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P497: COMPARATIVE MOLECULAR AND TUMOUR MICROENVIRONMENT PROFILES OF SPORADIC AND NF2-RELATED SCHWANNOMATOSIS VESTIBULAR SCHWANNOMAS: A SYSTEMATIC REVIEW
Gabriel Berberi, BSc¹; Lea Stephan¹; Marie Kametani, BSc²; Jo Anne Stratton, PhD²; Emily Kay-Rivest, MD, FRCSC³; ¹Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada; ²Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; ³Department of Otolaryngology-Head and Neck Surgery, McGill University, Montreal, QC, Canada

Objective: Vestibular schwannomas can arise sporadically (sVS) or be associated with NF2-related schwannomatosis (NF2-VS). Although they share an identical cellular origin, they exhibit distinct clinical and biological features. To date, no systematic review has synthesized the fragmented literature on the molecular and tumor microenvironmental (TME) differences between sVS and NF2-VS. The aim of this study was to characterize and compare the molecular and microenvironmental characteristics of sVS and NF2-VS to detect research gaps and future research directions.

Methods: We searched Medline, Embase, Web Of Science, and Scopus from inception to April 26th, 2025, for original articles reporting on the molecular or TME characteristics of sVS or NF2-VS. Studies investigating fresh patient tumor samples were included, while in vitro model results were excluded. Descriptive statistics were performed to summarize patient and study characteristics, while qualitative descriptions were used to synthesize the molecular and TME findings.

Results: Seventy publications were included, reporting on 4380 unique VS cases (3866 sVS and 514 NF2-VS) derived from 4364 patients. While 31.4% of studies included both NF2-VS and sVS samples, 61.4% and 7.14% focused exclusively on sVS and NF2-VS, respectively. The studies were classified into five major categories according to their methodological approach: transcriptomic-based (n=15, 20.4%), proteomic-based (n=33, 47.2%), single-cell-based (n=5, 7.14%), radiomic-based (n=6, 8.57%), and multimodal investigations (n=11, 15.7%). Transcriptomic investigations of sVS and NF2-VS samples identified differentially expressed genes involved in cell proliferation, apoptosis, microtubule stability and cell cycle inhibition. Single-cell analyses also revealed increased transcriptional and proteomic activation of myelination, extracellular matrix maintenance, glycolysis/hypoxic metabolism, stress responses, and immune signaling. Similarly, surface receptor tyrosine kinases (EGFR/ErbB, VEGFR, ROR2, Tie2, Axl and YAP-derived Her2/Her3) were frequently activated. Across both VS subtypes, TME investigations demonstrated a macrophage-rich environment low in T-cell markers with broadly comparable cell-cell interactions and overall immunological landscape.

Direct comparisons and well-aligned indirect evidence also revealed differences. NF2-VS demonstrated higher CD3/CD8+ T-cell densities, with higher CD163+ tumor-associated macrophages, greater PD-L1 positivity, hypoxia markers and larger, poorly pericyte-covered vessels. By contrast, sVS exhibits more pericyte-covered small vessels. Other notable differences include the proportion of certain signaling pathways, with NF2-VS exhibiting higher EGF-EGFR/ErbB2 compared to Nrg-ErbB2/ErbB3 signaling in sVS. Molecular markers such as COX2, ADAM9, or MACC1 also seem underexpressed in NF2-VS compared to sVS. Within each VS subtype, expression of signaling markers such SAPK/JNK, PTEN, or MAPK/ERK varied depending on radiation status. Growing tumors revealed a more regulatory-skewed immune milieu marked by M2 macrophages compared to static tumors. Beyond those studies, MRI/PET, miRNA profiling, and perilymph proteomics also revealed differences both between and within VS subtypes (by growth, size, treatment response, or hearing status).

Conclusion: Overall, sVS and NF2-VS seem to share core oncogenic and angiogenic programs, along with a comparable macrophage-predominant TME. Subtype-specific differences exist but were inconsistent across studies, warranting further investigation, whereas state-specific differences (hearing status, irradiation, size, growth) were more reproducible. Our findings suggest that future studies should focus on deeper molecular profiling and using modelling systems to further clarify defined mechanisms critical for targeted therapeutic interventions.

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