PATH-47 - Molecular markers associated with survival in grade 3 meningioma

Meningiomas have historically been graded using histologic features. However, a subset of meningiomas progress in manners inconsistent with their histologic grading. While TERT promoter (TERTp) mutations and CDKN2A/B homozygous deletion were recently added to the WHO 2021 classification criterion for grade 3 meningioma, the precise prognostic implications of these and other molecular features remain to be fully characterized. In this case series, we explored whether molecular markers were associated with clinical outcomes in a single-center cohort of grade 3 intracranial meningiomas. Demographic, clinical and histopathological information were obtained from the electronic medical records of all grade 3 meningioma cases surgically treated at a tertiary center between 2007-2020. Tissue blocks were reviewed by a neuropathologist and tested for TERTp mutations, BAP1 and CDKN2A/B copy number profiles, and BAP1, p16 and MTAP expression by immunohistochemistry (IHC). Predictors of survival were identified by Cox regression. Fifteen patients (8 female, 7 male) with a median age of 64 (IQR: 48, 74) years were included. Eight (53%) tumors were classified as anaplastic, 6 (40%) as rhabdoid and 1 (6.7%) as papillary. One (7%) rhabdoid tumor exhibited BAP1 loss, while four (27%) tumors harbored TERTp mutations and 3 (20%) demonstrated homozygous CDKN2A/B loss. All three tumors exhibiting homozygous CDKN2A/B loss were MTAP-negative, while two were p16-negative and the third showed focal ( < 50%) p16 loss by IHC. TERTp mutations and CDKN2A/B copy number status were associated with significant reductions in RFS (HR = 6.90, 95% CIs: 1.13-42.2 and HR = 12.0, 05% CIs: 1.51-95.4, respectively) and OS (HR = 8.72, 95% CIs: 1.87-40.6 and HR = 6.18, 95% CIs: 1.30-29.4, respectively). The associations between reduced OS and TERTp mutations and CDKN2A/B status remained significant after adjusting for Simpson resection grade. Our findings support using TERTp mutations and CDKN2A/B status for prognostication in grade 3 meningioma.