VGLL-fusions define a new class of intraparenchymal CNS schwannoma

Background: Intracerebral schwannomas are rare tumors resembling their peripheral nerve sheath counterparts but localized in the CNS. They are not classified as a separate tumor type in the 2021 WHO classification. This study aimed to compile and characterize these rare neoplasms morphologically and molecularly. // Methods: We analyzed 20 tumor samples by histology, RNA Next-Generation Sequencing, DNA-methylation profiling, copy number analyses, and single nucleus RNA sequencing (snRNA-seq). Clinical data, including age, sex, and disease progression, were collected. MRI series were included when available. // Results: All cases with tissue available for histology review (n=13) were morphologically consistent with intracerebral schwannoma, but differed in their extent of GFAP staining. All (n=20) shared DNA-methylation profiles distinct from other CNS tumors, as well as from VGLL-altered peripheral nerve sheath tumors. Most cases (n=14/17) harbored fusions of either VGLL3 or VGLL1 (CHD7::VGLL3 (n=9/17) and EWSR1::VGLL1 (n=5/17)). In two cases the presence of a VGLL3 fusion was also confirmed by CNA analyses (n=2/17). MRI (n=4) showed well-defined, nodular tumors with strong, homogeneous enhancement and no diffusion restriction. Tumors were located throughout the neuroaxis [supratentorial (n=15), infratentorial (n=4), and spinal (n=1)]. snRNA-seq of a VGLL1-fused tumor indicated VGLL1 upregulation in 28.6% of tumor cells (n=1). During median follow-up of 1.8 years (range 3 months-9 years), none of the tumors recurred (n=10). // Conclusions: We identify and define a new benign tumor class, designated VGLL-altered intraparenchymal CNS schwannomas. These tumors feature VGLL alterations and a specific DNA-methylation profile, with schwannoma-like histopathology and CNS localization, akin to previously classified intracerebral schwannomas.