Meningioma

2023-09-02 Scott Ryall, PhD Affiliation

1.Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)

Classification

Definition

Meningiomas are the most common intracranial neoplasms, accounting for approximately a third of all central nervous system (CNS) tumors. ¹ Traditionally, they are benign, slow-growing lesions likely derived from the meningothelial cells of the arachnoid mater. ² Despite their benign reputation, meningioma may lead to significant morbidity, often dependent on the tumor's location.

In the 2021 edition of The World Health Organization (WHO) classification of CNS tumors, meningioma is considered a single tumor entity. However, its broad spectrum of morphological features is reflected in 15 subtypes. ³ These subtypes include i) meningothelial meningioma (grade 1), ii) fibrous meningioma (grade 1), iii) transitional meningioma (grade 1), iv) psammomatous meningioma (grade 1), v) angiomatous meningioma (grade 1), vi) microcystic meningioma (grade 1), vii) secretory meningioma (grade 1), viii) lymphoplasmacyte-rich meningioma (grade 1), ix) metaplastic meningioma (grade 1), x) chordoid meningioma (grade 2), xi) clear cell meningioma (grade 2), xii) atypical meningioma (grade 2), xiii) papillary meningioma (grade 3), xiv) rhabdoid meningioma (grade 3), and xv) anaplastic meningioma (grade 3). Importantly, the 2021 WHO classification emphasizes the need to evaluate the criteria defining atypical or anaplastic meningioma regardless of the tumor's subtype. ³

Meningioma - Emerging Molecular Entities	Genetic Event(s)
Meningothelial Meningioma	Meningothelial meningioma often harbor co-occuring mutations in AKT1 (primarily as p.E17K) and TRAF7, or SMO and PIK3CA. ^4-7 Meningothelial meningioma are often genomically stable and rarely harbor mutations in NF2 and/or deletions of chromosome 22q. DNA methylation analysis classifies meningiothelial meningioma as "Meningioma, subtype benign, subclass 2," which also includes secretory meningioma. ⁸
Fibrous Meningioma	Fibrous meningioma, also referred to as fibroblasic meningioma, frequently harbor one-copy deletions of chromosome 22q and mutations in NF2 on the retained 22q allele. DNA methylation analysis classifies fibroblastic meningioma as "Meningioma, subtype benign, subclass 1," which also includes psammomatous and transitional meningioma. ⁸
Transitional Meningioma	Transitional meningioma, like fibrous and psammomatous meningioma, frequently harbor one-copy deletions of chromosome 22q and mutations in NF2 on the retained 22q allele. DNA methylation analysis classifies transitional meningioma as "Meningioma, subtype benign, subclass 1," which also includes psammomatous and fibrous meningioma. ⁸
Psammomatous Meningioma	Psammomatous meningioma, like fibrous and transitional meningioma, frequently harbor one-copy deletions of chromosome 22q and mutations in NF2 on the retained 22q allele. DNA methylation analysis classifies psammomatous meningioma as "Meningioma, subtype benign, subclass 1," which also includes transitional and fibrous meningioma. ⁸
Angiomatous Meningioma	Angiomatous meningioma typically have trisomy of chromosome 5 in addition to several other less common polysomies including 20, 6, 12, 13, 7, 17, and 18 , in order of prevalence. ^9,10 Infrequently, they harbor one-copy deletions of chromosome 22q and mutations in NF2 on the retained 22q allele. ⁹ DNA methylation analysis classifies angiomatous meningioma as "Meningioma, subtype benign, subclass 3," which also includes metaplastic and microcytic meningioma. ⁸
Microcystic Meningioma	Microcystic meningioma, like angiomatous and metaplastic meningioma, typically have trisomy of chromosome 5 in addition to several other less common polysomies including 6, 12, 17, 18 and 20. ¹⁰ Infrequently, they harbor one-copy deletions of chromosome 22q and mutations in NF2 on the retained 22q allele. DNA methylation analysis classifies microcystic meningioma as "Meningioma, subtype benign, subclass 3," which also includes metaplastic and angiomatous meningioma. ⁸
Secretory Meningioma	Secretory meningioma are defined by co-occurring mutations in KLF4 (primarily as p.K409Q) and TRAF7, with rare instances of KLF4 arising in isolation. ^5,11 Secretory meningioma do not harbor mutations in NF2 and/or deletions of chromosome 22q. DNA methylation analysis classifies secretory meningioma as "Meningioma, subtype benign, subclass 2," which also includes meningothelial meningioma. ⁸
Lymphoplasmacyte-rich Meningioma	Lymphoplasmacyte-rich meningioma is an extremely rare subtype of meningioma, characterized histologically by the presence of inflammatory infiltrates. Currently, the genetics of lymphoplasmacyte-rich meningioma are unknown. DNA methylation analysis has not been completed for these tumors due to the overwhelming amount of non-neoplastic DNA traditionally seen in these specimens. ⁸
Metaplastic Meningioma	Metaplastic meningioma, like angiomatous and microystic meningioma, typically have trisomy of chromosome 5 in addition to several other less common polysomies: 6, 12, 17, 18 and 20. ¹⁰ Infrequently, they harbor one-copy deletions of chromosome 22q and mutations in NF2 on the retained 22q allele. DNA methylation analysis classifies metaplastic meningioma as "Meningioma, subtype benign, subclass 3," which also includes microcystic and angiomatous meningioma. ⁸
Chordoid Meningioma	Chordoid meningiomas are considered grade 2 neoplasms due to their high rate of recurrence, despite lacking any high-grade histopathological features. ¹² They harbor genetic abberrations including 1p, 2p, 6q, 14q, and 22q loss (the latter with co-ocurring mutations in NF2 on the retained 22q allele). Chromosome 2p deletions are more common in chordoid meningiomas than in other grade 2 meningiomas. Chordoid meningioma are not classified into a distinct DNA methylation group, but rather, segregate with other meningioma subtypes including those classified as benign (~60%), intermediate (~35%), and malignant (~5%). ¹³
Clear cell Meningioma	Clear cell meningioma frequently harbor germline or somatic SMARCE1 mutations and/or deletions. Infrequently, they harbor one-copy deletions of chromosome 22q and mutations in NF2 on the retained 22q allele. DNA methylation analysis classifies clear cell meningioma as "Meningioma intermediate-A", ⁸ now further resolved into the distinct entity "Meningioma, clear cell subtype, SMARCE1-altered."
Atypical Meningioma	Atypical meningioma is recongized as an intermediate-grade meningioma with a heightened risk of recurrence post-surgery. Genetically, atypical meningiomas commonly harbor one-copy deletions of chromosome 22q and mutations in NF2 on the retained 22q allele. In addition, losses of chromosomes 1p, 14, 6q and 10q are common. ¹⁴ DNA methylation analysis does not segregate atypical meningiomas into their own distinct classification, but rather, assigns them across the benign, intermediate, or malignant subtypes. ^8,14 This suggests that further stratification based on the inclusion of additional clinicopathological and genetic factors is possible. ^15-17
Papillary Meningioma	Papillary meningioma frequently harbor mutations or deletions of PBRM1. ¹⁸ Co-occuring mutations and/or deletions of BAP1, a gene more commonly altered in rhabdoid meningioma, have also been noted. ¹⁸ DNA methylation analysis does not segregate papillary meningioma into a unique classification, but rather, with tumors classifying as benign (subclass 3) or intermediate (subclass A or B). ⁸
Rhabdoid meningioma	Rhabdoid meningioma commonly harbor mutations and/or deletions in BAP1, either somatically or in the context of BAP1 tumor predisposition syndrome OMIM:614327. ^18,19 Rhabdoid meningiomas with papillary-like histologic features may also harbor mutations and/or deletions of PBRM1. ^18,19 As with papillary meningioma, DNA methylation analysis does not segregate rhabdoid meningioma into a unique classification, but rather, with tumors classified as benign (subclass 3) or intermediate (subclass A or B). ⁸
Anaplastic meningioma	Anaplastic meningioma often harbor TERT promoter mutations and/or homozygous deletions of CDKN2A/CDKN2B, both of which confer a high risk of recurrence and worse progression-free survival. ^20-23 Loss of H3 p.K28me3 (K27me3), seen in ~10-20% of anaplastic meninigomas, is likewise associated with a worsened clinical course. ^16,24 DNA methylation analysis primarily classifies anaplastic meningioma as "Meningioma, subtype malignant," although some may be classified as intermediate, depending on their underlying genetics. ⁸

Bibliography

Reference Number	Pubmed ID	Last Year	Title	Authors
1	31675094	2019	CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012-2016.	Ostrom QT et al
2	33194703	2020	Meningioma: A Review of Clinicopathological and Molecular Aspects.	Huntoon K et al
3	34185076	2021	The 2021 WHO Classification of Tumors of the Central Nervous System: a summary.	Louis DN et al
4	23334667	2013	Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations.	Brastianos PK et al
5	23348505	2013	Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.	Clark VE et al
6	24096618	2013	AKT1E17K mutations cluster with meningothelial and transitional meningiomas and can be detected by SFRP1 immunohistochemistry.	Sahm F et al
7	26826201	2016	Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma.	Abedalthagafi M et al
8	28314689	2017	DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis.	Sahm F et al
9	25347344	2014	Angiomatous meningiomas have a distinct genetic profile with multiple chromosomal polysomies including polysomy of chromosome 5.	Abedalthagafi MS et al
10	32642661	2019	Identification of shared genomic aberrations between angiomatous and microcystic meningiomas.	Kuroi Y et al
11	23404370	2013	Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations.	Reuss DE et al
12	10895812	2000	Chordoid meningioma: a clinicopathologic study of 42 cases.	Couce ME et al
13	30382370	2018	Chordoid meningiomas can be sub-stratified into prognostically distinct DNA methylation classes and are enriched for heterozygous deletions of chromosomal arm 2p.	Sievers P et al
14	36845294	2023	Genomic markers of recurrence risk in atypical meningioma following gross total resection.	Vaubel RA et al
15	24536048	2014	Proposal for a new risk stratification classification for meningioma based on patient age, WHO tumor grade, size, localization, and karyotype.	Domingues PH et al
16	29627952	2018	Loss of histone H3K27me3 identifies a subset of meningiomas with increased risk of recurrence.	Katz LM et al
17	32232472	2020	A Risk Score Based on 5 Clinico-Pathological Variables Predicts Recurrence of Atypical Meningiomas.	Fioravanzo A et al
18	32405805	2020	Frequent inactivating mutations of the PBAF complex gene PBRM1 in meningioma with papillary features.	Williams EA et al
19	28170043	2017	Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas.	Shankar GM et al
20	24261697	2014	High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression.	Goutagny S et al
21	26668184	2016	TERT Promoter Mutations and Risk of Recurrence in Meningioma.	Sahm F et al
22	29312603	2017	Intratumoral heterogeneity and TERT promoter mutations in progressive/higher-grade meningiomas.	Juratli TA et al
23	32642869	2020	CDKN2A/B homozygous deletion is associated with early recurrence in meningiomas.	Sievers P et al
24	32447376	2020	Prognostic Value of Histopathological Features and Loss of H3K27me3 Immunolabeling in Anaplastic Meningioma: A Multicenter Retrospective Study.	Gauchotte G et al

External Links

Citation

Scott Ryall

Meningioma

Atlas Genet Cytogenet Oncol Haematol. 2023-09-02

Online version: http://atlasgeneticsoncology.org/solid-tumor/209204