Unlike many cancers, they rarely spread outside the brain, which is why clinicians focus on tumor grade and molecular features rather than traditional cancer “stage.” These tumors are all considered malignant due to their infiltrative nature, though their aggressiveness varies.

As Dr Jacob Young, a Neurosurgeon focused on glioma surgery at the University of California San Francisco, explains, “Rather than thinking of them as benign or malignant… they sort of fall on a continuum… we don’t often think about stage when we think about diffuse gliomas… we worry a lot more about grade and… certain mutations that are present.”

A Grade 2 tumor is slow‑growing but diffuse, meaning it blends into healthy brain tissue and cannot be fully removed surgically.

Amabile underwent brain surgery earlier this year, and as his hair grows back, the surgical site remains faintly visible. Like many patients, he’s working to reclaim normalcy—an important part of the healing process. He recently shared an Instagram story showing himself running seven miles.

In another post, Amabile reflected on the emotional adjustment that comes with a lifelong diagnosis.

“Overall, I’m doing wonderful, but there are some things I still struggle with. Overstimulation – watching TV too long,” he said.

“Anxiety is something I’ve dealt with my whole life, but it’s definitely ramped up every time I’ve read something about the type of tumor I have. My hands sweat; I get anxious,” he continued.

While remaining positive, Amabile says he’s getting “better and better every day.”

How Diffuse Gliomas Are Graded

Doctors grade gliomas to understand how the tumor behaves and to guide the safest, most effective treatment plan. A glioma’s grade reflects how quickly the tumor is growing, how abnormal the cells appear under a microscope, and how likely it is to spread within the brain.

WATCH: Diffuse Gliomas Explained — Making Sense of a Complex Diagnosis 

Lower‑grade tumors tend to grow slowly and may not require aggressive treatment immediately, while higher‑grade tumors grow faster and often call for a combination of surgery, radiation, and chemotherapy. Grading helps doctors predict outcomes, set expectations, and tailor care to the tumor’s biology.

Grading Diffuse Gliomas

• Grade 1 — Slow‑growing, usually well‑defined, often seen in children; typically does not infiltrate the brain like other gliomas.
• Grade 2 — Slow‑growing but diffuse (infiltrative); blends into normal brain tissue, making complete surgical removal impossible.
• Grade 3 — Faster‑growing, more aggressive diffuse glioma; usually treated with surgery, radiation, and chemotherapy.
• Grade 4 — The most aggressive form, rapidly growing and invading; requires intensive treatment. Prognosis depends on molecular features, age, and overall health.

Dr. Young explains, “When we think about diffuse gliomas, they can either be grade two, grade three, or grade four… we have a pretty good sense if it looks like it’s going to be the more aggressive grade four variety… or the less aggressive lower grade, either two or three variety.”

What Pathologists Look For

To determine whether a tumor is grade 2, 3, or 4, pathologists examine tissue under a microscope and assess:

• Growth rate
• Cell presentation
• Genetic mutations
• Tumor cell appearance
• Presence of necrosis (dead tumor cells)

As Dr. Young notes, “grade two and grade three are also sort of on a continuum… the pathologists have to look under the microscope and tell us how many cells are dividing [and] if there’s evidence… that might push it from a grade two or a grade three.”

The Importance of IDH Mutation Status

An isocitrate dehydrogenase (IDH) mutation is a small change in a gene involved in cellular energy production. When mutated, the IDH1 or IDH2 enzyme stops functioning normally, leading to a buildup of a chemical that disrupts cell processes and contributes to tumor growth.

IDH mutation status is one of the most important markers in diagnosing diffuse gliomas today.

Dr. Young highlights its significance: “One of the key differentiations is whether these tumors have something called an IDH mutation… if there’s an IDH mutation present and it’s a diffuse glioma, they can no longer be considered glioblastomas, but they can still be grade four tumors.”

This means a tumor may look aggressive under the microscope yet behave differently depending on its genetics.

Putting It All Together: How Doctors See the Big Picture

No single feature determines a glioma’s grade. Instead, doctors evaluate:

• How tumor cells look
• How quickly they divide
• Whether necrosis or microvascular proliferation is present
• The tumor’s genetic profile, including IDH and other mutations

As Dr. Young summarizes, “It’s a combination of the appearance under the microscope, the genetic profile, and certain mutations that are present.”

The Treatment Making a Difference for IDH‑Mutant Glioma Patients

Vorasidenib, an FDA‑approved IDH inhibitor, represents a major advance for patients with IDH‑mutant gliomas—especially grade 2 tumors.

Updated INDIGO trial data showed median progression‑free survival of 44.1 months with vorasidenib, compared with 11 months in the original placebo arm.

WATCH: FDA‑Approved Vorasidenib for IDH‑Mutant Gliomas 

“In terms of when we are thinking about who is the best candidate for IDH inhibitor therapy, so ideally it’s firstly a patient who meets the criteria for the clinical trial that was done,” says Dr. Akanksha Sharma, a Neuro-oncologist at Sutter House California Pacific Medical Center in San Francisco, California.

When INDIGO was first published in 2023, median PFS was 27.7 months. By the 2025 Lancet Oncology update, the curve hadn’t even reached a median—too few patients had progressed to calculate one.

But real‑world decision‑making is more nuanced. Some patients fit the INDIGO profile perfectly; others fall into “gray zones,” where the benefit of starting vorasidenib is less clear. These cases require individualized conversations between patients and their care teams.

More and more patients are asking: “Should I start vorasidenib now, or is another approach better for me?” Sometimes, there is no simple answer.

Questions to Ask Your Doctor

• What would happen if we waited 3–6 months before deciding on therapy?
• If I start vorasidenib, what would make us stop or switch to radiation?
• What does everyday life look like on radiation therapy versus vorasidenib?
• If I’m not a perfect match for vorasidenib, can I still consider taking it?

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