Case 6 -

Angiomatoid (Malignant) Fibrous Histiocytoma John R. Goldblum Cleveland Clinic Cleveland, OH

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Clinical History: 12-year-old male with a 3.5-cm soft tissue mass of the left forearm Case 6 - Figure 1 Case 6 - Figure 2 Case 6 - Figure 3 Case 6 - Figure 4 Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: This is a very well-circumscribed neoplasm limited to the subcutaneous tissue. There is a peripheral fibrous rim underneath which there is a prominent lymphoplasmacytic infiltrate, including the presence of lymphoid aggregates with germinal centers, closely simulating a lymph node. The central portion of the lesion is composed of a solidly cellular proliferation of fairly uniform spindled to ovoid- shaped cells with finely stippled chromatin and variably sized, although generally small, nucleoli. Scattered lymphocytes are found among the neoplastic cells. The cells have slightly eosinophilic vacuolated cytoplasm, and mitotic figures are not conspicuous. Some areas of the tumor are more cellular and, focally, there is even a hint of a storiform growth pattern. Pertinent laboratory data: Immunophenotype / molecular genetic findings AE1/AE3 negative Desmin focal positive CD99 focal positive EMA negative S100 protein negative SMA negative EWS FISH positive Differential Diagnoses: The differential diagnosis includes a number of neoplasms metastatic to a lymph node, including metastatic melanoma, metastatic epithelioid sarcoma and even metastatic granular cell tumor. Other considerations might include a follicular dendritic cell tumor and even a cellular fibrous histiocytoma. Final Diagnosis: Angiomatoid (malignant) fibrous histiocytoma Case Discussion: This case is a fairly typical example of a relatively uncommon neoplasm, angiomatoid fibrous histiocytoma, formerly referred to as angiomatoid malignant fibrous histiocytoma. The World Health Organization Committee for the Classification of Soft Tissue Tumors renamed this entity to reflect the rarity of metastasis and excellent prognosis. [1] This tumor most commonly occurs in young patients, typically less than 20 years of age, and is rarely found in patients over the age of 40 years. [2] The lesion most often occurs as a well-circumscribed nodule in the deep dermis or subcutis of the extremities. They may be painful, and occasionally patients manifest systemic symptoms such as fever, anemia and weight loss, possibly due to the production of cytokines by the neoplastic cells. Histologically, angiomatoid FH is typically nodular or multinodular and is surrounded by a dense fibrous pseudocapsule. The most characteristic feature is the presence of irregularly shaped blood-filled spaces lined by tumor cells (not endothelium). The surrounding tumor cells may be spindled or have a round to ovoid shape, often resembling histiocytes, although their true nature remains unknown. These histiocyte-like cells have a faintly staining eosinophilic cytoplasm that often contains a dusky yellow-brown pigment, due to the phagocytosis of hemosiderin by tumor cells. Although most cases are characterized by a monomorphic population of these histiocyte-like cells, about 20% of cases show nuclear pleomorphism, usually as a focal feature. [3] Mitotic figures are present but are not numerous. The nodules of histiocyte- like cells are typically surrounded by a dense lymphoplasmacytic infiltrate that may have germinal centers, and this may cause confusion because of the striking resemblance to a lymph node. The differential diagnosis of angiomatoid FH is relatively limited, especially if one has encountered such a case before. Firstly, the presence of a peripherally located lymphoplasmacytic infiltrate with germinal centers may cause confusion with a metastasis to a lymph node. Considerations might include metastatic melanoma, metastatic epithelioid sarcoma and even metastatic granular cell tumor. More commonly, this lesion may be mistaken for a variant of a benign fibrous histiocytoma, particularly the aneurysmal variant. The aneurysmal variant of benign fibrous histiocytoma tends to occur in older patients (as opposed to younger patients with angiomatoid FH), is not associated with systemic symptoms, is typically located in the dermis (as opposed to the deep dermis and subcutis) and, most importantly, will show other areas of typical benign fibrous histiocytoma. Angiomatoid FH does not have a characteristic immunophenotype, thus causing controversy regarding its histogenesis. Smith et al evaluated the immunophenotype of 19 cases of angiomatoid FH and found almost 50% to stain for CD68. [4] It is likely, however, that CD68 positivity represents the phenotypic expression of the acquisition of lysosomes and phagocytic activity, as indicated by the presence of hemosiderin in many of the neoplastic cells. Fanburg-Smith and Miettinen evaluated the immunophenotype of a much larger number of cases of angiomatoid FH. [5] Desmin positivity was noted in 51% of cases, most of which showed scattered similar desmin-positive cells in the surrounding lymphoid infiltrate adjacent to the tumor. Muscle-specific and smooth muscle actin were positive in 14% of cases, although MyoD1 and myogenin were negative in all tumors studied. 45% of cases stained for CD99, and 15% were positive for CD68. All cases were negative for CD21, CD35, S100 protein, CD34 and cytokeratins, although some cases may stain for EMA. [6] Recently, cytogenetic and molecular studies have demonstrated specific translocations in this tumor which, interestingly, are identical to those found in clear cell sarcoma. While some cases of angiomatoid FH do have a t (12;22) involving ATF1 gene on 12q13 and the EWSR1 gene on 22q12, others have a t(12;16) involving ATF1 and FUS (found on chromosome 16). [7] However, several recent reports have found the most common gene fusion in angiomatoid FH to be a t(2;22) involving the CREB1 gene on 2q33 with the EWSR1 gene on 22q12. [8, 9] This same t(2;22) has also been described in clear cell sarcomas involving the gastrointestinal tract. Review of the Literature/Treatment Options: In Enzinger's original series (which he classified as angiomatoid MFH), 11 of 24 (46%) patients developed local recurrence, 5 patients (21%) developed metastatic disease, and 3 patients (13%) died of disease. [10] However, in a much larger study of 108 patients by Costa et al, local recurrence developed in only 12% of patients, all of which were cured by re-excision. [2] Only 5% of patients developed metastatic disease, and only one patient died of disease. These authors explain this difference in clinical behavior by the fact that their cases were diagnosed prospectively and in most instances had been treated adequately with wide local excision. In the study by Fanburg-Smith and Miettinen,5 clinical follow-up on 86 patients indicated that only one patient was alive with local nodal metastasis (1% frequency of metastasis) within one year, and two others had local recurrence, all over a mean follow-up period of 6 years. Conclusion(s): Angiomatoid fibrous histiocytoma is classified as a fibrohistiocytic tumor of low malignant potential (intermediate malignancy) and, although capable of metastasizing, has an excellent prognosis. It is best treated by complete excision with tumor-free margins and close clinical follow-up. Take home message/key points Angiomatoid FH is a relatively uncommon tumor that most commonly arises in the extremities of young patients, typically less than 20 years of age. The lesion usually arises in the deep dermis or subcutis and may be associated with systemic manifestations which remit following excision. The differential diagnosis often includes a number of lesions that have metastasized to a lymph node, given the prominent lymphoid response that surrounds the neoplasm, often imparting a superficial resemblance to a lymph node. Angiomatoid FH does not have a characteristic immunophenotype, but may stain for CD68, desmin, CD99 and EMA. Use of the paraffin block for FISH is extremely helpful in confirming the diagnosis, as the majority of cases have a translocation involving the EWS gene. References: World Health Organization Classification of Tumours: Tumours of Soft Tissue and Bone. Fletcher CDM, Unni KK, Mertens F (eds). IARC Press, Lyons 2002, 109-125. Costa MJ, Weiss SW. Angiomatoid malignant fibrous histiocytoma: A follow-up study of 108 cases with evaluation of possible histologic predictors of outcome. Am J Surg Pathol 1990; 14:1126-32. Weinreb I, Rubin BP, Goldblum JR. Pleomorphic angiomatoid fibrous histiocytoma: a case confirmed by fluorescence in situ hybridization analysis for EWSR1 rearrangement. J Cutan Pathol 2008;35:855-860. Smith ME, Costa MJ, Weiss SW. Evaluation of CD68 and other histiocytic antigens in angiomatoid malignant fibrous histiocytoma. Am J Surg Pathol 1991; 15:757-63. Fanburg-Smith JC, Miettinen M. Angiomatoid "malignant" fibrous histiocytoma: a clinicopathologic study of 158 cases and further exploration of the myoid phenotype. Hum Pathol 1999;30:1336- 43. Thway K. Angiomatoid fibrous histiocytoma: a review with recent genetic findings. Arch Pathol Lab Med 2008;132:273-277. Antonescu CR, Dal Cin P, Nafa K, et al. EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma. Genes Chromosomes Cancer 2007;46:1051-1060. Rossi S, Szuhai K, Ijszenga M, et al. EWSR1-CREB1 and EWSR1-ATF1 fusion genes in angiomatoid fibrous histiocytoma. Clin Cancer Res 2007;13:7322-7328. Tanas MR, Rubin BP, Montgomery E, et al. Utility of FISH in the diagnosis of angiomatoid fibrous histiocytoma: a series of 18 cases. Mod Pathol (in press) Enzinger FM. Angiomatoid malignant fibrous histiocytoma. A distinctive fibrohistiocytic tumor of children and young adults simulating a vascular neoplasm. Cancer 1979; 44:2147-57.