The 2021 WHO classification in one paragraph
Until 2021, "glioblastoma" was a diagnosis made under the microscope, and it included both IDH-mutant and IDH-wildtype tumors. The 2021 WHO classification separated them. A grade 4 diffuse glioma without an IDH mutation is glioblastoma, IDH-wildtype. A grade 4 tumor with an IDH mutation is astrocytoma, IDH-mutant, grade 4, a different disease with a longer natural history. If you were diagnosed before 2021, or your report just says "glioblastoma", ask which one you have. Published survival figures and trial results from before 2021 often mix the two, which makes them look different from today's numbers.
| Marker | What it tells you | Changes first-line treatment? |
|---|---|---|
| IDH1/IDH2 | Defines the diagnosis: wildtype = glioblastoma; mutant = astrocytoma, IDH-mutant, grade 4 | Diagnosis and prognosis; some newer drugs only for IDH-mutant |
| MGMT promoter methylation | Predicts benefit from temozolomide; methylated tumors respond better | Expectations and trial stratification; drug still given |
| EGFR amplification, TERT promoter, +7/−10 | Make a lower-grade-looking IDH-wildtype glioma a glioblastoma | Label and prognosis; some targeted trials |
| CDKN2A/B deletion | Upgrades IDH-mutant astrocytoma to grade 4 | Prognosis |
| Ki-67 / MIB-1 | Proliferation index; higher = faster growth | No |
| H3 K27M | Diffuse midline glioma if positive | Yes: a targeted drug exists (US, 2025) |
IDH: the diagnosis-defining marker
IDH1 and IDH2 are metabolic enzymes. A mutation in one of them, found in a minority of grade 4 gliomas and mostly in younger patients, marks a tumor that grows more slowly and responds better to treatment. Testing is by immunohistochemistry for the common IDH1 R132H mutation, with sequencing if that is negative in a patient under about 55. If your report says "IDH-wildtype", the tumor has no mutation and the diagnosis is glioblastoma. If it says "IDH-mutant", you have the other disease, and some newer drugs (such as vorasidenib for lower-grade IDH-mutant gliomas) may become relevant.
MGMT promoter methylation: the treatment-predicting marker
MGMT is a DNA-repair enzyme that undoes the damage temozolomide causes. When the gene's promoter is methylated, the enzyme is switched off, and temozolomide works better. In the trial that established the standard of care, patients with methylated tumors lived a median of about 21.7 months with chemoradiation versus 12.7 months for unmethylated tumors. Methylation does not change whether temozolomide is given; nearly everyone receives it. It changes expectations, and it is used as a stratification factor in trials, so you will be asked for it repeatedly. Note that the test is not perfectly reproducible between labs, and results near the cut-off can be reported differently.
- 1Methylated promoterThe MGMT gene is switched off, so the repair enzyme is missing. Damage from temozolomide stays in the tumor DNA and the cell dies.
- 2Unmethylated promoterThe enzyme is active and removes the damage as fast as temozolomide causes it. The drug still helps, but less.
Schematic. Nearly all patients still receive temozolomide; the result changes expectations, not whether it is given.
EGFR, TERT, CDKN2A/B and the "molecular glioblastoma"
Under WHO 2021, an IDH-wildtype diffuse glioma that looks lower-grade under the microscope is still diagnosed as glioblastoma if it has EGFR amplification, a TERT promoter mutation, or the chromosome pattern +7/-10. CDKN2A/B deletion upgrades an IDH-mutant astrocytoma to grade 4. These markers matter for the label and the prognosis; at present they do not change first-line treatment, although several target-specific trials select patients by them.
Other things on the report
- Ki-67 or MIB-1: a proliferation index. Higher numbers mean faster growth; it is not used to choose treatment.
- H3 K27M: tested mainly in midline tumors; if positive the diagnosis is diffuse midline glioma, for which a targeted drug (dordaviprone) was approved in the United States in 2025.
- Extent of resection: not on the pathology report but on the post-operative MRI; ask for it in writing.
Which results change what you do next
IDH status changes the diagnosis and the expected course. MGMT status changes expectations and trial eligibility. For vaccine and immunotherapy programs, including ours, neither result excludes you, but both are recorded because they affect how results are interpreted. If your report lacks either result, ask for it to be done on the stored tissue; it usually can be.
Questions families ask
My report says "glioblastoma, IDH-mutant". Is that still glioblastoma?
Under the 2021 classification, no. It is astrocytoma, IDH-mutant, grade 4. The treatment sequence is similar, but the outlook is better and some newer drugs apply only to IDH-mutant tumors. Ask your pathologist to confirm the current terminology.
Can MGMT status change over time?
It can differ between the original tumor and a recurrence, and between labs. If a treatment decision hinges on it, a repeat test on new tissue is reasonable.
Does a "methylated" result mean I should skip radiotherapy?
No. Radiotherapy with temozolomide remains standard for fit patients regardless of MGMT status. In elderly or frail patients, MGMT status is sometimes used to choose between shorter radiotherapy and temozolomide alone.
Related guides
- Newly diagnosed glioblastoma: what to do in the first two weeks
- Standard treatment for glioblastoma explained: surgery, radiotherapy, temozolomide and TTFields
- How to read glioblastoma treatment numbers: survival, progression and what a "median" means
Sources
- Louis DN, et al. The 2021 WHO Classification of Tumors of the Central Nervous System. Neuro-Oncology 2021 doi.org
- Hegi ME, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. NEJM 2005 doi.org
- NCCN Guidelines for Patients: Brain Cancer, Gliomas (2026) nccn.org
Considering treatment in China?
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