Hybrid schwannoma–perineurioma frequently harbors VGLL3 rearrangement

Abstract

Benign peripheral nerve tumors include schwannoma, neurofibroma and perineurioma, as well as a recently recognized group of tumors with dual patterns of differentiation. The molecular pathogenesis of these so-called ‘hybrid’ tumors remains poorly understood. Following identification of a novel CHD7-VGLL3 fusion gene in a hybrid schwannoma-perineurioma, we evaluated an expanded cohort of this tumor-type – as well as tumors with VGLL3 rearrangement identified from a curated molecular database – to characterize the prevalence of fusion genes among these tumors. Eighteen tumors met the inclusion criteria for this study. RNA sequencing identified VGLL3 rearrangement in 14 of these cases; the partner genes included CHD7 (ten cases), CHD9 (two cases), and MAMLD1 (two cases). Two cases possessed altogether unrelated fusions, including: DST-BRAF and SQSTM1-CDX1 fusion genes. Finally, two cases lacked identifiable fusion products. These findings highlight the molecular diversity of these neoplasms, with frequent rearrangement of VGLL3 . More importantly, despite their dual pattern of differentiation, our results reveal the pathogenesis of hybrid schwannoma-perineurioma is unrelated to conventional schwannoma and perineurioma, thereby implying this tumor represents an altogether pathologically distinct entity.

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

“…HNST may occasionally occur in the setting of genetic conditions such as neurofibromatosis type 1 for hybrid neurofibroma/perineurioma tumors,5 schwannomatosis, and neurofibromatosis types 1 and 2 for hybrid schwannoma/neurofibroma tumors6 but no association with the genetic condition has been reported for hybrid schwannoma/perineurioma tumors 1. While we investigated these tumors, an independent group described recurrent VGLL3 fusions in hybrid schwannoma/perineurioma tumors7 in a series of 18 cases, supporting the hypothesis that they represent a subtype of tumors distinct from other HNSTs. To investigate HNST, we characterized by whole RNA sequencing and genetic profiling a series of 10 hybrid neural tumors that we compared with 28 tumors associated with varied neural phenotypes.…”

“…Of note, gene expression analysis shows that VGLL3 is upregulated in VGLL3 -fused tumors related to the control cohort (data not shown). In the other series, VGLL3 was also found fused to MAMLD1 in 2 cases 7. Finally, 1 hybrid tumor harbored a CHD9-ZFHX3 fusion which does not seem to be equivalent to VGLL3 fusion as the case clustered among perineuriomas.…”

“…In the other series, VGLL3 was also found fused to MAMLD1 in 2 cases. 7 Finally, 1 hybrid tumor harbored a CHD9-ZFHX3 fusion which does not seem to be equivalent to VGLL3 fusion as the case clustered among perineuriomas. Therefore, Zinc Finger Homeobox 3 (ZFHX3) does not seem to represent an alternative partner gene to VGLL3.…”

Practical Approach to Histological Diagnosis of Peripheral Nerve Sheath Tumors: An Update

“…Although histologically similar to soft tissue perineurioma, such tumors are composed of two different cytotypes, namely, perineurial cells (EMA/claudin/GLUT1-positive) variably arranged into fascicular, storiform, or reticular arrangements and spindled cells (S100/SOX10-positive) with wavy nuclei, closely reminiscent of schwannian differentiation. Only rarely, hybrid tumors with both neurofibroma and perineurioma features have been reported in the literature [ 69 , 70 , 71 , 72 ]. Their classification is still to be defined, as it is not clear if they represent a “true” distinct category or simply neurofibromas rich in perineurial cells.…”

Paediatric astroblastoma‐like neuroepithelial tumour of the spinal cord with a MAMLD1‐BEND2 rearrangement

“…13) and encodes a protein characterised by two DNA binding BEN domains which are involved in transcription and chromatin regulation[14]. It may be hypothesised that the fusion of MN1, MAMLD1 or EWSR1 with F I G U R E 1 Radiological and pathological features.…”