Abstract
A new edition of the WHO classification of tumours of the CNS was published in 2021. Although the previous edition of this classification was published just 5 years earlier, in 2016, rapid advances in our understanding of the molecular underpinnings of CNS tumours, including the diversity of clinically relevant molecular types and subtypes, necessitated a new classification system. Compared with the 2016 scheme, the new classification incorporates even more molecular alterations into the diagnosis of many tumours and reorganizes gliomas into adult-type diffuse gliomas, paediatric-type diffuse low-grade and high-grade gliomas, circumscribed astrocytic gliomas, and ependymal tumours. A number of new entities are incorporated into the 2021 classification, especially tumours that preferentially or exclusively arise in the paediatric population. Such a substantial revision of the WHO scheme will have major implications for the diagnosis and treatment of patients with CNS tumours. In this Perspective, we summarize the main changes in the classification of diffuse and circumscribed gliomas, ependymomas, embryonal tumours and meningiomas, and discuss how each change will influence post-surgical treatment, clinical trial enrolment and cooperative studies. Although the 2021 WHO classification of CNS tumours is a major conceptual advance, its implementation on a routine clinical basis presents some challenges that will require innovative solutions.
Key points
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The new 2021 WHO classification of CNS tumours has further integrated molecular data into the typing, subtyping and grading of major tumour groups.
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Such integration especially affects the classification of adult-type and paediatric-type diffuse gliomas, circumscribed astrocytic gliomas, ependymomas, embryonal tumours and (to a lesser extent) meningiomas.
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The strengths of this revised scheme include more accurate conceptualization of CNS tumour types, improved diagnostic accuracy and more reliable prognostic subgroups.
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Challenges include greater need for faster, more widespread molecular testing, more issues with third party payor reimbursement, and greater difficulty in finding and enrolling patients who are eligible for specific clinical trials.
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References
Louis, D. N. et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 23, 1231–1251 (2021). A comprehensive summary of the new WHO classification of CNS tumours, with an emphasis on new tumour types.
WHO Classification of Tumours Editorial Board. WHO Classification of Tumours: Central Nervous System Tumours, 5th edn (WHO, 2021). The new WHO classification of CNS tumours, the largest and most molecularly driven classification to date.
Kleihues, P., Burger, P. C. & Scheithauer, B. W. The new WHO classification of brain tumours. Brain Pathol. 3, 255–268 (1993).
Louis, D. N. et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 131, 803–820 (2016).
Brat, D. J. et al. cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol. 139, 603–608 (2020).
Brat, D. J. et al. cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”. Acta Neuropathol. 136, 805–810 (2018).
Ellison, D. W. et al. cIMPACT-NOW update 7: advancing the molecular classification of ependymal tumors. Brain Pathol. 30, 863–866 (2020).
Ellison, D. W. et al. cIMPACT-NOW update 4: diffuse gliomas characterized by MYB, MYBL1, or FGFR1 alterations or BRAF(V600E) mutation. Acta Neuropathol. 137, 683–687 (2019).
Louis, D. N. et al. Announcing cIMPACT-NOW: the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy. Acta Neuropathol. 133, 1–3 (2017).
Louis, D. N. et al. cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant. Acta Neuropathol. 135, 639–642 (2018).
Louis, D. N. et al. cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading. Brain Pathol. 30, 844–856 (2020).
Louis, D. N. et al. cIMPACT-NOW update 1: not otherwise specified (NOS) and not elsewhere classified (NEC). Acta Neuropathol. 135, 481–484 (2018).
Hinrichs, B. H. et al. Farewell to GBM-O: genomic and transcriptomic profiling of glioblastoma with oligodendroglioma component reveals distinct molecular subgroups. Acta Neuropathol. Commun. 4, 4 (2016).
Sahm, F. et al. Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma. Acta Neuropathol. 128, 551–559 (2014).
Ostrom, Q. T. et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2013–2017. Neuro Oncol. 22, iv1–iv96 (2020).
Jenkins, R. B. et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res. 66, 9852–9861 (2006).
Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).
Horbinski, C. What do we know about IDH1/2 mutations so far, and how do we use it? Acta Neuropathol. 125, 621–636 (2013).
Brat, D. J. et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N. Engl. J. Med. 372, 2481–2498 (2015). A seminal paper summarizing The Cancer Genome Atlas data on WHO grade 2–3 adult-type diffuse gliomas, which provided the basis for classifiying those tumours by IDH mutation status and codeletion of chromosomes 1p and 19q.
Appay, R. et al. CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas. Neuro Oncol. 21, 1519–1528 (2019).
Pollack, I. F. et al. IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children’s Oncology Group. Childs Nerv. Syst. 27, 87–94 (2011).
Ramkissoon, L. A. et al. Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc. Natl Acad. Sci. USA 110, 8188–8193 (2013).
Labussiere, M. et al. All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2. Neurology 74, 1886–1890 (2010).
Yip, S. et al. Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. J. Pathol. 226, 7–16 (2012).
Horbinski, C. et al. Isocitrate dehydrogenase 1 analysis differentiates gangliogliomas from infiltrative gliomas. Brain Pathol. 21, 564–574 (2011).
Fontebasso, A. M. et al. Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. Acta Neuropathol. 125, 659–669 (2013).
Khuong-Quang, D. A. et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 124, 439–447 (2012).
Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).
Sturm, D. et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22, 425–437 (2012).
Eckel-Passow, J. E. et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N. Engl. J. Med. 372, 2499–2508 (2015). Along with ref. 20, this paper provides the molecular framework for classifying diffusely infiltrative gliomas in adults.
Shirahata, M. et al. Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathol. 136, 153–166 (2018).
Horbinski, C. et al. The medical necessity of advanced molecular testing in the diagnosis and treatment of brain tumor patients. Neuro Oncol. 21, 1498–1508 (2019).
Wen, P. Y. & Packer, R. J. The 2021 WHO Classification of Tumors of the Central Nervous System: clinical implications. Neuro Oncol. 23, 1215–1217 (2021).
Bell, E. H. et al. Comprehensive genomic analysis in NRG oncology/RTOG 9802: a phase III trial of radiation versus radiation plus procarbazine, lomustine (CCNU), and vincristine in high-risk low-grade glioma. J. Clin. Oncol. 38, 3407–3417 (2020).
van den Bent, M. J. et al. Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 22, 813–823 (2021).
Tesileanu, C. M. S. et al. Temozolomide and radiotherapy versus radiotherapy alone in patients with glioblastoma, IDH-wildtype: post hoc analysis of the EORTC randomized phase 3 CATNON trial. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-21-4283 (2022).
Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005). A clinical trial that established the combination of radiotherapy and temozolomide for high-grade infiltrative gliomas, a regimen that remains standard-of-care to this day.
Weller, M. et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat. Rev. Clin. Oncol. 18, 170–186 (2021).
Stupp, R. et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318, 2306–2316 (2017). A clinical trial that established electromagnetic tumour-treating fields as a therapeutic option in patients with IDH-wildtype glioblastoma.
Armstrong, T. S. et al. Glioma patient-reported outcome assessment in clinical care and research: a Response Assessment in Neuro-Oncology collaborative report. Lancet Oncol. 21, e97–e103 (2020).
van den Bent, M. J. et al. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet 390, 1645–1653 (2017).
van den Bent, M. J. et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J. Clin. Oncol. 31, 344–350 (2013).
Cairncross, G. et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J. Clin. Oncol. 31, 337–343 (2013).
Buckner, J. C. et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N. Engl. J. Med. 374, 1344–1355 (2016).
National Comprehensive Cancer Network. NCCN Guidelines: Central Nervous System Cancers. Version 2.2021 (NCNN, 2021).
US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT00887146 (2022).
Ryall, S. et al. Integrated molecular and clinical analysis of 1,000 pediatric low-grade gliomas. Cancer Cell 37, 569–583.e5 (2020).
Clarke, M. et al. Infant high-grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes. Cancer Discov. 10, 942–963 (2020).
Drilon, A. et al. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 7, 400–409 (2017).
Ziegler, D. S. et al. Brief report: potent clinical and radiological response to larotrectinib in TRK fusion-driven high-grade glioma. Br. J. Cancer 119, 693–696 (2018).
Jones, D. T. W. et al. Pediatric low-grade gliomas: next biologically driven steps. Neuro Oncol. 20, 160–173 (2018).
Fangusaro, J. et al. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 20, 1011–1022 (2019).
Qaddoumi, I. et al. Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol. 131, 833–845 (2016).
US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02684058 (2022).
US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04201457 (2022).
US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02124772 (2021).
US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT01089101 (2022).
US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT05180825 (2022).
US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02285439 (2022).
US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03155620 (2022).
US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT01748149 (2022).
US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT05222165 (2022).
Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).
Chen, C. C. L. et al. Histone H3.3G34-mutant interneuron progenitors co-opt PDGFRA for gliomagenesis. Cell 183, 1617–1633.e22 (2020).
Jakacki, R. I. et al. Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children’s Oncology Group ACNS0423 study. Neuro Oncol. 18, 1442–1450 (2016).
Cohen, K. J. et al. Temozolomide in the treatment of high-grade gliomas in children: a report from the Children’s Oncology Group. Neuro Oncol. 13, 317–323 (2011).
Mançano, B. M. et al. A unique case report of infant-type hemispheric glioma (gliosarcoma subtype) with TPR-NTRK1 fusion treated with larotrectinib. Pathobiology 89, 178–185 (2022).
Reinhardt, A. et al. Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. Acta Neuropathol. 136, 273–291 (2018).
Karajannis, M. A. et al. Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro Oncol. 16, 1408–1416 (2014).
US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03871257 (2022).
Bouffet, E. et al. Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J. Clin. Oncol. 30, 1358–1363 (2012).
Ater, J. L. et al. Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children’s Oncology Group. J. Clin. Oncol. 30, 2641–2647 (2012).
Schindler, G. et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 121, 397–405 (2011).
Kaley, T. et al. BRAF inhibition in BRAF(V600)-mutant gliomas: results from the VE-BASKET study. J. Clin. Oncol. 36, 3477–3484 (2018).
Wen, P. Y. et al. Dabrafenib plus trametinib in patients with BRAF(V600E)-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet Oncol. 23, 53–64 (2022).
Packer, R. J. et al. Pediatric low-grade gliomas: implications of the biologic era. Neuro Oncol. 19, 750–761 (2017).
Neumann, J. E. et al. Molecular characterization of histopathological ependymoma variants. Acta Neuropathol. 139, 305–318 (2020).
Pajtler, K. W. et al. Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27, 728–743 (2015).
Arabzade, A. et al. ZFTA-RELA dictates oncogenic transcriptional programs to drive aggressive supratentorial ependymoma. Cancer Discov. 11, 2200–2215 (2021).
Ramaswamy, V. et al. Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis. J. Clin. Oncol. 34, 2468–2477 (2016).
Ghasemi, D. R. et al. MYCN amplification drives an aggressive form of spinal ependymoma. Acta Neuropathol. 138, 1075–1089 (2019).
Bandopadhayay, P. et al. Myxopapillary ependymomas in children: imaging, treatment and outcomes. J. Neuro Oncol. 126, 165–174 (2016).
Abdallah, A. et al. Long-term surgical resection outcomes of pediatric myxopapillary ependymoma: experience of two centers and brief literature review. World Neurosurg. 136, e245–e261 (2020).
Pajtler, K. W. et al. The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol. 133, 5–12 (2017).
Panwalkar, P. et al. Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome. Acta Neuropathol. 134, 705–714 (2017).
Massimino, M. et al. Treatment and outcome of intracranial ependymoma after first relapse in the 2nd AIEOP protocol. Neuro Oncol. 24, 467–479 (2021).
Thomas, C. et al. TERT promoter mutation and chromosome 6 loss define a high-risk subtype of ependymoma evolving from posterior fossa subependymoma. Acta Neuropathol. 141, 959–970 (2021).
Baroni, L. V. et al. Ultra high-risk PFA ependymoma is characterized by loss of chromosome 6q. Neuro Oncol. 23, 1360–1370 (2021).
Macdonald, S. M. et al. Proton radiotherapy for pediatric central nervous system ependymoma: clinical outcomes for 70 patients. Neuro Oncol. 15, 1552–1559 (2013).
Saleh, A. H. et al. The biology of ependymomas and emerging novel therapies. Nat. Rev. Cancer 22, 208–222 (2022).
Ruda, R., Bruno, F., Pellerino, A. & Soffietti, R. Ependymoma: evaluation and management updates. Curr. Oncol. Rep. https://doi.org/10.1007/s11912-022-01260-w (2022).
Le Rhun, E. et al. Prospective validation of a new imaging scorecard to assess leptomeningeal metastasis: a joint EORTC BTG and RANO effort. Neuro Oncol. https://doi.org/10.1093/neuonc/noac043 (2022).
Kukreja, S., Ambekar, S., Sin, A. H. & Nanda, A. Cumulative survival analysis of patients with spinal myxopapillary ependymomas in the first 2 decades of life. J. Neurosurg. Pediatr. 13, 400–407 (2014).
Zhukova, N. et al. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J. Clin. Oncol. 31, 2927–2935 (2013).
Gajjar, A. et al. Outcomes by clinical and molecular features in children with medulloblastoma treated with risk-adapted therapy: results of an international phase III trial (SJMB03). J. Clin. Oncol. 39, 822–835 (2021).
Coltin, H. et al. Subgroup and subtype-specific outcomes in adult medulloblastoma. Acta Neuropathol. 142, 859–871 (2021).
Goschzik, T. et al. Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial. Lancet Oncol. 19, 1602–1616 (2018).
Sharma, T. et al. Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of group 3 and group 4 subtypes. Acta Neuropathol. 138, 309–326 (2019).
Johann, P. D. et al. Cribriform neuroepithelial tumor: molecular characterization of a SMARCB1-deficient non-rhabdoid tumor with favorable long-term outcome. Brain Pathol. 27, 411–418 (2017).
Cotter, J. A. & Judkins, A. R. Evaluation and diagnosis of central nervous system embryonal tumors (non-medulloblastoma). Pediatr. Dev. Pathol. 25, 34–45 (2022).
Sturm, D. et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164, 1060–1072 (2016).
Ferris, S. P. et al. High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication– a comprehensive clinical, radiographic, pathologic, and genomic analysis. Brain Pathol. 30, 46–62 (2020).
Kool, M. et al. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS ONE 3, e3088 (2008).
Mynarek, M. et al. Nonmetastatic medulloblastoma of early childhood: results from the prospective clinical trial HIT-2000 and an extended validation cohort. J. Clin. Oncol. 38, 2028–2040 (2020).
Clifford, S. C. et al. Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: results from the multi-center HIT-SIOP-PNET4 clinical trial. Oncotarget 6, 38827–38839 (2015).
US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02724579 (2022).
Ramaswamy, V. et al. Risk stratification of childhood medulloblastoma in the molecular era: the current consensus. Acta Neuropathol. 131, 821–831 (2016).
Michalski, J. M. et al. Children’s Oncology Group phase III trial of reduced-dose and reduced-volume radiotherapy with chemotherapy for newly diagnosed average-risk medulloblastoma. J. Clin. Oncol. 39, 2685–2697 (2021).
Packer, R. J. et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J. Clin. Oncol. 24, 4202–4208 (2006).
Leary, S. E. S. et al. Efficacy of carboplatin and isotretinoin in children with high-risk medulloblastoma: a randomized clinical trial from the Children’s Oncology Group. JAMA Oncol. 7, 1313–1321 (2021).
Rutkowski, S. et al. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N. Engl. J. Med. 352, 978–986 (2005).
Lafay-Cousin, L. et al. Phase II study of nonmetastatic desmoplastic medulloblastoma in children younger than 4 years of age: a report of the Children’s Oncology Group (ACNS1221). J. Clin. Oncol. 38, 223–231 (2020).
Lafay-Cousin, L. & Dufour, C. High-dose chemotherapy in children with newly diagnosed medulloblastoma. Cancers 14, 837 (2022).
Lafay-Cousin, L. et al. Clinical, pathological, and molecular characterization of infant medulloblastomas treated with sequential high-dose chemotherapy. Pediatr. Blood Cancer 63, 1527–1534 (2016).
Robinson, G. W. et al. Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial. Lancet Oncol. 19, 768–784 (2018).
Hovestadt, V. et al. Medulloblastomics revisited: biological and clinical insights from thousands of patients. Nat. Rev. Cancer 20, 42–56 (2020).
Maas, S. L. N. et al. Integrated molecular-morphologic meningioma classification: a multicenter retrospective analysis, retrospectively and prospectively validated. J. Clin. Oncol. 39, 3839–3852 (2021).
Sahm, F. et al. TERT promoter mutations and risk of recurrence in meningioma. J. Natl Cancer Inst. 108, djv377 (2016).
Driver, J. et al. A molecularly integrated grade for meningioma. Neuro Oncol. 24, 796–808 (2021).
Nassiri, F. et al. A clinically applicable integrative molecular classification of meningiomas. Nature 597, 119–125 (2021).
Nassiri, F. et al. DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management. Neuro Oncol. 21, 901–910 (2019).
Sahm, F. et al. DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol. 18, 682–694 (2017).
Choudhury, A. et al. Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities. Nat. Genet. 54, 649–659 (2022).
Brastianos, P. K. et al. Advances in multidisciplinary therapy for meningiomas. Neuro Oncol. 21, i18–i31 (2019).
Rogers, C. L. et al. High-risk meningioma: initial outcomes from NRG Oncology/RTOG 0539. Int. J. Radiat. Oncol. Biol. Phys. 106, 790–799 (2020).
Ruda, R. et al. EANO guidelines for the diagnosis and treatment of ependymal tumors. Neuro Oncol. 20, 445–456 (2018).
Merchant, T. E. et al. Conformal radiation therapy for pediatric ependymoma, chemotherapy for incompletely resected ependymoma, and observation for completely resected, supratentorial ependymoma. J. Clin. Oncol. 37, 974–983 (2019).
Capper, D. et al. DNA methylation-based classification of central nervous system tumours. Nature 555, 469–474 (2018). A landmark study that demonstrated the ability of whole-genomic DNA methylation profilng to classify CNS tumours, including those that are difficult to classify by traditional microscopy and next-generation sequencing.
Acknowledgements
The authors thank N. Wadhwani for providing the paediatric neuropathology materials used to generate the representative photomicrographs included in the supplementary information of this manuscript. The authors thank L. Jennings, L. Santana dos Santos and P. Jamshidi for the copy number plots in Supplementary Fig. 2. C.H. was supported by grants R01NS102669, R01NS117104, R01NS118039, the Northwestern University P50CA221747 SPORE in Brain Tumour Research, and the Lou and Jean Malnati Brain Tumour Institute at Northwestern.
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C.H., R.J.P. and P.Y.W. researched data for the article, made a substantial contribution to discussion of content, wrote the article, and reviewed and edited the manuscript before submission. T.B. researched data for the article, wrote the article, and reviewed and edited the manuscript before submission.
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Glossary
- WHO grade
-
World Health Organization tumour grading system; the higher the grade, the greater the tumour malignancy.
- Anaplastic
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Old term referring to CNS WHO grade 3 tumours.
- Chromosome 1p/19q codeletion
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Unbalanced translocation leading to a hybrid 1p/19q chromosome that is subsequently lost; one of the hallmark molecular alterations in oligodendrogliomas.
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Horbinski, C., Berger, T., Packer, R.J. et al. Clinical implications of the 2021 edition of the WHO classification of central nervous system tumours. Nat Rev Neurol 18, 515–529 (2022). https://doi.org/10.1038/s41582-022-00679-w
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DOI: https://doi.org/10.1038/s41582-022-00679-w
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