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Clinicopathologic and Molecular Study of Hybrid Nerve Sheath Tumors Reveals Their Common Association With Fusions Involving VGLL3

A subset of benign peripheral nerve sheath tumors are “hybrid” combining several lines of differentiation, most often schwannian and perineurial features. The pathogenesis of these tumors was poorly described until the recent discovery of recurrent VGLL3 rearrangements in hybrid schwannoma/perineuriomas, supporting the hypothesis that this entity represents a distinct subgroup of tumors and not only a morphologic variation of other peripheral nerve sheath tumors. Following this finding, we investigated 10 cases of hybrid peripheral nerve sheath tumors with immunohistochemistry, RNA sequencing, and array comparative genomic hybridization. By light microscopy, 7 tumors were hybrid schwannoma/perineurioma tumors, and 3 were hybrid schwannoma/neurofibroma. Most cases of hybrid schwannoma/perineuriomas displayed VGLL3 rearrangements fused in 5′ either to CHD7 or CHD9 (n=6/7) and had simple diploid genetic profiles with few copy number alterations. Compared with a control group composed of 28 tumors associated with varied neural phenotypes, all VGLL3-fused tumors clustered together by transcriptomic analysis. In contrast, 1 case of hybrid schwannoma/perineurioma tumor harbored a CDH9-ZFHX3 fusion, a prominent perineurial component identified by immunohistochemistry and clustered with perineuriomas. No recurrent genetic alteration was seen in the 3 hybrid schwannoma/neurofibromas. To summarize, this study confirms and expands the recent findings on hybrid schwannoma/perineurioma, highlighting the predominance of VGLL3 fusions in these tumors.