Clinical Predictors of Malignant Peripheral Nerve Sheath Tumor Risk and Overall Survival in Neurofibromatosis Type 1 at a Tertiary Referral Center

Abstract

Neurofibromatosis type 1 (NF-1), the most common neurogenetic cancer predisposition syndrome, is caused by germline mutation of the NF1 gene. NF-1 individuals exhibit marked clinical heterogeneity and malignant tumor risk. We retrospectively identified 348 people treated at the University of California San Francisco between 2015–2026 who met diagnostic criteria for NF-1. Germline NF1 variant information was available in 149 patients (42.8%). NF-1 diagnostic criteria included café-au-lait macules (n = 281/81%), ≥2 neurofibromas (n = 252/72%), axillary/inguinal freckling (n = 225/65%), cutaneous neurofibromas (n = 175/50%), and plexiform neurofibromas (PN) (n = 188/54%). Nervous system tumors were common including malignant peripheral nerve sheath tumors (MPNSTs) (n = 63/18%), non-optic low-grade gliomas (n = 51/15%), optic glioma (n = 47/13%), and atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP) (n = 27/8%). Multivariable Cox proportional hazards analysis revealed MPNST (HR 15.18, 95% CI 6.26-36.83, p < 0.001) and high-grade gliomas (HR 13.35, 95% CI 3.14-56.75, p < 0.001) were significantly associated with decreased OS. On multivariable analysis, plexiform neurofibroma (OR 2.43, 95% CI 1.30–4.57, p = 0.006) and ANNUBP (OR 3.34, 95% CI 1.42–7.87, p = 0.006) were significantly associated with increased MPNST risk; age and female sex were not independently associated with MPNST risk (Table 2). Germline NF1 variant class was not associated with MPNST risk. MPNST was the predominant cause of cancer-related death within this tertiary-referral cohort, consistent with population-based series identifying MPNST as a leading cause of NF-1-associated mortality. Germline NF1 variant class was not associated with MPNST risk.