Molecular diagnosis and treatment of meningiomas: an expert consensus (2022) : Chinese Medical Journal

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Molecular diagnosis and treatment of meningiomas: an expert consensus (2022)

Deng, Jiaojiao1,2; Hua, Lingyang3,4,5; Bian, Liuguan6; Chen, Hong7; Chen, Ligang8; Cheng, Hongwei9; Dou, Changwu10; Geng, Dangmurenjiapu11; Hong, Tao12; Ji, Hongming13; Jiang, Yugang14; Lan, Qing15; Li, Gang16; Liu, Zhixiong17; Qi, Songtao18; Qu, Yan19; Shi, Songsheng20; Sun, Xiaochuan21; Wang, Haijun22; You, Yongping23; Yu, Hualin24; Yue, Shuyuan25; Zhang, Jianming26; Zhang, Xiaohua27; Wang, Shuo28; Mao, Ying1; Zhong, Ping3,4,5; Gong, Ye1,2;  Group of Neuro-Oncology, Society of Neurosurgery, Chinese Medical Association

Editor(s): Wei, Peifang; Pan, Xiangxiang

Author Information
doi: 10.1097/CM9.0000000000002391

Abstract

Introduction

Meningiomas are the most common primary tumors of the central nervous system with diverse pathological types and complicated clinical manifestations.[1] It is considered a single type in the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (WHO CNS5), with its broad morphological spectrum reflected in 15 subtypes.[2] Approximately 80% of cases are benign lesions and correspond to grade 1 according to the current WHO classification, whereas up to 20% of cases show signs of malignancy at histology and correspond to grade 2 or grade 3 meningiomas.[1] Most low-grade meningiomas can be cured by surgical resection and/or radiotherapy. However, meningiomas that are at surgically inaccessible locations, incompletely resected and/or with features of aggressive histology (WHO grade 2 and 3) tend to grow progressively or recur, and thereby pose a therapeutic challenge.[3,4] In the past few years, key genetic and epigenetic alterations that are strongly associated with clinicopathologic features, such as localization and prognosis, have been identified in meningiomas, and could represent targets for molecularly driven therapies.[1,5–8] However, some uncertainty still remains as to whether histopathological evaluation is the single best criterion for risk assessment in meningiomas. The inclusion of the newly identified frequent molecular alterations in the diagnostic assessment might further improve accuracy in the identification of meningioma patients who need close surveillance and more aggressive treatment.[1,5–8] Consistent with the updated WHO classification of brain tumors published in 2021, the present expert consensus aims to incorporate some molecular features, laying the foundation for improving future diagnosis and therapeutic efforts of meningiomas through the integration of essential molecular findings.

Advances in WHO Classification of Tumors of the Central Nervous System

Since 1979, the WHO has periodically published consensus classification and grading criteria of the central nervous system (CNS) tumors to ensure uniform histopathologic diagnostic criteria worldwide.[5–8] In 2016, the WHO published the fourth edition of the classification of CNS tumors that represents the consensus of 117 contributors and for the first time uses molecular parameters in addition to traditional histology to diagnose CNS tumors.[9] This results in major adjustment of the classification for many tumors, especially gliomas, ependymomas, and medulloblastomas.[9] In contrast to previous versions of the classification, the WHO CNS5 introduces major changes that advance the role of molecular diagnostics in meningioma for the first time.[2,10]

The WHO classification system describes 15 different meningioma subtypes, nine of which are WHO grade 1, three are WHO grade 2, and three are WHO grade 3 [Supplementary Table 1, https://links.lww.com/CM9/B285].[2,10] Besides histological features, secretory meningiomas (WHO grade 1) can also be diagnosed on the basis of detecting KLF4/tumor necrosis factor receptor associated factor 7 (TRAF7) mutations.[2,10,11] Among WHO grade 2 meningiomas, virtually all clear cell meningiomas harbor SMARCE1 mutations (97%).[2,10,11] Likewise, regardless of the histological criteria of anaplasia, any meningioma with TERT promoter mutation and/or cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion is allotted to WHO grade 3.[2,8,11]

Integrated Grading Scheme for Meningiomas

Genome-wide molecular-profiling studies have revealed the characteristic genetic alterations and epigenetic profiles associated with different types of meningiomas.[3,4,12,13] However, the development of prognosis relevant grading scheme with combined histologic and molecular features remains inchoate for meningioma.[3,4,14,15] In 2017, Sahm et al[14] demonstrated that unsupervised clustering of DNA methylation data divided meningiomas into two distinct subgroups associated with recurrence-free survival. After adjusting for clinical factors, such as WHO grade and Simpson grade, a statistically significant association between DNA methylation subclasses and tumor recurrence was found. Later, Maas et al[4]conducted a comprehensive investigation of 3031 meningiomas on multiple levels, from copy number through epigenomics to mutations. In 2021, Nassiri et al[3] defined four molecular groups of meningioma by combining somatic copy-number aberrations, somatic DNA point mutations, DNA methylation and messenger RNA abundance in a unified analysis. Each molecular group showed distinctive and prototypical biological characteristics (immunogenic type, MG1; benign neurofibromin 2 (NF2) wild-type, MG2; hypermetabolic type, MG3; and proliferative type, MG4). Importantly, these molecular groups more accurately predicted clinical outcomes compared with existing classification schemes. Besides, Driver et al[16] formulated a grading scheme that incorporates mitotic index and multiple high-risk copy number alterations (CNAs) to identify patients at risk for tumor recurrence.

On the basis of WHO CNS5, a consensus integrating molecular parameters with traditional histology to diagnose and manage meningioma might promote the development and clinical translation of novel pathogenesis-based therapeutic approaches, thereby paving the way towards precision medicine in meningiomas.

Consensus Development Process

The current consensus statements were formed jointly by the Group of Neuro-Oncology, Society of Neurosurgery, Chinese Medical Association together with neuropathologists and evidence-based experts. All clinical questions were developed using the Population, Intervention, Comparison, and Outcome format, which is beneficial for developing inclusion and exclusion criteria for retrieved literature and identifying relevant studies for inclusion. The consensus has been registered on the International Practice Guideline Registry Platform (Registration number: IPGRP-2022CN234). All statements were assessed and graded using the criteria for the recommendation grades of Chinese Society of Clinical Oncology clinical practice guidelines [Supplementary Tables 2 and 3, https://links.lww.com/CM9/B285].[17] The consensus process was based on three rounds through online-meeting in 2021. Each member voted each statement according to the Delphi method.[18] Statements with agreement <75% (threshold value) were revised and entered in the subsequent round. The consensus document consists of 23 statements which benefited from expert discussion and fine-tuning, serving clinicians and researchers for the management of patients with meningioma.

Key Biomarkers Screening in Meningiomas

The consensus focuses on epigenomic and genomic features of sporadic meningiomas. Key biomarkers screening was performed by collecting available evidence on molecular landscape of meningiomas [Figure 1]. The following databases were queried for literature review: Medline (PubMed interface, www.pubmed.gov) and National Guidelines Clearinghouse (www.guideline.gov).

F1
Figure 1:
Work flow of biomarkers screening in meningiomas. n: Number of articles, AR: Andregen receptor, EGFR: Epidermal growth factor receptor, ER: Estrogen receptor, HR: Hormone receptor, PR: Progesterone Receptor, SSTR2: Somatostatin receptor 2, TKR: Tyrosine kinases receptors, VEGFR: Vascular endothelial growth factor receptor, PDGFR, Plateletderived growth factor receptor.

Key Molecular Alterations of Meningiomas Impacting on Clinical Management

Copy number alterations

Loss of chromosome 22q

Somatic CNAs play a critical role in meningiomagenesis by dysregulating oncogene and tumor suppressor activity.[1] The first cytogenetic study on meningiomas, published in 1967, showed loss of a G-group chromosome (either chromosome 21 or 22) in all tumor samples under investigation and multiple chromosomal aberrations in half of the samples.[1] Subsequent studies validated the increased incidence of monosomy 22 in meningiomas.[19] These landmark studies led to the critical insight that loss of chromosome 22 is pivotal in meningiomagenesis for a large subset of the tumors. Convexity and spinal meningiomas predominantly harbour 22q loss, whereas skull-base meningiomas are characterized by other frequent mutations.[20] Loss of heterozygosity (LOH) studies showed that chromosome 22q was lost in 60% to 70% of sporadic meningiomas.[21–24] The incidence of 22q LOH increases with WHO grade, with a 50% prevalence in WHO grade 1 tumors and 75% to 85% prevalence in WHO grades 2 and 3 tumors.[22–24] In 2004, Pfisterer et al[25] concluded the deletion of 22q was significantly associated with radiologically detected recurrence in 77 paraffin-embedded meningioma samples (P < 0.05). Hilton et al[26] investigated the expression and activation of epidermal growth factor receptor (EGFR) and downstream signalling pathways in 30 meningiomas. They found that the anti-EGFR based therapies may be less effective in meningiomas with 22q loss. Recently, Hong et al[27]reported a novel mutation concurrent with 1p/22q co-deletion in a patient with multiple recurrent meningiomas responding to sunitinib. The first identification of a specific genetic aetiology of meningiomas was the discovery of alterations in the tumor suppressor gene NF2, located on chromosome 22, which encodes the protein merlin.[28] A few clinical trials of drugs targeting NF2 alterations have achieved promising results, and the details are presented in the following “Neurofibromin 2 (NF2) Mutations” section in this consensus.

Recommendation 1 22q testing should be considered for postoperative meningiomas (Evidence 2A; Grade I recommendation). Follow-up of meningiomas with 22q loss could be done annually within 5 years (Evidence 3; Grade III recommendation).

Loss of chromosome 1p

Deletion of chromosome 1p is the second most common CNA identified after 22q loss and is mainly associated with higher WHO grade.[25,29] Besides, 1p loss is considered as an early event in the malignant progression of meningiomas.[25,29] 1p loss most frequently involves the 1p33–34 and 1p36 regions, which may cause methylation-mediated inactivation of TP73 and ALPL genes.[30–33] Linsler et al[31] performed a prospective study on 124 tumor samples from 105 meningioma patients. In WHO grade 1 meningiomas, loss of 1p36 was detectable in 27.4% (17/62), in grade 2 in 37.1% (13/35) and in anaplastic meningiomas in 87.5% (7/8) of cases. They thus concluded that the deletion of 1p36 emerged as a significant predictor of shorter overall survival in meningiomas (log-rank test, P < 0.001). Accumulated CNAs, such as the 1p/14q co-alteration, have been postulated to increase the risk of malignant behavior of sporadic meningiomas.[34] Combined 1p/14q deletions were encountered in 7% benign, 39% atypical, and 63% anaplastic meningiomas (P < 0.001). There was a trend for WHO grade 2 meningiomas with combined 1p/14q deletions to have poorer overall survival.[29] In 2007, Krayenbühl et al compared differences between de novo malignant meningiomas and meningiomas that progressed to malignancy. There was an increased monosomy or derivative chromosome 1 combined with monosomy of chromosome 14. These phenomena occurred mainly in patients with malignant transformation who had a worse outcome.[35,36]

Recommendation 2 1p testing should be considered for postoperative meningiomas (Evidence 2A; Grade I recommendation). Follow-up of meningiomas with 1p loss could be done every 6 months within 5 years (Evidence 3; Grade III recommendation).

Loss of chromosome 14q

Loss of chromosome 14q is involved in the pathological progression of meningioma, but the specific mechanism remains unknown. Lusis et al[37] considered that 14q loss leads to low transcript expression of the tumor suppressor gene NDRG2 at 14q11.2, thereby playing an essential role in meningioma progression. A few retrospective clinical studies showed that 14q loss is associated with higher tumor invasiveness and recurrence risk in meningiomas of all pathological grades.[38–41] In 2013, Balik et al[42] found that maternally expressed 3 (MEG3), a long non-coding RNA on 14q, suppressed meningioma growth to a certain degree, but further relevant clinical trials were needed. Gupta et al[43] published the results from 46 meningioma samples in a single-center retrospective clinical study conducted in 2016, reporting an association between 14q loss and a high mitotic index of tumors (P < 0.05).

Recommendation 3 14q testing should be considered for postoperative meningiomas (Evidence 2A; Grade I recommendation). Follow-up of meningiomas with 14q loss could be done every 6 months within 5 years (Evidence 3; Grade III recommendation).

Loss of chromosome 18q

Loss of chromosome 18q in meningiomas was previously identified as indicators of poor outcome.[44] 18q loss is primarily located at the end of 18q22, but the specific mechanism of this CNA in tumor progression remains unclear. Weber et al[45] collected 90 meningioma samples to conduct a retrospective study in 1997, with 18q loss observed in up to 43% of WHO grade 2 meningiomas. In 2021, Barresi et al[46] reported a retrospective study enrolling 22 patients with atypical meningioma, which revealed a significant association between 18q loss and tumor recurrence (with recurrence-free survival shortened remarkably; P = 0.008). Limited by relevant studies, further research of 18q loss in meningiomas remains to be determined.

Recommendation 4 18q testing could be considered for postoperative meningiomas (Evidence 2B; Grade III recommendation). Follow-up of meningiomas with 18q loss could be done annually within 5 years (Evidence 3; Grade III recommendation).

Gene mutation signatures

NF2 mutations

The NF2 gene contains 17 exons and is located on chromosome 22q12.2. NF2 produces a 69 kDa protein, merlin, that functions as a tumor suppressor by inhibiting cell growth through contact inhibition and resultant activation of multiple pathways.[28]NF2 mutations are generally associated with convexity meningiomas rather than meningiomas of the anterior skull base.[12] In 2019, Youngblood et al[13] reported sequencing analysis of 3016 meningiomas. NF2-mutated meningiomas were commonly found in the spinal cord and non-skull base locations. Focal NF2 inactivating mutations are found in 40% to 60% of sporadic meningiomas and identified in meningiomas of all 3 histopathological grades.[12,23,47,48] Wellenreuther et al[49] found NF2 mutations mainly occur in fibrous (70%) and transitional (83%) subtypes after sequencing a cohort of 70 meningiomas. Yuzawa et al[50] reported a single-center retrospective study of 103 meningioma samples in 2016, which showed that the recurrence rate of NF2-mutated meningiomas was significantly increased compared with that of NF2 wild-type meningiomas (Kaplan–Meier survival analysis: 48% vs. 25%, P = 0.037). Gupte et al[51] reviewed clinical and genomic sequencing data on 394 patients surgically treated for meningioma. While NF2-mutated tumors are significantly associated with preoperative seizures (P = 0.012), the association appears to be mediated through edema and atypical histology. In 2020, Deng et al[52] found that low merlin expression in meningiomas was associated with worse overall survival (OS, P = 0.014) and progression-free survival (PFS, P = 0.024) in a large patient series. In another single-center retrospective clinical study reported in 2021, Youngblood et al[53] also found that the 2-year recurrence rate of NF2-mutated meningiomas reached 16.8% (26/155), and the 5-year recurrence rate increased to 43.7%. Accordingly, the mutation status of the NF2 gene in meningioma has a certain role in indicating patient survival, prognosis, and tumor recurrence risk.

The NF2 mutation plays a crucial role in the pathogenesis of meningioma by activating the mammalian target of rapamycin (mTOR) biological pathway through modulation of the mTOR complex 1 (mTORC1).[54,55] In 2020, Williams et al[56] analyzed the genomic data from 850 patients with refractory meningioma, among which at least three distinct patterns of biological invasion were observed. Of these, the NF2-mutated type was the most common (n = 426, 50%) and was associated with the male sex (64.4%). Moreover, additional mutations were often observed, such as those in CDKN2A/B (24%) and chromatin remodeling factor genes ARID1A (9%) and KDM6A (6%). Increasing chromosomal instability due to inactivation, homozygous loss, or point mutation in NF2 together with CDKN2A/B can promote meningioma development in murine models.[56,57] The results of a preclinical study showed that everolimus, a selective inhibitor of mTOR, exhibited excellent tumor-suppressive effects in a meningioma mouse model.[58] Moreover, Shih et al[59] published a multi-center prospective phase II clinical study in 2016, which found no disease progression in ∼35% of patients for >6 months following meningioma treatment with combined everolimus and bevacizumab. Combined everolimus and octreotide also effectively suppressed the growth of aggressive meningiomas in another multi-center phase II clinical trial (NCT02333565) reported by Graillon et al in 2020. Among the 20 samples included, a >50% reduction in tumor volume was observed in 78% of patients within 3 months following treatment, and the median tumor growth rate decreased from 16.6% to 0.02% over the 3-month period.[60] This combined therapeutic regimen showed similar effects in improving the PFS and OS of meningioma patients to the multi-targeted tyrosine kinase inhibitor sunitinib.[61] However, in 2021, Karajannis et al published a phase 0 pharmacokinetic study showing that the downstream effector protein phospho-S6 was inhibited incompletely by everolimus in NF2-mutated meningioma tissues, which may explain the limited therapeutic effect of everolimus on some NF2-mutated meningiomas.[62] Furthermore, an ongoing phase II clinical trial (NCT02523014) preliminarily indicated that a focal adhesion kinase (FAK) inhibitor (GSK2256098) improved the 6-month PFS of patients with NF2-mutant meningioma, but the specific research conclusions remain to be further reported.[63]

Recommendation 5NF2 mutation testing should be considered for postoperative meningiomas (Evidence 2A; Grade I recommendation). Follow-up of meningiomas with NF2 mutation could be done annually within 5 years (Evidence 3; Grade III recommendation).

TERT promoter (TERTp) mutations

Telomeres are conserved, repetitive (TTAGGG) DNA-protein complexes that are added to the ends of chromosomes by the enzyme telomerase to prevent DNA damage and maintain replicative potential.[64,65] Telomere attrition during DNA replication induces genomic instability that can result in tumorigenesis.[64,65]TERTp mutations were initially detected in melanoma and subsequently found in intracranial tumors, such as low-grade glioma, gliosarcoma, oligodendroglioma, and medulloblastoma.[64–68]TERTp mutations, occurring specifically in the hotspot regions C228T and C250T, are detected in 6.5% to 11.0% of meningiomas.[14,69,70] The presence of TERTp mutation is a potential biomarker for meningiomas with a higher likelihood of clinically aggressive behavior that exhibits higher rates of recurrence and shorter time to progression.[70–74] In 2016, Sahm et al[70] assessed the TERTp for mutations in the hotspot regions C228T and C250T in meningioma samples from 252 patients. Mutations were detected in 16 samples (6.4% across the cohort, 1.7%, 5.7%, and 20.0% of WHO grade 1, 2, and 3 cases, respectively). Besides, TERTp mutations were statistically significantly associated with shorter time to progression (mean time to progression [TTP]: 10.1 months vs. 179 months, P < 0.001). Goutagny et al[71] sequenced the TERTp in 73 meningiomas patients. They found a high incidence of TERTp mutations in patients with meningiomas undergoing malignant histological progression. In 2020, Mirian et al[72] compiled data from eight studies and allocated patients to TERTp alterations (n = 59) or TERTp wild-type (n = 618). TERTp alterations occurred in WHO 1 to 3 meningiomas, which is an important biomarker for significantly higher risk of recurrence and death in meningiomas. In 2021, Biczok et al[73] conducted Sanger sequencing of TERTp with samples obtained from 170 meningioma patients at a single center. Among patients with WHO grade 3 meningioma, both the recurrence rate and mortality were substantially higher in the TERTp-mutant group than in the TERTp wild-type group. Deng et al[74] found that TERT alterations were the predictor of tumor progression (P = 0.003) and were associated with decreased PFS (P = 0.0114) in de novo high-grade meningiomas after radiotherapy. The above findings suggest that TERTp mutations are associated with a high recurrence rate of meningiomas and high mortality of patients. Therefore, WHO CNS5 incorporated TERTp mutations in the molecular diagnostic criteria of WHO grade 3 meningioma for the first time.[2,70]

TERTp mutations provide a new target for targeted drug therapy in meningioma. However, the telomerase-based therapies that have been developed to date, mainly imetelstat and first-generation cancer vaccines, failed to achieve a satisfactory clinical efficacy.

Recommendation 6TERTp mutation testing is recommended for postoperative meningiomas (Evidence 1A; Grade I recommendation). Follow-up of meningiomas with TERTp mutation could be done every 3 to 6 months indefinitely (Evidence 3; Grade III recommendation).

CDKN2A/B homozygous deletions

The CDKN2A gene, located at 9p21.3, regulates the cell cycle and acts as a tumor suppressor.[75] Homozygous losses of CDKN2A and CDKN2B have been shown to be associated with an increased frequency of meningioma in murine models inactivated for the NF2 gene.[57] In 2019, Guyot et al[76] identified a CDKN2A SNV (NM_000077, exon2, c.G442A, p.Ala148Thr) in a 30 meningioma series. The presence of such CDKN2A alterations was strongly associated with recurrence (P < 0.0001) and a Ki-67 labeling index > 7% (P = 0.004). In 2020, Sievers et al[77] determine the overall prognostic role of the CDKN2A/B status in a cohort of 528 meningioma patients. They found meningiomas carrying CDKN2A/B homozygous deletions had a significantly worse outcome and more rapid progression from the time of surgery (P < 0.001; median time to progression: 8 vs. 101 months). This observation combined with other groups demonstrating a strong association between homozygous deletion of CDKN2A/B mutations and aggressive clinical outcome led to a significant revision in the WHO CNS5 criteria.[2,4,11]

Recommendation 7CDKN2A/B testing is recommended for postoperative meningiomas (Evidence 2A; Grade I recommendation). Follow-up of meningiomas with CDKN2A/B homozygous deletion could be done every 6 months indefinitely (Evidence 3; Grade III recommendation).

AKT1 and PIK3CA mutations in the phosphatidylinositol-3 kinase (PI3K) pathway

Aberrant activation of PI3K pathway is one of the most frequent events in human cancer and serves to disconnect the control of cell growth, survival and metabolism from exogenous growth stimuli.[78] The relevance of PI3K pathway in meningiomas is underlined by the existence of several PI3K mutations.[79]AKT1E17K, PIK3CAE545K, and PIK3CAH1047R are the most common mutation sites in PI3K pathway-related driver genes.[12,80] Meningiomas with AKT1E17K mutation are almost exclusively observed in WHO grade 1 tumors and tend to have meningothelial and transitional histopathological morphology.[81] Besides, AKT1E17K mutant tumors are more commonly located in anterior and middle fossa skull base.[79–84]AKT1E17K mutation is found in 7% to 12% sporadic meningiomas, leading to abnormal activation of AKT1 and facilitating the proliferation of tumor cells.[79,85]PIK3CA is mutated in approximately 4% to 7% of meningiomas.[12]PIK3CA mutations are mutually exclusive of NF2, SMO, and AKT1 and in few cases co-occur with TRAF7 or KLF4 mutations.[12]PIK3CAH1047R and PIK3CAE545K, which are two of many mutations observed in PIK3CA, constitutively phosphorylate and activate AKT1.[86,87] Based on current evidence, PI3K-activated meningiomas exhibited a significantly shorter time to recurrence than other subgroups (mean time to recurrence: 14.3 months).[53]

Recommendation 8AKT1 and PIK3CA mutation testing should be considered for postoperative meningiomas (Evidence 2A; Grade I recommendation). Follow-up of meningiomas with AKT1 or PIK3CA mutation could be done every 6 months within 5 years (Evidence 3; Grade III recommendation).

In 2017, Weller et al[88,89] reported durable control of lung metastatic AKT1 mutant WHO Grade 1 meningothelial meningioma by the AKT inhibitor, AZD5363 (capivasertib). The patient has been on that treatment for more than one year with ongoing clinical and radiographic response. As described in “NF2 mutations” part, molecular analysis of meningiomas has identified numerous driver mutations involving PI3K pathway that can be targeted with everolimus, a small-molecule mTOR kinase inhibitor, or combined with other therapeutic strategies.[59–61] The combination of everolimus and bevacizumab has been promising, with a median PFS of 22 months in grade 2 and 3 meningiomas.[59] The phase II CEVOREM trial of 20 patients reported a median PFS of 6.6 months of the combination of octreotide and everolimus,[60] while a median PFS of 12.1 months was reported by Cardona et al[61] for their retrospective study of 14 patients treated with everolimus, octreotide, and sunitinib.

Recommendation 9 The combination therapy of everolimus with bevacizumab or octreotide could be considered for PI3K-activated meningiomas (Evidence 2B; Grade III recommendation).

SMO and SUFU mutations in the hedgehog pathway

The hedgehog pathway has also been implicated in the development of WHO grade 1 meningiomas, specifically via mutations in SMO and SUFU genes.[12,47]SMOL412F and SMOW535L mutations are found in 3% to 6% of meningiomas, mostly occurring in the anterior midline skull base.[13,53,79,83] Approximately 66% of meningioms with SUFU allele loss tend to have a long-term recurrence.[53] Additionally, SUFU mutated in less than 1% of sporadic meningiomas. However, familial cases of meningiomas are known to harbor germline mutations in SUFU.[48]

Recommendation 10SMO and SUFU mutation testing should be considered for postoperative meningiomas (Evidence 2A; Grade I recommendation). Follow-up of meningiomas with SMO or SUFU mutation could be done annually within 5 years (Evidence 3; Grade III recommendation).

TRAF7 mutations

TRAF7, located on chromosome 16p13, has been linked to modulation of Janus kinase and mitogen-activated protein kinase signaling pathways, and induction of apoptosis.[86,90]TRAF7 mutations often lead to structural alterations in the protein WD40.[86,90] This mutation is found in 25% of meningiomas, which occur in 50% of NF2 wild-types.[12,53] Tumors with mutations in TRAF7 are often located at the sphenoid wing and floor of the middle fossa.[12]TRAF7 mutations predominantly occur in WHO grade 1 meningiomas, whereas only 4% of high-grade meningioma samples have mutations in this gene.[91] It is currently considered that the coexistence of TRAF7 and PIK3CA mutations indicates long-term recurrence of skull base meningiomas.[86,92] Youngblood et al[53] reported a multi-center retrospective clinical study with 469 meningioma samples in 2021, which found that meningiomas harboring TRAF7 mutation were more prone to recurr within 2 years. Mutations in TRAF7 are mutually exclusive of NF2 mutations but often have a concomitant mutation in AKT1 or KLF4.[12,48,86,93,94] According to WHO CNS5, besides histological features, secretory meningiomas can also be diagnosed on the basis of detecting KLF4/TRAF7 mutations.[2]

Recommendation 11TRAF7 mutation testing should be considered for postoperative meningiomas (Evidence 2A; Grade I recommendation).

KLF4 mutations

Recurrent mutations in KLF4 (c.1225A>C, KLF4K409Q) are potential candidate drivers of WHO grade 1 meningiomas.[12]KLF4 mutant meningiomas occur in up to 28% of NF2 wild-types,[95] which are usually found in the non-midline anterior and central skull base.[13] More severe brain edema is observed in KLF4 mutant meningiomas than other subtypes, while such patients have a longer 5-year PFS.[13,53] According to WHO CNS5, KLF4/TRAF7 mutations constitute the driver alteration in secretory meningiomas and can serve as alternative criterium, besides secretory granula, to identify this subtype.[2]

Recommendation 12KLF4 mutation testing should be considered for postoperative meningiomas (Evidence 2A; Grade I recommendation).

SMARCE1 mutations

Converging lines of evidence suggest an essential role for the switch/sucrose non- fermentable (SWI/SNF) chromatin-remodeling complex in meningioma formation and aggressiveness.[96,97]SMARCE1, also known as BAF57, encoding proteins of the SWI/SNF complex, has been implicated in hereditary meningiomatosis.[96,97] Spinal cord meningiomas show frequent SMARCE1 mutations, whereas other frequent mutations are rare in this localization.[98] Loss-of-function mutations in SMARCE1 are a molecular signature of the clear-cell subtype of meningiomas.[98–100] In 2021, Sievers et al[99] described a molecularly distinct subset of tumors among a cohort of 3093 meningiomas, identifying mutations in SMARCE1 in 33 of the 34 clear cell cases (97%). Furthermore, there are no significant differences in tumor recurrence rates between clear cell meningiomas with SMARCE1 mutation and other types in WHO grade 2 meningiomas.[99] Clear cell meningiomas harboring a SMARCE1 mutation have been commonly described in children and young adults. This finding has important clinical implications because of the risk of the possibility of familial disease. Young patients presenting with multiple clear cell meningiomas could be referred for genetic testing.[100,101] How the SMARCE1 mutation of meningioma affects potential treatment options is another question that needs to be addressed in future studies.

Recommendation 13SMARCE1 mutation testing should be considered for postoperative meningiomas (Evidence 2A; Grade I recommendation).

BRCA1-associated protein 1 (BAP1) mutations

BAP1 is a tumor suppressor gene that encodes a deubiquitylating enzyme which has been identified in a rare subset of aggressive meningiomas with rhabdoid morphology.[102]BAP1 mutation in rhabdoid meningiomas was an important step towards the separation of rhabdoid-appearing meningiomas into aggressive and less-aggressive tumor types.[103] Identification of a germline BAP1 mutation calls for increased vigilance in cancer surveillance in individuals who harbor this mutation.[104] Additionally, loss of BAP1 protein expression indicates early meningioma recurrence.[103,105] More importantly, BAP1 immunohistochemistry could be a promising tool for risk stratification in patients with rhabdoid meningiomas, and is associated with classification and grading of meningiomas in WHO CNS5.[2]

Recommendation 14BAP1 mutation testing should be considered for postoperative meningiomas (Evidence 2A; Grade I recommendation). Familial germline testing could be considered for BAP1 inactivated meningiomas (Evidence 2B; Grade III recommendation).

Duchenne muscular dystrophy (DMD) mutations

The DMD gene encodes the protein dystrophin, and germline mutations in this gene are driving factors of DMD.[106] Inactivation of the DMD plays a vital role in the development and progression of various solid tumors.[107–110] In 2018, Juratli et al[111] reported a retrospective clinical study with 169 high-grade meningioma samples from 53 patients. DMD gene inactivation was found to be associated with shorter PFS and OS; it was an independent risk factor for poor prognosis in meningioma patients (P = 0.033, hazard ratio [HR] = 2.6, 95% confidence interval [CI] 1.0–6.6). In 2019, Paramasivam et al[112] reported that aberrations of DMD were found to be enriched in meningiomas with NF2 mutations, and DMD was among the most differentially upregulated genes in NF2 mutant compared to NF2 wild-type cases. However, the specific role of DMD in meningiomas remains to be determined.

Recommendation 15DMD mutation testing could be considered for postoperative meningiomas (Evidence 2B; Grade II recommendation).

Polybromo-1 (PBRM1) mutations

PBRM1 is a tumor suppressor gene encoding the BAF180 subunit of the SWI/SNF complex and is involved in the regulation of tumor cell proliferation and migration.[113] Alterations in the PBRM1 gene are present in 40% of renal clear cell carcinomas, papillary renal carcinomas, and bladder carcinomas.[114,115] In 2020, Williams et al[116] reported the presence of high-frequency mutations in PBRM1 in papillary meningiomas (WHO grade 3, with updated criteria of WHO CNS5). This conclusion was corroborated in a follow-up study with 850 meningioma samples, which found that 87.5% of PBRM1 mutations occurred in WHO grade 2 and 3 meningiomas.[56] These studies have enhanced our understanding of the molecular biosignatures of high-grade meningiomas. However, further studies are still necessary to clarify whether PBRM1 alterations are associated with clinical prognosis in patients with meningioma.

Recommendation 16PBRM1 mutation testing could be considered for postoperative meningiomas (Evidence 3; Grade III recommendation).

RNA polymerase II subunit A (POLR2A) mutations

POLR2A, the protein that mediates transcription of all protein-coding genes in eukaryotes, has been identified in approximately 6% of grade 1 meningiomas. The recurrent somatic hotspot mutations include POLR2AL438H and POLR2AQ403K.[48]POLR2A mutant meningiomas are exclusively WHO grade 1 tumors that are most likely to be found in anterior skull base tumors, especially tuberculum sellae, and tend to harbor a meningothelial histopathological morphology.[12,48] In 2021, Youngblood et al[53] observed a longer time to recurrence in meningiomas with POLR2A mutation compared with that in other meningioma types (P = 0.49, HR 0.61, 95% CI 0.15–2.50). However, in this study, the meningioma samples with POLR2A mutation only constituted 4.9% (n = 23) of the total samples, and tumor recurrence was observed in 13% (n = 3) of patients during subsequent follow-up. Youngblood et al[53] also found an association between POLR2A mutations and female gender in another study. Furthermore, in a single-center clinical study enrolling 269 meningioma patients, Okano et al[21] observed tumor recurrence in 29.4% of meningioma patients harboring POLR2A mutation (5/17), with a mean time to recurrence of 45.6 months (range: 33.6–57.6 months). Moreover, POLR2A mutation was a risk factor for the tumor recurrence in WHO grade 1 skull base meningiomas.[117,118]

Recommendation 17POLR2A mutation testing could be considered for postoperative meningiomas (Evidence 2B; Grade III recommendation).

Epigenomic alterations in meningioma

H3K27me3 alterations

Histones are highly conserved proteins composed of core proteins, which together with DNA constitute nucleosomes. Histone modification not only reversibly represses or facilitates gene transcription but also affects other processes, such as DNA repair, replication, stem cell formation, and cell state changes. The trimethylation of lysine 27 on histone 3 (H3K27me3) is a chromatin modification that is tightly linked to gene repression and plays an essential role in the development and progression of intracranial tumors.[119,120] An explicit association between H3K27me3 loss and meningioma recurrence has been shown in multiple retrospective clinical studies.[121,122] Based on the results from 232 meningioma studies, Katz et al[122] reported in 2018 that H3K27me3 loss increased the clinical recurrence risk of meningiomas and displayed a prominent effect on the clinical prognosis of WHO grade 1 and 2 cases. In another multi-center retrospective study, H3K27me3 immunohistochemical staining of paraffin sections and clinical variable analysis were conducted in 181 meningioma samples. The results showed that H3K27me3 loss increased the risk of tumor recurrence in WHO grade 1 and 2 meningiomas.[121]

Recommendation 18 H3K27me3 detection should be considered for postoperative meningiomas (Evidence 2A; Grade I recommendation). Follow-up of H3K27me3 negative meningiomas could be done every 6 months within 5 years (Evidence 3; Grade III recommendation).

TIMP3 methylation

DNA methylation is one of the earliest discovered and most well-studied epigenetic regulatory mechanism. This process is catalyzed by the DNA methyltransferase family and involves the transfer of a methyl group to carbon 5’ of cytosine in genomic CpG dinucleotides. DNA methylation controls gene expression by inducing changes in chromatin structure, DNA conformation, DNA stability, and DNA-protein interactions.[123] The hypermethylation of TIMP3, CDKN2A, and TP73 occurs in 10% of meningiomas.[124]TIMP3 hypermethylation causes a downregulation in transcription product and then loss of tumor suppressor activity.[125] Hypermethylated TIMP3 is present in 40% to 60% of high-grade meningiomas, and these cases often experience rapid recurrence after therapy.[124,125] Furthermore, because TIMP3 is located on chromosome 22 (22q12), almost all meningioma patients with TIMP3 hypermethylation are accompanied by allelic loss of 22q.[125] Olar et al[44] reported the results from a multi-center retrospective clinical study conducted in 2017, which demonstrated for the first time that meningiomas could be divided into two distinct subtypes associated with PFS through clustering analysis of global DNA methylation data. Similarly, Sahm et al[14] divided meningiomas into two major classes and six subtypes based on clustering data of DNA methylation; these subtypes showed distinct genomic features and clinical manifestations. The expression profile and epigenomic feature in meningiomas highlight the value of molecular analysis both in prediction of tumor recurrence and in development of novel therapies.[126]

Recommendation 19TIMP3 methylation testing could be considered for postoperative meningiomas (Evidence 2B; Grade II recommendation). Follow-up of meningiomas with TIMP3 methylation could be done every 6 months within 5 years (Evidence 3; Grade III recommendation).

TP73 promoter (TP73p) methylation

The human TP73 gene on the short arm of chromosome 1 (1p36.32) is a TP53 homologous family gene with a sequence highly similar to that of TP53. TP73 is transcribed into two major functional subunits: TAp73 and DNp73. TAp73 is a tumor suppressor that plays a compensatory role in suppressing p53-mutated tumors, whereas DNp73 acts as a tumor promotor. p53 is widely mutated in tumors, but its mutation rate in primary tumors is only 0.6%.[127] Allelic loss and promoter hypermethylation of TP73 are the principal pathways that cause the aberrant expression of p73. Existing studies have confirmed that TP73p methylation is present in 70% to 80% of high-grade meningiomas; however, this phenomenon is not common in WHO grade 1 meningiomas,[128] indicating a certain specificity of TP73p methylation in high-grade meningiomas. Lomas et al[129] considered that TP73p methylation accounted for 20% of meningiomas and was not associated with tumor grade. Bello et al[124] found that the methylation rates of the TP73p in WHO grade 1 to 3 meningiomas were 13% (9/68), 19% (5/27), and 33% (1/3), respectively. However, these two studies included only three WHO grade 3 meningioma samples and used different methylation primer sequences for polymerase chain reaction detection, which might cause biases in their results.[124,129] Hence, more research should be carried out to clarify the relationship between TP73p methylation and meningioma development and progression.

Recommendation 20TP73p methylation testing could be considered for postoperative meningiomas (Evidence 2B; Grade II recommendation). Follow-up of meningiomas with TP73p methylation could be done every 6 months within 5 years (Evidence 3; Grade III recommendation).

Potential Targets for Individualized Management of Meningiomas

Hormone receptors: estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), and somatostatin receptor 2 (SSTR2)

The expression of sex hormone receptors, including the ER, PR, and AR, has been reported in meningiomas by several retrospective clinical studies; however, their association with clinical prognosis in meningioma patients is still inconclusive.[130–133] In 2018, Hua et al[131] enrolled 87 WHO grade 3 meningiomas for a single-center retrospective study, which found that ER expression was associated with poor prognosis. However, survival benefits of tamoxifen, an ER inhibitor, were not observed for patients in several phase II clinical trials.[134,135] Similarly, the PR inhibitor mifepristone showed no benefit in meningioma patients in another phase III clinical trial (SWOG S9005).[136] Various studies have reported differences in PR expression in meningiomas.[137–141] Roser et al[142] conducted a single-center retrospective study with 588 meningioma samples in 2004, revealing an association of PR expression with a favorable clinical prognosis of patients. In 2006, Pravdenkova et al[143] conducted a retrospective study with 239 meningioma samples, which also found that PR expression was associated with a good clinical prognosis. To date, there have been no clinical trials of AR inhibitors for the treatment of meningioma.

Recommendation 21 ER (Evidence 2B; Grade III recommendation) and PR (Evidence 3; Grade III recommendation) detection should be considered for postoperative meningiomas.

SSTR2, which is specifically and highly expressed in meningioma, plays a major role in the pathological diagnosis of meningioma.[137–139] SSTR2 is associated with WHO grade and pathological subtype.[144] Fodi et al[145] analyzed the expression of SSTRs (SSTR1A, SSTR2A, SSTR3A, SSTR4A, and SSTR5A) in >700 meningioma samples in 2021, among which SSTR2A expression was found to be associated with poor clinical prognosis of patients (P = 0.0143). Owing to the wide expression of SSTR2 in meningioma, radiolabeled SSTR2 ligands (ie, octreotide) have been applied in the radiographic diagnosis of meningiomas.[146–161] This exploration, not yet available as standard practice, is helpful in distinguishing tumor from healthy tissue and postoperative tissue changes [Table 1].[162] Although somatostatin receptors are expressed in meningiomas, the long-acting somatostatin analogue (octreotide or pasireotide) did not significantly increase PFS and OS in several small and uncontrolled studies or patient series.[163–165] A phase II clinical trial involving 34 subtotal resection meningioma samples showed that using Yttrium-90-DOTATOC and lutetium-DOTATOC for SSTR2-targeted radiotherapy achieved higher rates of radionuclide uptake and improved therapeutic effects.[166] Another ongoing phase I clinical study of 177Lu-DOTA-JR11 for the treatment of meningiomas (NCT04997317) is conducted by the Swiss Cancer League Dominic in Switzerland in 2021. Somatostatin analogs like octreotide and pasireotide have shown some effects on disease stabilization in meningiomas with SSTR2 expression, which has been described in “NF2 mutations” part.[60,61]

Table 1 - Clinical studies using radiolabeled SSTR2 ligands for meningioma diagnosis.
Image diagnostic methods Radiolabeled SSTR2 ligand Sample sizes Major/novel functions References
PET 68 Ga-DOTATATE 21 pts (81 MG) Discriminating meningioma and tumor-free tissue even in recurrent tumors after previous therapy. 144
64 MG Selecting the time point for treatment initiation; predicting tumor growth rate. 145
30 pts (49 MG) Discriminating meningioma and post-treatment change; improving diagnosis and evaluation for the severity of disease. 146
68 Ga-DOTATOC 3 pts (8 Ms) Offering excellent imaging properties and a very high tumor-to-background ratio even in small meningiomas. 147
21 pts Showing higher specificity for meningioma diagnosis than FET PET. 148
PET/CT 68 Ga-DOTATATE 82 pts Improving detection of the transosseous extension of intracranial meningiomas. 149
68 Ga-DOTATOC 26 pts Improving target volume delineation for IMRT, especially for skull base meningioma and recurrent disease after surgery. 150
134 pts Providing additional information in patients with uncertain or equivocal results on MRI; helping to confirm MRI-based diagnosis of meningiomas in cases of biopsy limitations. 151
PET/MRI 68 Ga-DOTATOC 10 pts Sketching treatment target volume; benefiting radiosurgical treatment plan. 152
SPECT SRS 111 In-octreotide 27 pts Discriminating meningioma and nonspecific hyper-perfusion; displaying remaining tumor tissue or relapse of meningioma in postsurgical follow-up. 153
22 pts Detecting MG with an extremely high sensitivity (100%). 154
47 pts Discriminating MG and other CNS tumors, combined with MRI. 155
70 pts Discriminating MG and other tumors, postoperative scar or radionecrosis at the skull base. 156
95 pts Discriminating MG and other CNS tumors. 157
50 pts Discriminating MG and other cranial dural-based lesions, combined with MRI. 158
SPECT/CT SRS 99m Tc-HYNIC-octreotide 30 pts Showing high meningioma radioactivity accumulation with a sensitivity of 100%. 159
CNS: Central nervous system; CT: Computerized tomography; DOTATATE: DOTA-D-Phe1-Tyr3-octreotate; DOTATOC: DOTA-(Tyr3)-octreotide; FET: Fluoro-ethyl-tyrosine; HYNIC: Hydrazinonicotinamide; IMRT: Intensity modulated radiotherapy; 111In: 111-Indium; MG: Meningiomas; MRI: Magnetic resonance imaging; PET: Positron emission tomography; pts: Patients; SPECT: Single-photon emission computed tomography; SRS: Somatostatin receptor scintigraphy; SSTR2: Somatostatin receptor 2.

Recommendation 22 SSTR2 detection should be considered for postoperative meningiomas (Evidence 2A; Grade I recommendation). SSTR2 directed radiological diagnosis could be considered for meningiomas (Evidence 2B; Grade II recommendation).

Tyrosine kinases receptors (TKRs): epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR)

TKRs are transmembrane proteins that facilitate interactions between tissue cells and their adjacent cells. In contrast to other cell surface receptors, TKRs exhibit specific enzymatic activity. When signaling molecules bind to TKRs to activate tyrosine kinases in the cytoplasmic tail of the receptor, a series of enzymatic reactions are initiated to transmit the signal to the nucleus, thereby altering the protein transcription pattern.[167] TKRs expressed in meningioma include EGFR, VEGFR, and PDGFR.[167] An experimental study indicated that TKR inhibitors improve the clinical prognosis of patients through different mechanisms, such as suppressing tumor cell proliferation, reducing tumor volume, and alleviating peritumoral edema.[168]

EGFR is expressed at different levels in meningioma. Notably, The expression of EGFR seems higher in low-grade meningiomas, but their association with the clinical prognosis of patients remains unclear.[169–171] In a phase II clinical trial reported by Norden et al[172] in 2010, no significant effects of gefitinib or erlotinib (EGFR inhibitor) were observed on PFS and OS improvements among meningioma patients. Later, Osorio et al[173] reported the results of a literature review in 2018, which found that lapatinib had a certain control effect on neurofibromatosis type 2-related meningioma, but further randomized controlled trials should be carried out for verification. Varied levels of VEGFR expression were observed in all meningiomas, and a higher expression was associated with a higher tumor grade and shorter PFS in most cases.[174–178] These findings suggest that VEGFR inhibitors may exhibit a certain therapeutic effect on refractory meningiomas. In a multi-center prospective phase II clinical trial reported in 2015, Kaley et al[179] enrolled 36 patients with high-grade meningioma who received sunitinib therapy. After treatment, the PFS rate at 6 months was 42%, and the median PFS reached 5.2 months (95% CI: 2.8–8.3 months), with a median OS of 24.6 months (95% CI: 16.5–38.4 months). However, certain adverse reactions to sunitinib were also observed, such as intratumoral hemorrhage, thrombotic microangiopathy and gastrointestinal perforation. Bevacizumab is a monoclonal antibody against recombinant humanized immunoglobulin G1 that inhibits VEGF-A and represses its binding to VEGF receptor-2. As a result, the biological functions of VEGF, including vascular permeability and proliferation, as well as endothelial cell migration and survival, are influenced, thereby achieving the suppression of tumor angiogenesis, growth, and metastasis.[180] To date, bevacizumab has been extensively used in the treatment of many tumors, such as colorectal carcinoma, pulmonary carcinoma, ovarian carcinoma, cervical carcinoma, and glioblastoma.[181–183] Presently, bevacizumab is considered to delay the postoperative growth of meningioma.[11,184] Shih et al[59] reported another prospective phase II clinical trial in 2016, demonstrating the therapeutic effects of bevacizumab combined with the mTORC1 inhibitor everolimus on recurrent and progressive meningiomas. Among all cases included in the trial (n = 17), the median tumor PFS was 10 months (range: 2–19 months), and the PFS of patients with WHO grade 2–3 meningioma was higher than that of patients with WHO grade 1 meningioma (PFS: 22 months vs. 17 months). Collectively, these results suggest that patients with refractory meningioma can benefit from this combined therapy with bevacizumab and everolimus. Additionally, three phase II clinical trials evaluating the therapeutic effects of bevacizumab (NCT01125046), bevacizumab coupled with electric field therapy (NCT02847559), and bevacizumab plus the programmed death-1 inhibitor pembrolizumab (NCT03279692) for recurrent and progressive meningiomas are still ongoing.

Platelet-derived growth factor and its receptors (PDGFR) are frequently co-expressed in meningiomas, potentially contributing to their pathogenesis.[185,186] Wen et al[187] published the results from a prospective phase II clinical trial that evaluated the therapeutic effects of the PDGFR inhibitor imatinib mesylate in 23 patients with different grades of meningioma. However, single-agent imatinib was well tolerated but had no significant activity in recurrent meningiomas (PFS: 2 months; range: 0.7–34.0 months).

Recommendation 23 Pharmacotherapy using bevacizumab targeting VEGER could only be considered if no further local treatment option exists (Evidence 2A; Grade II recommendation).

Limitations

Based on the update of WHO CNS5, this consensus mainly focuses on the application of key molecular biomarkers for meningioma in clinical diagnosis and treatment. Despite revisions according to expert opinions proposed on several revision meetings, the consensus still has the following limitations: (1) The consensus recommends expert opinions that can reach a consensus only based on evidence that can be retrieved at the current stage. Consequently, it cannot completely cover or solve all questions in the clinical diagnosis and treatment of meningioma patients, including preoperative diagnosis, postoperative radiotherapy and chemotherapy decisions, prognosis evaluation, and disease monitoring. (2) Other molecular markers not listed for recommendation in this consensus have also been reported in previous studies of meningiomas. However, the association of such biomarkers with the clinical prognosis has not yet been clarified; therefore, they are not currently included in the recommendations. (3) In recent years, there has been rapid progress in molecular underpinnings of meningiomas, and updated studies have been reported continuously. Therefore, the recommendations presented in this consensus are time-limited and need to be updated regularly.

These limitations will be gradually addressed in our further work according to the advances in this field.

Conclusions

In recognition of the value of molecular features in meningioma subtyping in WHO CNS5, the present expert consensus aims to incorporate some of these molecular features, setting the stage for the improvement of future diagnosis and therapeutic efforts through the integration of key molecular findings in meningiomas [Tables 2 and 3]. It is hoped that our work could provide practical guidance to specialists and pathologists in meningiomas, and benefit the patients who are affected by meningiomas.

Table 2 - A summary of recommended biomarkers for testing.
Adjuvant therapy (evidence level)
Biomarkers Function Tumor location Clinical significance (evidence level) Diagnosis (evidence level) Radiation therapy Systemic therapy Follow-up (evidence level) Test method Recommendation grade
Copy number alterations
 22q A critical role in meningiomagenesis by dysregulating oncogene and tumor suppressor activity Convexity and spine 22q loss is significantly associated with worse clinical outcome (evidence 2B) Unknown Unknown Sensitive to sunitinib (evidence 3) Annually within 5 years (evidence 3) Karyotyping, FISH, Array-CGH, NGS Grade I
 1p Unknown Unknown 1p loss is associated with worse clinical outcome (evidence 2A). 1p/14q loss increases the risk of tumor recurrence (evidence 2A) Unknown Unknown Sensitive to sunitinib (evidence 3) Every 6 months within 5 years (evidence 3) Karyotyping, FISH, Array-CGH, NGS Grade I
 14q Unknown Unknown 1p/14q loss increases the risk of tumor recurrence (evidence 2A) Unknown Unknown Unknown Every 6 months within 5 years (evidence 3) Karyotyping, FISH, Array-CGH, NGS Grade I
 18q Unknown Unknown 18q loss increases the risk of tumor short-term recurrence (evidence 2B) Unknown Unknown Unknown Annually within 5 years (evidence 3) Karyotyping, FISH, Array-CGH, NGS Grade III
Gene mutation signatures
NF2 NF2 produces merlin that functions as a tumor suppressor by inhibiting cell growth Convexity and spine NF2 mutation is associated with worse clinical outcome, increases the risk of tumor recurrence (evidence 2A) Unknown Unknown Unknown Annually within 5 years (evidence 3) NGS, Sanger sequence, MLPA, FISH, IHC Grade I
TERT promoter TERTp regulates TERT gene expression and maintains normal cell mitosis Unknown TERTp mutation is associated with worse clinical outcome, and increases the risk of tumor recurrence (evidence 1A) Histological criteria of WHO grade 3 (evidence 3) TERTp alteration is associated with radiation sensitivity in de novo high-grade meningiomas (evidence 2B) Unknown Every 3–6 months indefinitely (evidence 3) NGS, Sanger sequence Grade I
CDKN2A/B CDKN2A/B regulates cell cycle and inhibits tumor cell proliferation Unknown CDKN2A/B mutation is associated with worse clinical outcome, and increases the risk of tumor recurrence (evidence 2A) Histological criteria of WHO grade 3 (evidence 3) Unknown Unknown Every 6 months within 5 years (evidence 3) NGS, Sanger sequence Grade I
AKT1, PIK3CA PI3K pathway serves to disconnect the control of cell growth, survival and metabolism from exogenous growth stimuli Middle fossa skull base AKT1 and PIK3CA mutation increases the risk of tumor recurrence (evidence 2A) Unknown Unknown Everolimus-octreotide (evidence 2A); everolimus-bevacizumab (evidence 2A) Every 6 months within 5 years (evidence 3) AKT1: NGS, RT-PCR; PIK3CA: NGS, Sanger sequence, RT-PCR Grade I
SMO, SUFU Driver genes in Hedgehog pathway Middle fossa skull base SMO and SUFU mutation increases the risk of tumor recurrence (evidence 2A) Unknown Unknown Unknown Annually within 5 years (evidence 3) SMO: NGS, Sanger sequence; SUFU: NGS, IHC Grade I
TRAF7 Transduction molecules in TNFR mediated signaling pathway Middle fossa skull base TRAF mutation increases the risk of tumor short-term recurrence (evidence 2A) Histological criteria of secretory subtype (evidence 3) Unknown Unknown NGS, Sanger sequence Grade I
KLF4 Zinc finger protein transcription factor, which involves in the regulation of cell proliferation, differentiation and embryonic development Non-midline anterior and central skull base KLF4 mutation is associated with better 5-year progression-free survival and peritumoral brain edema (evidence 2A) Histological criteria of secretory subtype (evidence 3) Unknown Unknown NGS, Sanger sequence Grade I
SMARCE1 Chromatin remodeling complex SWI/SNF involves in encoding part of ATP Spine Common mutation in clear cell subtype (evidence 2A) Reference for diagnosis of secretory subtype (evidence 3) Unknown Unknown NGS, IHC Grade I
BAP1 A tumor suppressor gene that encodes a deubiquitylating enzyme, and inhibits tumor growth by binding to the ring finger domain of BRCA1 Unknown BAP1 mutation is associated with worse clinical outcome, and increases the risk of tumor recurrence (evidence 2A) Reference for diagnosis of rhabdoid subtype (evidence 3) Unknown Unknown Every 6 months within 5 years (evidence 3) NGS, IHC Grade I
DMD DMD locates at Xp21.1-p21.3, encoding dystrophin Unknown DMD mutation is associated with worse clinical outcome, and increases the risk of tumor recurrence (evidence 2B) Unknown Unknown Unknown Annually within 5 years (evidence 3) NGS, IHC Grade I
PBRM1 A tumor suppressor gene encoding the BAF180 subunit of the SWI/SNF complex, and involving in the regulation of tumor cell proliferation and migration Unknown Common mutation in papillary subtype (evidence 2B) Unknown Unknown Unknown NGS Grade III
POLR2A The protein that mediates transcription of all protein-coding genes in eukaryotes Anterior skull base, especially tuberculum sellae POLR2A mutation is associated with better clinical outcome (evidence 2B) Unknown Unknown Unknown NGS, Sanger sequence Grade III
Epigenomic alterations
 H3K27me3 A chromatin modification that is tightly linked to gene repression and plays an essential role in the development and progression of intracranial tumors Unknown H3K27me3 loss increases the risk of tumor short-term recurrence (evidence 2A) Unknown Unknown Unknown Every 6 months within 5 years (evidence 3) IHC Grade I
TIMP3 methylation TIMP3 methylation causes a down-regulation in transcription product and then loss of tumor suppressor activity Unknown TIMP3 methylation increases the risk of tumor short-term recurrence (evidence 2B) Unknown Unknown Unknown Every 6 months within 5 years (evidence 3) Pyrosequencing Grade II
TP73 promoter methylation TP73 promoter methylation regulates downstream transcripts and inhibits tumor growth Unknown TP73 promoter methylation increases the risk of tumor short-term recurrence (evidence 2B) Unknown Unknown Unknown Every 6 months within 5 years (evidence 3) Pyrosequencing Grade II
Hormone receptors
 ER ER participates in regulation of multiple hormones, inhibits cell proliferation and promotes cell apoptosis Unknown High expression of ER is associated with worse clinical outcome (evidence 2B) Unknown Unknown Unknown IHC Grade III
 PR PR participates in regulation of multiple hormones, inhibits cell proliferation and promotes cell apoptosis Unknown High expression of PR is associated with worse clinical outcome (evidence 2B) Unknown Unknown Unknown IHC Grade III
 SSTR2 SSTR2 participates in regulation of multiple hormones, inhibits cell proliferation and promotes cell apoptosis Unknown SSTR2 alterations increase the risk of tumor recurrence (evidence 2B) Octreotide-scanning (evidence 2B) Unknown Everolimus-octreotide (evidence 2B) IHC Grade I
Tyrosine kinases receptors
 VEGFR VEGFR involves in regulation of lymphatic endothelial cells and vascular endothelial cells, and promotes the formation of lymphatic vessels and blood vessels Unknown Expressien of VEGFR is associated with higher WHO grade and shorter progression-free survival (evidence 2B) Unknown Unknown Bevacizumab (evidence 2A) IHC Grade II
AKT1: Protein kinase B; Array-CGH: Array-comparative genomic hybridization; ATP: Adenosine triphosphate; BAF: BRM-associated factor; BAP1: BRCA1 associated protein 1; BRCA1: Breast cancer 1; CDKN2A/B: Cyclin-dependent kinase inhibitor 2A/B; DMD: Duchenne muscular dystrophy; ER: Estrogen receptor; FISH: Fluorescence in situ hybridization; H3K27me3: Trimethylation of lysine 27 on histone 3; IHC: Immunohistochemistry; KLF4: Krüppel-like factor 4; MLPA: Multiple ligation-dependent probe amplification; NF2: Neurofibromin 2; NGS: Next generation sequencing; PBRM1: Polybromo-1; PI3K: Phosphosphatidylinositol-3-kinase; PIK3CA: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha isoform; POLR2A: RNA polymerase II; PR: Progesterone Receptor; RT-PCR: Reverse transcription-polymerase chain reaction; SMARCE1: SWI/SNF Related, matrix associated, actin dependent regulator of chromatin, subfamily E, member 1; SMO: Smoothened; SSTR2: Somatostatin receptor 2; SUFU: Suppressor of fused homolog; SWI/SNF: Switching defective/sucrose non-fermenting; TERT: Telomerase reverse tranase; TERTp: Telomerase reverse transcriptase promoter; TIMP3: Tissue inhibitor of matrix metalloproteinase 3; TNFR: Tumor necrosis factor receptor; TP73: Tumor protein p73; TRAF7: Tumor necrosis factor receptor associated factor 7; VEGFR: Vascular endothelial growth factor receptor; WHO: World Health Organization; -: Not available.

Table 3 - Biomarkers of meningiomas with different locations and WHO grades.
Tumor location WHO grade Recommendation grade I Recommendation grade II Recommendation grade III Adjuvant therapy
Midline anterior and central skull base Grade 1 AKT1, PIK3CA, SMO, SUFU, TRAF7, H3K27me3, SSTR2 VEGFR POLR2A Everolimus-octreotide (SSTR2, AKT1, PI3K), bevacizumab (VEGFR)
Grade 2 AKT1, PIK3CA, SMO, SUFU, TRAF7, BAP1, H3K27me3, SSTR2 VEGFR Everolimus-octreotide (SSTR2, AKT1, PI3K), bevacizumab (VEGFR)
Grade 3 TERTp, CDKN2A/B, AKT1, PIK3CA, SMO, SUFU, TRAF7, BAP1, H3K27me3, SSTR2 VEGFR Everolimus-octreotide (SSTR2, AKT1, PI3K), bevacizumab (VEGFR)
Non-midline anterior and central skull base Grade 1 KLF4, H3K27me3, SSTR2 VEGFR Everolimus-octreotide (SSTR2), bevacizumab (VEGFR)
Grade 2 KLF4, BAP1, H3K27me3, SSTR2 VEGFR Everolimus-octreotide (SSTR2), bevacizumab (VEGFR)
Grade 3 TERTp, CDKN2A/B, KLF4, BAP1, H3K27me3, SSTR2 VEGFR Everolimus-octreotide (SSTR2), bevacizumab (VEGFR)
Convexity Grade 1 22q, NF2, H3K27me3, SSTR2 VEGFR Sunitinib (22q), everolimus-octreotide (SSTR2), bevacizumab (VEGFR)
Grade 2 22q, NF2, BAP1, H3K27me3, SSTR2 VEGFR Sunitinib (22q), everolimus-octreotide (SSTR2), bevacizumab (VEGFR)
Grade 3 22q, NF2, TERTp, CDKN2A/B, BAP1, H3K27me3, SSTR2 VEGFR Sunitinib (22q), everolimus-octreotide (SSTR2), bevacizumab (VEGFR)
Spine Grade 1 22q, NF2, SMARCE1, H3K27me3, SSTR2 VEGFR Sunitinib (22q), everolimus-octreotide (SSTR2), bevacizumab (VEGFR)
Grade 2 22q, NF2, BAP1, SMARCE1, H3K27me3, SSTR2 VEGFR Sunitinib (22q), everolimus-octreotide (SSTR2), bevacizumab (VEGFR)
Grade 3 22q, NF2, TERTp, CDKN2A/B, BAP1, SMARCE1, H3K27me3, SSTR2 VEGFR Sunitinib (22q), everolimus-octreotide (SSTR2), bevacizumab (VEGFR)
AKT1: Protein kinase B; BAP1: BRCA1 associated protein 1; CDKN2A/B: cyclin-dependent kinase inhibitor 2A/B; H3K27me3: Trimethylation of lysine 27 on histone 3; KLF4: Krüppel-like factor 4; NF2: Neurofibromin 2; PI3K: Phosphosphatidylinositol-3-kinase; PIK3CA: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha isoform; POLR2A: RNA polymerase II; SMARCE1: SWI/SNF Related, matrix associated, actin dependent regulator of chromatin, subfamily E, member 1; SMO: Smoothened; SUFU: Suppressor of fused homolog; SSTR2: Somatostatin receptor 2; TERT: Telomerase reverse transcriptase; TERTp: Telomerase reverse transcriptase promoter; TRAF7: Tumor necrosis factor receptor associated factor 7; VEGFR: Vascular endothelial growth factor receptor; -: Not available.

Conflicts of interest

This consensus was sponsored by the Shanghai KR Pharmtech, Inc., Ltd. and the Genetron Health (Beijing) Co., Ltd. The funders had no role in the consensus development process or in the writing and preparation of the manuscript or the decision to publish.

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Keywords:

Clinical diagnosis; Expert consensus; Meningioma; Molecular subtyping; Therapeutic treatment

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