Section 3 -

The Evolving Classification of Stromal Tumors Alena Skálová

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 [1] and stromal-epithelial interactions in fibroepithelial breast tumors [2] 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 [3] 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 [4]. 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 [4, 5, 6, 7]. In addition, locally aggressive mammary fibromatosis and rare true primary breast sarcomas have spindle cell morphology [4]. 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) [8, 9]. Major Clinicopathological Entities and Their Differential Diagnosis Mammary myofibroblastoma is a rare benign tumor first recognized by Wargotz et al [10]. 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 [10]. 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 [11]. 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 [12]. Moreover, some cases of myofibroblastoma show a prominent adipocytic component resulting in similarity with spindle cell lipoma [13]. Chromosomal rearrangements of 13q and 16q, characteristic of spindle cell lipoma, have been identified in some cases of myofibroblastoma [14] supporting a proposition of a relationship between these two tumors. Moreover, recently Powell et al [15] 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 [5, 6]. 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% [9, 16]. 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 [17]. The term „stromal sarcoma of the breast" initially referred to all sarcomas of the breast excluding phyllodes tumor with stromal overgrowth and angiosarcoma [18], 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 [19]. 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 [20]. 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" [21]. 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. References Kim JB, Stein R, O´Hare MJ. 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