Glioblastoma (GBM)
Summary
Glioblastoma (formerly Glioblastoma Multiforme) is the most common and most lethal primary malignant brain tumour in adults. It is an Astrocytoma (WHO Grade 4) characterised by rapid, infiltrative growth, necrosis, and neovascularisation. Despite maximal therapy, recurrence is inevitable near the resection margin. The 2021 WHO classification requires IDH-wildtype status for the diagnosis (IDH-mutant grade 4s are now called "Astrocytoma, IDH-mutant, Grade 4" and have better prognosis). [1,2]
Key Facts
- Butterfly Glioma: A hallmark pattern where the tumour crosses the midline via the Corpus Callosum, resembling butterfly wings.
- MGMT Status: A crucial biomarker. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme. If the MGMT promoter is Metylayed (silenced), the tumour cannot repair the damage caused by chemotherapy (Temozolomide), making treatment more effective and prognosis better.
- 5-ALA (The Pink Drink): Patients drink this solution before surgery. Under blue light in theatre, the tumour cells fluoresce intense pink, helping the surgeon distinguish tumour from normal brain.
Clinical Pearls
The Dexamethasone Effect: The "mass effect" of a GBM is often 20% tumour and 80% oedema. Giving High Dose Dexamethasone (e.g. 8-16mg) can produce a "Lazarus-like" recovery in a comatose patient within 24 hours by stripping away the fluid. It does not treat the cancer, but buys time.
Morning Headache: The classic "Brain Tumour Headache" (worse on waking, improves when standing) is due to CO2 retention during sleep (vasodilation) and gravity increasing ICP.
First Seizure: A first seizure in an adult requires imaging (CT/MRI) essentially to rule out this diagnosis.
Demographics
- Incidence: 3-4 per 100,000.
- Age: Median age 64.
- Sex: Male > Female (1.6 : 1).
- Risk Factors: Ionising radiation. (Mobile phones have not been proven to cause it).
Molecular Subtypes (WHO 2021)
- Glioblastoma, IDH-wildtype: The classic "GBM". De novo (arises rapidly). Older patients. Worst prognosis.
- Astrocytoma, IDH-mutant, Grade 4: Formerly "Secondary GBM". Arises from lower grade precursor. Younger patients. Better prognosis.
Microscopic Features
- Pseudopalisading Necrosis: Tumour cells lining up around a central area of death (outgrowing blood supply).
- Microvascular Proliferation: Chaotic new vessels (angiogenesis).
Symptoms
- Eyes: Papilloedema (Fundoscopy).
- Neurology: Hemiparesis? Upper Motor Neuron signs (Brisk reflexes, Upgoing plantars).
- Cognition: ACE-III / AMTS deficits.
Imaging
- MRI Brain (Contrast Enhanced): Gold Standard.
- Appearance: Irregular, ring-enhancing mass (contrast leaks from leaky vessels) with a central dark core (necrosis) and extensive surrounding T2/FLAIR hyperintensity (vasogenic oedema).
- Spectroscopy: High Choline (membrane turnover), Low NAA (neuronal loss).
Diagnosis
- Biopsy: Stereotactic or Open. Required for definitive diagnosis and molecular markers (IDH, MGMT).
Management Algorithm (The "Stupp Protocol")
DIAGNOSIS (MRI/Bio)
↓
MAXIMAL SAFE SURGICAL RESECTION
(Debulking / Craniotomy)
(Using 5-ALA guidance)
↓
CONCURRENT CHEMORADIATION
(6 weeks)
Radiotherapy (60 Gy) +
Temozolomide (Daily)
↓
ADJUVANT CHEMOTHERAPY
(6 months)
Temozolomide (5 days/month)
↓
SURVEILLANCE MRI
1. Supportive
- Dexamethasone: Loading dose then wean. Monitor blood sugar. Prescribe PPI (Gastric protection).
- Anticonvulsants: Levetiracetam (Keppra) if seizures occur. Not recommended prophylactically (some controversy).
2. Surgical
- Goal: Gross Total Resection (GTR) without causing new deficits.
- Technologies: Neuronavigation, Awake Craniotomy (for speech areas), 5-ALA fluorescence.
3. Oncological (The Stupp Regimen)
- Temozolomide (TMZ): An oral alkylating agent. Unlike most chemo, it crosses the Blood Brain Barrier.
- Radiotherapy: Targeted beam.
- Tumour Treating Fields (Optune): Wearable device creating electric fields to disrupt mitosis. FDA approved, shown to extend survival, but expensive/cumbersome.
- Cerebral Oesema / Herniation: Coning. Immediate death.
- DVT/PE: Glioblastomas secrete tissue factor, making blood hypercoagulable. Patients are often immobile. LMWH prophylaxis is balanced against bleed risk.
- Treatment Toxicity: Bone marrow suppression (TMZ).
- Median Survival: 12-15 months with treatment. (3-4 months without).
- 5-Year Survival: less than 5%.
- Prognostic Factors:
- Age: Younger is better.
- Performance Status: KPS score.
- Extent of Resection: GTR is better.
- MGMT Methylation: Methylated is better (responds to chemo).
- IDH Mutation: Mutant is better.
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| NG99 | NICE (2018) | Refer all suspected tumours to MDT. Use Stupp protocol for fit patients (PS 0-1). |
| Driving | DVLA | Diagnosis bans driving for 2 years (usually permanent due to prognosis). |
Landmark Trials
1. The Stupp Trial (NEJM 2005)
- Comparison: Radiotherapy alone vs Radiotherapy + Temozolomide.
- Findings: Addition of TMZ increased median survival from 12.1 to 14.6 months. 2-year survival increased from 10% to 26%.
- Impact: Established the global standard of care.
What is a Glioblastoma?
It is a fast-growing, aggressive brain tumour. It grows "roots" into the surrounding healthy brain, making it impossible to remove completely without damaging the brain itself.
Is it curable?
Currently, we cannot cure GBM. The goal of treatment is to extend life and maintain quality of life for as long as possible.
What is the treatment plan?
We usually start with surgery to remove as much as we safely can. After you heal, you will have 6 weeks of radiotherapy combined with chemotherapy tablets. Then, you continue the tablets for another 6 months.
Can I drive?
No. You must surrender your licence immediately. The risk of sudden seizures is too high.
Primary Sources
- Stupp R, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996. PMID: 15758009.
- Louis DN, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021.
- NICE Guideline NG99. Brain tumours (primary) and brain metastases in adults. 2018.
Common Exam Questions
- Pathology: "Features of GBM histology?"
- Answer: Pseudopalisading necrosis and microvascular proliferation.
- Oncology: "Biomarker for chemo response?"
- Answer: MGMT Promoter Methylation.
- Radiology: "Contrast enhancing ring with butterfly appearance?"
- Answer: Glioblastoma.
- Pharmacology: "Why use Temozolomide?"
- Answer: It crosses the Blood Brain Barrier.
Viva Points
- Pseudoprogression: After radiotherapy, the scan can look WORSE (more oedema/enhancement). This is inflammation, not tumour growth. Treat with steroids and wait.
- IDH Mutation: Why does it matter? It fundamentally changes the biology. IDH-mutant tumours have a much slower growth rate and different metabolic pathway (D-2-HG production).
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.