In the 2021 classification, the term "Glioblastoma" is reserved exclusively for IDH-wildtype tumors. If a tumor is IDH-mutant and shows high-grade features, it is now called "Astrocytoma, IDH-mutant, WHO grade 4." This distinction is critical as survival and treatment responses differ significantly.

For an IDH-wildtype diffuse astrocytoma, the presence of EGFR amplification, TERT promoter mutation, or the gain of chromosome 7 with loss of chromosome 10 is sufficient to upgrade the diagnosis to Glioblastoma, WHO Grade 4. This ensures aggressive treatment is initiated even for "visually" low-grade lesions.