Glioblastoma, IDH-Wildtype: Understanding Your Pathology Report

by Brian Keller MD PhD and John Woulfe MD PhD
April 24, 2026

Glioblastoma, IDH-wildtype, is an aggressive type of brain tumor that develops from glial cells, the supporting cells of the central nervous system. It belongs to a larger group of tumors called diffuse gliomas. Diffuse gliomas are infiltrative, which means the tumor cells spread into the normal brain tissue around them and cannot be fully separated from it — unlike another group of gliomas called circumscribed gliomas (such as pilocytic astrocytoma), which have a clear border and can often be completely removed by surgery. In glioblastoma, the infiltrative growth pattern has major consequences: even when all visible tumor is removed during surgery, microscopic tumor cells remain behind in the normal-appearing brain and regrow over time. Treatment, therefore, combines surgery with additional therapies — radiation, chemotherapy, and often tumor-treating fields — to target the microscopic tumor that surgery cannot reach.

Glioblastoma is the most common cancerous brain tumor in adults. It most often arises in the cerebral hemispheres, especially the frontal and temporal lobes, and typically starts in the white matter (the deeper brain tissue that contains nerve fibers) before invading the cortex (the brain’s outer layer). In some cases, the tumor crosses the corpus callosum — the thick band of nerve fibers that connects the two halves of the brain — and involves both sides, a pattern sometimes called a “butterfly glioma.” Less commonly, glioblastoma arises in the brainstem, cerebellum, or spinal cord.

The term IDH-wildtype means that the tumor lacks a mutation in the IDH1 or IDH2 genes. This is important because tumors with IDH mutations (called IDH-mutant astrocytomas) behave very differently, respond differently to treatment, and have a much better prognosis. Glioblastoma is always classified as World Health Organization (WHO) grade 4, the highest grade used for central nervous system tumors.

This article will help you understand the findings in your pathology report — what each term means and why it matters for your care.

What are the symptoms of glioblastoma?

The symptoms of glioblastoma depend on where the tumor grows and on the functions the affected part of the brain controls. Because glioblastoma grows quickly, symptoms often develop over weeks to a few months — sometimes faster — and frequently prompt urgent medical evaluation.

Common symptoms include:

• Headache — often worse in the morning, sometimes with nausea or vomiting. This is caused by a build-up of pressure inside the skull as the tumor and surrounding swelling take up space.
• Seizures — sometimes the first sign of the tumor, particularly for tumors in the cortex.
• Weakness or numbness on one side of the body — usually on the opposite side to the tumor, because the two sides of the brain control the opposite sides of the body.
• Difficulty speaking, understanding language, or finding words — common when the tumor is in the left frontal or temporal lobe.
• Vision changes — partial vision loss, double vision, or blurred vision.
• Changes in thinking, memory, personality, or behavior — especially with frontal lobe tumors. Family members often notice these changes before the patient does.
• Fatigue and drowsiness — can be caused by the tumor itself, by swelling in the brain, or by treatment.

What causes glioblastoma?

For most people diagnosed with glioblastoma, the exact cause is not known. The tumor develops through a series of genetic changes that accumulate in glial cells over time. These changes switch on genes that drive rapid cell growth and switch off genes that normally restrain it. Glioblastoma is not caused by anything the patient did or did not do, and it is not contagious.

The only well-established environmental risk factor for glioblastoma is high-dose ionizing radiation to the head, usually from previous cancer treatment. Most other factors commonly discussed in the media — including cell phone use, head injuries, diet, and electromagnetic fields — have not been consistently shown to cause glioblastoma.

A small number of glioblastomas develop in the setting of an inherited condition. Inherited conditions are caused by a genetic change that is present in every cell of the body from birth and can be passed from parent to child. Inherited conditions that can increase the risk of glioblastoma include:

• Li-Fraumeni syndrome — caused by a change in the TP53 gene. This syndrome increases the risk of many cancers, including brain tumors, sarcomas, breast cancer, and leukemia.
• Lynch syndrome and constitutional mismatch repair deficiency (CMMRD) — caused by changes in DNA mismatch repair genes such as MLH1, MSH2, MSH6, and PMS2. These conditions also increase the risk of colon cancer, endometrial cancer, and several other cancers.
• Turcot syndrome — an older term that describes the combination of colon polyps and brain tumors. Most cases are now recognized as either familial adenomatous polyposis (caused by a change in the APC gene) or Lynch syndrome.
• Neurofibromatosis type 1 (NF1) — caused by a change in the NF1 gene. Most brain tumors in NF1 are low-grade, but adults with NF1 have a slightly increased risk of glioblastoma.

Because most glioblastomas are not associated with an inherited condition, genetic counseling and germline (inherited) genetic testing are not routinely recommended. They may be offered when there is a strong family history of related cancers, when a patient is diagnosed at an unusually young age, or when tumor testing suggests a possible inherited change.

How common is glioblastoma?

Glioblastoma is the most common cancerous brain tumor in adults, accounting for about 15% of all brain tumors and about half of all cancerous brain tumors. The yearly incidence is approximately 3 cases per 100,000 people in North America. Glioblastoma becomes more common with age and is most often diagnosed between 55 and 85 years of age, with a median age at diagnosis of around 65. It is slightly more common in men than in women and is uncommon in people under 40.

How is the diagnosis made?

The diagnosis of glioblastoma usually begins when brain imaging — most often magnetic resonance imaging (MRI) — reveals a mass. Glioblastoma has a characteristic appearance on MRI: the tumor typically forms a bright ring of enhancement after intravenous contrast, surrounding a darker center where tumor cells have died (a pattern called “ring enhancement”). The tumor is usually surrounded by a large area of swelling (edema) in the adjacent brain tissue. The borders are irregular, the tumor may extend across the corpus callosum into the opposite side of the brain, and occasionally, more than one tumor is seen. Although these imaging features strongly suggest a glioblastoma diagnosis, a definitive diagnosis requires tissue examination.

The diagnosis is confirmed after a tissue sample is examined under the microscope by a pathologist. In most cases, the tissue is obtained during surgery to remove as much of the tumor as can be safely taken out. This operation, called a craniotomy, serves two purposes: it reduces the amount of tumor in the brain (which improves outcomes and relieves pressure) and provides the tissue needed for diagnosis and molecular testing. When the tumor is in a location where surgery would be too risky, a smaller biopsy is performed instead — typically a stereotactic biopsy, in which a thin needle is guided into the tumor using imaging to sample a small amount of tissue.

Under the microscope, glioblastoma is a densely cellular tumor made up of abnormal glial cells that vary in size and shape. The cells divide rapidly, and mitotic figures (cells caught in the act of dividing) are easy to find. Two additional microscopic features are especially important and support the diagnosis of WHO grade 4:

• Microvascular proliferation — abnormal new blood vessel growth, with small blood vessels stacked in multiple layers, sometimes forming ball-like tufts.
• Necrosis — areas of dead tumor tissue, often surrounded by living tumor cells arranged in a fence-like (“palisading”) pattern around the dead area.

To confirm the diagnosis, the pathologist uses immunohistochemistry, a laboratory test that uses antibodies to detect specific proteins in the tumor cells. Glioblastomas typically express GFAP (glial fibrillary acidic protein) and OLIG2, two proteins that confirm the tumor has arisen from glial cells. The pathologist also performs an IDH1 R132H immunohistochemistry stain, which detects the most common IDH mutation; a negative result is required for the diagnosis of IDH-wildtype glioblastoma.

The diagnosis of glioblastoma now depends on a combination of microscopic features and molecular testing. In a diffuse astrocytic tumor in an adult without an IDH mutation, the diagnosis of glioblastoma can be made when microvascular proliferation and/or necrosis are present. It can also be made when these features are absent but molecular testing reveals one or more of the following: a TERT promoter mutation, EGFR amplification, or a specific chromosome pattern known as +7/–10 (gain of chromosome 7 and loss of chromosome 10). These molecular findings are described in detail in the biomarker section below.

Histological patterns of glioblastoma

Most glioblastomas have a classic microscopic appearance, but a small number exhibit distinctive patterns worth describing separately. These are not separate tumor types; they are patterns within the broader category of IDH-wildtype glioblastoma and are treated with the same general approach. Recognizing the pattern remains important because some are associated with specific molecular features that may influence treatment.

Giant cell glioblastoma

This pattern contains many large, abnormal tumor cells with multiple nuclei (multinucleated giant cells). It tends to occur in younger adults and may be better circumscribed on imaging than a classic glioblastoma. Despite its alarming appearance under the microscope, giant cell glioblastoma may have a slightly better prognosis than classic glioblastoma, although it remains WHO grade 4.

Gliosarcoma

Gliosarcoma has two distinct components: a glial (astrocytic) component that resembles a typical glioblastoma and a sarcomatous component that resembles a connective-tissue tumor. On imaging, gliosarcoma can appear more well-defined and is sometimes mistaken for a metastatic tumor or a meningioma. Prognosis and treatment are similar to those of classic glioblastoma.

Epithelioid glioblastoma

Epithelioid glioblastoma is composed of tumor cells that resemble epithelial cells, with abundant cytoplasm and prominent nucleoli (small, dense structures within the nucleus). It tends to occur in younger patients and is more likely than other glioblastomas to have a BRAF V600E mutation. This is clinically important because tumors with a BRAF V600E mutation may be eligible for targeted therapy with BRAF and MEK inhibitors (discussed in the biomarker section).

WHO grade

The World Health Organization (WHO) assigns tumors of the central nervous system a grade from 1 to 4 that reflects how the tumor is expected to behave. Glioblastoma is always WHO grade 4 — the highest grade used for central nervous system tumors. This grade reflects the aggressive, infiltrative nature of the disease and is assigned to every glioblastoma regardless of the histological pattern. Grade 4 does not vary between glioblastomas; prognosis depends on other features such as age, overall health, extent of surgical removal, and the tumor’s molecular profile.

Biomarker and molecular testing

Molecular testing is a routine part of the workup for every glioblastoma. The results confirm the diagnosis, distinguish glioblastoma from other diffuse gliomas, predict response to standard treatment, and identify tumors that may be eligible for targeted therapies or clinical trials.

IDH1 and IDH2

The IDH1 and IDH2 genes normally help cells produce energy. Mutations in these genes are common in other diffuse gliomas (IDH-mutant astrocytoma and oligodendroglioma), where they are associated with a much better prognosis and a different treatment approach. The diagnosis of glioblastoma, IDH-wildtype, requires that both IDH1 and IDH2 are unmutated. Testing is performed in two steps: an immunohistochemistry stain for the most common IDH1 mutation (R132H), followed by DNA sequencing of IDH1 and IDH2 in patients under 55 whose R132H stain is negative, to rule out rarer IDH mutations.

MGMT promoter methylation

The MGMT gene makes a protein that repairs DNA damage. When the MGMT promoter (a regulatory region that controls whether the gene is turned on) is methylated, MGMT protein levels drop, making the tumor cells less able to repair damage caused by the chemotherapy drug temozolomide. Patients whose tumors are MGMT-methylated tend to respond better to temozolomide and live longer than those whose tumors are unmethylated. MGMT methylation testing is performed on tumor DNA using specialized molecular methods, and the result is reported as either MGMT-methylated or MGMT-unmethylated. MGMT status is one of the most important biomarkers in glioblastoma and directly influences treatment decisions, particularly in older patients, where it can help determine whether to use temozolomide, radiation, or both.

TERT promoter mutation

The TERT gene makes a protein that lengthens telomeres, the protective caps on the ends of chromosomes. Mutations in the TERT promoter allow tumor cells to divide indefinitely. TERT promoter mutations are found in most glioblastomas and, in combination with other findings, support the diagnosis. The result is reported as TERT-mutated or TERT-wildtype.

EGFR amplification and EGFRvIII

The EGFR gene makes a growth factor receptor protein that promotes cell growth. In many glioblastomas, the gene is present in many extra copies — a change called amplification — which drives rapid growth. Some amplified tumors also produce an altered form of the EGFR protein called EGFRvIII. EGFR amplification is detected by copy-number testing, and the result is reported as EGFR-amplified or not amplified. While several EGFR-targeted therapies have been studied in glioblastoma, none have yet become standard treatment outside of clinical trials.

Chromosome 7 gain and chromosome 10 loss (+7/–10)

Gain of chromosome 7 and loss of chromosome 10 is one of the most characteristic molecular signatures of glioblastoma. Copy-number testing is used to detect this pattern, and its presence — even in a tumor that lacks microvascular proliferation and necrosis under the microscope — supports the diagnosis of glioblastoma.

BRAF V600E mutation

A small number of glioblastomas, particularly those with an epithelioid pattern, have a BRAF V600E mutation. The BRAF protein is part of a cell signaling pathway called MAPK that normally helps control cell growth. The V600E mutation switches this pathway on inappropriately. Tumors with a BRAF V600E mutation may be eligible for targeted therapy with a combination of a BRAF inhibitor (such as dabrafenib) and a MEK inhibitor (such as trametinib). This combination received tumor-agnostic approval from the U.S. Food and Drug Administration in 2022 for adult and pediatric patients with BRAF V600E-mutant solid tumors that have progressed after prior treatment and for which no good alternatives exist.

NTRK gene fusions

A gene fusion occurs when two genes that are normally separate are joined, creating a new gene that functions abnormally. Rare glioblastomas have fusions involving an NTRK gene (NTRK1, NTRK2, or NTRK3). Tumors with an NTRK fusion may be eligible for targeted therapy with an NTRK inhibitor (larotrectinib or entrectinib), both of which have tumor-agnostic approvals for solid tumors with NTRK fusions. NTRK fusions are uncommon in glioblastoma but are worth testing for because of the availability of effective targeted therapy.

Other molecular changes

Comprehensive molecular testing often identifies additional changes that characterize the tumor biology. These include changes in the PI3K pathway (PIK3CA, PIK3R1, PTEN) and the cell cycle pathway (CDKN2A/B, CDK4, RB1), as well as occasional fusions involving FGFR3–TACC3 or MET. These results do not usually change the diagnosis but may provide prognostic information or identify targets for clinical trials.

DNA methylation profiling

DNA methylation refers to small chemical tags attached to DNA that help control which genes are turned on or off. Different tumor types have distinct methylation patterns, almost like a fingerprint. DNA methylation profiling compares a tumor’s pattern to a large reference database and is increasingly used in specialized centers to confirm the diagnosis of glioblastoma and to distinguish it from other diffuse gliomas. This testing is especially useful in difficult cases where microscopic findings are ambiguous.

For more information about biomarkers and molecular testing across all cancer types, visit the Biomarkers and Genetic Testing section.

What is the prognosis?

Glioblastoma is a serious diagnosis with a generally poor prognosis. With standard treatment — maximal safe surgical removal followed by radiation combined with temozolomide chemotherapy — the median survival is approximately 15 to 20 months from diagnosis. About 25–30% of patients are alive two years after diagnosis, and fewer than 10% are alive at five years. Some patients live substantially longer, and a small number survive in the long term.

Several features are associated with better outcomes:

• Younger age — patients under 50 generally do better than older patients.
• Good overall health and performance status — the ability to carry out normal daily activities at the time of diagnosis — are among the strongest predictors of survival.
• Complete or near-complete surgical removal — patients whose tumors can be largely or entirely removed generally live longer than those whose tumors cannot be safely resected.
• MGMT promoter methylation — tumors with MGMT methylation respond better to temozolomide, and patients with methylated tumors live significantly longer on average — median survival around 21 months with standard treatment, and longer with tumor-treating fields.
• Lack of high-risk molecular features — tumors without deletions of CDKN2A/B or amplifications of driver genes tend to have somewhat better outcomes.
• Tumor location — tumors that can be safely removed and are not in critical functional areas tend to do better than deep or midline tumors.

Features associated with a worse prognosis include older age, poor performance status, inability to safely remove the tumor, and MGMT-unmethylated status.

Despite these statistics, treatment can meaningfully improve quality of life and provide additional time with family, even when cure is not possible. Research into new treatments — including targeted therapies, immunotherapy, vaccines, and drugs that can cross the blood-brain barrier — is active, and clinical trial participation is an important option for many patients.

What happens after the diagnosis?

Glioblastoma is managed by a multidisciplinary team that typically includes a neurosurgeon, a neuro-oncologist, a radiation oncologist, a neuropathologist, a neuroradiologist, and — often from the beginning — palliative care and rehabilitation specialists. Other members of the team may include a neurologist for seizure management, a neuropsychologist, a physical therapist, an occupational therapist, a speech therapist, and a social worker.

The standard treatment for newly diagnosed glioblastoma, sometimes called the “Stupp protocol” after the physician who led the trial that established it, involves three main components:

• Maximal safe surgical removal — the neurosurgeon removes as much of the tumor as possible without injuring critical functional areas. Complete removal of the visible tumor is associated with better outcomes, but complete cure is not possible because microscopic tumor cells always remain in the surrounding brain.
• Radiation combined with temozolomide — beginning 3–6 weeks after surgery, the patient receives radiation therapy to the tumor area over about six weeks (typically 60 Gy delivered in 30 sessions), along with daily oral temozolomide chemotherapy.
• Maintenance temozolomide — after a short break, six cycles of temozolomide are given, each lasting five days out of a 28-day cycle.

In addition to the Stupp protocol, several newer options are available:

• Tumor-treating fields (Optune) — a device worn on the scalp that delivers low-intensity alternating electrical fields to the tumor area. Tumor-treating fields interfere with cell division and, when added to temozolomide, extend median survival by approximately 5 months in newly diagnosed glioblastoma. The device is worn for most of the day and requires regular replacement of the arrays and shaving of the scalp.
• Targeted therapy — patients whose tumors have a BRAF V600E mutation or an NTRK fusion may be eligible for targeted drugs (described in the biomarker section).
• Clinical trials — trials testing immunotherapy, vaccines, new drugs, and novel drug delivery methods are widely available and an important option to discuss with your team, both at the time of initial diagnosis and if the tumor returns.
• Modified regimens for older or frail patients — patients over 70, or those with other serious medical problems, may be treated with shorter courses of radiation (hypofractionated radiation) with or without temozolomide. For patients whose tumor is MGMT-methylated and who cannot tolerate radiation, temozolomide alone may be a reasonable option.

When glioblastoma returns after initial treatment (which nearly always happens), treatment options include additional surgery, a second course of radiation (re-irradiation), additional chemotherapy (including lomustine or bevacizumab), additional tumor-treating fields, and clinical trials. The choice depends on the patient’s overall health, previous treatments, time since the last treatment, and the location of the recurrent tumor.

Follow-up includes regular MRI scans, typically every 2–3 months during active treatment and at longer intervals afterward. The scans are reviewed for tumor growth, treatment-related changes (which can sometimes appear as tumor growth on imaging), and any new problems. Supportive care is an essential part of treatment and includes seizure management, treatment of brain swelling with steroids, rehabilitation, mental health support, and symptom management.

Palliative care, which focuses on comfort, symptom management, and emotional and spiritual support, is compatible with ongoing cancer-directed treatment and is increasingly introduced early in the course of glioblastoma rather than only at the end of life. Early palliative care has been shown to improve quality of life for both patients and families.

Questions to ask your doctor

• What is the exact diagnosis, and is the tumor IDH-wildtype?
• How much of the tumor was removed during surgery?
• What molecular features were found — MGMT methylation, TERT promoter mutation, EGFR amplification, the +7/–10 chromosome pattern, or others?
• Does my tumor have a BRAF V600E mutation or an NTRK fusion that would make me eligible for targeted therapy?
• What is my MGMT status, and how does it affect my treatment plan?
• Do you recommend the standard Stupp protocol, or a modified approach based on my age and overall health?
• Should I consider adding tumor-treating fields (Optune) to my treatment, and what would that involve day-to-day?
• Are there clinical trials that I should consider, either now or if the tumor returns?
• How often will I need MRI scans, and how will we know if the treatment is working?
• What symptoms should I watch for that might indicate the tumor is growing or coming back?
• What supportive care services are available — seizure management, rehabilitation, neuropsychology, palliative care, and mental health support?
• Should I be referred for genetic counselling or germline genetic testing?
• What should I expect about my ability to work, drive, and continue other daily activities during treatment?
• How can my family and I best prepare for the road ahead?

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