What is the current World Health Organization (WHO) classification of brain tumors including molecular signatures?

Current WHO Classification of Brain Tumors Including Molecular Signatures

The 2021 WHO Classification of Central Nervous System Tumors represents a major paradigm shift, incorporating molecular signatures alongside histological features to define tumor entities, with diffuse gliomas now divided into adult and pediatric types based on distinct molecular characteristics.

Major Changes in the 2021 WHO Classification

The 2021 WHO classification (5th edition) builds upon the 2016 classification (4th edition) that first introduced the concept of "integrated diagnoses" requiring molecular testing alongside histological assessment. Key changes include:

Adult-Type Diffuse Gliomas

• Now consolidated into three main types based on molecular features 1:

  1. Astrocytoma, IDH-mutant (WHO grades 2-4)

     • Characterized by IDH1/IDH2 mutations
     • Usually shows loss of nuclear ATRX expression and TP53 mutations
     • Lacks 1p/19q codeletion
     • Grade 4 replaces the former "glioblastoma, IDH-mutant" 2
     • CDKN2A/B homozygous deletion is a marker of WHO grade 4 2

  2. Oligodendroglioma, IDH-mutant and 1p/19q-codeleted (WHO grades 2-3)

     • Requires both IDH mutation and 1p/19q codeletion
     • Often has TERT promoter mutations, CIC and FUBP1 mutations 3

  3. Glioblastoma, IDH-wildtype (WHO grade 4)

     • Term "glioblastoma" now restricted to IDH-wildtype tumors 1
     • Molecular features include EGFR amplification, TERT promoter mutation, +7/-10 cytogenetic signature, and CDKN2A/B homozygous deletion 2
     • In patients >55 years with typical histology and non-midline location, immunonegativity for IDH1 R132H is sufficient for diagnosis 2

New Diffuse Glioma Entities

• Diffuse midline glioma, H3 K27M-mutant (WHO grade 4)

  • Located in thalamus, brainstem, or spinal cord
  • Defined by H3 K27M mutation and loss of nuclear K27-trimethylated histone H3 2

• H3.3 G34-mutant diffuse hemispheric glioma (WHO grade 4)

  • More common in younger patients (<50 years)
  • Characterized by H3.3 G34R/V mutations 2

Embryonal Tumors

• Medulloblastoma - now classified by molecular subgroups 2:

  1. WNT-activated
  2. SHH-activated (with or without TP53 mutation)
  3. Group 3
  4. Group 4

• Embryonal tumor with multilayered rosettes (ETMR), C19MC-altered

  • Defined by C19MC microRNA cluster amplification or fusion 2
  • Previously included tumors classified as ependymoblastoma, medulloepithelioma, and embryonal tumor with abundant neuropil and true rosettes

• Atypical teratoid/rhabdoid tumor (AT/RT)

  • Requires demonstration of inactivation of either SMARCB1 (INI1) or SMARCA4 (BRG1) genes 2, 4

Ependymomas

• Now classified based on integration of anatomical location, histopathology, and molecular alterations 5
• Ependymoma, RELA fusion-positive - a new entity accounting for ~70% of supratentorial pediatric ependymomas 2

Diagnostic Algorithm for Molecular Testing

1. Initial Assessment:

   • Immunohistochemistry for IDH1 R132H mutation
   • ATRX nuclear expression
   • Location assessment (midline vs. hemispheric)

2. For IDH1 R132H-negative diffuse gliomas:

   • If patient >55 years with typical glioblastoma histology and non-midline location: classify as IDH-wildtype glioblastoma
   • Otherwise: perform IDH1/IDH2 sequencing to detect non-canonical mutations 2

3. For IDH-wildtype diffuse gliomas without necrosis/microvascular proliferation:

   • Test for EGFR amplification, TERT promoter mutation, and +7/-10 cytogenetic signature
   • If positive for these molecular features: diagnose as IDH-wildtype glioblastoma 2

4. For midline gliomas:

   • Test for H3 K27M mutation and loss of H3K27me3
   • If positive: diagnose as diffuse midline glioma, H3 K27M-mutant (WHO grade 4) 2

5. For young patients with IDH-wildtype hemispheric gliomas:

   • Test for H3.3 G34R/V mutations, especially if ATRX loss is present
   • If positive: diagnose as H3.3 G34-mutant diffuse hemispheric glioma 2

Clinical Implications

The molecular classification has significant implications for patient management:

• Prognosis: Different molecular entities have distinct natural histories and survival outcomes
• Treatment selection: Molecular features guide therapy decisions and eligibility for clinical trials
• Clinical trial design: More homogeneous patient populations based on molecular features
• Targeted therapies: Molecular alterations provide potential therapeutic targets

Common Pitfalls to Avoid

1. Inadequate tissue sampling: Ensure sufficient tumor tissue is obtained for both histological and molecular analyses
2. Relying solely on histology: Morphologically similar tumors may have different molecular features and clinical behaviors
3. Incomplete molecular testing: Missing key molecular markers can lead to misclassification
4. Not preserving tissue: When possible, cryopreserve some tumor tissue for molecular assessments requiring high-quality DNA/RNA 2
5. Overlooking location: Tumor location is important for interpreting molecular findings, especially for midline gliomas

The integration of molecular parameters with histology provides more accurate diagnoses, better prognostication, and improved guidance for therapeutic decisions in patients with brain tumors.