Anaplastic Astrocytoma vs Glioblastoma: What Grade Really Means

A grade III or grade IV glioma diagnosis is frightening - and the difference between them really matters. It affects your treatment plan and what to expect from your illness.

What Is the Core Difference Between Grade III and Grade IV Glioma?

Anaplastic astrocytoma - now formally called astrocytoma, IDH-mutant, grade 3 under 2021 WHO brain tumor guidelines - has a mutation in the IDH1 or IDH2 gene. That mutation slows tumor metabolism and helps the tumor respond better to chemotherapy that damages DNA. Glioblastoma (grade IV, IDH-wildtype) lacks that mutation. It grows faster, resists treatment more effectively, and carries a shorter expected survival. The two diagnoses also call for different chemotherapy timing and duration after surgery and radiation.

How Did the WHO 2021 Classification Change the Naming?

Before 2021, the term anaplastic astrocytoma described grade III tumors regardless of their molecular profile. That was a problem, because IDH status drives both prognosis and treatment response. The 2021 WHO Classification of Tumours of the Central Nervous System created a clearer line between tumor types based on biology, not just appearance under a microscope.

Under the new system:

• Astrocytoma, IDH-mutant, grade 3 replaces the old label anaplastic astrocytoma. An IDH mutation is now a required feature of the diagnosis.
• Glioblastoma, IDH-wildtype, grade 4 is the formal name for what most people still call GBM. A tumor can now be classified as grade 4 even without visible necrosis on MRI if it has a TERT promoter mutation, EGFR amplification, or combined chromosome 7 gain and chromosome 10 loss.
• IDH-mutant tumors that reach grade 4 - through CDKN2A/B homozygous deletion or necrosis - form a separate category called astrocytoma, IDH-mutant, grade 4. These are not classified as glioblastoma.

If your pathology report predates 2021 and IDH testing was not performed, a re-review of the preserved tissue block may lead to a different classification under the current system. Our guide on what each marker in your pathology report actually means explains how to read and question those results.

What Does a Pathologist Look for to Separate Grade III from Grade IV?

Under a microscope, grade III astrocytoma shows dense cellularity, nuclear atypia (abnormal-looking cell nuclei), and active cell division known as mitoses. Grade IV glioblastoma has all of those features plus two additional findings that define it as the highest grade:

• Microvascular proliferation: Abnormal blood vessel growth within the tumor. The tumor uses these new blood vessels to grow faster.
• Necrosis: Dead tissue at the core of the tumor. In GBM, this is often surrounded by a ring of densely packed tumor cells - a pattern called pseudopalisading necrosis - which is a defining marker of grade IV disease.

These findings matter. They show how fast the tumor is growing and why grade IV tumors are harder to treat with standard therapy.

How Does Anaplastic Astrocytoma Compare to Glioblastoma on Key Measures?

Grade III survival data from a 2024 single-center retrospective study using 2021 WHO criteria. GBM median OS from a 2025 US National Cancer Database analysis. MGMT methylation survival difference from the MGMT-GBM observational study.

The survival gap reflects the underlying biology. IDH mutation changes how tumor cells produce energy and how well they can repair DNA damage from chemotherapy. IDH mutation is the strongest positive sign for survival in high-grade glioma.

Which Molecular Tests Matter Most?

Both grade III and grade IV tumors should have a full molecular panel run on biopsy tissue. Key markers include:

• IDH1/IDH2 mutation: The most important marker in either direction. It increases survival odds and changes the treatment sequence in grade III disease. Testing can be done on preserved tissue (FFPE block) even after the initial biopsy. Our article on IDH status and what it means for treatment planning explains this in detail.
• MGMT promoter methylation: Indicates whether the tumor has silenced a DNA-repair enzyme that limits chemotherapy effectiveness. In GBM, research from the MGMT-GBM study found methylation is strongly associated with longer survival and better temozolomide response. In IDH-mutant grade 3 tumors, MGMT status matters less because the IDH mutation itself is the dominant prognostic factor.
• 1p/19q codeletion: When both chromosome arms are deleted together, doctors classify the tumor as an oligodendroglioma rather than an astrocytoma. This changes prognosis and the preferred chemotherapy approach. If 1p/19q codeletion is present, the tumor is not anaplastic astrocytoma regardless of grade.
• TERT promoter mutation, EGFR amplification, chromosome 7/10 status: Doctors use these markers to classify IDH-wildtype grade 3-looking tumors as grade 4 GBM, even when necrosis is not visible on imaging.
• CDKN2A/B homozygous deletion: Doctors automatically upgrade an IDH-mutant tumor to grade 4 when this deletion is present, no matter what the microscope shows.

How Does Treatment Differ Between Grade III and Grade IV?

Surgery is the first step for both grades. The goal is maximal safe resection - removing as much tumor as possible without causing new neurological deficits. After surgery, the treatment paths diverge significantly.

For Grade III Anaplastic Astrocytoma (IDH-mutant)

Standard practice is radiotherapy followed by 12 cycles of adjuvant temozolomide. The phase 3 CATNON trial, which enrolled patients at 137 institutions across Europe, Australia, and North America, found that adding temozolomide during radiotherapy did not improve survival. Patients got benefit from 12 temozolomide cycles after radiation ended. Final CATNON trial results published in 2025 confirmed this pattern specifically in IDH-mutant tumors. This is a meaningful difference from the GBM approach, where chemotherapy runs concurrently with radiation from the start.

Some centers use PCV chemotherapy - procarbazine, CCNU, and vincristine - as an alternative to temozolomide in IDH-mutant grade 3. Current European neuro-oncology guidelines allow either option. Your team's choice may depend on age, side-effect tolerance, and functional status.

For Grade IV Glioblastoma (IDH-wildtype)

Standard treatment follows the Stupp protocol: surgery, then six weeks of radiotherapy with daily temozolomide running concurrently, followed by six cycles of maintenance temozolomide. MGMT-methylated patients respond better to the temozolomide component. For patients with unmethylated MGMT and good functional status, some centers also evaluate Tumor Treating Fields (Optune) as an addition to the standard regimen.

Deciding on next steps is especially difficult when a pathology report returns borderline results or when two centers disagree on grade. If you want an expert review of your pathology and MRI, the Art of Healing Cancer team can confirm your grade and molecular classification before you start treatment.

Can a Grade III Tumor Progress to Grade IV?

Yes. IDH-mutant grade 3 astrocytomas can transform over time into grade 4 disease. Under the 2021 WHO classification, these progressed tumors fall into a new category called astrocytoma, IDH-mutant, grade 4 - a distinct category from primary IDH-wildtype glioblastoma. Progression may show up as new contrast enhancement or necrosis on MRI and may require a repeat biopsy to confirm. When the cancer progresses, your doctors will look at treatment options again and check if you qualify for clinical trials right away.

Does Age Change the Treatment Approach?

Age affects treatment intensity for both grades. For GBM patients over 65, doctors often use hypofractionated radiotherapy - a shorter course with a higher dose per session - sometimes combined with temozolomide depending on MGMT status. For older patients with grade III tumors, doctors may choose a sequential approach instead of concurrent treatment. In some cases, they use just one type of therapy based on functional status and how well you tolerate treatment. Talk with your neuro-oncology team about your treatment goals before making these decisions.

When Should You Request a Second Opinion?

A second opinion from a specialized neuro-oncology center is worth considering in any of these situations:

• The pathology report lacks IDH testing, MGMT methylation results, or 1p/19q codeletion status.
• Doctors graded the tumor based on how it looks under the microscope, without testing the molecular markers.
• The grade falls on the borderline between III and IV.
• The treating team did not discuss clinical trial eligibility at diagnosis.

Our guide on when to get a second opinion and how to prepare for it explains how to gather your records and what a specialist review covers. You can also upload your MRI and pathology reports for a remote review at glioblastoma.center/patient-journey.

When to Talk to Your Doctor

Talk to your neuro-oncologist if your pathology report does not include a full molecular panel - at minimum IDH mutation status, MGMT promoter methylation, and 1p/19q codeletion. Ask your team whether they've reviewed the tumor against the 2021 WHO criteria. If your biopsy was done before 2022 and your doctors didn't test for IDH, ask them to test the preserved tissue block. The result could change your prognosis and the best treatment sequence after radiation.

This article is for general information and is not a substitute for medical advice. Always consult your oncologist or care team about your specific situation.