Beyond Hybrid Morphology: A Large Series of Fusion-Driven Benign Peripheral Nerve Sheath Tumors Including 5 Tumors...

Benign peripheral nerve sheath tumors (PNSTs) represent a heterogeneous group of neoplasms with varying histologic and molecular characteristics. Although traditional classifications categorize these tumors based on predominant cell types, recent advances in molecular pathology have revealed the presence of hybrid tumors featuring elements from at least 2 nerve sheath tumors (hybrid peripheral nerve sheath tumor [hPNST]). We herein studied 20 cases of hPNST involving 15 female and 5 male patients (median age, 29.5 years; range, 3 weeks-71 years). Tumors occurred on the upper extremity (6), scalp (3), trunk (3), face (3), lower extremity (2), right lateral neck (1), nasal sinus (1), and retroperitoneum (1). Follow-up information was available in 9 of 20 cases (45%; median, 10 months; range, 2 weeks-144 months) and documented local recurrence in 2 of 9 patients (22%) at 10 and 144 months after incomplete excision. Next-generation sequencing demonstrated vestigial-like family member 3 (VGLL3) fusions in 14 cases, fused with CHD7 (10 tumors), CHD9 (3 tumors), and MAMLD1 (1 tumor), an alternative TEAD1::NCOA2 (1 tumor) fusion and several novel fusions including TOX::TEAD1 (2 tumors), RREB1::LPP (1 tumor), SRF::MYOCD (1 tumor), and KANK1::CDK5RAP2 (1 tumor). Most tumors with VGLL3 fusions showed morphologically and immunophenotypically classic features of hybrid schwannoma-perineurioma, whereas rare cases showed unusual microscopic features, such as prominent myxoid stroma, pseudolipoblasts, prominent Schwannian nodules, or solely schwannomatous morphology. The RREB1::LPP-driven tumor showed features of hybrid schwannoma-neurofibroma. Lastly, 1 tumor with a novel SRF::MYOCD fusion displayed morphologic features reminiscent of desmoplastic melanoma although exhibiting a combined neural and smooth muscle phenotype. Our data expand on the morphologic and molecular spectrum of fusion-driven hPNSTs, including 5 previously undescribed fusions, and further expand on noncentral nervous system schwannomas with VGLL3 fusions.