Makindo Medical Notes

Related Subjects: |Brain tumours |Astrocytomas |Brain Metastases |Tuberous sclerosis |Turcot's syndrome |Lhermitte Duclos Disease |Oligodendroglioma |Acute Hydrocephalus |Intracranial Hypertension |Primary CNS Lymphoma (PCNSL) |Astrocytomas |Glioblastoma

Glioblastoma is the most aggressive primary malignant brain tumour in adults and is classified as a WHO Grade 4 astrocytic tumour. It is characterised by rapid growth, diffuse infiltration into surrounding brain tissue, and profound resistance to therapy. Despite advances in surgery, radiotherapy, and chemotherapy, prognosis remains poor, making understanding its biology and management essential for clinicians.

Epidemiology

• Most common malignant primary brain tumour in adults.
• Peak incidence in the 6th–7th decades of life.
• Slight male predominance.
• Rare in children, where molecular features differ significantly.

Pathophysiology

Glioblastomas arise from astrocytic lineage cells or neural stem cells that acquire multiple oncogenic mutations. Their lethality stems from diffuse infiltration along white matter tracts, making complete surgical resection impossible. Rapid angiogenesis and areas of hypoxia drive further genetic instability and aggressive behaviour.

• Pseudopalisading necrosis: hallmark histological feature caused by tumour hypoxia.
• Microvascular proliferation: abnormal leaky vessels driven by VEGF.
• Infiltrative growth: tumour cells extend far beyond visible margins.

Molecular Classification (WHO 2021)

Modern classification integrates molecular genetics with histology. Adult glioblastoma is defined as an IDH-wildtype diffuse astrocytic tumour with specific molecular features, even if classical histology is incomplete. This molecular shift reflects improved prognostic accuracy and trial stratification.

• IDH-wildtype status (key defining feature).
• TERT promoter mutations.
• EGFR amplification or mutation.
• Chromosomal +7 / −10 signature.

Clinical Presentation

Symptoms depend on tumour location and mass effect. Rapid progression over weeks to months is typical, distinguishing GBM from lower-grade gliomas. Raised intracranial pressure and focal neurological deficits are common.

• Persistent or progressive headache (often morning-predominant).
• New-onset seizures in adults.
• Focal deficits such as weakness, aphasia, or visual field loss.
• Cognitive and personality changes.

Neuroimaging

MRI with contrast is the imaging modality of choice. Radiological features reflect necrosis, angiogenesis, and surrounding vasogenic oedema. Advanced imaging helps differentiate GBM from mimics such as abscess or metastasis.

• Irregular ring-enhancing mass on T1 post-contrast.
• Central necrosis with heterogeneous signal.
• Extensive surrounding T2/FLAIR oedema.
• Elevated perfusion and restricted diffusion in solid tumour regions.

Diagnosis

Definitive diagnosis requires histological confirmation, usually obtained via surgical resection or stereotactic biopsy. Tissue sampling allows both morphological assessment and molecular profiling, which is now essential for classification and management planning.

• Surgical resection where safely feasible.
• Stereotactic biopsy if lesion is deep or unresectable.
• Mandatory molecular testing.

Management

Treatment is multimodal and palliative in intent. The aim is maximal tumour control while preserving neurological function. UK practice follows neuro-oncology MDT decision-making with early palliative care involvement.

• Maximal safe surgical resection.
• Radiotherapy (typically 60 Gy in 30 fractions).
• Concurrent and adjuvant temozolomide chemotherapy.
• Corticosteroids for cerebral oedema.

Prognosis

Glioblastoma carries a poor prognosis due to its infiltrative nature and treatment resistance. Median survival is approximately 12–18 months, with long-term survival rare. Molecular features and functional status strongly influence outcomes.

• Median survival: ~12–18 months.
• Better outcomes with good performance status.
• MGMT promoter methylation predicts better response to temozolomide.

Key Learning Points

• Glioblastoma is defined by molecular criteria, not histology alone.
• Diffuse infiltration explains inevitable recurrence.
• Management is multidisciplinary and primarily palliative.
• Early honest prognostic discussions are essential in UK practice.