A subset of high-grade sarcomas with myogenic differentiation are associated with recurrent FGFR fusions.

Recurrent fusions involving FGFR1-4 genes have been previously described in rare subsets of mostly benign chondroid and mesenchymal neoplasms involving bone and soft tissue. However, a more comprehensive analysis of sarcomas associated with FGFR fusions, including their incidence and histotypes, has not been performed. Triggered by an FGFR1-rearranged unclassified high-grade sarcoma with myogenic differentiation, we investigated our molecular database for sarcomas with FGFR gene fusions to assess their recurrent potential and morphologic spectrum. A total of six unclassified sarcomas were identified, occurring in five females and one male, with a median age of 66.5 years. Tumors were located in the uterus and retroperitoneal/trunk soft tissue. Histologically, all tumors were high grade, composed predominantly of spindle cell morphology with variable cytologic atypia, high mitotic activity, and areas of necrosis. By immunohistochemistry, all tumors demonstrated evidence of myogenic differentiation, with focal or diffuse positivity for one or more markers (desmin, h-caldesmon, smooth muscle actin). However, none of the cases displayed diagnostic features of leiomyosarcoma or other known pathologic entities. Molecular studies revealed recurrent fusions involving FGFR1 (n = 3), FGFR2 (n = 1), and FGFR4 (n = 2), retaining the kinase domain. Additional recurrent genomic alterations included TP53 mutations, CDKN2A homozygous deletions, and RB1 alterations. Most patients followed an aggressive clinical course, including metastases and disease-related mortality. These findings expand the spectrum of sarcomas driven by FGFR gene fusions, underscoring the importance of molecular testing for accurate diagnosis and potential targeted therapy in high-grade sarcomas with myogenic features.