A genetic dichotomy between pure sclerosing epithelioid fibrosarcoma (SEF) and hybrid SEF/low‐grade fibromyxoid sarcoma: A pathologic and molecular study of 18 cases

Abstract

Sclerosing epithelioid fibrosarcoma (SEF) is a rare soft tissue tumor exhibiting considerable morphologic overlap with low grade fibromyxoid sarcoma (LGFMS). Moreover, both SEF and LGFMS show MUC4 expression by immunohistochemistry. While the majority of LGFMS cases are characterized by a FUS-CREB3L1 fusion, both FUS-CREB3L2 and EWSR1-CREB3L1 fusions were recently demonstrated in a small number of LGFMS and SEF/LGFMS hybrid tumors. In contrast, recent studies pointed out that SEF harbor frequent EWSR1 rearrangements, with only a minority of cases showing FUS-CREB3L2 fusions. In an effort to further characterize the molecular characteristics of pure SEF and hybrid SEF/LGFMS lesions, we undertook a clinicopathologic, immunohistochemical and genetic analysis of a series of 10 SEF and 8 hybrid SEF/LGFMS tumors. The mortality rate was similar between the two groups, 44% within the pure SEF group and 37% in the hybrid SEF/LGFMS with a mean overall follow-up of 66 months. All but one pure SEF and all hybrid SEF/LGFMS tested cases showed MUC4 immunoreactivity. The majority (90%) of pure SEF cases showed EWSR1 gene rearrangements by FISH with only one case exhibiting FUS rearrangement. Of the 9 EWSR1 positive cases, 6 cases harbored CREB3L1 break-apart, two had CREB3L2 rearrangement (a previously unreported finding) and one lacked evidence of CREB3L1/2 abnormalities. In contrast, all hybrid SEF/LGFMS tumors exhibited FUS and CREB3L2 rearrangements. These results further demarcate a relative cytogenetic dichotomy between pure SEF, often characterized by EWSR1 rearrangements, and hybrid SEF/LGFMS, harboring FUS-CREB3L2 fusion; the latter group recapitulating the genotype of LGFMS.

Sclerosing Epithelioid Fibrosarcoma – A Rare Sacral Lesion and Literature Review

“…Histopathologic features a conglomerate of epithelioid cells arranged in strands, cords, nests, and sheets embedded in a sclerosed and hyalinized stroma [17]. It may resemble infiltrating carcinoma, sclerosing lymphoma, and other sarcomas [4,5], and it may contain areas of conventional fibrosarcoma or minor areas resembling a lowgrade fibromixosarcoma, with transition to higher-grade fibrosarcoma, especially in recurrent cases [18].…”

“…This is particularly difficult to the diagnosis on visceral organs because of its rarity and its epithelioid appearance, closely mimicking carcinomas [18]. A strong and diffuse cytoplasmic reactivity for vimentin is a characteristic feature of sclerosing epithelioid fibrosarcoma, and 70% of the cases show MUC4 positivity [7,14,16,17]. It lacks immunoreactivity for epithelial membrane antigen; cytokeratins (CAM5.2 or AE1/3), HMB-45, neuronspecific enolase, desmin, smooth muscle actin, or muscle common actin (HHF-35) [8] Focal and weak immunostaining for EMA, S-100 protein and more rarely for cytokeratins may be seen in a minority of cases [19].…”

“…The first marker is important to another entity that was essential to exclude, the low-grade fibromyxoid sarcoma (LGFMS). Due to a subset of overlapping morphologic and immunohistochemical features, related members in the fibroblastic family, both display hyalinized spindle cell tumours with giant rosetes [7,16,17,20].…”

“…LGFMS is characterized by expression of the MUC4 protein, like SEF, and about 90% of cases show a distinctive t (7; 16) (q33; p11) that results in FUS-CREB3L2 gene fusion [3,11,17,21]. The use of MUC4 immunostaining and molecular techniques to identify FUS and EWSR1 rearrangements has clear utility in the recognition of SEF, despite the reports of immunoexpression in up to 70% of cases suggesting that at least a subset are related to LGFMS [3,20].…”

“…The use of MUC4 immunostaining and molecular techniques to identify FUS and EWSR1 rearrangements has clear utility in the recognition of SEF, despite the reports of immunoexpression in up to 70% of cases suggesting that at least a subset are related to LGFMS [3,20]. MUC4 upregulation results on a tumorigenic effect elicited through interactions with ERBB2 (HER2) to enhance the proliferation, motility, and tumorigenic capacity of epithelial cancer and fibroblastic cells [17]. Concerning cytogenetic findings on bone lesions, immunohistochemistry for SATB2, a recently described marker for osteoblastic differentiation could present a useful weapon, with wildtype presentation on SEF [5,17].…”