Your pathology report for glioblastoma (IDH wildtype)

by Brian Keller MD PhD and John Woulfe MD PhD
December 2, 2025

Glioblastoma (IDH-wildtype) is an aggressive type of brain tumor that starts from astrocytes, the star-shaped support cells in the brain. It is the most common malignant (cancerous) brain tumor in adults. The term IDH-wildtype means that the tumor does not have a mutation in the IDH1 or IDH2 genes. This is important because glioblastomas without IDH mutations behave differently and are more aggressive than IDH-mutant astrocytomas.

Glioblastoma grows quickly, often invades nearby brain tissue, and can spread through the brain along white matter pathways. It is always classified as WHO grade 4, the highest grade for brain tumors.

Where do glioblastomas occur?

Glioblastomas most often develop in the cerebral hemispheres, especially the frontal and temporal lobes. They usually start in the white matter (the deeper brain tissue that contains nerve fibers), then infiltrate the cortex (the brain’s outer layer). Some glioblastomas spread across the corpus callosum into the opposite side of the brain. Less commonly, they occur in the brainstem, cerebellum, or spinal cord.

What are the symptoms?

The symptoms of glioblastoma depend on where the tumor is located. Because glioblastomas grow rapidly, symptoms often progress over weeks to months.

Common symptoms include:

  • Headaches are often worse in the morning.

  • Seizures.

  • Weakness or numbness on one side of the body.

  • Difficulty speaking or understanding language.

  • Vision problems, including partial vision loss.

  • Changes in personality, behavior, or memory, especially with frontal lobe tumors.

  • Nausea and vomiting due to increased pressure in the brain.

Most patients develop symptoms less than six months before diagnosis.

How common is glioblastoma

Glioblastoma is the most common malignant brain tumor in adults, accounting for about 15% of all brain tumors and nearly half of all malignant brain tumors. It becomes more common with age and most often affects adults aged 55 to 85. It is slightly more common in men than in women.

What causes glioblastoma

For most patients diagnosed with glioblastoma, the exact cause is unknown. A small number of cases occur due to inherited genetic conditions such as Li-Fraumeni syndrome, Lynch syndrome, or neurofibromatosis type 1. The only known environmental risk factor is high-dose ionizing radiation to the head, usually from prior cancer treatment.

Most glioblastomas develop sporadically, meaning they arise through a series of genetic changes that accumulate over time in brain cells. Having allergies or atopic conditions (such as eczema) has been associated with a lower risk of glioblastoma, although the reason is unclear.

How is this diagnosis made?

Imaging

Glioblastoma is usually first seen on MRI or CT. A typical MRI shows a ring-enhancing mass, meaning the tumor forms a bright ring around a darker center of necrosis (dead tissue). The tumor is often surrounded by edema, which appears as swelling in the brain tissue.

Imaging may show:

  • Irregular borders.

  • Extension into nearby brain structures.

  • Spread across the corpus callosum (creating a “butterfly glioma”).

  • Multiple lesions in some patients.

Although MRI strongly suggests glioblastoma, a diagnosis cannot be made without examining tumor tissue.

Biopsy and surgery

Glioblastoma is diagnosed by examining tumor tissue under the microscope. This tissue is obtained either by a stereotactic biopsy, where a small piece of tumor is removed with a needle guided by imaging, or by surgery to remove as much of the tumor as safely possible. A pathologist, a doctor who specializes in diagnosing disease by examining tissues and cells, examines the specimen to confirm that it is a glioblastoma and to perform additional tests that help guide treatment.

Microscopic features

Under the microscope, glioblastoma is a high-grade astrocytic tumor. It usually shows a high number of tumor cells packed together (increased cellularity), with abnormal cells that vary in size and shape (nuclear atypia and pleomorphism). Pathologists see many mitotic figures, which are cells actively dividing.

Two hallmark features are especially important:

  • Microvascular proliferation, where small blood vessels grow in multiple layers, sometimes forming “glomeruloid” tufts.

  • Necrosis, areas where tumor cells have died. Often, living tumor cells form a “palisading” pattern around necrotic regions.

These features indicate rapid growth and poor blood supply within the tumor and support a diagnosis of WHO grade 4 glioblastoma.

Immunohistochemistry

Immunohistochemistry (IHC) uses antibodies labeled with dyes to highlight specific proteins in tumor cells, allowing them to be seen under the microscope. In glioblastoma, IHC helps confirm the tumor type and distinguish it from other brain tumors.

Common IHC findings include:

  • IDH1 R132H: This stain is negative in IDH-wildtype glioblastoma, confirming the absence of the common IDH mutation.

  • GFAP (glial fibrillary acidic protein) and OLIG2: These markers show that the tumor cells are glial (supporting brain cells), supporting an astrocytic tumor.

  • Ki-67: This marker shows how many cells are dividing. In glioblastoma, the Ki-67 index is usually high, reflecting rapid growth.

  • EGFR: Overexpression of EGFR, especially when accompanied by gene amplification, supports the diagnosis of a typical IDH-wildtype glioblastoma.

IHC results are interpreted together with the microscopic findings and molecular tests to arrive at the final diagnosis.

Molecular tests

In addition to routine microscopy and IHC, glioblastoma diagnosis now relies heavily on molecular tests. These tests examine the tumor’s DNA and sometimes its DNA methylation patterns to identify key genetic changes.

Common molecular tests include:

  • IDH1 and IDH2 sequencing to confirm the tumor is IDH-wildtype.

  • TERT promoter mutation testing is recommended because TERT promoter mutations are common in glioblastoma and support the diagnosis.

  • EGFR amplification analysis, usually by copy-number testing, to see if the EGFR gene is present in extra copies.

  • Chromosome copy-number analysis to detect the characteristic combination of chromosome 7 gain and chromosome 10 loss (+7/–10).

  • MGMT promoter methylation testing to predict how well the tumor will respond to the chemotherapy drug temozolomide.

  • Additional panels that may include genes in the PI3K pathway (e.g., PIK3CA, PIK3R1), PTEN, and cell-cycle genes such as CDKN2A/B, CDK4, and RB1.

These molecular findings are important not only for confirming the diagnosis but also for providing prognostic information and identifying potential targets for clinical trials or experimental treatments.

Integrated diagnosis

Today, the diagnosis of glioblastoma is made using an integrated approach that combines microscopic features, immunohistochemical findings, and molecular results. A diffuse astrocytic tumor in an adult is classified as glioblastoma, IDH-wildtype (CNS WHO grade 4) when:

  • It has IDH-wildtype status (no IDH1 or IDH2 mutation).

  • It shows microvascular proliferation and/or necrosis under the microscope.

In some cases, even if microvascular proliferation and necrosis are not seen in a small biopsy, the tumor can still be diagnosed as glioblastoma if molecular testing shows one or more of the following:

  • A TERT promoter mutation.

  • EGFR gene amplification.

  • The combined +7/–10 chromosome pattern (gain of chromosome 7 and loss of chromosome 10).

This integrated system ensures that tumors with aggressive molecular features are correctly recognized as glioblastomas, even when sampled in a limited way.

Histologic subtypes of glioblastoma

Glioblastoma has several histologic subtypes. These subtypes look different under the microscope but are all considered WHO grade 4 and have similar overall treatment approaches.

Giant cell glioblastoma

This subtype contains many large, abnormal, multinucleated tumor cells (giant cells). It tends to occur in younger patients and may have a slightly better prognosis than classic glioblastoma.

Gliosarcoma

Gliosarcoma has both glial (astrocytic) and sarcomatous (connective-tissue-like ) components. It may appear more well-defined on imaging and can sometimes mimic a metastasis or meningioma. Prognosis is similar to that of a typical glioblastoma.

Epithelioid glioblastoma

This subtype has tumor cells that resemble epithelial cells, with abundant cytoplasm and prominent nucleoli. It often affects younger patients and is associated with BRAF V600E mutations. Prognosis is generally poor.

WHO grade

WHO grade describes how aggressive a brain tumor is expected to be. Glioblastoma is always WHO grade 4, the highest grade. Grade 4 tumors grow quickly, invade surrounding brain tissue, and often develop necrosis and microvascular proliferation.

Glioblastoma is distinguished from other diffuse gliomas by:

  • IDH-wildtype status.

  • Characteristic microscopic features.

  • Aggressive molecular changes, such as TERT promoter mutation or EGFR amplification.

WHO grade is a significant predictor of prognosis and guides treatment decisions.

Biomarkers

Biomarkers are specific genetic or protein changes in tumor cells that help predict how the tumor will behave and how well it might respond to treatment. In glioblastoma, biomarkers help define the diagnosis, guide prognosis, and influence treatment choices—especially regarding chemotherapy and clinical trials.

What types of biomarkers are tested?

Most biomarker tests examine tumor DNA using next-generation sequencing and promoter methylation testing. Key biomarkers for glioblastoma include MGMT promoter methylation, TERT promoter mutation, EGFR amplification, gains on chromosome 7 and losses on chromosome 10, and alterations in the PI3K, PTEN, or CDK4/6 pathways.

MGMT promoter methylation

MGMT is a DNA repair gene. When the MGMT promoter is methylated, MGMT protein levels decrease, making tumor cells more sensitive to certain chemotherapy drugs (especially temozolomide). Patients with MGMT promoter methylation often respond better to chemotherapy and may live longer.

Testing is performed on tumor tissue using molecular methods that measure methylation of the MGMT promoter region. Your tumor is described as MGMT-methylated or MGMT-unmethylated. Methylation predicts a better response to chemotherapy.

TERT promoter mutation

The TERT promoter controls the gene that helps maintain telomeres, the ends of chromosomes. Mutations in the TERT promoter allow tumor cells to divide indefinitely and are associated with more aggressive behavior.

TERT promoter mutation is detected using DNA sequencing. Your report will indicate TERT-mutated or TERT-wildtype. Most glioblastomas are TERT-mutated.

EGFR amplification

EGFR is a growth-promoting gene located on chromosome 7. Many glioblastomas have extra copies of this gene, called amplification, which leads to increased tumor growth.

Molecular tests such as copy number analysis detect extra copies of the EGFR gene. The tumor is described as EGFR-amplified or not amplified. Amplified tumors may also produce an altered form called EGFRvIII.

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

One of the most common molecular signatures in glioblastoma is the gain of chromosome 7 and the loss of chromosome 10. This genetic pattern helps confirm the diagnosis of glioblastoma.

Copy number analysis evaluates the amount of DNA from each chromosome. Reports state whether chromosome 7 is gained, chromosome 10 is lost, or both are present (+7/–10).

PI3K pathway genes (PIK3CA, PIK3R1) and PTEN

The PI3K pathway controls cell growth. Mutations in PIK3CA or PIK3R1, or loss of PTEN, can activate this pathway and promote tumor progression.

DNA sequencing identifies mutations and copy number changes. Reports identify the specific gene that is mutated, deleted, or intact.

CDK4/6 pathway (CDKN2A/B, CDK4, RB1)

This pathway controls the cell cycle. Loss of CDKN2A/B, amplification of CDK4, or inactivation of RB1 allows cells to divide uncontrollably.

Reports list CDKN2A/B deletion, CDK4 amplification, or RB1 mutation/deletion, which are considered high-risk features.

Gene fusions (FGFR3–TACC3, NTRK, MET)

Some glioblastomas harbor gene fusions involving FGFR3, TACC3, NTRK, or MET that create abnormal proteins that drive tumor growth.

These gene fusions can be detected by next-generation sequencing or RNA sequencing. Your report will list any detected fusion, such as FGFR3::TACC3, NTRK1/2/3, or MET. These may make the tumor eligible for targeted therapy.

Prognosis

Glioblastoma, IDH-wildtype, has an aggressive clinical course. Even with the best available treatment, which usually includes maximal safe surgery followed by radiation and chemotherapy, most patients live about 15 to 18 months after diagnosis. A small percentage of patients survive several years, and very long-term survivors are rare.

Several factors influence prognosis. Age is important: younger patients generally do better than older patients. Patients in good overall health with fewer other medical problems and a good performance status (ability to carry out daily activities) also tend to have better outcomes. The extent of surgical resection matters as well; patients whose tumors can be largely or entirely removed often live longer than those whose tumors cannot be safely resected.

Molecular features provide additional prognostic information. Tumors with MGMT promoter methylation respond better to temozolomide chemotherapy and are associated with more prolonged survival. In contrast, tumors without MGMT promoter methylation (unmethylated) are less responsive to this treatment. Other genetic changes, such as TERT promoter mutations, EGFR amplification, or complex chromosomal alterations, help define the tumor’s biology but are not yet used routinely to predict survival in the same way.

Despite its aggressive nature, many patients benefit from treatment in terms of symptom control and quality of life, even when a cure is not possible. Research is ongoing to develop better treatments, including targeted therapies and immunotherapies, and some patients may be eligible for clinical trials that offer access to new and experimental approaches. Your healthcare team will consider your age, overall health, tumor location, extent of resection, and biomarker results when discussing prognosis and planning your care.

What happens after the diagnosis?

Treatment usually begins with maximal safe surgery to remove as much of the tumor as possible. This is followed by radiation therapy combined with temozolomide chemotherapy. Additional treatments, such as tumor-treating fields, clinical trials, and targeted therapies, may be offered depending on biomarker results.

Regular MRI scans are required to monitor treatment response and detect recurrence. Supportive care, including seizure management, rehabilitation, and symptom control, is an integral part of ongoing treatment.

Questions to ask your doctor

  • What molecular features were found (MGMT methylation, EGFR amplification, TERT promoter mutation, +7/–10)?

  • How much of the tumor was removed during surgery?

  • What treatments do you recommend next?

  • Am I eligible for any clinical trials or targeted therapies?

  • How often will I need MRI scans?

  • What symptoms should I watch for after treatment?

  • Should my family members undergo genetic counseling?

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