Novel, improved grading system(s) for IDH-mutant astrocytic gliomas

Area of Science:

• Neuro-oncology
• Molecular Pathology
• Cancer Genomics

Background:

• The 2016 WHO classification of CNS tumors introduced IDH-mutant status as a primary criterion for astrocytic gliomas.
• Current grading relies on histological features established before the significance of IDH status was recognized, leading to blurred prognostic distinctions between grades II and III.
• IDH-mutant glioblastoma (GBM_IDHmut) retains a significantly worse prognosis compared to lower-grade IDH-mutant astrocytomas.

Purpose of the Study:

• To develop prognostically significant grading strategies for IDH-mutant astrocytic gliomas in the context of the IDH era.
• To integrate molecular, morphological, and clinical data for improved tumor grading.
• To validate novel grading algorithms against existing WHO criteria.

Main Methods:

• A discovery cohort of 211 IDH-mutant astrocytic gliomas (excluding 1p/19q codeletion) underwent histological review, image analysis, and DNA methylation/copy number variation (CNV) profiling.
• Algorithms for automated CNV analysis and grading based on prognostic parameters were developed.
• Performance validation was conducted using three independent cohorts (108, 154, and 224 tumors).

Main Results:

• CDKN2A/B homozygous deletion emerged as the most significant prognostic factor for overall survival (OS), followed by necrosis and total CNV count.
• Mitotic count, a key WHO grading parameter, showed only minor prognostic influence in this cohort.
• Two novel grading models, utilizing the most relevant OS parameters, demonstrated significantly superior performance compared to WHO grading in both discovery and validation sets.

Conclusions:

• Novel grading algorithms based on molecular and clinical data offer improved prognostic accuracy for IDH-mutant astrocytic gliomas.
• These revised grading approaches address limitations of the current WHO classification in the IDH era.
• The proposed algorithms warrant consideration for future WHO classification criteria for diffuse astrocytic tumors.