Glioblastoma: Etiology and Pathophysiological Prognosis
Etiology and Risk Factors
The cause of glioblastoma remains largely unknown, with only ionizing radiation exposure and rare hereditary syndromes (Li-Fraumeni, neurofibromatosis type 1, Turcot, Lynch, and Cowden syndromes) established as definitive risk factors. 1, 2 Notably, epidemiological studies have failed to confirm any association between cell phone use and glioblastoma development 1.
The disease shows a slight male predominance with peak incidence in the fifth and sixth decades of life, occurring at an annual rate of 3-5 per 100,000 population 1, 2.
Pathophysiological Classification and Molecular Drivers
Glioblastoma represents WHO grade 4 astrocytic tumors characterized by distinct molecular profiles that fundamentally drive prognosis 1:
Primary (IDH-wild-type) Glioblastoma
- Accounts for >90% of cases and arises de novo without precursor lesions 3
- Defined by specific molecular alterations including:
- These tumors lack IDH mutations and carry the worst prognosis 1
Secondary (IDH-mutant) Glioblastoma
- Develops from lower-grade precursor lesions and represents <10% of glioblastomas 1, 3
- Characterized by:
- IDH-mutated glioblastomas have significantly better prognosis than IDH-wild-type anaplastic astrocytomas, underscoring the dominant prognostic value of IDH status 1
Pathophysiological Behavior
Glioblastomas diffusely infiltrate surrounding brain tissue and frequently cross the midline to involve the contralateral hemisphere 1. Key pathophysiological features include:
- Tumor cells extend beyond visible imaging abnormalities into peritumoral edema zones (T2-weighted MRI abnormalities) 1
- Histologically characterized by high cellularity, nuclear pleomorphism, frequent mitosis, endothelial proliferation, and necrosis 1
- Contrast enhancement occurs in 96% of glioblastomas due to blood-brain barrier disruption rather than tumor size alone 1
- This creates diagnostic challenges, as surgery, radiation, and corticosteroid tapering can mimic tumor progression through increased contrast enhancement 1
Prognosis from Pathophysiological Standpoint
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 1. The median survival is less than 2 years despite maximal therapy 4.
Critical Prognostic Factors
The most important prognostic determinants are histologic diagnosis, age, and performance status 1. From a molecular standpoint:
- MGMT promoter methylation has emerged as the single most important prognostic factor in the current treatment era, as it predicts response to alkylating chemotherapy 1
- IDH mutation status, while previously prognostic, is now disease-defining and separates glioblastoma into fundamentally different biological entities 1
- Younger age and better performance status remain major therapy-independent favorable prognostic factors 1
Pathophysiological Basis for Poor Prognosis
The dismal prognosis stems from several pathophysiological characteristics:
- The infiltrative nature renders gross total resection impossible, as tumor cells extend far beyond visible margins 1
- Nearly all glioblastomas recur despite aggressive multimodal therapy 1
- The blood-brain barrier limits systemic therapy penetration 4
- The unique tumor microenvironment and immune privilege of the brain create substantial therapeutic challenges 4
- Temporal and spatial heterogeneity within individual tumors drives treatment resistance 5
Comparative Prognosis by Subtype
Oligodendrogliomas with 1p/19q codeletion demonstrate markedly better prognosis, with 50% of patients alive at 5 years due to heightened chemotherapy sensitivity 1. In contrast, anaplastic astrocytomas show intermediate prognosis with 27% 5-year survival 1.
The distinction between primary and secondary glioblastoma based on IDH status represents the most clinically significant pathophysiological classification, as IDH-mutant tumors demonstrate prolonged survival regardless of histological grade 1, 3.