YAP1::MAML2 fusion-positive high-grade neuroepithelial tumors with rhabdoid morphology and inflammatory microenvironment: Implications for integrated diagnosis.
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YAP1 fusions are well documented in pediatric central nervous system (CNS) tumors, particularly in supratentorial ependymomas and meningiomas where they are generally associated with a favorable prognosis. Outside these entities, YAP1 fusions have rarely been reported in gliomas or other high-grade neuroepithelial tumors. Here, we describe 2 high-grade neuroepithelial tumors harboring a recurrent YAP1::MAML2 fusion. Comprehensive histopathologic evaluation, immunohistochemistry, whole-exome sequencing using the SimcereDx neuro-oncology panel, and DNA methylation profiling were performed. Both tumors were IDH- and H3-wildtype and lacked canonical alterations in the RTK, TP53, or MAPK pathways. DNA methylation profiling did not match any established CNS tumor class. Histologically, both tumors demonstrated rhabdoid morphology accompanied by a prominent inflammatory microenvironment enriched in CD68- and CD163-positive macrophages. Despite sharing the same fusion event, the 2 tumors exhibited divergent morphologic and immunophenotypic features, indicating substantial heterogeneity. These findings suggest a potentially distinct, molecularly defined tumor subgroup characterized by YAP1::MAML2 fusion, high-grade neuroepithelial morphology, rhabdoid features, and an inflammatory microenvironment. They highlight the limitations of current methylation-based classification for such rare entities. Accurate diagnosis requires an integrated approach incorporating histologic features, clinical context, immunophenotype, and molecular alterations.