Prognostic significance of H3.K27me3 loss in CNS WHO grade 2 meningiomas: a multicentre clinicopathological study.

PURPOSE: CNS WHO grade 2 meningiomas display heterogeneous biological behaviour, and reliable prognostic markers are needed to refine risk stratification. Loss of histone H3 lysine 27 trimethylation (H3.K27me3) has emerged as a potential immunohistochemical marker of aggressive behaviour, but its prognostic role within CNS WHO grade 2 tumours remains uncertain.

METHODS

A retrospective multicentre cohort of 109 patients with histologically confirmed CNS WHO grade 2 meningioma diagnosed between 2006 and 2024 was analysed. Immunohistochemistry for H3.K27me3 was performed on representative tumour sections and independently assessed by three neuropathologists. Associations between H3.K27me3 status and clinicopathological variables were evaluated using Fisher’s exact and Mann–Whitney tests. Disease-free survival (DFS) and overall survival (OS) were estimated by Kaplan–Meier analysis, Cox proportional hazards regression and Aalen-Johansen estimation.

RESULTS

H3.K27me3 loss was detected in 32 (29.4%) tumours and was significantly associated with older age (p = 0.034), higher mitotic index (p = 0.019), and necrosis (p = 0.005). Inter-observer agreement for H3.K27me3 scoring was substantial (κ = 0.77). On univariate analysis, H3.K27me3 loss (HR = 3.243, p < 0.001), subtotal resection (HR = 2.461, p = 0.013), and Ki-67 > 10% (HR = 2.136, p = 0.026) predicted shorter DFS. Multivariate analysis confirmed H3.K27me3 loss (aHR = 3.314, p = 0.001) and Ki-67 > 10% (aHR = 2.154, p = 0.041) as independent prognostic factors. For OS, H3.K27me3 loss (aHR = 3.314, p = 0.045), age ≥ 65 years (aHR = 3.721, p = 0.007), and brain invasion (aHR = 2.242, p = 0.009) were adverse predictors.

CONCLUSIONS

H3.K27me3 loss is a reproducible, accessible, and independent marker of aggressive clinical behaviour in atypical meningiomas. Its routine assessment may improve postoperative prognostic evaluation and guide adjuvant management in CNS WHO grade 2 meningiomas.