Molecular Biology and Genetics of Meningiomas: Classification and Diagnostic Methods

Meningioma diagnosis is currently based on the criteria established by the latest WHO Classification of Central Nervous System Tumours, published in 2021. Histopathological evaluation still retains its critical role for the initial diagnosis and the subsequent subtyping and grading. Many different and morphologically heterogenous meningioma subtypes are recognized and their correct distinction has clinical relevance since clear cell and chordoid meningiomas are associated with a higher recurrence rate and are thus classified as grade 2 neoplasms. A careful morphological evaluation is also necessary to establish tumor grade since multiple features must be assessed, including mitotic count and presence of brain invasion. Meningiomas are also molecularly heterogenous; the oncogenic significance of multiple genes has been demonstrated with specific associations in terms of tumor location, morphology, and prognosis. CDKN2A/B homozygous deletion and TERT promoter mutations are now considered as grading markers since their presence, either alone or in combination, mandates a grade 3 allocation. Tumor DNA methylation profiling is also an important tool to confirm, in selected cases, meningioma diagnosis and prognostically stratify these tumors. In terms of methods, a wide range of techniques can be exploited to characterize a meningioma sample. Even immunohistochemistry can be relevant to explore meningioma molecular profile, for example, to assess loss of SMARCE1 expression in clear cell meningiomas. On the other side, extensive molecular profiling can be achieved by NGS, but the specific molecular diagnostic workflow has to be adapted to each laboratory according the clinical requirements, platform availability and expertise.