Mesenchymal neoplasms with RAF/BRAF alterations: eight cases revealing novel fusions, V600E mutation and clonal evolution.
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OBJECTIVE: While kinase-altered spindle cell tumours were classically recognised in paediatric superficial soft tissues, recent literature indicates an expanding clinicopathologic spectrum. This study investigates a cohort of RAF/BRAF-altered mesenchymal tumours to further characterise their presentations in adults, deep-seated/visceral locations, variable immunophenotypes and complex molecular evolution. METHODS: Eight molecularly confirmed RAF/BRAF-altered mesenchymal tumours were retrospectively evaluated. Clinical characteristics, histomorphology, immunohistochemistry, targeted next-generation sequencing profiles and follow-up data were comprehensively analysed. RESULTS: The cohort comprised seven females and one male (median age, 34.5 years). Tumours arose in soft tissues (n=5, including the deep pelvis) and visceral organs (n=3; two breast, one lung). Histologically, the neoplasms exhibited a broad morphologic spectrum: three demonstrated low-grade spindle cell morphology, whereas five displayed high-grade pleomorphic or fibrosarcoma-like features, including one pelvic tumour mimicking myxoid leiomyosarcoma. Immunophenotypes diverged significantly with histologic grade: low-grade tumours retained CD34 and S100 coexpression, whereas high-grade lesions consistently lost both markers, with one case exhibiting focal Desmin positivity. Molecular profiling revealed ubiquitous mitogen-activated protein kinase pathway activation, identifying six kinase gene fusions (including novel IQSEC1::RAF1 and PLEKHH3::BRAF variants) and two BRAF V600E mutations. High-grade tumours frequently harboured concurrent tumour suppressor gene alterations (eg, TP53, PTEN). Notably, one pelvic tumour exhibited a trunk NTRK1 mutation alongside a subclonal BRAF V600E mutation. Notably, despite the alarming high-grade histomorphology in several cases, clinical behaviour remained relatively indolent, with no disease-related deaths to date. CONCLUSIONS: RAF/BRAF-driven mesenchymal tumours possess a broader clinicopathologic spectrum than traditionally recognised, frequently affecting adults and deep/visceral sites. Their inherently variable immunophenotypes and the presence of high-grade morphologic features do not strictly predict an aggressive clinical trajectory. Comprehensive molecular profiling is essential to refine diagnostic criteria, accurately identify these neoplasms, and elucidate the genomic events associated with tumour progression.