Meningioma: Molecular Updates from the 2021 World Health Organization Classification of CNS Tumors and Imaging Correlates

Neetu Soni; Manish Ora; Girish Bathla; Denes Szekeres; Amit Desai; Jay J. Pillai; Amit Agarwal

doi:10.3174/ajnr.A8368

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RE: Reply
Neetu Soni, Manish Ora, Amit Agarwal and Girish Bathla

Published on: 10 May 2025
Beyond WHO Classification: The Case for Molecular Integration in Meningioma Imaging
Ali Nabavizadeh

Published on: 20 April 2025

Published on: (10 May 2025)
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RE: Reply
Neetu Soni, Neuroradiologist, Mayo Clinic Florida
Other Contributors:
Manish Ora, Nuclear Medicine

Amit Agarwal, Neuroradiologist

Girish Bathla, Neuroradiologist
Reply
Neetu Soni, Manish Ora, Girish Bathla, and Amit Agarwal

We thank you for your insightful and valuable comments on our recent review article, "Meningioma: Molecular Updates from the 2021 World Health Organization Classification of CNS Tumors and Imaging Correlates," particularly regarding recent updates not addressed in our original publication.
The 2021 WHO Classification of Central Nervous System Tumors ("CNS5") introduced key molecular markers, including TERT promoter mutations and homozygous CDKN2A/B deletions, as criteria for CNS WHO grade 3, recognizing their association with increased recurrence risk.1 We appreciate your emphasis on cIMPACT-NOW Update 8 and the growing role of DNA methylation-based classifiers, reflecting the evolving landscape of meningioma classification and risk stratification.2, 3
Based on morphology, WHO criteria, and cIMPACT-NOW update 8, key recommendations include: (1) Brain-invasive but otherwise benign (BIOB) meningiomas should not be graded without molecular data; (2) Borderline morphological cases should undergo molecular testing, with broader testing advised in select scenarios; (3) Histologically low-grade or borderline tumors with chromosome 1p deletion and concurrent 22q deletion/NF2 oncogenic variant should be classified as CNS WHO grade 2 unless grade 3 markers are present, though routine 1p testing in all low-grade cases is not advised; (4) Insufficient data currently limit recomme...
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Reply
Neetu Soni, Manish Ora, Girish Bathla, and Amit Agarwal

We thank you for your insightful and valuable comments on our recent review article, "Meningioma: Molecular Updates from the 2021 World Health Organization Classification of CNS Tumors and Imaging Correlates," particularly regarding recent updates not addressed in our original publication.
The 2021 WHO Classification of Central Nervous System Tumors ("CNS5") introduced key molecular markers, including TERT promoter mutations and homozygous CDKN2A/B deletions, as criteria for CNS WHO grade 3, recognizing their association with increased recurrence risk.1 We appreciate your emphasis on cIMPACT-NOW Update 8 and the growing role of DNA methylation-based classifiers, reflecting the evolving landscape of meningioma classification and risk stratification.2, 3
Based on morphology, WHO criteria, and cIMPACT-NOW update 8, key recommendations include: (1) Brain-invasive but otherwise benign (BIOB) meningiomas should not be graded without molecular data; (2) Borderline morphological cases should undergo molecular testing, with broader testing advised in select scenarios; (3) Histologically low-grade or borderline tumors with chromosome 1p deletion and concurrent 22q deletion/NF2 oncogenic variant should be classified as CNS WHO grade 2 unless grade 3 markers are present, though routine 1p testing in all low-grade cases is not advised; (4) Insufficient data currently limit recommendations for H3K27me3 status, isolated gene variants, and hemizygous CDKN2A/B deletions. These chromosomal alterations correlate with higher recurrence risk, even without atypical histology. As meningioma prognostication advances, these recommendations guide neuropathologists between CNS5 and CNS6 toward more consistent application of emerging data in patient care.2
Meningiomas demonstrate significant clinical and biological heterogeneity. DNA methylation-based classifiers stratify meningiomas into discrete molecular groups (immunogenic, benign NF2-wildtype, hypermetabolic, and proliferative) with distinct biological behavior and demonstrate superior prognostic value over WHO 2021 grading criteria. The stratification into distinct biological and prognostic groups has profound implications for surveillance strategies and treatment decisions.4, 5 However, limited availability and slow turnaround remain major challenges of DNA methylation profiling. Emerging metabolic profiling also shows promise; elevated N6-trimethyllysine is associated with earlier recurrence, particularly in WHO grade 2 and hypermetabolic meningiomas.6 Additionally, proliferative subtypes show limited response to adjuvant radiotherapy, whereas immunogenic and NF2-wildtype tumors respond favorably, supporting risk-adapted surveillance and treatment strategies.7
We fully agree that integrating molecular data into clinical decision-making is essential. Neuroradiologists play a pivotal role by identifying high-risk imaging features, advancing radiogenomic modeling, guiding interventions, and advocating for molecular testing when imaging and histopathology are discordant.
References:
1. Louis DN, Perry A, Wesseling P, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro-oncology 2021;23:1231-1251
2. Sahm F, Aldape KD, Brastianos PK, et al. cIMPACT-NOW Update 8: Clarifications on molecular risk parameters and recommendations for WHO grading of meningiomas. Neuro-oncology 2025;27:319-330
3. Sahm F, Schrimpf D, Stichel D, et al. DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. The lancet oncology 2017;18:682-694
4. Landry AP, Wang JZ, Patil V, et al. Validation and next-generation update of a DNA methylation–based recurrence predictor for meningioma: A multicenter prospective study. Neuro-Oncology 2024:noae236
5. Landry AP, Wang JZ, Liu J, et al. Development and validation of a molecular classifier of meningiomas. Neuro-Oncology 2025:noae242
6. Landry AP, Wang JZ, Yefet LS, et al. Metabolic profiling of meningioma reveals novel subgroup-specific biologic insights and outcome dependencies. Neuro-Oncology 2025:noae281
7. Wang JZ, Patil V, Landry AP, et al. Molecular classification to refine surgical and radiotherapeutic decision-making in meningioma. Nature medicine 2024:1-11
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Competing Interests: None declared.
Published on: (20 April 2025)
Page navigation anchor for Beyond WHO Classification: The Case for Molecular Integration in Meningioma Imaging
Beyond WHO Classification: The Case for Molecular Integration in Meningioma Imaging
Ali Nabavizadeh, Associate Professor of Radiology, University of Pennsylvania
I read with interest the recent review by Soni et al, “Meningioma: Molecular Updates from the 2021 WHO Classification of CNS Tumors and Imaging Correlates(1). The authors provide a clear overview of histologic grading and emerging molecular insights. However, there are critical updates from cIMPACT-NOW Update 8 and recent studies that were not addressed and are essential for neuroradiologists aiming to stay current and contribute meaningfully to meningioma care.

First, cIMPACT-NOW Update 8 offers specific guidance on grading tumors that show benign histologic features but harbor high-risk molecular alterations. Notably, it proposes upgrading tumors with CNS WHO grade 1 morphology to grade 2 if combined 1p and 22q losses and/or NF2 variants are present(2). This underscores the importance of integrating chromosomal and molecular profiling into the risk assessment of meningiomas that appear histologically indolent.

Second, recent large-scale efforts have validated DNA methylation–based classifiers that outperform the 2021 WHO grading in predicting recurrence. These classifiers, now publicly available, stratify meningiomas into biologically and prognostically distinct groups—immunogenic, NF2-wildtype, hypermetabolic, and proliferative—with important implications for surveillance and treatment(3, 4).

Furthermore, recent metabolic profiling highlights that hypermetabolic and proliferative meningiomas harbor distinct metabolic signatures, such as N6-trimethyl...
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I read with interest the recent review by Soni et al, “Meningioma: Molecular Updates from the 2021 WHO Classification of CNS Tumors and Imaging Correlates(1). The authors provide a clear overview of histologic grading and emerging molecular insights. However, there are critical updates from cIMPACT-NOW Update 8 and recent studies that were not addressed and are essential for neuroradiologists aiming to stay current and contribute meaningfully to meningioma care.

First, cIMPACT-NOW Update 8 offers specific guidance on grading tumors that show benign histologic features but harbor high-risk molecular alterations. Notably, it proposes upgrading tumors with CNS WHO grade 1 morphology to grade 2 if combined 1p and 22q losses and/or NF2 variants are present(2). This underscores the importance of integrating chromosomal and molecular profiling into the risk assessment of meningiomas that appear histologically indolent.

Second, recent large-scale efforts have validated DNA methylation–based classifiers that outperform the 2021 WHO grading in predicting recurrence. These classifiers, now publicly available, stratify meningiomas into biologically and prognostically distinct groups—immunogenic, NF2-wildtype, hypermetabolic, and proliferative—with important implications for surveillance and treatment(3, 4).

Furthermore, recent metabolic profiling highlights that hypermetabolic and proliferative meningiomas harbor distinct metabolic signatures, such as N6-trimethyllysine, which correlate with outcomes (5). In addition, a recent study has shown that response to surgery and radiotherapy varies by molecular and metabolic subtype, and has the potential to meaningfully impact clinical decision making and treatment selection for patients (6).

These studies strongly support incorporating molecular data into treatment planning—a shift in which neuroradiologists should play an active role by identifying high-risk features, supporting radiogenomic modeling, and adopting advanced imaging protocols to guide biopsy, resection, and follow-up. In conclusion, while the AJNR review sets a strong foundation, future discussions must expand to include cIMPACT-NOW recommendations, methylation classifiers, and metabolic signatures. Neuroradiologists should be proactive not only in recognizing molecular imaging correlates but also in driving their clinical integration.

References

1. Soni N, Ora M, Bathla G, et al. Meningioma: Molecular Updates from the 2021 World Health Organization Classification of CNS Tumors and Imaging Correlates. AJNR Am J Neuroradiol. 2025;46(2):240–250. doi:10.3174/ajnr.A8368
2. Sahm F, Aldape KD, Brastianos PK, et al. cIMPACT-NOW update 8: Clarifications on molecular risk parameters and recommendations for WHO grading of meningiomas. Neuro Oncol. 2025;27(2):319–330.
3. Landry AP, Wang JZ, Patil V, et al. Validation and next-generation update of a DNA methylation–based recurrence predictor for meningioma: A multicenter prospective study. Neuro Oncol. 2024 Nov 6: noae236. doi: 10.1093/neuonc/noae236. Online ahead of print.
4. Landry AP, Wang JZ, Liu J, et al. Development and validation of a molecular classifier of meningiomas. Neuro Oncol. 2025 Jan 8:noae242. doi: 10.1093/neuonc/noae242. Online ahead of print.
5. Landry AP, Wang JZ, Yefet LS, et al. Metabolic profiling of meningioma reveals novel subgroup-specific biologic insights and outcome dependencies. Neuro Oncol
. 2025 Jan 24:noae281. doi: 10.1093/neuonc/noae281. Online ahead of print.
6. Wang JZ, Patil V, Landry AP, et al.Nature Medicine. Molecular classification to refine surgical and radiotherapeutic decision-making in meningioma. Nat Med. 2024;30:3173–3183.
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Competing Interests: None declared.