permeative border in borderline phyllodes tumor, 40x magnification. (b) Stromal mitosis and increased
stromal cellularity in borderline phyllodes tumor, 200x magnification.

painless mass with subsequent spontaneous resolution within a
month to up to two years.70
Nodular fasciitis appears as irregular
unencapsulated hypoechoic nodule on ultrasound71
or irregular
spiculated mass on mammography.72
Presentation at the prolif-
erative phase, along with the suspicious imaging findings, may
simulate a malignant neoplasm.
Histologically, nodular fasciitis shows a reactive background
with chronic inflammatory cells, small capillary proliferation,
extravasated red cells and myxoid material.73
The spindle cells
are arranged in bundles or fascicles in a loose myxoid stroma and
show variable cellularity. They can feature distinct nucleoli but
do not show significant cellular atypia. Mitosis, however, can be
numerous.70
The spindle cells show myofibroblastic differentia-
tion and are reactive to SMA and vimentin70. Nodular fasciitis
harbors a specific MYH9-USP6 translocation, which is detectable
by fluorescence in situ hybridization (FISH).74
Desmoid fibromatosis
Extra-abdominal desmoid fibromatosis is a locally infiltrative
tumor without metastatic potential.75
Most cases of fibromatosis
of the breast are sporadic76
but some are observed in post-
operative patients and in proximity to breast implants.77
A sub-
set of desmoid fibromatosis occurs in patients with familial
adenomatous polyposis (FAP) and is associated with germline
adenomatous polyposis coli (APC ) gene inactivating mutation.78
Fibromatosis can display a constellation of suspicious radiolog-
ical features with spiculated borders, tethering of Cooper’s liga-
ments and involvement of intercostal or pectoralis muscle.79
Histologically, desmoid fibromatosis is composed of fibro-
blasts and myofibroblasts arranged in characteristic long sweep-
ing fascicles. Background myxoid degeneration, dense keloid-like
collagen and inflammatory infiltrate including mast cells, plasma
cells and lymphocytes may be observed. Muscle invasion can be
seen, and rare cases may show perineural invasion.80
Confirma-
tion of its benign nature relies on the recognition of bland nuclear
features with minimal pleomorphism and scarcity of mitotic
Figure .81
Desmoid fibromatosis is positive for SMA, vimentin and
negative for S-100, CD31, CD34, cytokeratins and epithelial
membrane antigen (EMA).82
Mutations in the APC/beta-catenin
pathway in FAP associated and sporadic desmoid fibromatosis
results in accumulation of nuclear beta-catenin, which can be
detected by immunohistochemistry.78
Sporadic desmoid fibro-
matosis often harbors mutations in exon 3 of CTNNB1 gene,
which encodes beta-catenin83, and detection of CTNNB1 muta-
tion can serve as a diagnostic adjunct in problematic cases.83
Monophasic spindle cell lesions e neoplastic, low grade
Myofibroblastoma
Mammary myofibroblastoma is a benign tumor occurring in
most commonly post-menopausal women and men of similar
age, without any sex predilection.84
Mammary myofibro-
blastoma runs a benign clinical course without recurrence after
adequate resection.85
It appears radiologically as solid circum-
scribed or smoothly lobulated lesion.86
Uncommonly, intra-
tumoral adipose tissue (heterogeneity) and deep location can
raise suspicion for malignancy.86
Figure 6 Biphasic and monophasic spindle cell carcinomas. (a) Biphasic spindle cell carcinoma with spindle cell (left) and epithelial (right)
component, 40x magnification. (b) Heterologous chondroid component, 200x magnification.
Figure 7 Fibrous scar/reactive spindle cell nodule. Reactive spindle
cell nodule with a reactive background containing red cells and in-
flammatory cells, 100x magnification.

Microscopically, mammary myofibroblastoma is composed of
short fascicles of myofibroblasts with bland nuclei, indistinct
pale cytoplasm with indistinct cell borders in a background of
thick, ropey collagen bundles.84
Variants have been described
including symplastic, epithelioid, invasive, lipomatous, myxoid,
deciduoid cell, palisaded/schwannian-like and mammary myo-
fibroblastoma with extensive myxo-edematous stromal
changes.84,87
Epithelioid and invasive variants can mimic inva-
sive carcinoma but can be readily differentiated by immunohis-
tochemistry. In the symplastic variant, atypical and
multinucleated cells are only seen focally and are mitotically
inactive.84
Mammary myofibroblastoma is reactive to CD34,
CD99, vimentin, desmin, SMA, bcl-2, ER and PR.85
Chromosome
13 rearrangement affecting tumor suppressor gene RB1, which
encodes the retinoblastoma (Rb) protein, can be found in some
mammary myofibroblastoma.88
Loss of Rb can be detected by
FISH or loss of nuclear Rb1 staining84,88
Fibromatosis-like metaplastic carcinoma
Fibromatosis-like metaplastic carcinoma is an indolent subtype
of metaplastic carcinoma with potential for local recurrence but
low risk of metastasis.63,89
Fibromatosis-like metaplastic carci-
noma may appear rounded and circumscribed on mammog-
raphy90
and histologically is composed of spindle cells with low
to moderate cellularity with finger-like edges infiltrating and
entrapping adjacent breast lobules. The spindle cells can
display mild atypia with occasional small nucleoli.63
The
carcinomatous nature of the spindle cells is evidenced by their
reactivity to cytokeratins and p63.91
In contrast to extra-
abdominal fibromatosis, nuclear beta-catenin expression is
absent.91
Other mesenchymal tumors
Rarely other mesenchymal tumors that are of non-breast origin
may also occur, most commonly neural tumors (schwannoma,
neurofibroma) and lipomatous tumors (lipomas, angiolipomas).
Vascular tumors are discussed below.
Monophasic spindle cell lesions e neoplastic, high grade
Monophasic/spindle cell metaplastic carcinoma
In general, high grade monophasic metaplastic carcinoma is re-
ported to be particularly aggressive among metaplastic carci-
nomas.64
There are no distinguishing radiologic features.90
The
sarcomatous component in monophasic metaplastic carcinoma is
identical to that of biphasic metaplastic carcinoma. The only
difference is the absence of a phenotypically obvious carcino-
matous component (with characteristic and diagnostic features of
cellular cohesion, glandular/tubule formation, or squamous dif-
ferentiation). Nevertheless, the spindle cell component, albeit
phenotypically sarcomatous, usually possesses subtle epithelial
features, at least focally within the tumor. These features
commonly include focal areas of vague cellular adhesion, and
focal to diffuse reactivity to high molecular weight cytokeratins,
p63, and other basal and epithelial markers (Figures 8a, 8b). The
presence of any of these evidence should trigger a diagnostic
label of spindle cell metaplastic carcinoma.48
A diagnosis of
primary sarcoma, notably with osteosarcomatous or chon-
drosarcomatous stroma, is extremely uncommon, should only be
made only if no subtle evidence of epithelial differentiation could
be made after a diligent search.92
Sarcomas
Primary sarcomas of the breast are very rare, and within this
group, angiosarcoma is the commonest. Primary angiosarcoma
can occur in three settings: de novo, post-irradiation and in as-
sociation with chronic lymphedema (Stewart Treves syndrome).
Clinically, angiosarcoma presents as painless bruises, not
necessarily associated with a detectable mass.93
Ultrasound and
mammography findings are non-specific and diagnosis
frequently requires magnetic resonance imaging.94
Histological-
ly, angiosarcoma is characterized by complex anastomosing
vascular channels and can be graded into low, intermediate and
high-grade based on the degree of atypia of the lining endothelial
cells and the formation of papillary and solid areas.95
CD31,
Figure 8 Monophasic spindle cell carcinomas. (a) Monophasic spindle cell carcinoma, 200x magnification. (b) Epithelial membrane antigen (EMA),
200x magnification.

CD34, FLI-1 and ERG and factor VIIIerelated antigen are useful
vascular markers.95
Radiation-associated angiosarcoma are more
commonly histologically high-grade96
and harbors MYC ampli-
fication, detectable by FISH and immunohistochemistry.97
Other
primary breast sarcomas described include fibrosarcoma, pleo-
morphic sarcoma, leiomyosarcoma, osteosarcoma and myxofi-
brosarcoma, which all are histologically similar to their soft
tissue counterparts.98
Irrespective of the phenotypic differentia-
tion, all primary breast sarcomas have dismal prognosis.97
Metastasis
Metastasis to the breast is rare and constitutes only 0.3e2.7% of
malignant breast tumors.99,100
Cutaneous melanoma, pulmonary
and ovarian carcinomas are the most frequent primary sources.99
Sarcomatoid squamous cell carcinoma and spindle cell mela-
noma are potential imitators of malignant spindle cell lesions.
Periductal distribution of tumor cells and absence of an in-situ
component are histologic features that may hint to a metastatic
origin100. Relevant clinical history is probably the most impor-
tant clue to the diagnosis. Ancillary IHC, including gross cystic
disease fluid protein-15 (GCDFP-15), mammaglobin (MGB) and
GATA-3 have been described as useful breast cancer markers. In
general, GATA-3 is more sensitive but also reacts with urothelial
neoplasms whereas GCDFP-15 and MGB exhibit a relatively high
specificity. All these markers show similarly higher detection rate
for ER positive breast cancers than triple negative breast can-
cers.101e104
The use of multiple breast cancer markers may
improve the sensitivity.
Conclusion
Spindle cell lesions remain a diagnostically challenging area in
breast pathology, as defining clinical, radiologic and pathologic
features may not be present for each entity. A practical diagnostic
algorithm is to stratify spindle cell lesions into monophasic or
biphasic lesions (by identification of an epithelial element), fol-
lowed by categorization into reactive, low-grade and high-grade
lesions by background inflammation and nuclear features.
Careful examination of morphologic clues, and judicious use of
IHC staining and molecular techniques will allow an accurate
diagnosis in most cases. A
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