GirishBathla, Neuroradiologist, Mayo Clinic, Roochester
10 May 2025
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
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