Malignant Progression of Meningiomas: Occurrence, Outcomes, and Underpinning Factors.

Malignant transformation in meningiomas remains an undercharacterized phenomenon, with scarce long-term evidence delineating its incidence, outcomes, and molecular drivers. We conducted a retrospective study of 101 patients with histologically confirmed malignant progression among 2499 meningiomas treated between 1990 and 2025. Clinical, radiological, and treatment data were analyzed. Primary endpoints included transformation-free survival, progression-free survival, and cause-specific overall survival (OS). Molecular alterations were evaluated in a subset of tumors. Malignant transformation occurred most frequently at first recurrence (64%), with a mean transformation time of 8 years. Recurrence intervals shortened progressively, while tumor size increased over time. Mean progression-free survival and OS were 4.4 and 12.5 years, respectively, with a 10-year OS of 52%. Outcomes were poor and independent of initial WHO grade after transformation. Irradiation was associated with significantly increased recurrence risk (P = 0.007). Genetic analyses revealed increased genomic complexity, including losses of chromosomes 1p, 6q, and 22. Postradiation and post-transformation specimens demonstrated enrichment of alterations involving NOTCH1/2/3, CDKN2A/2 B/2C, NTRK1/3, XRCC-family genes, ARID1A/1B, SMARCA4/SMARCB1, and TP53. Notably, there was a high alteration in XRCC6 in both radiation and malignant transformation. The protein encoded by this gene is a single-stranded DNA-dependent ATP-dependent helicase, involved in the repair of double-strand DNA breaks, induced by ionizing radiation. Malignant progression in meningiomas appears to reflect a process of clonal evolution shaped by genomic instability and therapeutic selection pressures. In this context, the observed association between irradiation and adverse outcomes underscores the need to critically reassess its role, while surgical resection remains the cornerstone of management.