Genomic Landscape of Superficial Malignant Peripheral Nerve Sheath Tumor

Superficial malignant peripheral nerve sheath tumors (SF-MPNSTs) are rare cancers and can be difficult to distinguish from spindle cell (SCM) or desmoplastic (DM) melanomas. Their biology is poorly understood. We performed whole-exome sequencing and RNA sequencing (RNA-seq) on SF-MPNST (n = 8) and compared them with cases of SCM (n = 7), DM (n = 8), and deep MPNST (DMPNST, n = 8). Immunohistochemical staining for H3K27me3 and PRAME was also performed. SFMPNST demonstrated intermediate features between D-MPNST and melanoma. Patients were younger than those with melanoma and older than those with D-MPNST; the outcome was worse and better, respectively. SF-MPNST tumor mutational burden (TMB) was higher than D-MPNST and lower than melanoma; differences were significant only between SF-MPNST and SCM (P = .0454) and between D-MPNST and SCM (P = .001, Dunn's Kruskal-Wallis post hoc test). Despite having an overlapping mutational profile in some common cancer-associated genes, the COSMIC mutational signatures clustered DM and SCM together with UV light exposure signatures (SBS7a, 7b), and SFand D-MPNST together with defective DNA base excision repair (SBS30, 36). RNA-seq revealed differentially expressed genes between SF-MPNST and SCM (1670 genes), DM (831 genes), and DMPNST (614 genes), some of which hold promise for development as immunohistochemical markers (SOX8 and PLCH1) or aids (MLPH, CALB2, SOX11, and TBX4). H3K27me3 immunoreactivity was diffusely lost in most D-MPNSTs (7/8, 88%) but showed variable and patchy loss in SF-MPNSTs (2/8, 25%). PRAME was entirely negative in the majority (0+ in 20/31, 65%), including 11/15 melanomas, and showed no significant difference between groups (P = .105, KruskaleWallis test). Expression of immune cell transcripts was upregulated in melanomas relative to MPNSTs. Next- generation sequencing revealed multiple differential features between SFMPNST, D-MPNST, SCM, and DM, including tumor mutation burden, mutational signatures, and differentially expressed genes. These findings help advance our understanding of disease pathogenesis and improve diagnostic modalities. (c) 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.