Classification and Grading of Central Nervous System Tumors According to the World Health Organization 5th Edition

Abstract

The World Health Organization (WHO) released the 5th edition of its classification of central nervous system (CNS) tumors in 2021. Advances in the landscape of molecular tumor pathophysiology prompted major revisions to the previous edition released in 2016, some of which were first introduced by the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy—Not Official WHO (cIMPACT-NOW). The 2021 classification system integrates newly gained molecular insights to guide changes in tumor taxonomy and nomenclature, introduces several new types of tumors, and expands the use of molecular testing for diagnosis and grading, with a particular impact on adult-type and pediatric-type gliomas, ependymomas, and embryonal tumors. These updates aim to promote clear and accurate diagnoses, yield more reliable prognostic information, and enable the selection of optimal therapies. Familiarity with these changes will be of great importance for clinicians involved in the management of CNS tumor patients.

Keywords

central nervous system - World Health Organization - neuropathology - brain tumor - classification

Publication History

Article published online:
10 November 2023

• References

• 1 Brat DJ, Aldape K, Colman H. et al. cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol 2020; 139 (03) 603-608
• 2 Brat DJ, Aldape K, Colman H. 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 2018; 136 (05) 805-810
• 3 Ellison DW, Aldape KD, Capper D. et al. cIMPACT-NOW update 7: advancing the molecular classification of ependymal tumors. Brain Pathol 2020; 30 (05) 863-866
• 4 Ellison DW, Hawkins C, Jones DTW. et al. cIMPACT-NOW update 4: diffuse gliomas characterized by MYB, MYBL1, or FGFR1 alterations or BRAF^V600E mutation. Acta Neuropathol 2019; 137 (04) 683-687
• 5 Louis DN, Giannini C, Capper D. et al. cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant. Acta Neuropathol 2018; 135 (04) 639-642
• 6 Louis DN, Wesseling P, Aldape K. 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 2020; 30 (04) 844-856
• 7 Louis DN, Wesseling P, Paulus W. et al. cIMPACT-NOW update 1: not otherwise specified (NOS) and not elsewhere classified (NEC). Acta Neuropathol 2018; 135 (03) 481-484
• 8 Ramani B, Gupta R, Wu J. et al. The immunohistochemical, DNA methylation, and chromosomal copy number profile of cauda equina paraganglioma is distinct from extra-spinal paraganglioma. Acta Neuropathol 2020; 140 (06) 907-917
• 9 Torres-Mora J, Dry S, Li X, Binder S, Amin M, Folpe AL. Malignant melanotic Schwannian tumor: a clinicopathologic, immunohistochemical, and gene expression profiling study of 40 cases, with a proposal for the reclassification of “melanotic schwannoma”. Am J Surg Pathol 2014; 38 (01) 94-105
• 10 Ellison DW, Onilude OE, Lindsey JC. et al; United Kingdom Children's Cancer Study Group Brain Tumour Committee. Beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee. J Clin Oncol 2005; 23 (31) 7951-7957
• 11 Weber DC, Wang Y, Miller R. et al. Long-term outcome of patients with spinal myxopapillary ependymoma: treatment results from the MD Anderson Cancer Center and institutions from the Rare Cancer Network. Neuro-oncol 2015; 17 (04) 588-595
• 12 Lee JC, Sharifai N, Dahiya S. et al. Clinicopathologic features of anaplastic myxopapillary ependymomas. Brain Pathol 2019; 29 (01) 75-84
• 13 Brat DJ, Verhaak RG, Aldape KD. et al; Cancer Genome Atlas Research Network. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 2015; 372 (26) 2481-2498
• 14 Louis DN, Perry A, Burger P. et al; International Society of Neuropathology–Haarlem. International Society of Neuropathology–Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol 2014; 24 (05) 429-435
• 15 Bracamonte E, Gibson BA, Klein R, Krupinski EA, Weinstein RS. Communicating uncertainty in surgical pathology reports: a survey of staff physicians and residents at an academic medical center. Acad Pathol 2016; 3: 2374289516659079
• 16 Tanboon J, Williams EA, Louis DN. The diagnostic use of immunohistochemical surrogates for signature molecular genetic alterations in gliomas. J Neuropathol Exp Neurol 2016; 75 (01) 4-18
• 17 Gillet E, Alentorn A, Doukouré B. et al. TP53 and p53 statuses and their clinical impact in diffuse low grade gliomas. J Neurooncol 2014; 118 (01) 131-139
• 18 Takami H, Yoshida A, Fukushima S. et al. Revisiting TP53 mutations and immunohistochemistry – a comparative study in 157 diffuse gliomas. Brain Pathol 2015; 25 (03) 256-265
• 19 Purkait S, Miller CA, Kumar A. et al. ATRX in diffuse gliomas with its mosaic/heterogeneous expression in a subset. Brain Pathol 2017; 27 (02) 138-145
• 20 Ball MK, Kollmeyer TM, Praska CE. et al. Frequency of false-positive FISH 1p/19q codeletion in adult diffuse astrocytic gliomas. Neurooncol Adv 2020; 2 (01) vdaa109
• 21 Ballester LY, Huse JT, Tang G, Fuller GN. Molecular classification of adult diffuse gliomas: conflicting IDH1/IDH2, ATRX, and 1p/19q results. Hum Pathol 2017; 69: 15-22
• 22 Sahm F, Schrimpf D, Jones DT. et al. Next-generation sequencing in routine brain tumor diagnostics enables an integrated diagnosis and identifies actionable targets. Acta Neuropathol 2016; 131 (06) 903-910
• 23 Carter JH, McNulty SN, Cimino PJ. et al. Targeted next-generation sequencing in molecular subtyping of lower-grade diffuse gliomas: application of the World Health Organization's 2016 revised criteria for central nervous system tumors. J Mol Diagn 2017; 19 (02) 328-337
• 24 Synhaeve NE, van den Bent MJ, French PJ. et al. Clinical evaluation of a dedicated next generation sequencing panel for routine glioma diagnostics. Acta Neuropathol Commun 2018; 6 (01) 126
• 25 Cimino PJ, Bredemeyer A, Abel HJ, Duncavage EJ. A wide spectrum of EGFR mutations in glioblastoma is detected by a single clinical oncology targeted next-generation sequencing panel. Exp Mol Pathol 2015; 98 (03) 568-573
• 26 Cimino PJ, McFerrin L, Wirsching HG. et al. Copy number profiling across glioblastoma populations has implications for clinical trial design. Neuro-oncol 2018; 20 (10) 1368-1373
• 27 Slocum CC, Park HJ, Baek I. et al. Towards a single-assay approach: a combined DNA/RNA sequencing panel eliminates diagnostic redundancy and detects clinically-relevant fusions in neuropathology. Acta Neuropathol Commun 2022; 10 (01) 167
• 28 Torre M, Vasudevaraja V, Serrano J. et al. Molecular and clinicopathologic features of gliomas harboring NTRK fusions. Acta Neuropathol Commun 2020; 8 (01) 107
• 29 Nikiforova MN, Wald AI, Melan MA. et al. Targeted next-generation sequencing panel (GlioSeq) provides comprehensive genetic profiling of central nervous system tumors. Neuro-oncol 2016; 18 (03) 379-387
• 30 Capper D, Jones DTW, Sill M. et al. DNA methylation-based classification of central nervous system tumours. Nature 2018; 555 (7697) 469-474
• 31 Pratt D, Sahm F, Aldape K. DNA methylation profiling as a model for discovery and precision diagnostics in neuro-oncology. Neuro-oncol 2021; 23 (23, suppl 5): S16-S29
• 32 Wu Z, Abdullaev Z, Pratt D. et al. Impact of the methylation classifier and ancillary methods on CNS tumor diagnostics. Neuro-oncol 2022; 24 (04) 571-581
• 33 Cimino PJ, Ketchum C, Turakulov R. et al. Expanded analysis of high-grade astrocytoma with piloid features identifies an epigenetically and clinically distinct subtype associated with neurofibromatosis type 1. Acta Neuropathol 2023; 145 (01) 71-82
• 34 Reinhardt A, Stichel D, Schrimpf D. 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 2018; 136 (02) 273-291
• 35 Deng MY, Sill M, Sturm D. et al. Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters (DGONC) - a molecularly defined glioneuronal CNS tumour class displaying recurrent monosomy 14. Neuropathol Appl Neurobiol 2020; 46 (05) 422-430
• 36 Pickles JC, Mankad K, Aizpurua M. et al. A case series of diffuse glioneuronal tumours with oligodendroglioma-like features and nuclear clusters (DGONC). Neuropathol Appl Neurobiol 2021; 47 (03) 464-467