Case 3 -

Low Grade, Fibromatosis-like Metaplastic Carcinoma Arising in Association with a Complex Sclerosing Lesion Stuart J. Schnitt Beth Israel Deaconess Medical Center and Harvard Medical School Boston, MA

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Clinical History: A 54 year old female presented with a 1.6 cm palpable breast mass. An excisional biopsy was performed. Case 3 - Figure 1 Low power view of the lesion showing central sclerotic zone with entrapped glands and slightly more cellular areas at the periphery. Case 3 - Figure 2 High power view of glands in the central sclerotic zone, some of which show usual ductal hyperplasia. Case 3 - Figure 3 Medium power view of the periphery of the lesion showing spindle cells in a collagenous stroma extending irregularly into surrounding adipose tissue. Case 3 - Figure 4 High power view to demonstrate the bland cytologic features of the spindle cells and low cellularity that characterized most of the lesion. Case 3 - Figure 5 High power view of the most cellular area of the lesion. A rare mitotic figure is present. Pathologic Features: The specimen contained an irregular, firm, grey white area measuring approximately 1.5 cm. Histologic sections of this area revealed a central focus of hyalinized collagen with scattered entrapped benign ducts, a few of which showed papillary hyperplasia. The histologic features in this area were consistent with those of a complex sclerosing lesion. Circumferentially around this central sclerotic area, there was a proliferation of spindle cells that extended irregularly into the surrounding adipose tissue. The stroma associated with the spindle cells was variably collagenized. In most areas the cellularity of the lesion was relatively low imparting a scar-like appearance. In a few areas, the density of spindle cells was somewhat higher. The spindle cells were cytological bland and only rare mitotic figures were observed. The differential diagnosis included a scar or other reactive spindle cell proliferation, fibromatosis and low grade, fibromatosis-like metaplastic carcinoma. Immunostains showed that the spindle cells were negative for cytokeratin using antibodies AE1/AE3 and CAM5.2. However, these cells were variably cytokeratin-positive with pan-keratin antibody MNF-116 and cytokeratin antibody 34βE12. The spindle cells also showed variable nuclear staining for p63. These cells were negative for estrogen receptor and progesterone receptor and lacked HER2 protein overexpression. Final Diagnosis: Low grade, fibromatosis-like metaplastic carcinoma arising in association with a complex sclerosing lesion Discussion: A variety of reactive and neoplastic lesions of the breast are characterized by a proliferation of spindle cells. Among these are spindle cell carcinomas, a subtype of metaplastic carcinomas. These tumors may occur in pure spindle cell form or may consist primarily of spindle cells with associated glandular, squamous, or heterologous elements (most often chondroid or osseous). Tumors of this type have been variously designated metaplastic carcinoma, sarcomatoid carcinoma, and spindle cell carcinoma [1, 2, 3, 4, 5, 6, 7, 8, 9]. Spindle cell carcinomas are uncommon, accounting for <1% of invasive breast cancers. On gross examination, the tumors are most often gray or white, firm masses that are frequently circumscribed. Microscopically, the appearance of the spindle cells can vary from bland to highly pleomorphic and may show fascicular, fasciitis-like, storiform, or haphazard growth patterns. Areas suggestive of vascular spaces may sometimes be seen. The mitotic rate is highly variable. The borders of the lesion are usually infiltrative with entrapment of mammary ducts and lobules, but some cases exhibit pushing margins. Higher grade lesions tend to obliterate the normal breast architecture. In some cases, the spindle cells aggregate into small clusters that exhibit a more epithelioid appearance or merge with an overt epithelial component. Areas of squamous differentiation are not infrequent and foci of heterologous chondroid or osseous differentiation may be seen. Foci of conventional types of invasive breast carcinoma and/or ductal carcinoma in situ may be seen in association with the spindle cell component, and when present provide useful clues to the epithelial nature of the tumor. However, in pure spindle cell carcinomas without associated DCIS, immunohistochemical stains for cytokeratin may be required to arrive at the correct diagnosis. It should be noted however, that cytokeratin immunoreactivity may be focal and a panel of anti-cytokeratin antibodies may be required to demonstrate cytokeratin positivity. In our experience broad spectrum cytokeratin antibodies (such as antibody MNF116) and antibodies to high molecular weight/basal cytokeratins (such as antibody 34βE12 or antibodies to cytokeratin 5/6) are the most sensitive for the detection of cytokeratin expression in this setting [7]. The neoplastic cells also commonly express vimentin, smooth muscle actin, muscle specific actin and p63. Expression by these tumors of actins, p63, basal cytokeratins and other markers commonly associated with myoepithelial cells has been used as evidence supporting a myoepithelial or basal phenotype for many of these tumors [10, 11, 12]. Indeed, the distinction between spindle cell carcinomas and lesions previously described as myoepithelial carcinomas/malignant myoepitheliomas is probably just one of semantics. Spindle cell carcinomas are typically negative for estrogen receptor and progesterone receptor expression and for HER2 protein overexpression. One type of spindle cell carcinoma that may create particular diagnostic problems is low grade fibromatosis-like metaplastic carcinoma, as illustrated by this case [13, 14]. These lesions may arise de novo but may also be seen arising in association with papillomas and benign sclerosing lesions [15]. They are composed of bland spindle cells resembling those seen in scars or fibromatosis. In contrast to the cells of scars or fibromatosis, however, the spindle cells comprising these lesions show expression of cytokeratin, and some cases show epithelioid cell clusters or small foci of squamous differentiation. These tumors have been reported to be associated with a high rate of local recurrence. While no instances of metastasis were observed in the intial report of these cases [13] regional and distant metastases have subsequently been reported in a small proportion of patients with these lesions [14]. Spindle cell carcinomas are rarely associated with axillary lymph node metastases. Recent studies suggest a poorer prognosis than for conventional mammary carcinomas [7] and some have suggested that the clinical behavior of these tumors, particularly those that lack or have a minimal recognizable epithelial component is more akin to that of sarcomas than carcinomas [5]. Given the wide range of appearances of spindle cell carcinomas, the differential diagnosis is broad. Spindle cell carcinomas composed of cytologically bland spindle cells must be distinguished from scars, fibromatosis, myofibroblastoma, the fascicular form of pseudoangiomatous stromal hyperplasia, adenomyoepithelioma, and the stromal component of benign phyllodes tumors. Spindlec cell carcinomas composed of cytologically atypical spindle cells must be distinguished from the stromal component of malignant phyllodes tumors, nodular fasciitis, primary mammary sarcoma, metatstatic sarcoma and metastatic malignant melanoma. It is important to note that a malignant spindle cell tumor of the breast is much more likely to represent a spindle cell carcinoma or a malignant phyllodes tumor than a sarcoma. As noted above, the presence of areas of overt epithelial differentiation and/or associated DCIS are valuable clues to the diagnosis of spindle cell carcinoma. However, in cases without such features, the demonstration of cytokeratin expression by the neoplastic cells may be required to arrive at the correct diagnosis. A panel of cytokeratin antibodies may be required. In our experience and that of others, broad spectrum cytokeratin antibodies (such as MNF-116) and antibodies to high molecular weight cytokeratins (e.g., CK5/6, CK14, 34βE12) are the most sensitive for detecting epithelial differentiation in spindle cell carcinomas. The most important take-home message from this case is that when any spindle cell lesion is encountered in the breast, no matter how bland and benign-appearing at first glance, the diagnosis of spindle cell/metaplastic carcinoma should always be considered, and that diagnosis should not be dismissed unless there is histologic and/or immunophenotypic evidence to exclude it. It is also important to note that the definitive categorization of any spindle cell lesion of the breast may be difficult or impossible in the limited sampling afforded by core needle biopsy and a cautious approach to the diagnosis of spindle cell lesions on needle biopsy specimens is prudent. References Wargotz ES, Deos PH, Norris HJ. Metaplastic carcinomas of the breast. II. Spindle cell carcinoma. Hum Pathol 1989;20(8):732-40. Foschini MP, Dina RE, Eusebi V. Sarcomatoid neoplasms of the breast: proposed definitions for biphasic and monophasic sarcomatoid mammary carcinomas. Semin Diagn Pathol 1993;10(2):128-36. Al-Nafussi A. Spindle cell tumours of the breast: practical approach to diagnosis. Histopathology 1999;35(1):1-13. McMenamin ME, DeSchryver K, Fletcher CD. Fibrous Lesions of the Breast: A Review. Int J Surg Pathol 2000;8(2):99-108. Davis WG, Hennessy B, Babiera G, Hunt K, Valero V, Buchholz TA, et al. Metaplastic sarcomatoid carcinoma of the breast with absent or minimal overt invasive carcinomatous component: a misnomer. Am J Surg Pathol 2005;29(11):1456-63. Brogi E. Benign and malignant spindle cell lesions of the breast. Semin Diagn Pathol 2004;21(1):57-64. Carter MR, Hornick JL, Lester S, Fletcher CD. Spindle cell (sarcomatoid) carcinoma of the breast: a clinicopathologic and immunohistochemical analysis of 29 cases. Am J Surg Pathol 2006;30(3):300-9. Tse GM, Tan PH, Lui PC, Putti TC. Spindle cell lesions of the breast-the pathologic differential diagnosis. Breast Cancer Res Treat 2007. Lee AH. Recent developments in the histological diagnosis of spindle cell carcinoma, fibromatosis and phyllodes tumour of the breast. Histopathology 2008;52(1):45-57. Koker MM, Kleer CG. p63 expression in breast cancer: a highly sensitive and specific marker of metaplastic carcinoma. Am J Surg Pathol 2004;28(11):1506-12. Leibl S, Gogg-Kammerer M, Sommersacher A, Denk H, Moinfar F. Metaplastic breast carcinomas: are they of myoepithelial differentiation?: immunohistochemical profile of the sarcomatoid subtype using novel myoepithelial markers. Am J Surg Pathol 2005;29(3):347-53. Reis-Filho JS, Milanezi F, Steele D, Savage K, Simpson PT, Nesland JM, et al. Metaplastic breast carcinomas are basal-like tumours. Histopathology 2006;49(1):10-21. Gobbi H, Simpson JF, Borowsky A, Jensen RA, Page DL. Metaplastic breast tumors with a dominant fibromatosis-like phenotype have a high risk of local recurrence. Cancer 1999;85(10):2170-82. Sneige N, Yaziji H, Mandavilli SR, Perez ER, Ordonez NG, Gown AM, et al. Low-grade (fibromatosis-like) spindle cell carcinoma of the breast. Am J Surg Pathol 2001;25(8):1009-16. Gobbi H, Simpson JF, Jensen RA, Olson SJ, Page DL. Metaplastic spindle cell breast tumors arising within papillomas, complex sclerosing lesions, and nipple adenomas. Mod Pathol 2003;16(9):893-901.