Comprehensive Clinicopathologic and Molecular Analysis of Mesenchymal Tumors With BRAF Fusions

BRAF fusions are rare but recurrent driver events in a spectrum of mostly pediatric and young adult mesenchymal soft tissue tumors, including infantile fibrosarcoma, lipofibromatosis-like neural tumors, and other kinase fusion spindle cell neoplasms. Their clinicopathologic spectrum, co-occurring secondary genomic events, and frequency among various sarcoma histotypes remain incompletely characterized. The purpose of this study is to comprehensively investigate the incidence and structural variants of BRAF fusions among a large clinicopathologic and molecular sarcoma cohort. The additional goal was to distinguish primary driver BRAF fusions from potential passenger events and correlate with sarcoma histotypes. We identified a total of 24 cases harboring BRAF fusions, with 18 (75%) occurring in canonical BRAF-driven histotypes, including kinase-associated spindle cell tumors (n = 12), myxoinflammatory fibroblastic sarcoma (n = 3), GIST (n = 2) and one hybrid nerve sheath tumor. The remaining six cases were detected in various established pathologic entities (undifferentiated pleomorphic sarcoma, angiosarcoma, embryonal rhabdomyosarcoma, dedifferentiated liposarcoma, PEComa), likely as secondary or passenger events. Among the 12 kinase-associated spindle cell tumors, the most common histologies included tumors resembling infantile fibrosarcoma (n = 4), malignant peripheral nerve sheath tumor (n = 3), lipofibromatosis (n = 2), and myoid/pericytic lesions (n = 2). This predominant group had a wide age range at diagnosis (median 15.5 years), a predilection for soft tissues of extremities, trunk, and head/neck and showed CD34 and S100 co-expression in 45% of cases. In this group, BRAF breakpoints clustered in exons 8-11 retaining an intact kinase domain, and fusion partners were diverse (AGK, AHNAK, NRF1, PAK2, TMEM245, FNBP1, STEAP4, TSC1, KIAA1549). Tumor mutation burden was consistently low, with CDKN2A homozygous deletion being the only recurrent secondary event (4/5 cases profiled). Among the five patients with follow-up (median 34 months), one patient died of disease, with two developing local recurrences at 5 and 84 months. The BRAF fusions occurring in non-canonical histotypes had similar breakpoint patterns and various partners. These results highlight the heterogeneity of mesenchymal neoplasms harboring BRAF fusions, including both driver and likely secondary genetic events, which often require a comprehensive approach that integrates clinical, histopathologic, and detailed molecular data, for a definitive classification.