Spatial Lipidomics Reveals Myelin Defects and Protumor Macrophage Infiltration in Malignant Peripheral Nerve Sheath Tumor Adjacent Nerves

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas arising from peripheral nerves, accounting for 3% to 5% of soft tissue sarcomas. MPNSTs often recur locally, leading to poor survival. Achieving tumor-free surgical margins is essential to prevent recurrence, but current methods for determining tumor margins are limited, highlighting the need for improved biomarkers. In this study we investigated the degree to which MPNST extends into nerves adjacent to tumors. Alterations to the lipidome of MPNST and adjacent peripheral nerves were assessed using spatial lipidomics. Tissue samples from 5 patients with MPNST were analyzed, revealing alterations of the lipid profile extending into the peripheral nerves beyond what was expected based on macroscopic and histologic observations. Integration of spatial lipidomics and high-resolution accurate-mass profiling identified distinct lipid profiles associated with healthy nerves, connective tissue, and tumors. Notably, histologically normal nerves exhibited myelin degradation and infiltration of protumoral M2 macrophages, particularly near the tumor. Furthermore, aberrant osmium staining patterns and loss of H3K27me3 staining in the absence of atypia were observed in a case with tumor recurrence. This exploratory study thereby highlights the changes occurring in the nerves affected by MPNST beyond what is visible on hematoxylin and eosin staining and provides leads for further biomarker studies, including aberrant osmium staining, to assess resection margins in MPNST.