Expanding the clinicopathologic spectrum of EWSR1::SSX-rearranged sarcomas: series of 11 cases including osteosarcomas and a Novel EWSR1::SSX4 fusion

Gross, J.M.; Suster, D.I.; Zou, Y.; Mata, D.A.; Amary, F.; Noon, S. de; Flanagan, A.M.; Wakeman, K.M.; Wangsiricharoen, S.; Dong, F.; Lam, S.W.; Bovée, J.V.M.G.; Baltres, A.; Pissaloux, D.; Pasmant, E.; Larousserie, F.; Miettinen, M.; Hameed, M.; Charville, G.W.

doi:doi:10.1016/j.modpat.2025.100922

Gene rearrangements involving EWSR1 or SSX genes are known to play a role in sarcomagenesis; however, sarcomas harboring EWSR1::SSX fusions are rare. To better understand tumors associated with this distinctive genetic event, we studied 11 additional EWSR1::SSX sarcomas, affecting 10 women and 1 man with an average age of 46 years (range, 22-72 years). Eight tumors arose in the bone (rib, femur, pelvis, or vertebra with multifocal bone involvement at presentation in 3 cases); 2 tumors arose in soft tissue (deep thigh or groin); and 1 patient presented with a visceral (lung) mass. The tumors were bulky, averaging 12.1 cm (range, 4-20 cm). Histologically, in keeping with a translocation-driven sarcoma, all tumors were cytologically monotonous. Seven tumors were osteosarcomas, 6 of which were classified as sclerosing osteosarcomas with extensive bone matrix production. Three tumors were composed of uniform fascicles of spindle cells, punctuated in 2 cases by a biphasic glandular or...Show moreGene rearrangements involving EWSR1 or SSX genes are known to play a role in sarcomagenesis; however, sarcomas harboring EWSR1::SSX fusions are rare. To better understand tumors associated with this distinctive genetic event, we studied 11 additional EWSR1::SSX sarcomas, affecting 10 women and 1 man with an average age of 46 years (range, 22-72 years). Eight tumors arose in the bone (rib, femur, pelvis, or vertebra with multifocal bone involvement at presentation in 3 cases); 2 tumors arose in soft tissue (deep thigh or groin); and 1 patient presented with a visceral (lung) mass. The tumors were bulky, averaging 12.1 cm (range, 4-20 cm). Histologically, in keeping with a translocation-driven sarcoma, all tumors were cytologically monotonous. Seven tumors were osteosarcomas, 6 of which were classified as sclerosing osteosarcomas with extensive bone matrix production. Three tumors were composed of uniform fascicles of spindle cells, punctuated in 2 cases by a biphasic glandular or nested epithelioid component, reminiscent of synovial sarcoma. One tumor was an undifferentiated sarcoma with round to spindle cell cytomorphology and focal osteogenic differentiation. By immunohistochemistry, 5 of 5 cases tested were positive for SSXC-terminus; 1 of 5 showed patchy weak staining with SS18::SSX fusion-specific antibody. All tested tumors were positive for CD99 (4/4) and TLE1 (3/3). Next-generation sequencing identified EWSR1::SSX fusions in all cases, involving SSX1 (n = 7), SSX2 (n = 2), and SSX3 (n = 1), along with a novel EWSR1::SSX4 fusion. Follow-up was available for 9 patients; 5 patients died of disease 1.5 to 14 years (average, 6 years) after diagnosis, 2 patients were alive with metastatic disease, 1 patient was alive without disease at 25 months, and 1 patient presented recently. Sarcomas with EWSR1::SSX fusions are rare and clinically aggressive; the histologic patterns in this series and in prior reports are heterogeneous, consisting of essentially 3 phenotypes: (1) primitive round or epithelioid cells, (2) osteoblasts that produce bone, or (3) uniform small spindle cells arranged in tight fascicles, sometimes with a biphasic epithelioid component, as seen in synovial sarcoma. By studying 11 additional examples of these rare sarcomas, we provide an expanded view of their clinicopathologic and molecular genetic spectrum. (c) 2025 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.Show less

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Expanding the clinicopathologic spectrum of EWSR1::SSX-rearranged sarcomas: series of 11 cases including osteosarcomas and a Novel EWSR1::SSX4 fusion