cIMPACT-NOW update 12: Refining Pathology-based Risk Stratification and Grading for IDH-mutant Gliomas

Area of Science:

• Neuro-oncology
• Pathology
• Genetics

Background:

• Accurate risk stratification and grading of IDH-mutant gliomas are crucial for effective clinical management.
• Current grading systems require refinement, particularly at the boundary between CNS WHO grades 2 and 3.
• Understanding novel glioma subgroups and multidisciplinary treatment considerations is essential.

Purpose of the Study:

• To evaluate literature for improved pathology-based risk stratification and grading of IDH-mutant gliomas.
• To identify genetic alterations and molecular signatures associated with specific glioma grades.
• To propose refined criteria for CNS WHO grading, especially for IDH-mutant astrocytomas.

Main Methods:

• Literature review and analysis of genetic alterations in IDH-mutant gliomas.
• Evaluation of DNA methylation signatures (G-CIMP-low, A_IDH_HG).
• Assessment of specific genetic alterations including PDGFRA amplification, PIK3 mutations, EGFR amplification, MYCN amplification, and RB pathway alterations.

Main Results:

• PDGFRA amplification is linked to aggressive IDH-mutant astrocytomas (CNS WHO grade 4).
• Genetic alterations like PIK3 mutations, EGFR amplification, and RB pathway alterations suggest intermediate risk (CNS WHO grade 3).
• A mitotic count of ≥3 per 2.4 mm² is proposed as a CNS WHO grade 3 criterion; specific methylation signatures correlate with higher grades.

Conclusions:

• Implementing evidence-based criteria, including specific genetic markers and mitotic counts, will enhance risk stratification for IDH-mutant gliomas.
• Refined grading improves guidance for clinical decision-making in neuro-oncology.
• Further research may uncover grading improvements for oligodendrogliomas, though some grade 3 tumors show favorable outcomes.