What is glioblastoma?

What is Glioblastoma

Glioblastoma is the most common and lethal primary malignant brain tumor in adults, classified as WHO grade IV astrocytoma, characterized by aggressive infiltrative growth, microvascular proliferation, and necrosis, with a devastating prognosis where fewer than 5% of patients survive beyond 5 years. 1, 2

Epidemiology and Demographics

• Glioblastoma occurs at an annual incidence of 3-5 per 100,000 population, with peak incidence in the fifth and sixth decades of life 1, 2
• The disease shows a slight male predominance 2
• Ionizing radiation exposure and rare hereditary syndromes are the only definitively established risk factors; cell phone use has no confirmed association 2

Molecular Classification and Pathophysiology

The modern understanding of glioblastoma recognizes it as molecularly distinct entities rather than a single disease:

Primary (IDH-wild-type) Glioblastoma

• Accounts for >90% of all glioblastomas and carries the worst prognosis 1, 2
• Defined by absence of IDH gene mutations and absence of histone H3 gene mutations 1
• Characterized by specific molecular features including TERT promoter mutations, EGFR gene amplification, and/or a +7/-10 cytogenetic signature 1, 2
• Develops de novo without a known precursor lesion 2

Secondary (IDH-mutant) Glioblastoma

• Represents <10% of glioblastomas and is now referred to as "IDH-mutant astrocytoma, WHO grade 4" 1, 2
• Develops from lower-grade precursor lesions (WHO grade II or III gliomas) 2, 3
• Characterized by IDH1 or IDH2 mutations and demonstrates significantly better prognosis than IDH-wild-type tumors 1, 2
• Associated with younger age at diagnosis 3

Pathological Characteristics

• Glioblastoma diffusely infiltrates surrounding brain tissue, frequently crossing the midline to involve the contralateral hemisphere, with tumor cells extending beyond visible imaging abnormalities into peritumoral edema zones 2
• Defining histopathologic features include necrosis and endothelial proliferation, which distinguish it as WHO grade IV 3
• Contrast enhancement occurs in 96% of cases due to blood-brain barrier disruption 2

Clinical Presentation

Patients typically present with one or more of the following:

• New-onset epilepsy/seizures 1
• Focal neurological deficits such as pareses or sensory disturbances 1
• Neurocognitive impairment 1
• Symptoms and signs of increased intracranial pressure (headache, nausea, vomiting, altered consciousness) 1

Prognosis

• Glioblastoma remains the most lethal primary brain tumor, with only one-third of patients surviving 1 year and fewer than 5% living beyond 5 years 2
• The most important prognostic determinants are histologic diagnosis, age, performance status, and MGMT promoter methylation status 2
• Favorable prognostic factors include younger age (<50 years), good performance status, intact neurological function, and extent of surgical resection 1
• IDH mutation status is now disease-defining and separates glioblastoma into fundamentally different biological entities with distinct survival outcomes 2

Diagnostic Approach

• Brain MRI with T2-weighted, T2-FLAIR sequences, and 3D T1-weighted sequences before and after gadolinium-based contrast administration is the diagnostic gold standard 1
• Diagnosis requires tissue confirmation via biopsy or tumor resection, classified according to WHO criteria 1
• Perfusion MRI and amino acid PET can help define metabolic hotspots for tissue sampling 1
• Lumbar puncture is generally not necessary, and staging of other organs is not needed 1

Important Clinical Caveats

• Concordance between local diagnosis and central neuropathology review can be as low as 50%, thus careful review of histology is strongly recommended 1
• Molecular characterization including MGMT promoter methylation, IDH mutations, and 1p/19q codeletion status should complement standard histologic assessment to provide diagnostic and prognostic information 4
• The distinction between glioblastoma and oligodendroglioma is critical, as oligodendrogliomas with 1p/19q codeletion demonstrate markedly better prognosis with 50% of patients alive at 5 years 2