Breast Pathology

Monophasic Spindle Cell (Sarcomatous) Carcinoma

James L. Connolly
Beth Israel Deaconess Medical Center
Boston, MA


Clinical History
This is a biopsy of a breast mass in a 71 year old African American woman. The patient was in an automobile accident, with breast trauma, 8 months prior to the biopsy.

Pertinent Laboratory Data:
The lesional cells were positive for actin and vimentin and negative for keratin coctail(Ae1-Ae3 & Cam 5.2)


Slide 1
Click to view with ImageScope
Click to view with a Web-Based Viewer

Introduction:
Pure spindle cell lesions of the breast present a difficult diagnostic dilemma. The most important lesion not to miss is a metaplastic carcinoma. Metaplastic carcinomas with areas of traditional ductal carcinoma don't present diagnostic problems. Monophasic spindle cell (sarcomatoid) carcinomas present a diagnostic dilemma.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
This case presented in 1998 as a breast mass in the 71-year- old African-American female with a remote history of breast injury following an automobile accident. The lesion was relatively acellular with keloidal like areas and no nuclear atypicality. The spindle cells were positive for by vimentin and actin. The spindle cells were negative for cytokeratins (ae1-3,cam5.2). Our diagnosis at the time was a reactive process. The lesion was rebiopsied in 2000 and 2001 with similar findings. In 2003 the lesion was biopsied and the patient had a mastectomy. At that time the lesion had a much more epitheliod appearance and was strongly positive for pan- keratin(MNF-116 and p63.

Differential Diagnoses:
The differential diagnosis of the lesion in 1998 includes a reactive change, areas of fibromatosis, nodular fasciitis or a monophasic metaplastic carcinoma.

Final Diagnosis:
The final diagnosis for the 1998 lesion is still unclear. By the year 2003 the breast showed a high-grade spindle cell metaplastic carcinoma that extended from the skin to the chest wall. The patient ultimately died of metastatic carcinoma.

Case Discussion:
The limited samples that we had from 1998 through 2001 were not diagnostic with the tools the we had available at time. It wasn't until 2003 that we were you routinely using the high molecular weight cytokeratins and the p63 that are so useful in diagnosing this type of metaplastic carcinoma

Review of the Literature/Treatment Options (if applicable):
Diagnosis: Monophasic Spindle Cell (Sarcomatous) Carcinoma

Differential Diagnosis: Nodular fasciitis

Classically this lesion presents as a rapidly enlarging, tender or painful mass. Although it is a self limited process and will resolve spontaneously there is some evidence that there are clonal rearrangements on chromosome 15 and 16 supporting a benign neoplasm [1]. Most lesions are well defined but have no capsule. The size varies but is usually less than 3 cm. Grossly they are usually well defined and may appear fibrous, myxoid or cystic [2, 3, 4]. Microscopically they are composed of proliferating bland myofibroblasts. Mitoses are frequent but not atypical. The background is loose collagenous stroma often with microcystic change. Inflammatory cells, particularly lymphocytes and neutrophils are not uncommon particularly at the periphery of the lesion. Thin walled blood vessels with associated red cell extravisation are common. In most cases the spindle cells are arranged in short fascicles. The cellular proliferation tends to push away adjacent structures, such as breast ducts and lobules, rather than invade them. There may be myxoid stromal change and as lesions age fibrosis or even keloidal change. Multinucleated giant cells are not uncommon. Immunohistochemically the lesions should be positive for actins and negative for keratins. They are usually negative for desmins [5]. Fibromatosis Fibromatosis of the breast is analogous to fibromatosis in other sites and is characterized by a locally invasive, non-encapsulated proliferation of well- differentiated spindle cells [6, 7]. These tumors have the capacity to recur locally if inadequately excised, but they do no metastasize.Margins of excision are difficult to evaluate. Gross disease left behind predicts for recurrence but the microscopic margins are not predictive in some studies [8]. Most cases of fibromatosis have somatic beta- catenin or adenomatous polyposis coli (APC) gene mutations [9]. One of the main concerns is to distinguish these lesions from well differentiated "fibromatosis like" metaplastic carcinomas. Clinically the lesions can arise at any age but the median age is earlier than carcinoma [6, 7]. The lesions are usually painless and palpable as a firm or hard tumor which may be associated with skin retraction. These features clinically suggest breast cancer. Grossly the size is quite variable. The lesion is usually ill defined, firm, fibrous tissue. Microscopically the lesions typically are composed of long fascicles of bland spindle cells, there is no significant cellular atypia and mitotic figures are sparse. The stroma varies from cellular to keloidal like. A myxoid stroma is not uncommon. The lesions tend to be centrally hyalinized and more cellular at the periphery. Lymphoid infiltrates are frequently seen at the periphery. In contrast to nodular fasciitis, fibromatosis, is an infiltrative lesion. At the periphery breast ducts and lobules will typically be infiltrated. Centrally especially in large lesions parenchymal elements will be absent. Ocassionally areas of necrosis have been reported [10].

Immunohistochemically the lesions should be positive for actins and negative for keratins. They are usually negative for desmins. In contrast to other myofibroblastic proliferations these lesions often show nuclear staining for beta-catenin [9, 11, 12] The lesions require wide excision since they are infiltrative and can be locally aggressive. One of the main concerns is to distinguish these lesions from well differentiated "fibromatosis like" metaplastic carcinomas. Metaplastic Carcinoma Metaplastic carcinomas represent a morphologically heterogeneous group of invasive breast cancers in which a variable portion of the glandular epithelial cells comprising the tumor have undergone transformation into an alternate cell type – either a non-glandular epithelial cell type (e.g., squamous cell) or a mesenchymal cell type (e.g., spindle cell, chondroid, osseous, myoid, etc.). There are numerous published reports describing various aspects of metaplastic carcinomas, and numerous appellations have been applied to the various tumors comprising this group [13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33]. However, there is no uniformly agreed upon classification scheme for these tumors. Metaplastic carcinomas are uncommon lesions, representing less than 5% of all of breast cancers. The prognostic implications of metaplastic carcinomas are difficult to define, and relate to the type of metaplasia present, as discussed below. There is growing evidence that epithelial and sarcomatoid elements have a clonal origin [34]. In addition it is likely that most metaplastic carcinomas are of basal or myoepithelial origin [35, 36, 37, 38] Genetic studies indicate that metaplastic breast cancers are enriched in epithelial-to-mesenchymal transition and stem cell encoding genes. [39, 40] Clinical Presentation Patients with metaplastic carcinoma are similar to patients with invasive carcinoma of NST with regard to their age at presentation, the manner in which their tumors are detected, and the location within the breast in which these tumors arise [20, 41]. Most patients present with a single palpable lesion that often is associated with rapid growth [20]. Gross Pathology The gross appearance of metaplastic carcinomas is not distinctive, and these tumors can either be well- circumscribed or show an indistinct or irregular border. Cystic degenerative changes are not infrequent, particularly in lesions with squamous differentiation. In general, metaplastic carcinomas tend to be relatively large tumors, compared to invasive carcinomas of NST. Histopathology Metaplastic carcinomas may arise from DCIS or may be associated with papillary, sclerosing or adenomatous lesions [42, 43, 44] Microscopically, metaplastic carcinomas are highly distinctive, but vary in the types and extent of metaplastic changes. Most reports divide metaplastic carcinomas into two broad categories: those that show squamous differentiation [14, 15] and those that feature heterologous elements, such as cartilage, bone, muscle, adipose tissue, vascular elements and even melanoncytes, among others [19, 20, 21, 22, 23, 24, 25, 26, 27, 33, 38, 42]. While many patterns exist Lesions that are primarily spindle cell in nature present the most difficult differential diagnosis [18]. Spindle-cell differentiation is common in metaplastic carcinomas, and is frequently seen in association with squamous differentiation. A low-grade metaplastic breast tumor composed of spindle cells that resemble those seen in fibromatosis is particularly difficult to diagnose [45, 46]. Metaplastic carcinomas resembling sarcomas are far more common than primary or metastatic sarcomas to the breast. The correct diagnosis in such cases may require extensive tissue sampling in order to demonstrate epithelial elements and immunohistochemical staining for epithelial markers, such as keratin, may be required for proper diagnosis. In general high molecular weight cytokeratins and basal or myoepithelial markers such as p63 and 34beta E12 are the most sensitive [36, 37]. There is increasing evidence that metaplastic carcinomas are variants of basal like tumors [47, 48]. While this is often helpful in tumors with spindle cell differentiation, not all metaplastic carcinomas show expression of epithelial markers, particularly those with heterologous differentiation. The results of immunohistochemical staining for other markers have been even more variable and this subject has been reviewed in detail [49, 50]. The frequency of DCIS seen in association with metaplastic carcinoma varies among published reports. In lesions characterized by a prominent mesenchymal component in which a true sarcoma is in the differential diagnosis, the presence of DCIS or ADH argues in favor of metaplastic carcinoma. Estrogen and progesterone receptor studies in metaplastic carcinomas are typically negative, regardless of the histologic subtype examined [15, 17, 18, 20, 21, 22, 23, 26, 32, 51, 52]. Metaplastic carcinomas are typically aneuploid or tetraploid [23, 28]. A small study of metaplastic carcinomas demonstrated identical clonality of the epithelial and mesenchymal components The conclusion was that the mesenchymal component of these lesions arose from mutation of the epithelial component [29] . "Fibromatosis-like" metaplastic carcinoma is a well differentiated variant of monophasic (sarcomatoid) metaplastic carcinoma .Similar to fibromatosis, these lesions are composed of a monotonous proliferation of bland, elongated spindle cells with an infiltrative pattern of growth and an invasive edge. The neoplastic cells have mild (or no) nuclear pleomorphism, variable (but low) mitoses and are disposed within a collagenous stroma. Focal biphasic (epithelial), heterologous (e.g. cartilage, bone) and/or in situ areas may be found in metaplastic carcinoma, which will not be present in fibromatosis. Therefore, multiple sections of a low grade spindle cell lesion such as this should be submitted for microscopic examination. Furthermore, immunohistochemistry for cytokeratins and epithelial membrane antigen (EMA) are very useful if positive as fibromatosis is negative for these markers, whereas metaplastic carcinoma usually stains positively. Immunostaining may be focal in metaplastic carcinoma, and therefore, a negative result still does not rule out the diagnosis. Clinical Course and Prognosis In most cases, the routes of metastatic dissemination in biphasic metaplastic carcinomas are similar to those seen in breast cancers of no special type, including lymphatic spread to axillary lymph nodes rather than the hematogenous spread characteristic of mammary sarcoma. Metastatic lesions may either demonstrate an epithelial phenotype, the metaplastic phenotype, or both. A large recent study of biphasic metaplastic carcinomas indicated that they were aggressive(52% 5yr relapse free survival) and treatment refractory with a prognosis of poorly differentiated, receptor negative adenocarcinomas [53]. Tumors in which the sarcomatous elements predominate are more likely to have metastatic spread similar to a sarcoma [38]. In a recent study spindle cell (sarcomatoid) carcinoma of the breast rarely involved axillary nodes(5%) and commonly spread to the lungs(46%) [38]. In the same study these lesions had a dire prognosis with 42% of patients dead of disease at a median interval of 11.5 months. [38]. High- grade spindle cell metaplastic carcinomas have a considerably worse prognosis than low-grade lesions [54]. The fibromatosis like" metaplastic carcinoma may have a more favorable prognosis [45, 55].

Conclusion(s):
Metaplastic carcinomas resembling sarcomas are far more common than primary or metastatic sarcomas to the breast. The correct diagnosis in such cases may require extensive tissue sampling in order to demonstrate epithelial elements and immunohistochemical staining for epithelial markers, such as keratin, may be required for proper diagnosis. In general high molecular weight cytokeratins and basal or myoepithelial markers such as p63 and 34beta E12 are the most sensitive

References:
  1. Donner LR, Silva T, Dobin SM. Clonal rearrangement of 15p11.2, 16p11.2, and 16p13.3 in a case of nodular fasciitis: additional evidence favoring nodular fasciitis as a benign neoplasm and not a reactive tumefaction. Cancer Genet Cytogenet 2002;139(2):138-40.

  2. Shimizu S, Hashimoto H, Enjoji M. Nodular fasciitis: an analysis of 250 patients. Pathology 1984;16(2):161-6.

  3. Konwaler BE, Keasbey L, Kaplan L. Subcutaneous pseudosarcomatous fibromatosis (fasciitis). Am J Clin Pathol 1955;25(3):241-52.

  4. Maly B, Maly A. Nodular fasciitis of the breast: report of a case initially diagnosed by fine needle aspiration cytology. Acta Cytol 2001;45(5):794-6.

  5. Montgomery EA, Meis JM. Nodular fasciitis. Its morphologic spectrum and immunohistochemical profile. Am J Surg Pathol 1991;15(10):942-8.

  6. Wargotz ES, Norris HJ, Austin RM, Enzinger FM. Fibromatosis of the breast. A clinical and pathological study of 28 cases. Am J Surg Pathol 1987;11(1):38-45.

  7. Rosen PP, Ernsberger D. Mammary fibromatosis. A benign spindle-cell tumor with significant risk for local recurrence. Cancer 1989;63(7):1363-9.

  8. Gronchi A, Casali PG, Mariani L, Lo Vullo S, Colecchia M, Lozza L, et al. Quality of surgery and outcome in extra-abdominal aggressive fibromatosis: a series of patients surgically treated at a single institution. J Clin Oncol 2003;21(7):1390-7.

  9. Bhattacharya B, Dilworth HP, Iacobuzio-Donahue C, Ricci F, Weber K, Furlong MA, et al. Nuclear beta-catenin expression distinguishes deep fibromatosis from other benign and malignant fibroblastic and myofibroblastic lesions. Am J Surg Pathol 2005;29(5):653-9.

  10. Melato M, Rizzardi C, Bertoli G. Mammary fibromatosis with extensive necrosis. Histopathology 2002;40(4):397-8.

  11. Abraham SC, Reynolds C, Lee JH, Montgomery EA, Baisden BL, Krasinskas AM, et al. Fibromatosis of the breast and mutations involving the APC/beta-catenin pathway. Hum Pathol 2002;33(1):39-46.

  12. Ng TL, Gown AM, Barry TS, Cheang MC, Chan AK, Turbin DA, et al. Nuclear beta-catenin in mesenchymal tumors. Mod Pathol 2005;18(1):68-74.

  13. Cornog JL, Mobini J, Steiger E, Enterline HT. Squamous carcinoma of the breast. Am J Clin Pathol 1971;55(4):410-7.

  14. Eusebi V, Lamovec J, Cattani MG, Fedeli F, Millis RR. Acantholytic variant of squamous-cell carcinoma of the breast. Am J Surg Pathol 1986;10(12):855-61.

  15. Wargotz ES, Norris HJ. Metaplastic carcinomas of the breast. IV. Squamous cell carcinoma of ductal origin. Cancer 1990;65(2):272-6.

  16. Gersell DJ, Katzenstein AL. Spindle cell carcinoma of the breast. A clinocopathologic and ultrastructural study. Hum Pathol 1981;12(6):550-61.

  17. Merino MJ, LiVolsi VA, Kennedy S, al. e. Spindle- cell carcinoma of teh breast: A clinicopathologic, ultrastructural and immunohistochemical study of eight cases. Surg Pathol 1988;1:193.

  18. Wargotz ES, Deos PH, Norris HJ. Metaplastic carcinomas of the breast. II. Spindle cell carcinoma. Hum Pathol 1989;20(8):732-40.

  19. Kahn LB, Uys CJ, Dale J, Rutherfoord S. Carcinoma of the breast with metaplasia to chondrosarcoma: a light and electron microscopic study. Histopathology 1978;2(2):93-106.

  20. Oberman HA. Metaplastic carcinoma of the breast. A clinicopathologic study of 29 patients. Am J Surg Pathol 1987;11(12):918-29.

  21. Wargotz ES, Norris HJ. Metaplastic carcinomas of the breast. I. Matrix-producing carcinoma. Hum Pathol 1989;20(7):628-35.

  22. Wargotz ES, Norris HJ. Metaplastic carcinomas of the breast. III. Carcinosarcoma. Cancer 1989;64(7):1490-9.

  23. Pitts WC, Rojas VA, Gaffey MJ, Rouse RV, Esteban J, Frierson HF, et al. Carcinomas with metaplasia and sarcomas of the breast. Am J Clin Pathol 1991;95(5):623-32.

  24. 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.

  25. Wargotz ES, Norris HJ. Metaplastic carcinomas of the breast: V. Metaplastic carcinoma with osteoclastic giant cells. Hum Pathol 1990;21(11):1142-50.

  26. Chhieng C, Cranor M, Lesser ME, Rosen PP. Metaplastic carcinoma of the breast with osteocartilaginous heterologous elements. Am J Surg Pathol 1998;22(2):188-94.

  27. Patterson SK, Tworek JA, Roubidoux MA, Helvie MA, Oberman HA. Metaplastic carcinoma of the breast: mammographic appearance with pathologic correlation. AJR Am J Roentgenol 1997;169(3):709-12.

  28. Flint A, Oberman HA, Davenport RD. Cytophotometric measurements of metaplastic carcinoma of the breast: correlation with pathologic features and clinical behavior. Mod Pathol 1988;1(3):193-7.

  29. Zhuang Z, Lininger RA, Man YG, Albuquerque A, Merino MJ, Tavassoli FA. Identical clonality of both components of mammary carcinosarcoma with differential loss of heterozygosity. Mod Pathol 1997;10(4):354-62.

  30. Rosen PP, Ernsberger D. Low-grade adenosquamous carcinoma. A variant of metaplastic mammary carcinoma. Am J Surg Pathol 1987;11(5):351-8.

  31. Van Hoeven KH, Drudis T, Cranor ML, Erlandson RA, Rosen PP. Low-grade adenosquamous carcinoma of the breast. A clinocopathologic study of 32 cases with ultrastructural analysis. Am J Surg Pathol 1993;17(3):248-58.

  32. Drudis T, Arroyo C, Van Hoeven KH, al. e. The pathology of low grade adenosquamous carcinoma of the breast. An immunohistochemical study. Path Ann part 2 1994.

  33. Ruffolo EF, Koerner FC, Maluf HM. Metaplastic carcinoma of the breast with melanocytic differentiation. Mod Pathol 1997;10(6):592-6.

  34. Lien HC, Lin CW, Mao TL, Kuo SH, Hsiao CH, Huang CS. p53 overexpression and mutation in metaplastic carcinoma of the breast: genetic evidence for a monoclonal origin of both the carcinomatous and the heterogeneous sarcomatous components. J Pathol 2004;204(2):131-9.

  35. Popnikolov NK, Ayala AG, Graves K, Gatalica Z. Benign myoepithelial tumors of the breast have immunophenotypic characteristics similar to metaplastic matrix-producing and spindle cell carcinomas. Am J Clin Pathol 2003;120(2):161-7.

  36. 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.

  37. 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.

  38. 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.

  39. Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee JS, et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res 2009;69(10):4116-24.

  40. Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S, Yang J, et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci U S A;107(35):15449-54.

  41. Kaufman MW, Marti JR, Gallager HS, Hoehn JL. Carcinoma of the breast with pseudosarcomatous metaplasia. Cancer 1984;53(9):1908-17.

  42. Denley H, Pinder SE, Tan PH, Sim CS, Brown R, Barker T, et al. Metaplastic carcinoma of the breast arising within complex sclerosing lesion: a report of five cases. Histopathology 2000;36(3):203-9.

  43. 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.

  44. Hayes MM, Lesack D, Girardet C, Del Vecchio M, Eusebi V. Carcinoma ex-pleomorphic adenoma of the breast. Report of three cases suggesting a relationship to metaplastic carcinoma of matrix-producing type. Virchows Arch 2005;446(2):142-9.

  45. 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.

  46. 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.

  47. 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.

  48. Weigelt B, Kreike B, Reis-Filho JS. Metaplastic breast carcinomas are basal-like breast cancers: a genomic profiling analysis. Breast Cancer Res Treat 2009;117(2):273- 80.

  49. Rosen PP. Rosen's Breast Pathology. 2nd ed. Philadelphia, PA: Lippincott-Raven; 2001.

  50. Dunne B, Lee AH, Pinder SE, Bell JA, Ellis IO. An immunohistochemical study of metaplastic spindle cell carcinoma, phyllodes tumor and fibromatosis of the breast. Hum Pathol 2003;34(10):1009-15.

  51. Bauer TW, Rostock RA, Eggleston JC, Baral E. Spindle cell carcinoma of the breast: four cases and review of the literature. Hum Pathol 1984;15(2):147-52. 52. Brenner RJ, Turner RR, Schiller V, Arndt RD, Giuliano A. Metaplastic carcinoma of the breast: report of three cases. Cancer 1998;82(6):1082-7.

  52. Hennessy BT, Giordano S, Broglio K, Duan Z, Trent J, Buchholz TA, et al. Biphasic metaplastic sarcomatoid carcinoma of the breast. Ann Oncol 2006;17(4):605-13.

  53. Yamaguchi R, Horii R, Maeda I, Suga S, Makita M, Iwase T, et al. Clinicopathologic study of 53 metaplastic breast carcinomas: their elements and prognostic implications. Hum Pathol;41(5):679-85.

  54. Podetta M, D'Ambrosio G, Ferrari A, Sgarella A, Dal Bello B, Fossati GS, et al. Low-grade fibromatosis-like spindle cell metaplastic carcinoma: a basal-like tumor with a favorable clinical outcome. Report of two cases. Tumori 2009;95(2):264-7.