FUS/EWSR1::TFCP2-rearranged bone and soft tissue tumors: evidence of gene promiscuity.

The FET(FUS/EWSR1)::TFCP2 fusion defines a distinct molecular subtype of spindle cell/sclerosing rhabdomyosarcoma (RMS), typically involving the mandible and maxilla. These tumors demonstrate myogenic differentiation and are clinically aggressive. In addition to the characteristic fusion, they often show features of homologous recombination deficiency (HRD), genomic instability, and expression of ALK and TERT truncated variants. This study presents a cohort of 25 patients with FET::TFCP2 fusion, representing the largest single-center series to date. While most tumors involve bones, 8 cases are soft tissue tumors, including the cheek (2 cases), epididymis, bladder, abdominal wall, neck, temporal part, and scalp. Genomically, approximately 40% of cases had additional genomic amplifications involving receptor tyrosine kinase pathways and cell cycle/proliferation-related genes. Immunohistochemically, 23 of 25 tumors expressed myogenic markers (Desmin, MyoD1 and Myogenin); however, two lacked myogenic differentiation. These two cases had distinct histopathologic features characterized by round blue cell morphology and dense myxoid stroma, rather than the typical spindle and epithelioid cell morphology of FET::TFCP2-rearranged sarcomas. Methylation profiling further revealed that neither case clustered with canonical FET::TFCP2-rearranged sarcomas; one grouped with Ewing sarcoma, and the other did not overlap with any known soft tissue tumor class. These findings expand the morphologic, immunophenotypic and epigenetic spectrum of FET::TFCP2-rearranged tumors and suggest that a subset of these tumors may extend beyond the conventional spindle cell/sclerosing rhabdomyosarcoma phenotype.