Low-Grade Glioma (IDH-mutant Astrocytoma)

Our Specialists for Low-Grade Glioma (IDH-mutant Astrocytoma)

Outcomes in low-grade glioma are driven more by how much tumor is safely removed and what the molecular profile shows than by any other single factor. At UChicago, these cases are handled by surgeons who operate on gliomas every week, use awake language and motor mapping routinely, and sit in the same tumor board as the neuro-oncologists running modern IDH-targeted trials.

Youssef G. Comair, M.D., FRCSC

Section Chief, Neurosurgical Oncology

Dr. Comair is Section Chief of Neurosurgical Oncology and a pioneer of awake craniotomy for tumors in eloquent cortex. He has authored over 120 peer-reviewed publications and two neurosurgery textbooks, and he founded the first comprehensive epilepsy surgery program in the Middle East and North Africa. He trained at the Montreal Neurological Institute and previously held faculty positions at Cleveland Clinic, UCLA, Johns Hopkins, Baylor, and the American University of Beirut. Dr. Comair is one of the pioneers of awake craniotomy for tumors in eloquent cortex, and for low-grade gliomas in speech, language, or motor areas he routinely performs awake mapping resections at UChicago. His background in epilepsy surgery is particularly useful here, since most low-grade glioma patients present with seizures (J Child Neurol, 1999).

Bakhtiar Yamini, M.D.

Vice Chair for Academic Affairs; Director, Neurosurgical Oncology

Dr. Yamini is a brain tumor surgeon and scientist who serves as Vice Chair for Academic Affairs and Director of Neurosurgical Oncology at UChicago. In the operating room, he uses advanced imaging and navigation tools for stereotactic biopsy, laser ablation, and image-guided maximal resection. In his lab, he runs NIH-funded research into why some tumors resist treatment and into biodegradable nanoparticle vectors that deliver drugs directly to CNS tumors. Dr. Yamini directs Neurosurgical Oncology at UChicago and runs an NIH-funded laboratory studying why gliomas resist treatment, with a particular focus on the NF-kB pathway and on nanoparticle drug delivery to brain tumors (Neuro-Oncology, 2016). If you have a low-grade glioma at UChicago, he is likely one of the surgeons involved in your care and will connect you to the neuro-oncology trials for which you are eligible, including IDH-inhibitor studies.

Peter Christian Warnke, M.D.

Section Chief, Functional Neurosurgery & Epilepsy

Dr. Warnke is an international leader in functional neurosurgery and has performed over 6,000 stereotactic surgeries and more than 3,000 brain tumor surgeries. He is only the second neurosurgeon worldwide to perform laser hemispherotomy, and he has completed over 400 laser ablation surgeries since arriving at UChicago. He is funded by four NIH grants including the BRAIN Initiative, and he directs the NAUTILUS trial for thalamic stimulation in drug-resistant epilepsy. For deep-seated or otherwise difficult-to-reach low-grade gliomas, Dr. Warnke offers frame-based stereotactic biopsy for a definitive molecular diagnosis with minimal risk, and MRI-guided laser interstitial thermal therapy (LITT) for select small recurrent lesions — a minimally invasive technique he has performed more than 400 times at UChicago.

What Is a Low-Grade Glioma?

A low-grade glioma is a slow-growing tumor that arises from glial cells — the support cells of the brain. Under the 2021 World Health Organization classification, the diffuse low-grade gliomas most adults hear about are IDH-mutant astrocytomas (WHO grade 2 or 3) and IDH-mutant, 1p/19q-codeleted oligodendrogliomas (also grade 2 or 3). They are grouped together because they share a single founding mutation in the IDH1 or IDH2 gene, and they behave very differently from the aggressive IDH-wildtype glioblastomas older patients tend to develop.

These tumors are uncommon — diffuse gliomas of all kinds make up only about 6 per 100,000 adults per year — and they disproportionately affect people in their 20s, 30s, and 40s. Because they grow slowly and infiltrate normal brain without destroying it, the first sign is often a seizure in someone who feels otherwise healthy.

"Low-grade" does not mean harmless. Over time, many of these tumors transform into higher-grade cancers. But the window before that happens is long, and what you do in that window — especially the first surgery — shapes the entire rest of the disease.

What Does It Feel Like?

Low-grade gliomas often announce themselves with a single, dramatic event in someone who had no prior medical history. The most common first symptom — by far — is a new seizure.

The most common presentations

• A first-time seizure. This can be a full convulsion, a brief staring spell, a sudden unfamiliar smell or taste, or a strange rising sensation in the stomach. Up to 80% of people with a low-grade glioma have a seizure at some point in the disease, and for most it is the symptom that leads to the MRI that finds the tumor.
• Headaches that are new, persistent, or worse in the morning.
• Subtle cognitive changes — trouble finding words, slower thinking, difficulty multitasking, or personality changes that coworkers and family notice before you do.
• Focal weakness, numbness, or clumsiness on one side of the body, depending on where the tumor is growing.
• Language problems if the tumor is in or near the left hemisphere speech areas.

Because the tumor grows slowly, these symptoms can creep in over months or years. If you had a first-time seizure as an adult, you should have a brain MRI — no matter how quickly you recovered.

How Is It Diagnosed?

The workup for a suspected low-grade glioma happens in a predictable order. Here is what you can expect.

Step 1: MRI with contrast

The first test is an MRI of the brain with and without gadolinium contrast. Classic low-grade gliomas appear as a non-enhancing, T2/FLAIR-bright area that expands the normal brain rather than destroying it. Advanced sequences — perfusion, spectroscopy, diffusion, and sometimes amino acid PET — help distinguish a low-grade glioma from a stroke, infection, or higher-grade tumor.

Step 2: Surgical tissue

Imaging alone cannot make the diagnosis. You need tissue, and how that tissue is obtained matters. Whenever it is safe, the preferred approach is a maximal safe resection — removing as much tumor as possible during the same operation that gives you the diagnosis. When the tumor sits in a location where resection would cause unacceptable deficits, a stereotactic needle biopsy can provide a diagnosis with minimal risk.

Step 3: Molecular classification

This is where modern neuro-oncology really changed. Under a microscope, two gliomas can look identical and yet behave completely differently. What separates them is their DNA. Every low-grade glioma in an adult is now tested for:

• IDH1 and IDH2 mutations — the defining feature of adult diffuse low-grade gliomas. IDH-mutant tumors have far better outcomes than IDH-wildtype tumors.
• 1p/19q codeletion — when present together with an IDH mutation, it defines an oligodendroglioma. These tumors are especially sensitive to chemotherapy and radiation.
• ATRX, TP53, CDKN2A/B, and TERT promoter status — these further refine grade and prognosis. A CDKN2A/B homozygous deletion in an IDH-mutant astrocytoma now makes it a grade 4 tumor, even if it looks low-grade under the microscope.
• MGMT promoter methylation — predicts response to temozolomide.

A complete integrated diagnosis — histology plus molecular profile plus WHO grade — is what drives every treatment decision that follows.

Types of Low-Grade Glioma

When people say "low-grade glioma," they are usually talking about one of three tumors in the adult diffuse glioma family. All are defined molecularly, not just visually.

Astrocytoma, IDH-mutant (WHO grade 2 or 3)

An IDH-mutant astrocytoma has the IDH mutation but no 1p/19q codeletion, and it typically carries ATRX loss and TP53 mutation. This is the most common low-grade glioma in young adults. Median survival in modern series is measured in over a decade, and much longer with gross-total resection and favorable molecular features. If CDKN2A/B is homozygously deleted, the tumor is reclassified as grade 4 and treated more aggressively.

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted (WHO grade 2 or 3)

Oligodendrogliomas have both an IDH mutation and codeletion of the short arm of chromosome 1 and long arm of chromosome 19. They are the most favorable of the diffuse gliomas. Median survival approaches or exceeds 15-20 years, and they respond especially well to the combination of radiation and PCV chemotherapy.

Glioblastoma, IDH-wildtype (WHO grade 4)

Included here only for contrast. If you're older (typically 55+), your MRI shows an enhancing mass, and your tumor is IDH-wildtype, the diagnosis is not a low-grade glioma at all — it is a glioblastoma, and the treatment pathway is completely different. This is why molecular testing matters: it sorts patients into entirely different diseases that would otherwise look similar on imaging and pathology.

How Is It Treated?

Maximal safe resection is the foundation

For almost every adult diffuse low-grade glioma, surgery comes first, and more is better. Across multiple studies, patients whose tumors are resected most completely live significantly longer than those whose tumors are only biopsied or subtotally removed. In the landmark UCSF series by Smith and colleagues, patients with at least 90% resection had 10-year overall survival of 91%, compared with 60% for patients with less than 90% resection. A Norwegian natural experiment comparing two cities — one that biopsied and watched, one that resected early — showed a clear survival advantage for the early-resection strategy.

The goal is not just to remove tumor. It is to remove as much tumor as possible without causing a new neurologic deficit. Modern glioma surgery uses several tools together to do this safely:

• Functional MRI and diffusion tensor imaging (DTI) before surgery to map out language, motor, and white matter tracts.
• Intraoperative neuronavigation to correlate the tumor's location with your anatomy in real time.
• Intraoperative MRI or ultrasound to confirm how much tumor has been removed before the operation ends.
• 5-ALA fluorescence, in select cases, to see the edge of more aggressive tumor under blue light.
• Direct cortical and subcortical electrical stimulation to map eloquent function as the surgeon works.

Awake craniotomy with brain mapping

When a tumor is in or near areas that control speech, language, or movement of the dominant hand, the safest approach is often an awake craniotomy. You are asleep for the opening and closing, but wake up during the critical part of the operation. A speech pathologist or neuropsychologist sits next to you and runs tasks — naming pictures, counting, moving a hand — while the surgeon delivers tiny electrical pulses to the brain surface and the white matter underneath. Any spot that causes a speech error or motor change is marked and spared. Everything else can be removed.

In a study of 250 consecutive glioma resections with language mapping, fewer than 2% of patients had a permanent language deficit at six months, even though most tumors were in dominant-hemisphere language cortex. Awake mapping is the reason an experienced surgeon can offer resection in places that used to be considered inoperable.

Vorasidenib: a new option before radiation

For IDH-mutant grade 2 gliomas that have been resected or biopsied but do not yet need radiation, there is now a pill. Vorasidenib is a brain-penetrant inhibitor of mutant IDH1 and IDH2. In the INDIGO phase 3 trial, vorasidenib more than doubled progression-free survival (about 27 months versus 11 months with placebo) and significantly delayed the time until patients needed their next treatment. The FDA approved it in August 2024. For many patients in the "watch-and-wait" or "post-surgery, pre-radiation" window, vorasidenib has become the preferred first medical therapy.

Radiation and PCV chemotherapy

For patients with high-risk features — older age, subtotal resection, grade 3 histology, tumor progression — the standard adjuvant regimen is radiation followed by PCV chemotherapy (procarbazine, CCNU, and vincristine). This regimen was established by RTOG 9802, which compared radiation alone to radiation plus PCV in high-risk grade 2 gliomas. Median overall survival in the combined-therapy arm was 13.3 years, compared with 7.8 years for radiation alone. A later molecular analysis showed the entire benefit was concentrated in IDH-mutant patients. Temozolomide is sometimes substituted for PCV because it is better tolerated, though PCV has the strongest randomized data.

If the tumor comes back

Recurrence happens — it is the natural history of the disease. Options at recurrence include repeat surgery, salvage radiation, temozolomide, re-challenge with PCV, targeted therapy such as continued vorasidenib, and clinical trials. The decision is individualized and made in multidisciplinary tumor board.

What Are the Outcomes?

Long-term survival in low-grade glioma depends on three things above all: the molecular subtype, how much tumor was removed, and your age and baseline function. Modern series show meaningfully better outcomes than the textbooks from 20 years ago, because molecular classification has let us identify the patients who were doing well all along.

Extent of resection matters — a lot

The Smith et al. 2008 UCSF series remains a reference point for what surgery actually does for this disease:

Molecular subtype matters even more

Since molecular classification became standard, we can sort outcomes by biology instead of just by appearance. Approximate long-term survival by subtype:

Two things follow from these numbers. First, the single most important thing that happens in this disease is the first operation — how much tumor comes out, and how well the surgeon protects the brain around it. Second, the neuro-oncology team matters over time, because this is a disease you live with for years and the decisions about when to add radiation, when to start vorasidenib, and when to change course are as consequential as the surgery itself. Where you have your care — and who is at the table when decisions get made — shapes how you live over the next decade and beyond.

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