Histo-Molecular Intratumoral Heterogeneity in Meningiomas: A Narrative Review.

Background: Meningiomas, the most common primary intracranial tumors, are predominantly benign, but high-grade variants show marked aggressiveness, histo-molecular heterogeneity, and treatment resistance. Although the 2021 WHO CNS classification integrates molecular and histopathologic criteria, substantial inter- and intratumoral variability still limits prognostic accuracy and treatment effectiveness. The goal was to provide insight regarding the histo-molecular intratumoral heterogeneity (ITH) of meningioma and examine its clinical implications. Methods: A narrative review was performed in accordance with PRISMA guidelines. PubMed and Google Scholar were screened for studies on "meningioma" and "intratumoral heterogeneity" published up to 28 July 2025. Eligible studies included original human research reporting histological or molecular heterogeneity with clinical relevance. Results: Eighteen studies comprising 2952 meningioma patients (mean age 59.4 ± 14.8 years, range 16-85) were included. Integrated cytogenetic, molecular, and spatial analyses, including FISH, karyotyping, scRNA-seq, CNV profiling, and spatial transcriptomics, revealed multilayered histo-molecular heterogeneity. Histologically, regional variations in morphology and proliferative index increased with tumor grade. Genomic diversity, marked by recurrent losses of 1p, 14q, and 22q and transcriptionally distinct subclones, defined a complex tumor architecture. Spatial and temporal analyses demonstrated subclonal expansion, stepwise clonal evolution, and therapy resistance, particularly in recurrent tumors. Functionally, SULT1E1+ subclones and COL6A3-mediated macrophage-tumor interactions emerged as potential key drivers of malignancy, recurrence, and radioresistance. Conclusions: Histo-molecular diversity underlies meningioma progression, recurrence, and therapeutic resistance. Standardization of ITH assessment, integration of AI-based spatial analytics, and the development of subclone-specific therapies are essential next steps toward advancing precision neuro-oncology.