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Glioblastoma Multiforme Signs Glioblastoma multiforme (GBM) is the most aggressive and deadly type of malignant primary brain tumor in humans. The tumour arises from glial cells in the brain (the support cells). That’s where the name comes from: “glio” for glial, “blastoma” for a tumor of immature cells, and “multiforme” for the tumor’s varied cell shapes and structures under the microscope. The term “multiforme” is now rarely used.
This change is important because IDH status affects how the tumor behaves and how patients respond to treatment.
GBM usually begins in the cerebrum, the largest part of our brain, and doesn’t spread outside the brain or spinal cord, but it’s ruthless within those boundaries.
This ruthlessness is because it multiplies quickly and invades surrounding brain tissue, making it nearly impossible to remove completely, even with surgery. Another factor is that these cells are highly vascular and self-sustaining, which helps them grow faster. Worse, the tumor cells look very different from one another, which makes it harder to treat. Some cells may even resist radiation or chemotherapy.
Epidemiology of Glioblastoma Multiforme: Glioblastoma Multiforme Signs
It is rare, but still the most common and deadliest malignant brain tumor in adults, accounting for more than half of all such tumors. Internationally, the incidence is estimated to be 3-5 people per 100,000 population per year, or about 120,000- 150,000 per year. It is about 45-50% of all malignant brain tumors, or 15% of all brain tumors.[1]
It usually occurs in adults aged 45-70, with median age at diagnosis of 64 years. It is very rare in children and young adults.
What Causes Glioblastoma Multiforme?
In most cases of GBM, it’s nearly impossible to know the exact cause. Scientists have found a few biological changes and genetic mutations that lead to the changes in major cell functions (like cell growth and division) that can cause cells to grow and divide too much, leading to tumor formation.
Risk Factors:
While glioblastoma doesn’t have clear lifestyle or environmental triggers like some other cancers, a few factors are associated with a higher risk:
1. Age: Biggest risk factor by far. Glioblastoma is rare in young people and becomes far more common after age 50. It’s most often diagnosed in adults aged 60–70.
2. Gender: GBM is more common in men than women (roughly a 1.6:1 ratio).[2] The reason may involve hormonal or genetic differences, but it’s not fully understood.
3. Genetics: Most GBMs are not inherited, but certain rare conditions increase the risk:
- Li-Fraumeni syndrome
- Turcot syndrome
- Neurofibromatosis type 1
4. Radiation Exposure: Even radiation treatment to the head during past years, especially during childhood, is a predisposing risk factor for GBM. This is well-established science. Some leukemia survivors (childhood) particularly have a higher risk of GBM.[3]
5. Ethnicity and Geography: White populations seem to have higher reported rates compared to Black or Asian populations, though the reasons aren’t fully understood (could be biological, environmental, or disparities in diagnosis and reporting).
At the Cellular Level:
At the cellular and genetic level, GBM develops when specific genes controlling growth, cell repair and cell death processes get mutated and don’t work properly. Cell growth control mechanisms go awry, these cells start to grow uncontrollably, invade other tissue, and resist normal aging or death. Some of the most common genetic alterations include:
| Gene/Pathway4Khabibov, M., Garifullin, A., Boumber, Y., Khaddour, K., Fernandez, M., Khamitov, F., Khalikova, L., Kuznetsova, N., Kit, O., & Kharin, L. (2022). Signaling pathways and therapeutic approaches in glioblastoma multiforme (Review). International Journal of Oncology, 60(6), 69. https://doi.org/10.3892/ijo.2022.5359 | Effect |
|---|---|
| TP53 mutations | Disables DNA repair and cell death |
| EGFR amplification | Fuels constant growth |
| PTEN loss | Removes tumor growth suppression |
| IDH1/IDH2 mutation | Seen in a subset of slower-growing gliomas |
| TERT promoter mutations | Promotes unlimited replication, making cells immortal |
| CDKN2A/B mutation | Loss of cell cycle checkpoints |
| MGMT promoter methylation | Predicts better response to chemotherapy |
| Chromosome 10 deletion | Common in primary GBM |
Classification & Subtypes of Glioblastoma Multiforme
In the past, a glioblastoma diagnosis was based simply on what the tumour cells looked like under a microscope. But with the 2016 and 2021 WHO CNS tumour classifications, we now classify glioblastomas according to their molecular characteristics, particularly mutations (changes) in genes including IDH1, IDH2 and TERT.
Before molecular testing was common, glioblastomas were often split into two types based on how they developed:
Primary Glioblastoma:
- Appears suddenly, without a known precursor
- Occurs mostly in older adults
- Driven by mutations like EGFR amplification, PTEN loss, TERT mutation
- Usually IDH-wildtype
- Makes up ~90% of GBM cases
Secondary Glioblastoma:
- Evolves from lower-grade gliomas (Grade II or III astrocytomas)
- More common in younger patients
- Features IDH mutations, TP53 mutations, ATRX loss
- Slower progression, but can still become Grade 4
- Now reclassified as IDH-mutant astrocytoma, Grade 4 under WHO 2021
Modern classification now includes:
- IDH-wildtype GBM: Most common; associated with older adults and worse prognosis
- IDH-mutant GBM: Less common; linked to younger patients and better outcomes
Important to note that the 2021 WHO classification now only uses “glioblastoma” to refer to IDH-wildtype tumors, meaning they lack a mutation in the IDH gene. Tumors that used to be called “secondary glioblastomas” (which evolve from lower-grade gliomas) are now categorized as IDH-mutant astrocytomas, Grade 4.[4] [5]
Glioblastoma Multiforme vs Glioblastoma
Both of these terms refer to the same type of brain cancer.
The term “Glioblastoma multiforme” is the older, more traditional name. The term “multiforme” described the way that the tumor looked under the microscope. The cells that make up a GBM tumor vary in their shapes and sizes.
Since then, the term has been shortened to just Glioblastoma, and this is the name that you will find throughout the medical literature. The 2021 WHO classification system removed the word “multiforme” from the descriptor, listing Glioblastoma as an IDH-wildtype, WHO Grade 4 astrocytoma.[6]
Histological Features of Glioblastoma
Glioblastoma has certain distinct histological features that are central to diagnosis. Under the microscope, pathologists see a chaotic mix of cells, blood vessels, and dead tissue. These features paint a better picture of the tumor’s rapid growth, diversity in cell shape, and aggressiveness.
- Abnormal appearance: Like all tumors, the cells show dark, irregular (pleomorphic) nuclei. Also, the cells are large.
- High mitotic rate: There are many cells visible in the process of dividing (“mitotic figures”), which indicates the high turnover rate of the tumor cells.
- Abnormal blood vessels: Glioblastomas make their own blood supply, forming tangled, irregular, “glomeruloid” (resembling a kidney glomerulus) vessels. This is driven by VEGF overexpression, helping the tumor feed its own growth,
- Dead zones (necrosis): Tumor cells outgrow their blood supply, leaving behind patches of dead tissue.
- Pseudopalisading: A signature pattern where tumor cells line up around areas of necrosis, like a fence around a fire, a “palisade” formation. A hallmark finding: almost pathognomonic for glioblastoma.[7]
Characteristic histological features of glioblastoma, including pseudopalisading necrosis. (A) Tumor cells surround a central necrotic area in a pseudopalisading pattern. (B) Diagram showing how vascular collapse and hypoxia drive this pattern of cell migration and necrosis. (Image Courtesy: Michelucci, A., Sforna, L., Franciolini, F., & Catacuzzeno, L. (2023). Hypoxia, Ion Channels and Glioblastoma Malignancy. Biomolecules, 13(12), 1742. Available fromMDPI. Licensed under CC by 4.0)
Pathophysiology of Glioblastoma Multiforme
- Uncontrolled Growth: Mutations in genes like EGFR and PDGFRA turn on growth signals permanently.
- Resistance to Apoptosis: Tumor cells avoid programmed cell death (thanks to TP53, PTEN mutations).
- Invasion: Unlike many tumors that form discrete masses, GBM sends out microscopic tendrils into surrounding brain tissue, making it nearly impossible to remove fully via surgery.
- Angiogenesis: GBM tumors hijack blood vessel growth (via VEGF) to build their own supply lines.
- Necrosis & Pseudopalisading: Rapid growth outpaces blood supply which causes cell death in the center. This results in the hallmark necrosis and “pseudopalisades”.
- Blood-Brain Barrier Breakdown: The blood-brain barrier gets leaky, which makes the brain more vulnerable, and worsens edema.
Key elements of glioblastoma pathophysiology, including rapid cell proliferation, vascular proliferation, necrosis, and infiltration into surrounding brain tissue.
Signs & Symptoms of Glioblastoma Multiforme
Glioblastoma mostly begins with subtle memory slips, mild headaches, or mood changes that are easy to dismiss. But over time, symptoms worsen and become impossible to ignore. The precise symptoms depend on which area of the brain the tumor is growing in.[8]
- Frequent headaches that tend to be worse in the early morning or when a patient is lying down due to increased intracranial pressure
- Seizures, which are one of the most common early symptoms and occur more frequently in younger patients and when the tumor is located close to the cortex
- Short-term memory problems or confusion in decision-making
- Less commonly, tumors in the frontal lobe trigger pronounced mood or behavior changes, including increased irritability, apathy and less conventional social interactions
- Trouble finding words, speaking clearly, or understanding language if the tumor affects the language centers
- Weakness or numbness, especially on one side of the body, if the tumor is near motor or sensory areas
- Blurred vision, double vision, or visual field loss depending on tumor location
| Brain Area | Possible Symptoms |
|---|---|
| Frontal lobe | Behavior changes, poor judgment, speech problems |
| Temporal lobe | Memory loss, seizures, emotional shifts |
| Parietal lobe | Numbness, spatial confusion, difficulty writing |
| Occipital lobe | Vision problems |
| Cerebellum | Coordination or balance issues |
Diagnosis of Glioblastoma Multiforme
Glioblastoma is fast-growing, so a prompt, accurate diagnosis is key. Because symptoms can be vague, most people don’t know they have it until a scan reveals a mass in their brain and then a biopsy is done to identify the type.
Step 1: Brain Imaging:
Brain scans are often ordered after headaches, seizures, or neurological symptoms.
- MRI with contrast: The gold standard. Glioblastomas typically show up as ring-enhancing lesions with surrounding swelling (edema) and central necrosis.
- CT scan: More widely available, but less detailed. Often used in emergency settings.
T1-weighted axial MRI scans with gadolinium contrast showing the progression of a left frontal-lobe glioblastoma. (A) Preoperative scan reveals irregular, heterogeneous enhancement. (B) One month after surgery, no residual enhancement is visible; arrow indicates surgical cavity. (C) Eighteen months post-op scan for long-term follow-up. (Image Courtesy: Pinarbasi Degirmenci, N., & Solaroglu, I. (2021). Tumor Cell Infiltration into the Brain in Glioblastoma: From Mechanisms to Clinical Perspectives. Cancers, 14(2), 443. Available fromMDPI. Licensed under CC by 4.0)
Step 2: Biopsy or Surgical Resection:
Once imaging suggests a brain tumor, doctors need tissue to make a definitive diagnosis.
- Stereotactic biopsy: A small sample is taken with a needle for diagnosis.
- Surgical resection: If possible, surgeons remove as much of the tumor as they safely can—this also provides more tissue for testing.
Step 3: Histological and Molecular Testing:
The tumor sample is sent to a lab, where pathologists confirm it’s a glioblastoma based on:
- Microscopic features: Necrosis, abnormal cells, and vascular growth
- Immunohistochemistry: Tests for markers like GFAP, Ki-67, IDH1, and MGMT
- Genetic/molecular testing:
| Marker | Use |
|---|---|
| IDH1 mutation | Better prognosis |
| MGMT promoter methylation | Predicts good response to temozolomide |
| EGFR amplification | Targeted therapy consideration |
| TERT mutation | Worse prognosis, often in primary GBM |
Glioblastoma Multiforme Stages
Unlike cancers of the lung, breast, or colon, glioblastoma isn’t staged using the common Stage I to IV system. That’s because:
- It does not spread outside the brain
- It’s already considered high-grade and aggressive at the time of diagnosis
- Tumor size and location matter less than its molecular profile and how deeply it infiltrates brain tissue
Instead of numbered stages, glioblastoma is classified as WHO Grade 4 Astrocytoma (the highest grade for brain tumors). This grade means:
- It grows rapidly
- It is capable of invading nearby tissues
- It shows histological features like central necrosis and vascular proliferation
- It’s the most aggressive type of glioma
Treatment of Glioblastoma Multiforme
Glioblastoma is among the most challenging brain cancers. It’s aggressive, growing and spreading quickly in the delicate tissue of the brain, and it’s prone to relapse despite the most painstaking efforts to remove it. While there’s no cure, the good news is that there are treatments that can slow the growth of glioblastoma, reduce symptoms, and help the patient live longer.
The standard treatment is to hit the cancer on three fronts: with surgery to cut out as much as possible, radiation therapy that targets the tissue left behind, and chemotherapy to kill any remaining cancer cells. This combination, known as the Stupp regimen, involves maximal safe surgical removal, followed by several weeks of radiotherapy given alongside the oral chemotherapy drug temozolomide. After that, temozolomide is continued in monthly cycles for several months.[9] This approach, named after the doctor who pioneered it, has been shown to extend survival compared to radiation alone, especially in patients whose tumors respond better to chemotherapy.[10]
Step 1: Surgery (Resection):
Whenever possible, doctors aim to remove as much of the tumor as they can. But complete removal is almost never possible, since glioblastoma infiltrates surrounding brain tissue. Still, removing even part of the tumor can:
- Relieve pressure
- Improve symptoms
- Make radiation and chemo more effective
Step 2: Radiation Therapy:
After surgery, patients receive radiation therapy to kill any tumor cells left behind. Typically delivered over 6 weeks, with the goal of slowing recurrence and controlling symptoms.
Step 3: Chemotherapy (Temozolomide):
At the same time as radiation therapy, and as maintenance, patients are given temozolomide, a chemotherapy drug in pill form, daily during radiation, then in monthly cycles.
Temozolomide works better if the tumor has MGMT promoter methylation (a biomarker that helps predict chemo sensitivity).
Standard of care for newly diagnosed glioblastoma. (A) Patients present with symptoms prompting imaging and biopsy. (B) Surgery aims to remove as much tumor as safely possible. (C) Post-op treatment includes radiation (60 Gy in fractions). (D) Temozolomide is given during and after radiation in monthly cycles. (Image Courtesy: Rodgers, L. T., Villano, J. L., Hartz, A. M., & Bauer, B. (2023). Glioblastoma Standard of Care: Effects on Tumor Evolution and Reverse Translation in Preclinical Models. Cancers, 16(15), 2638. Available fromMDPI. Licensed under CC by 4.0)
Optional Treatments:
- Tumor Treating Fields (TTFields).
- Bevacizumab (Avastin) to targets blood vessel growth.
- Some patients join research studies to try promising new treatments like immunotherapy.
What is the Prognosis for Glioblastoma?
Even with this aggressive treatment, glioblastoma has a poor prognosis. It’s one of the most challenging cancers to treat because it grows too quickly, almost always relapses, and hides deep in the brain, where total surgical removal is impossible.
- Median survival is 12–15 months with standard treatment (surgery + radiation + temozolomide)
- 2-year survival: ~25%
- 5-year survival: < 10% (and often closer to 5%)
- Without treatment, survival may be just a few months
New Research and Future Directions
Glioblastoma is one of the toughest types of cancer — it is also one of the most well-studied. Researchers and physicians all over the world are working to develop more effective treatments, better ways of diagnosing the disease, and finding a cure.
Immunotherapy:
Unlike cancers like melanoma orlung cancer, glioblastoma hasn’t responded well to immunotherapy yet. But researchers are exploring cancer vaccines, checkpoint inhibitors, and CAR-T cell therapy.[11]
Tumor Treating Fields (TTFields):
This wearable device sends low-intensity electrical fields through the scalp, disrupting cancer cell division. It’s already FDA-approved and can extend survival when combined with chemo, with minimal side effects.[12]
Targeted Therapies:
Some drugs aim to block specific mutations in GBM cells—like EGFR inhibitors, TERT blockers, and PI3K pathway suppressors. Results promising.
Gene Therapy & Oncolytic Viruses:
Gene editing tools (like CRISPR) are being tested to repair or silence harmful genes. Oncolytic viruses are engineered to infect and kill tumor cells while sparing healthy tissue
Mechanism of oncolytic virus therapy for glioblastoma. The virus infects tumor cells, causing lysis and release of transgenic products. This triggers antigen presentation, CD8+ T cell activation, and targeted immune attack on infected glioblastoma cells. (Image Courtesy: Shah, S. (2024). Novel Therapies in Glioblastoma Treatment: Review of Glioblastoma; Current Treatment Options; and Novel Oncolytic Viral Therapies. Medical Sciences, 12(1), 1. Available fromMDPI. Licensed under CC by 4.0)
Liquid Biopsies & Early Detection:
Researchers are developing blood and spinal fluid tests that could monitor tumor activity, detect recurrence earlier, and guide treatment decisions without repeated surgeries.
Conclusion
Glioblastoma is a fast-growing and super-aggressive brain tumor. While it remains one of the most difficult cancers to treat, research is advancing, and new therapies are offering hope, opening new doors, and every year brings new trials, tools, and insights. For now, glioblastoma remains a difficult opponent. But the more we learn, the better we fight, and the closer we get to hope that’s more than just a word.
References
[1] Grochans, S., Cybulska, A. M., Simińska, D., Korbecki, J., Kojder, K., Chlubek, D., & Baranowska-Bosiacka, I. (2022). Epidemiology of Glioblastoma Multiforme–Literature Review.Cancers,14(10), 2412. https://doi.org/10.3390/cancers14102412
[2] Slika, H., Karimov, Z., Alimonti, P., Abou-Mrad, T., Fazio, E. D., Alomari, S., & Tyler, B. (2023). Preclinical Models and Technologies in Glioblastoma Research: Evolution, Current State, and Future Avenues. International Journal of Molecular Sciences, 24(22), 16316. https://doi.org/10.3390/ijms242216316
[3] Ostrom, Q. T., Fahmideh, M. A., Cote, D. J., Muskens, I. S., Schraw, J. M., Scheurer, M. E., & Bondy, M. L. (2019). Risk factors for childhood and adult primary brain tumors. Neuro-Oncology, 21(11), 1357. https://doi.org/10.1093/neuonc/noz123
[4] Khabibov, M., Garifullin, A., Boumber, Y., Khaddour, K., Fernandez, M., Khamitov, F., Khalikova, L., Kuznetsova, N., Kit, O., & Kharin, L. (2022). Signaling pathways and therapeutic approaches in glioblastoma multiforme (Review). International Journal of Oncology, 60(6), 69. https://doi.org/10.3892/ijo.2022.5359
[5] Whitfield, B. T., & Huse, J. T. (2022). Classification of adult‐type diffuse gliomas: Impact of the World Health Organization 2021 update. Brain Pathology, 32(4), e13062. https://doi.org/10.1111/bpa.13062
[6] David N Louis, Arie Perry, Pieter Wesseling, Daniel J Brat, Ian A Cree, Dominique Figarella-Branger, Cynthia Hawkins, H K Ng, Stefan M Pfister, Guido Reifenberger, Riccardo Soffietti, Andreas von Deimling, David W Ellison, The 2021 WHO Classification of Tumors of the Central Nervous System: a summary,Neuro-Oncology, Volume 23, Issue 8, August 2021, Pages 1231–1251, https://doi.org/10.1093/neuonc/noab106
[7] Whitfield, B. T., & Huse, J. T. (2022). Classification of adult‐type diffuse gliomas: Impact of the World Health Organization 2021 update. Brain Pathology, 32(4), e13062. https://doi.org/10.1111/bpa.13062
[8] Proietti, G., Sica, G., & Scicchitano, B. M. (2019). Pathological and Molecular Features of Glioblastoma and Its Peritumoral Tissue. Cancers, 11(4), 469. https://doi.org/10.3390/cancers11040469
[9] Kanderi T, Munakomi S, Gupta V. Glioblastoma Multiforme. [Updated 2024 May 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK558954/
[10] Stupp, R., Mason, W. P., van den Bent, M. J., Weller, M., Fisher, B., Taphoorn, M. J., Belanger, K., Brandes, A. A., Marosi, C., Bogdahn, U., Curschmann, J., Janzer, R. C., Ludwin, S. K., Gorlia, T., Allgeier, A., Lacombe, D., Cairncross, J. G., Eisenhauer, E., & Mirimanoff, R. O. (2005). Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.New England Journal of Medicine, 352(10), 987–996. https://doi.org/10.1056/NEJMoa043330
[11] Kanderi T, Munakomi S, Gupta V. Glioblastoma Multiforme. [Updated 2024 May 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK558954/
[12] Wahyuhadi, J., Immadoel Haq, I. B., Arifianto, M. R., Sulistyono, B., Meizikri, R., Rosada, A., Sigit Prakoeswa, C. R., & Susilo, R. I. (2022). Active Immunotherapy for Glioblastoma Treatment: A Systematic Review and Meta-Analysis. Cancer Control : Journal of the Moffitt Cancer Center, 29, 10732748221079474. https://doi.org/10.1177/10732748221079474
[13] Colamaria, A., Leone, A., Fochi, N. P., Napoli, V. D., Giordano, G., Landriscina, M., Patel, K., & Carbone, F. (2023). Tumor treating fields for the treatment of glioblastoma: Current understanding and future perspectives. Surgical Neurology International, 14, 394. https://doi.org/10.25259/SNI_674_2023