CDKN2A/B status versus morphology in diagnosing WHO grade 4 IDH-mutated astrocytomas: what is the clinical relevance?

Purpose: In the 2021 WHO classification system for central nervous system tumors, the diffuse glioma subgroup IDH-mutated (IDHm) astrocytomas WHO grade 4 was introduced. The diagnosis can be based upon molecular or histopathological morphological criteria. Here we explore whether phenotype and survival of IDHm astrocytomas WHO grade 4 differed across the criteria used for diagnosis.

Methods: Patients with IDHm astrocytoma, WHO grade 4, were included from Sahlgrenska University Hospital and TCGA database. We created three subgroups based upon the criteria for diagnosis of WHO grade 4; (1) homozygous CDKN2A/B deletion; (2) morphological (necrosis and/or microvascular proliferation); (3) combined subgroup with both homozygous CDKN2A/B deletion and morphological grade 4 criteria.

Results: We included 90 patients (local cohort, n = 35, TCGA cohort, n = 55) with IDHm astrocytoma, WHO grade 4. The median survival was 4.1 years (95% CI 3.0-5.3). Survival was comparable when the diagnosis was based on homozygous CDKN2A/B deletion and on morphological WHO grade 4 criteria (5.2 vs. 5.3 years). However, in the combined subgroup, survival was significantly shorter (2.8 years, p = 0.006).

Conclusion: The different subgroups of IDHm astrocytoma WHO grade 4 share similar characteristics. Patients whose tumors exhibit combined criteria have worse prognosis.