Meningioma: International Consortium on Meningiomas consensus review on scientific advances and treatment paradigms for clinicians, researchers, and patients

Abstract

Meningiomas are the most common primary intracranial tumors in adults and are increasing in incidence due to the aging population and increased access to neuroimaging. While most exhibit nonmalignant behavior, a subset of meningiomas are biologically aggressive and are associated with treatment resistance, resulting in significant neurologic morbidity and even mortality. In recent years, meaningful advances in our understanding of the biology of these tumors have led to the incorporation of molecular biomarkers into their grading and prognostication. However, unlike other central nervous system (CNS) tumors, a unified molecular taxonomy for meningiomas has not yet been established and remains an overarching goal of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official World Health Organization (cIMPACT-NOW) working group. Additionally, clinical equipoise still remains on how specific meningioma cases and patient populations should be optimally managed. To address these existing gaps, members of the International Consortium on Meningiomas including field-leading experts, have prepared this comprehensive consensus narrative review directed toward clinicians, researchers, and patients. Included in this manuscript are detailed overviews of proposed molecular classifications, novel biomarkers, contemporary treatment strategies, trials on systemic therapies, health-related quality-of-life studies, and management strategies for unique meningioma patient populations. In each section, we discuss the current state of knowledge as well as ongoing clinical and research challenges to road map future directions for further investigation.

Keywords: extra-axial; meningioma; methylation; molecular; neurofibromatosis 2; nonmalignant; radiotherapy.

Figure 1.

(A) Distribution of all primary brain tumors (malignant and nonmalignant combined; 5-year total = 453 623; annual average cases = 90 725) by histopathology. (B) Distribution of all nonmalignant primary brain tumors (5-year total = 326 894; average annual cases = 65 379) by histopathology. (C) Annual age-adjusted incidence rates of meningioma based on sex, ethnicity, and race. (D) Incidence rate ratios by sex (female-to-male) for selected primary brain and other central nervous system (CNS) tumor histopathologies with malignant and nonmalignant meningiomas highlighted. (E) Female-to-male incidence rate ratios and 95% confidence intervals (CI) for meningioma, by age group at diagnosis and stratified by WHO tumor grade. (F) Incidence rate ratios by race (white:black and white:Asian or Pacific Islander [API]) for selected primary brain and other CNS tumor histopathologies with malignant and nonmalignant meningiomas highlighted. (G) Average annual age-adjusted incidence rate and 95% confidence interval (CI) for meningioma by race/ethnicity and stratified by grade. Incidence rate ratios (IRR) and their 95% CI appear above bars and are calculated relative to non-Hispanic White individuals as the reference. Rates are age-adjusted to the 2000 US standard population. CBTRUS statistical report: US Cancer Statistics—National Program of Cancer Registries (NPCR) and the Surveillance, Epidemiology, and End Results (SEER), 2016–2020.^, Image panels A–D, F reused with permission from Ostrom et al. (2023). Image panels E, G reused with permission from Walsh et al. (2023). GBM, glioblastoma; CBTRUS, Central Brain Tumor Registry of the United States.

Figure 1.

(A) Distribution of all primary brain tumors (malignant and nonmalignant combined; 5-year total = 453 623; annual average cases = 90 725) by histopathology. (B) Distribution of all nonmalignant primary brain tumors (5-year total = 326 894; average annual cases = 65 379) by histopathology. (C) Annual age-adjusted incidence rates of meningioma based on sex, ethnicity, and race. (D) Incidence rate ratios by sex (female-to-male) for selected primary brain and other central nervous system (CNS) tumor histopathologies with malignant and nonmalignant meningiomas highlighted. (E) Female-to-male incidence rate ratios and 95% confidence intervals (CI) for meningioma, by age group at diagnosis and stratified by WHO tumor grade. (F) Incidence rate ratios by race (white:black and white:Asian or Pacific Islander [API]) for selected primary brain and other CNS tumor histopathologies with malignant and nonmalignant meningiomas highlighted. (G) Average annual age-adjusted incidence rate and 95% confidence interval (CI) for meningioma by race/ethnicity and stratified by grade. Incidence rate ratios (IRR) and their 95% CI appear above bars and are calculated relative to non-Hispanic White individuals as the reference. Rates are age-adjusted to the 2000 US standard population. CBTRUS statistical report: US Cancer Statistics—National Program of Cancer Registries (NPCR) and the Surveillance, Epidemiology, and End Results (SEER), 2016–2020.^, Image panels A–D, F reused with permission from Ostrom et al. (2023). Image panels E, G reused with permission from Walsh et al. (2023). GBM, glioblastoma; CBTRUS, Central Brain Tumor Registry of the United States.

Figure 2.

Updated 2021 World Health Organization (WHO) Grading criteria for meningiomas including histological subtypes for CNS WHO grade 1 cases: (A) meningothelial, (B) fibrous, (C) transitional, (D) psammomatous, (E) secretory, (F) angiomatous, (G) microcystic, (H) lymphoplasmacyte-rich, (I) metaplastic; CNS WHO grade 2 cases: (J) atypical, (K) clear cell, (L) chordoid; and CNS WHO grade 3 cases: (M) anaplastic, (N) papillary, (O) rhabdoid. HPF- high-powered fields; N:C, nuclear to cytoplasm. Histological image panels (A–O) used with permission from Bi et al. (2016). CNS, central nervous system; HPF, high-powered fields; N:C, nuclear to cytoplasm; TERT, telomerase reverse transcriptase.

Figure 3.

(A) Different meningioma molecular/methylation classifications discovered by independent groups arranged based on approximately how they correlate with one another based on common biology, alterations, and outcome (read from top to bottom). (B) Relative distribution of meningiomas belonging to each WHO grade in each molecular or methylation group. (C) Relative proportion of meningiomas based on location in either a skull base or non-skull base location in the supratentorial or infratentorial compartment in datasets where tumor location was available. (D) Key transcriptomic pathways found to be overexpressed in meningiomas belonging to each molecular or methylation group, grouped into 4 main sets of pathways. (E) Relative distribution of common meningioma driver mutations found in cases with more benign biology (left) and more biologically aggressive cases (right). (F) Proportion of different chromosomal alterations seen in each molecular or methylation group. (G) progression-free survival (PFS) of meningiomas belonging to each recently published molecular or methylation group based on the original publication’s cohort. *Importantly to note, these groups may not correlate with one another precisely on a one-to-one basis and as a result, the PFS curves of different groups may be repeated in different panels. ^†For instance, while many meningiomas from the Ben-3 methylation subclass share commonalities with Merlin-intact or NF2-wild-type cases (eg, absence of 22q deletions, presence of chromosome 5 gain, angiomatous histology), some cases may classify into other molecular groups eg, immunogenic or hypermetabolic groups. Similarly, some cases of Ben-3 do have 22q deletions as well. Int-A and Int-B meningiomas may not precisely separate into hypermetabolic and proliferative cases. PMCRT, Princess Margaret Cancer Research Tower; DKFZ, German Cancer Research Center; UCSF, University of California San Francisco; MM-FAV, meningioma methylation group favorable; MM-UNFAV, meningioma methylation group unfavorable; Ben, benign; Int, intermediate; Mal, malignant; MG, Molecular Group; MenG, Meningioma Group; NF2, neurofibromatosis 2; TRAF7, Tumor necrosis factor receptor-associated factor 7; KLF4, Krüppel-like factor 4; AKT1, RAC(Rho family)-alpha serine/threonine-protein kinase; SMO, Smoothened; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; DNA-directed RNA polymerase II subunit RPB1; TERTp, Telomerase reverse transcriptase promoter; CDKN2A/B, cyclin-dependent kinase inhibitor 2A/B.

Figure 4.

(A) Postoperative magnetic resonance imaging suggesting a gross total resection with contrast-enhancing reactive changes only. (B) Positron emission tomography (PET) imaging showing focal uptake along the cribriform plate (standardized uptake value 7.43, white arrow) suspicious for residual disease. (C) Follow-up MRI 2 years later after patient declined to pursue recommended adjuvant RT with increased enhancing soft tissue signal (arrow). (D) Increased focal PET uptake in the cribriform plate suggests progression of residual disease (standardized uptake value 8.96, yellow arrow). (E) Axial brain MRI of a different patient: a 54-year-old woman with newly diagnosed breast cancer metastatic to axillary lymph nodes who was noted to have asymmetric photopenia in the left cerebellum on a staging fluorodeoxyglucose (FDG)-position emission tomography (PET) and computer tomography (CT) scan (left). T1 post-contrast brain magnetic resonance imaging (MRI) showed a multilobulated, homogeneously enhancing extra-axial mass adjacent to the left petrous temporal bone with associated edema and mass effect in the left cerebellum and cerebellar peduncle (middle). Leading differential diagnoses included a distant metastasis or a meningioma. DOTATATE PET/MRI showed markedly avid uptake in the intracranial mass (right), but not in the right breast or ipsilateral lymph nodes (not shown). A diagnosis of synchronous meningioma and locoregionally advanced breast cancer was made. The meningioma was treated with stereotactic radiosurgery (SRS). The patient underwent lumpectomy, sentinel lymph node biopsy, and adjuvant whole breast radiotherapy. At 24 months after meningioma treatment and 13 months after breast cancer treatment, the patient had no evidence of disease. (F) Sagittal T1 post-contrast brain MRI (left) and DOTATATE PET (right) of a 61-year-old male with recurrent atypical meningioma, CNS WHO grade 2, status post resection and stereotactic radiosurgery 8 years before developing multiple vertex recurrences that were treated with subtotal resection. Planning DOTATATE PET imaging revealed extensive tumor infiltration of the sagittal sinus from the vertex to the torcula. Part of this figure was originally published in The International Journal of Radiation Oncology, Biology, Physics. Prasad et al. ⁶⁸Ga-DOTATATE PET: The Future of Meningioma Treatment (2022). FDG, fluorodeoxyglucose; MRI, magnetic resonance imaging; PET, positron emission tomography; used with permission.

Figure 5.

Summary of most contemporary treatment guidelines for the management of meningiomas based on WHO grade, extent of resection, with the incorporation of molecular data if available. Content for this figure was partly adopted from Goldbrunner et al. EANO Guideline on The Diagnosis and Treatment of Meningiomas (2021) published in Neuro-Oncology. Used with permission. MRI, magnetic resonance imaging; SRS, stereotactic radiosurgery; fRT, fractionated external beam radiotherapy; GTR, gross total resection; STR, subtotal resection.