Non-Meningothelial Mesenchymal Tumor of the Central Nervous System: Case Report and Literature Review.

Non-meningothelial mesenchymal tumors (NMMTs) of the central nervous system (CNS) are rare and diagnostically challenging neoplasms. Although World Health Organization (WHO) updates have incorporated molecularly defined entities, a subset of tumors remains difficult to classify because of overlapping morphology, nonspecific immunophenotype, and absence of canonical gene fusions. We report a supratentorial NMMT tumor in a 40-year-old man presenting with progressive left-sided paresthesia. Neuroimaging demonstrated a parasagittal mass. Following gross total resection, histological examination revealed a predominantly myxoid proliferation with focal cortical and dural infiltration. Immunohistochemistry was noncontributory, showing focal CD99 expression. Fluorescence in situ hybridization excluded EWSR1, FUS, and CIC rearrangements. Extended RNA-based next-generation sequencing identified a putative low-confidence SHISA5::BRAF fusion. This case illustrates the persistent diagnostic complexity of NMMTs despite integrated histological and molecular evaluation. The absence of canonical alterations not only complicates classification but also contributes to uncertainty regarding prognosis and optimal therapeutic strategies. Emerging evidence suggests that a subset of these tumors may be driven by alternative oncogenic mechanisms, including MAPK pathway activation beyond currently recognized fusion-defined entities. In this context, the identification of a putative SHISA5::BRAF fusion expands the molecular spectrum of these neoplasms, although its functional relevance remains uncertain. These challenges underscore the need for cautious long-term follow-up and individualized multidisciplinary management.