Meningiomas: Overview and New Directions in Therapy

Nancy Wang, MD; Matthias Osswald, MD

Disclosures

Semin Neurol. 2018;38(1):112-120. 

In This Article

Pathogenesis and Genetics

Meningiomas can arise anywhere arachnoid cells are located in the central nervous system, with the most common locations being along the cerebral convexity, parasagitally, and along the sphenoid wing.[28] Atypically, they can also arise within the cranium, ventricles, or even brain parenchyma. Approximately 12% of meningiomas are spinal and comprise the most common intradural spinal cord and cauda equina tumor in adults.[1,25] More than 90% are solitary, with multiple meningiomas associated with radiation-induced lesions or genetic syndromes.[2] Interestingly, the majority of lesions from patients with three or more meningiomas have the same copy of X chromosome inactivated or carry the same NF2 mutation, suggesting dural spread of a clonal population even in the case of multiple meningiomas.[29,30]

Meningiomas may invade adjacent structures and spread locally. Extracranial or distant metastasis is only described in approximately 0.1% of all meningiomas, typically in association with anaplastic meningiomas, although cases with WHO grade I meningiomas have also been reported with good prognosis.[24,31,32] Reported sites have included the lung and pleura, musculoskeletal system, liver, reticuloendothelial system, and kidneys.[24,33]

Large-scale genomic analyses of meningiomas have elucidated potential pathways involved in tumorigenesis, as well as new therapeutic targets and better prognostic awareness. Loss of heterozygosity and inactivating mutations in the NF2 gene are seen in up to 60% of sporadic cases.[34–36] These mutations lead to decreased functional levels of the gene product Merlin, which is important for cytoskeletal function, cell growth, and motility, possibly through regulation of mammalian target of rapamycin (mTOR) C1/mTORC2 signaling.[37–41] Decreased messenger ribonucleic acid (mRNA) expression levels of another member of the same protein family Dal-1 is also observed in up to 76% of sporadic meningiomas, with loss of expression of either Dal-1 or merlin seen in 92%.[42] Both are thought to be early events in the development of meningiomas.[42,43] Karyotypic abnormalities are generally more common in atypical and anaplastic meningiomas.[24] Losses of chromosomes 6q, 9p, 10, 14q, and 18q are associated with higher grade tumors, as are gains of chromosomes 1q, 9q, 12q, 15q, 17q, and 20q.[44] Mutations in the promoter of telomerase reverse transcriptase (TERT) are associated with a poor prognosis in a subset of meningiomas.[27,45]

In addition to associations with grade, genetic profiles also appear to correlate with location and histological variant of tumor. NF2 mutations are more common in fibroblastic and transitional meningiomas located at the convexity, and are also more frequent in primary atypical meningioma.[46–50] Mutations in the AKT1 gene, particularly AKT1E17k, are present in 9 to 13% of meningiomas, predominantly meningothelial or transitional subtypes.[2,51–53] Among skull base tumors, AKT mutations are present in up to 19%.[54] Mutations in the smoothened (SMO) gene are present in 4 to 6% of WHO grade I meningiomas, but up to 11% of those located at the medial anterior skull base.[51,52,54] Oncogenic mutations in PIK3CA have been reported in 7% of non-NF2-mutant meningiomas.[55] SMARCE1 mutations have been identified in clear cell meningiomas, and TRAF7 mutations, typically occurring in combination with KLF4 mutations, are present in 93 to 100% of secretory meningiomas.[56,57] Collectively, these mutations have been found to lead to constitutive signaling through the sonic hedgehog and Phosphatidylinositol-3 kinase (PI3K)/AKT/mTOR pathways.[51,52] Inactivating mutations in BRCA1-associated protein 1, both familial and sporadic, are found in a subset of high-grade rhabdoid meningiomas and are correlated with an aggressive clinical course.[58]

Additional signaling pathways thought to play a role in the development or progression of meningiomas include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor, endothelins, the Notch signaling pathway, and insulin-like growth factor.[59–65]

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