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WHO classification


Editorial Board Member: P.J. Cimino, M.D., Ph.D.
Deputy Editor-in-Chief: Chunyu Cai, M.D., Ph.D.
Maria Martinez-Lage, M.D.

Last author update: 16 June 2023
Last staff update: 14 October 2024

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PubMed Search: WHO classification CNS 2021

Maria Martinez-Lage, M.D.
Table of Contents
Definition / general | Major updates | WHO (2021) | Diagrams / tables | Grading | Additional references | Board review style question #1 | Board review style answer #1
Cite this page: Martinez-Lage M. WHO classification. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cnstumorwhoclassification.html. Accessed December 26th, 2024.
Definition / general
Major updates
  • 2021 WHO classification, 5th edition (WHO CNS5) summary
    • Builds upon the updated fourth edition published in 2016 and the subsequent recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) (Brain Pathol 2017;27:851, Acta Neuropathol 2017;133:1, Acta Neuropathol 2018;135:481, Acta Neuropathol 2018;135:639, Acta Neuropathol 2018;136:805, Acta Neuropathol 2019;137:683, Acta Neuropathol 2020;139:603, Brain Pathol 2020;30:844, Brain Pathol 2020;30:863)
    • This fifth edition incorporates major changes including further advancing the role of molecular information in the diagnosis of CNS neoplasms, introducing the concept of CNS WHO grade distinct from WHO grade, grading within tumor type, endorsing the use of Arabic numerals for grading instead of Roman numerals and defining new entities based on molecular and histological characteristics (Neuro Oncol 2021;23:1231)
    • Taxonomy maintains a hybrid approach including histological and molecular features with some entities requiring specific molecular changes for a diagnosis (e.g., IDH mutant gliomas), while others display a looser association with molecular signatures that are not necessary for a diagnosis (e.g., pleomorphic xanthoastrocytoma and BRAF alteration); for each tumor type, diagnostic criteria are enumerated and listed as essential or desirable
    • Grading within tumor type and the use of Arabic (rather than Roman numerals) are both introduced for the first time in CNS classification to move closer to the grading approach of non-CNS neoplasms; however, some idiosyncrasies remain based on historical knowledge and practices, in addition to the use of molecular signatures to determine grade in some cases, which further warrants the introduction and use of CNS WHO grade instead of WHO grade
    • Grading within types in gliomas implies the elimination of the term anaplastic, which was previously linked to grade in these tumors
    • Anatomic site modifiers that were previously part of a tumor name are removed to make nomenclature simpler and more consistent (e.g., chordoid glioma of the third ventricle is now simply chordoid glioma)
    • In addition to NOS (not otherwise specified), NEC (not elsewhere classified) is introduced
      • NOS: terminology to be used when molecular information is insufficient, either because testing cannot be fully performed or because the results don't fit within a defined category
      • NEC: terminology to be used when necessary testing has been performed and results are available but the results do not fit perfectly in a defined tumor type
    • Glial, glioneuronal and neuronal tumors are entirely restructured into 6 different families in a scheme that introduces a distinction between adult type and pediatric type tumors
      • Adult type diffuse gliomas
      • Pediatric type diffuse low grade gliomas
      • Pediatric type diffuse high grade gliomas
      • Circumscribed astrocytic gliomas
      • Glioneuronal and neuronal tumors
      • Ependymomas
    • Classification of common adult type diffuse gliomas is drastically simplified to include only 3 types (with grading within tumor for the first 2): astrocytoma, IDH mutant (grade 2, 3 or 4), oligodendroglioma, IDH mutant and 1p / 19q codeleted (grade 2 or 3) and glioblastoma, IDH wild type (grade 4)
      • Consequently, glioblastoma is a term exclusively reserved for IDH wild type tumors and the nomenclature for IDH mutant astrocytomas is astrocytoma, IDH mutant, CNS WHO grade 2, 3 or 4
    • Classification of medulloblastomas remains largely similar to the 2016 classification, maintaining the incorporation of molecularly defined entities that determine prognostic categories, while adding novel subtypes (4 subgroups of SHH tumors and 8 subgroups of non-WNT / non-SHH medulloblastomas)
    • Ependymomas are restructured using a combination of histopathological features, molecular signatures and anatomic site (supratentorial, posterior fossa and spinal)
    • New tumor types have been added, such as diffuse hemispheric glioma, H3 G34 mutant or CNS tumor with BCOR internal tandem duplication
      • Some newly recognized types are considered provisional (e.g., diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters or intracranial mesenchymal tumor, FET::CREB fusion positive) while some lesions that were introduced in 2016 are no longer provisional (e.g., diffuse leptomeningeal glioneuronal tumor)
    • Meningioma is considered a single type with 15 subtypes; grading is significantly changed - while chordoid meningioma and clear cell meningioma are still considered CNS WHO grade 2 based on morphology (pending larger studies), the criteria that define atypical (grade 2) or anaplastic (grade 3) meningiomas should be applied to rhabdoid and papillary meningioma instead of assigning grade 3 based on morphology alone; furthermore, molecular alterations can influence grade, as the presence of TERT promoter mutation or homozygous deletion of CDKN2A/B is considered sufficient for a designation of CNS WHO grade 3 in meningiomas
    • New types of mesenchymal neoplasms are included, such as CIC rearranged sarcoma; hemangiopericytoma is now fully retired and solitary fibrous tumor is used instead, as it aligns with the soft tissue nomenclature (the 3 tiered CNS grading scheme remains)
    • Paragangliomas are understood as involving cells from the autonomic nervous system, therefore, they are now included in the chapter with nerve tumors and are renamed cauda equina neuroendocrine tumor; melanotic schwannoma is a term that is considered inadequate to reflect the unique features of this lesion, therefore this tumor type is now called malignant melanotic nerve sheath tumor
    • Some major changes are introduced to the tumors of the sellar region
      • Adamantinomatous craniopharyngioma and papillary craniopharyngioma are now considered 2 different tumor types (rather than subtypes) given their distinct clinicopathological and molecular characteristics
      • Tumors of the neurohypophysis are now considered to belong to 1 group, as they may represent morphologic variations of the same tumor
      • Pituitary neuroendocrine tumor (PitNET) is a newly introduced term, accompanying pituitary adenoma (pituitary adenoma / pituitary neuroendocrine tumor)
      • A new tumor type, characteristic of infancy and associated with DICER1 alterations, is included (pituitary blastoma)
WHO (2021)







Diagrams / tables

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Key diagnostic genes, molecules, pathways

CNS WHO grades of selected types

Newly recognized WHO 2021 tumor types

Grading
  • Histological grading is still used based on morphology in many instances; however, in this classification, the presence of certain molecular alterations is incorporated in the grading algorithm
    • For example, IDH mutant astrocytomas can be designated as grade 4 based on histology (presence of microvascular proliferation or necrosis) or if there is a homozygous deletion CDKN2A/B independent of histological features
    • Similarly, glioblastoma, IDH wild type can now be diagnosed in the absence of the aforementioned microscopic features, if certain molecular alterations are present in a diffuse astrocytic glioma in adults (TERT promoter mutation, EGFR gene amplification or combined gain of entire chromosome 7 and loss of entire chromosome 10 [+7 / -10])
  • In the clinical setting, tumor grade remains a key factor influencing choice of therapy
Board review style question #1
Which of the following terms is the only acceptable diagnosis in the 2021 WHO classification of tumors of the central nervous system?

  1. Anaplastic astrocytoma, IDH mutant
  2. Anaplastic astrocytoma, IDH wild type
  3. Glioblastoma, IDH mutant
  4. Glioblastoma, IDH wild type
Board review style answer #1
D. Glioblastoma, IDH wild type. The 2021 CNS WHO classification simplifies the diagnosis of diffuse gliomas and reserves the term glioblastoma for IDH wild type tumors. Additionally, the term can now be used for infiltrating astrocytomas that lack the classic histological features of glioblastoma (microvascular proliferation and necrosis) but show certain molecular alterations (TERT promoter mutation, EGFR amplification or combined gain of chromosome 7 with loss of chromosome 10), which in the past could have been designated as anaplastic astrocytoma, IDH wild type. The new scheme also introduces grading within tumor type, so that the term anaplastic is eliminated from the diagnostic line for diffuse gliomas. A CNS WHO grade 3 tumor with IDH mutation and astrocytic identity would be correctly diagnosed as astrocytoma, IDH mutant, CNS WHO grade 3 (and no longer called anaplastic astrocytoma).

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Reference: WHO classification of CNS tumors
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