World Health Organization Classification of Tumors of the Central Nervous System 2021

World Health Organization Classification of Tumors of the Central Nervous System 2021

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System 1).

The newest revision of the WHO classification of tumors of the central nervous system, also known as WHO 5th edition, introduces substantial changes, especially within the glial tumor category, and separates adult-type and pediatric-type glial tumors into different categories for the first time. In addition, another category of glial tumors, “Circumscribed Astrocytic Gliomas” was also created. This group includes pilocytic astrocytoma, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordoid glioma, astroblastoma, and the highly nebulous novel entity high-grade astrocytoma with piloid features 2).

Although the shift toward the molecular classification is inevitable, the current WHO classification system has limitations. WHO CNS5 should be regarded as an intermediate stage toward further refined, better structured classification systems in the future 3)

Gliomas, glioneuronal tumors, and neuronal tumors:

Adult-type diffuse gliomas

  Astrocytoma IDH-mutant

  Oligodendroglioma IDH-mutant and 1p/19q-codeleted

  Glioblastoma IDH-wildtype

Pediatric-type diffuse low-grade gliomas

  Diffuse astrocytoma MYB or MYBL1 altered

  Angiocentric glioma

  Polymorphous low-grade neuroepithelial tumor of the young

  Diffuse low-grade glioma, MAPK pathway-altered

Pediatric-type diffuse high-grade gliomas

  Diffuse midline glioma, H3 K27-altered

  Diffuse hemispheric glioma, H3 G34-mutant

  Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype

  Infant-type hemispheric glioma

Circumscribed astrocytic gliomas

  Pilocytic astrocytoma

  High-grade astrocytoma with piloid features

  Pleomorphic xanthoastrocytoma

  Subependymal giant cell astrocytoma

  Chordoid glioma

  Astroblastoma MN1-altered

Glioneuronal and neuronal tumors


  Desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma

  Dysembryoplastic neuroepithelial tumor

  Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters

  Papillary glioneuronal tumor

  Rosette-forming glioneuronal tumor

  Myxoid glioneuronal tumor

  Diffuse leptomeningeal glioneuronal tumor


  Multinodular and vacuolating neuronal tumor

  Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease)

  Central neurocytoma

  Extraventricular neurocytoma

  Cerebellar liponeurocytoma


   Intracranial mesenchymal tumor, FET-CREB fusion-positive

   CIC-rearranged sarcoma

   Primary intracranial sarcoma, DICER1-mutant

   Ewing sarcoma


   Mesenchymal chondrosarcoma



   Chordoma (including poorly differentiated chordoma)

CNS lymphomas

Miscellaneous rare lymphomas in the CNS

Other low-grade B-cell lymphomas of the CNS

Metastases to the brain and spinal cord parenchyma

 Metastases to the meninges

Wen PY, Packer RJ. The 2021 WHO Classification of Tumors of the Central Nervous System: clinical implications. Neuro Oncol. 2021 Aug 2;23(8):1215-1217. doi: 10.1093/neuonc/noab120. PMID: 34185090; PMCID: PMC8328017.

Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021 Aug 2;23(8):1231-1251. doi: 10.1093/neuonc/noab106. PMID: 34185076; PMCID: PMC8328013.
Köy Y, Tihan T. Circumscribed astrocytic gliomas: Contribution of molecular analyses to histopathology diagnosis in the WHO CNS5 classification. Indian J Pathol Microbiol. 2022 May;65(Supplement):S33-S41. doi: 10.4103/ijpm.ijpm_1019_21. PMID: 35562132.
Ichimura K. [World Health Organization Classification of Central Nervous System Tumours, 5th Edition:Points of the Update and the Current Status]. No Shinkei Geka. 2023 Mar;51(2):349-363. Japanese. doi: 10.11477/mf.1436204751. PMID: 37055056.
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