What is the 2023 World Health Organization (WHO) classification of Central Nervous System (CNS) tumors?

2023 WHO Classification of Central Nervous System Tumors

The 2021 WHO Classification of Central Nervous System (CNS) Tumors (5th Edition) represents a significant paradigm shift in CNS tumor classification, emphasizing molecular characteristics alongside histological features for more accurate diagnosis, prognosis, and treatment planning. 1, 2

Major Changes in the 5th Edition (CNS5)

Structural and Nomenclature Changes

• Tumor classification now focuses on tumor type alone, with grading defined within each tumor type rather than across types 1
• Arabic numerals replace Roman numerals for grading (e.g., CNS WHO grade 4 instead of WHO grade IV) 3
• Terms "entity" and "variant" have been replaced by "type" and "subtype" 4
• Introduction of "layered reporting" and "integrated diagnosis" combining histological and molecular parameters 4

Adult-Type Diffuse Gliomas

• Simplified into three main groups based on IDH and 1p/19q status 2:
  1. Oligodendroglioma, IDH-mutant and 1p19q codeleted (CNS WHO grade 2 or 3)
  2. Astrocytoma, IDH-mutant (CNS WHO grades 2-4)
  3. Glioblastoma, IDH-wildtype (CNS WHO grade 4)
• Former IDH-mutant glioblastomas are now classified as astrocytoma, IDH-mutant, CNS WHO grade 4 3
• Diffuse gliomas without IDH mutation but with molecular features of glioblastoma are classified as glioblastoma, IDH-wildtype 1

Pediatric-Type Diffuse Gliomas

• Now classified separately from adult-type gliomas 1, 2
• Four main types recognized 5:
  1. Diffuse hemispheric glioma, H3 G34-mutant
  2. Diffuse pediatric-type high-grade glioma, H3 wild-type and IDH wild-type
  3. Infant-type hemispheric glioma
  4. Diffuse midline glioma (DMG), H3 K27-altered (formerly H3 K27M-mutant) 3

Meningiomas

• Now classified as a single tumor type with molecular grading parameters 2
• Introduction of molecular biomarkers for grading: TERT promoter mutations and homozygous deletion of CDKN2A/B as markers for CNS WHO grade 3 5
• Rhabdoid and papillary meningiomas now stratified into grades 1-3 based on histological criteria rather than automatically assigned grade 3 5
• Recommendation to assign CNS WHO grade 2 for cases with CNS WHO grade 1 morphology but chromosomal arm 1p deletion in combination with 22q deletion and/or NF2 oncogenic variants 5

Ependymomas

• First-time classification based on integration of anatomical location, histopathology, and molecular alterations 2

Molecular Diagnostic Tools

• Endorsement of DNA methylation profiling for diagnosis of some tumor types/subtypes 4
• Multiple molecular characteristics now essential diagnostic criteria 6
• Recommended molecular testing methods include 6:
  • DNA and RNA next-generation sequencing
  • Methylome profiling
  • Select assays for single/limited target analyses
  • Immunohistochemistry
  • MGMT promoter methylation status analysis (especially for IDH-wildtype glioblastomas)

Targeted Therapy Considerations

• Molecular testing increasingly important for identifying potential therapeutic targets 5
• Common molecular alterations with therapeutic implications include:
  • BRAF alterations (especially BRAF::KIAA fusions)
  • NTRK fusions
  • MET fusions
  • FGFR alterations 5

Clinical Implications

• More objective and reproducible tumor classification based on molecular genetic alterations 2
• Better correlation between diagnosis and clinical behavior 1, 2
• Improved ability to offer individualized treatment options 2
• Enhanced capability to enroll homogeneous patient populations in clinical trials 2

Common Pitfalls and Caveats

• The current WHO classification system should be considered an intermediate stage toward further refinement 1
• Molecular testing may not be universally available, potentially limiting implementation 6
• Interpretation of molecular findings requires integration with histological features 4
• Different databases may result in different interpretations of molecular alterations 5

The 2023 WHO Classification represents a significant evolution in CNS tumor diagnosis, emphasizing the integration of molecular and histological features for more precise diagnosis and treatment planning.