New Frontiers in Breast Pathology
Moderator: Dr. Sunil Lakhani
Section 3 -
The Evolving Classification of Stromal Tumors
Coordination of growth of epithelium and stroma is essential event, not only in normal
postnatal development but also in repair after tissue injury and in tumor growth. The patterns of
epithelial-stromal interactions may be particularly disturbed in neoplasms. The crucial role of
myofibroblastic mammary stroma in breast carcinoma  and stromal-epithelial interactions in
fibroepithelial breast tumors  have been extensively studied previously. In this review, we focus on
specific mammary stromal tissue that may give rise to a broad spectrum of primary tumors and tumor-like
lesions. Fibroblasts and myofibroblasts are normal constituents of the intralobar and interlobar mammary
stroma, and they represent cells of origin of most spindle cell lesions of the breast (with exception of
metaplastic/spindle cell carcinoma). The myofibroblast is recognized by the combination of abundant
endoplasmic reticulum, which is typical of fibroblast, and actin microfilaments with focal densities,
typical of smooth muscle cells. Immunohistochemistry reveals a spectrum of phenotypical variants of
myofibroblast with variable positivity for alfa-smooth muscle (a-SM) actin, vimentin, desmin and
CD34 antigen. Gabbiani  has defined four imunophenotypical variants of myofibroblast: phenotype V, represented by myofibroblasts positive for vimentin only, phenotype VA, represented by myofibroblasts positive for vimentin and (a-SM) actin, phenotype VAD, represented by myofibroblasts positive for
vimentin, (a-SM) actin and desmin, and phenotype VD, represented by
myofibroblasts positive for vimentin and desmin. Accordingly, myofibroblasts have been found in broad
spectrum of benign and malignant tumors with variable morphology and immunophenotype.
Myofibroblastic and fibroblastic spindle cell tumors and pseudotumors of the breast are rare lesions.
They constitute a wide spectrum of benign or malignant proliferations of variable histogenesis, and they
often present a diagnostic challenge. They may display diverse morphological appearances within one
lesion with a considerable morphological overlap in several tumor entities with different biological
behavior . Purely benign mesenchymal spindle cell tumors of the mammary stroma occur infrequently and
there is a significant clinical and histological overlap between neoplastic and reactive lesions. Benign
neoplasms present a spectrum of tumor entities currently labeled under various terms, such as benign
spindle cell tumor, myogenic stromal tumor, fibroma, myofibroblastoma, spindle cell lipoma-like tumor,
solitary fibrous tumor, etc
In addition, locally aggressive mammary fibromatosis and rare true
primary breast sarcomas have spindle cell morphology . The other group of spindle cell non-neoplastic
myofibroblastic/fibroblastic proliferations of the breast encompass reactive conditions, such as scars,
nodular fasciitis, and pseudoangiomatous stromal hyperplasia (PASH)
Major Clinicopathological Entities and Their Differential Diagnosis
Mammary myofibroblastoma is a rare benign tumor first recognized by
Wargotz et al . In most cases, myofibroblastoma is composed of spindle shaped cells immunoreactive
for desmin, CD34 and vimentin with a variable positivity for α-smooth muscle actin .
Myofibroblastoma is the only mammary neoplasm more frequent in men than in women, and most cases display
strong staining for androgen receptor not seen in other spindle cell tumors . Myofibroblastoma can
express CD34 antigen and its morphology can be reminiscent of solitary fibrous tumor, and thus a common
origin of both tumors has been suggested . Moreover, some cases of myofibroblastoma show a prominent
adipocytic component resulting in similarity with spindle cell lipoma . Chromosomal rearrangements
of 13q and 16q, characteristic of spindle cell lipoma, have been identified in some cases of
myofibroblastoma  supporting a proposition of a relationship between these two tumors. Moreover,
recently Powell et al 
reported cases of pseudoangiomatous stromal hyperplasia (PASH) presenting as a
palpable tumor mass of the breast. The cells of PASH are positive for vimentin, CD34, desmin and actin,
and focally PASH has a fascicular growth pattern resembling myofibroblastoma. Although myofibroblastoma,
solitary fibrous tumor, spindle cell lipoma show considerable morphological and immunophenotypical
heterogeneity, they all seem to be related one to another, and arise from noncomitted vimentin+/CD34+
fibroblast of mammary stroma, capable of multidirectional mesenchymal differentiation
Primary mammary fibromatosis (PMF) can occur at any age after adolescence
and most frequent is in women between 20 and 40 years of age. The role of trauma in the pathogenesis is
still controversial. Microscopically, PMF is composed of long myofibroblastic fascicles penetrating into
the breast tissue. PMF can be locally aggressive, and risk of recurrence is about 20%
Nodular fasciitis (NF) is a well-known pseudosarcomatous proliferation of
fibroblasts and myofibroblasts that is considered to be reactive. NF in unusual anatomic location such
as breast still causes diagnostic difficulties. It is composed of spindle cells with plump nuclei,
occasional nucleoli and with myxoid stroma containing lymphocytes and extravasated red cells. Normal
mitoses may be present. Later cases are more fibrotic. Immunohistochemistry shows expression of actin.
The commonest spindle cell lesions of the breast that are biopsied are scars. The diagnosis is usually straightforward because of associated fat
necrosis or haemosiderin-laden macrophages. Occasionally there may be atypia of the spindle cells, which
can make diagnosis difficult, particularly on core biopsy.
Primary true sarcoma of the breast accounts for less than 1% of all
breast malignancies . The term „stromal sarcoma of the breast" initially referred to all sarcomas of
the breast excluding phyllodes tumor with stromal overgrowth and angiosarcoma , but it was later
redefined and now it is recommended to use the term „stromal sarcoma" only for those unusual cases
arising in intralobar stroma . Angiosarcoma rarely develops after radiotherapy for breast cancer,
postmastectomy angiosarcoma is an extremely rare highly lethal complication of chronic lymphedema.
The main differential diagnosis of all mammary spindle cell tumors and pseudotumors is
sarcomatoid/metaplastic carcinoma . Metaplastic carcinoma comprises
about 5% of breast malignancies. Spindle cell carcinoma of the breast is a
variant of metaplastic carcinoma in which spindle cells predominate, and may mimic a variety of benign
mesenchymal reactive and neoplastic lesions. Low grade metaplastic
carcinoma with hardly discernable epithelial component and with bland morphology has been
described recently as „fibromatosis-like metaplastic carcinoma" . The diagnosis of spindle cell
carcinoma is straightforward if there is admixed conventional invasive carcinoma or ductal carcinoma in situ. Spindle cell carcinoma may, however, be composed of pure
spindle cell component. Cytokeratin immunohistochemistry using a broad panel of antibodies is useful
particularly in core biopsy diagnosis. The spindle cells do not express CD34. Estrogen, progesterone
receptors and HER-2/neu protein stains are usually negative. Sarcomatoid carcinoma usually behaves in a
manner similar to high grade breast carcinoma.
- Kim JB, Stein R, O´Hare MJ. Tumour-stromal interactions in breast cancer: the role of stroma in tumorigenesis. Tumour Biol 2005:26:173-85.
- Sawhney N, Garrahan N, Douglas-Jones AG, et al. Epithelial-stromal interactions in tumors. A morphologic study of fibroepithelial tumors of the breast. Cancer 1992:70:2115-2120.
- Gabbiani G. The biology of myofibroblast. Kidney Intern 1992:41:350-352.
- Al-Nafussi A. Spindle cell tumours of the breast: practical approach to diagnosis. Histopathology 1999:35:1-13.
- Magro G, Michal M, Bisceglia M. Benign spindle cell tumors of the mammary stroma: diagnostic criteria, classification, and histogenesis. Path Res Pract 2001:197:453-466.
- Magro G, Bisceglia M, Michal M, Eusebi V. Spindle cell lipoma-like tumor, solitary fibrous tumor and myofibroblastoma of the breast: a clinico-pathologic analysis of 13 cases in favor of unifying histogenetic concept. Virchows Arch 2002:440:249-260.
- Magro G, Michal M, Vasquez E, Bisceglia M. Lipomatous myofibroblastoma: a potential diagnostic pitfall in the spectrum of the spindle cell lesions of the breast. Virchows Arch 2000:437:540-544.
- McMenamin ME, DeSchryver K, Fletcher CDM. Fibrous lesions of the breast: a review. Intern J Surg Pathol 2000:8:99-108.
- Brogi E. Benign and malignant spindle cell lesions of the breast. Semin Diagn Pathol 2004:21:57-64.
- Abraham SC, Reynolds C, Lee JH et al. Fibromatosis of the breast and mutations involving the APC/beta-catenin pathway. Hum Pathol 2002;33:39-46
- Wargotz ES, Weiss SW, Norris HJ. Myofibroblastoma of the breast. Sixteen cases of a distinctive benign mesenchymal tumor. Am J Surg Pathol 1987:11:493-502.
- Morgan MB, Pitha JV. Myofibroblastoma of the breast revisited: an etiologic association with androgens? Hum Pathol 1998:29:347-351.
- Damiani S, Miettinen M, Peterse L, Eusebi V. Solitary fibrous tumor (myofibroblastoma) of the breast. Virch Arch 1994:425:89-92.
- Magro G, Bisceglia M, Pasquinelli G. Benign spindle cell tumor of the breast with prominent adipocytic component. Ann Diagn Pathol 1998:2:306-311.
- Pauwels P, Sciot R, Croiset F, et al. Myofibroblastoma of the breast: genetic link with spindle cell lipoma. J Pathol 2000:191:282-285.
- Powell CM, Cranor ML, Rosen PP. Pseudoangiomatous stromal hyperplasia (PASH): a mammary stromal tumor with myofibroblastic differentiation. Am J Surg Pathol 1995:19:270-277.
- Barnes L, Pietruszka M. Sarcomas of the breast: a clinicopathologic analysis of ten cases. Cancer 1977:40:1577-1585.
- Berg JW, DeCossa JJ, Frachia AA, et al. Stromal sarcoma of the breast. A unified approach to connective tissue sarcomas other than cystosarcoma phylloides. Cancer 1962:15:418-24.
- Jones MW, Norris HJ, Wargotz ES, et al. Fibrosarcoma-malignant fibrous histiocytoma of the breast. Clinicopathological study of 32 cases. Am J Surg Pathol 1992:16:667-674.
- Sneige N, Yaziji H, Mandavilli SR, et al. Low-grade (fibromatosis-like) spindle cell carcinoma of the breast. Am J Surg Pathol 2001:25:1009-1016.
- Gobbi H, Simpson JF, Browsky A. Metaplastic breast tumors with a dominant fibromatosis-like phenotype have a high risk of local recurrence. Cancer 1999:85:2170-85.