Brain Pathology Report Interpretation: Glioblastoma, IDH-wildtype
This pathology report describes a Glioblastoma, IDH-wildtype, WHO grade 4—the most aggressive primary brain tumor with the poorest prognosis among diffuse gliomas.
Diagnostic Features
The histologic findings definitively establish this as WHO grade 4 disease:
- Microvascular proliferation and palisaded necrosis are the hallmark features that define glioblastoma histologically, distinguishing it from lower-grade astrocytomas 1
- Mitotically active small cells with infiltrative growth pattern confirm the high-grade astrocytic nature 1
Critical Molecular Profile
The molecular markers provide essential prognostic and therapeutic information:
- IDH1 R132H negative: This is the most important prognostic marker. IDH-wildtype glioblastomas represent approximately 90% of glioblastomas, typically occur in patients >55 years, and carry significantly worse prognosis than IDH-mutant tumors 1
- Retained ATRX: Combined with negative IDH1, this confirms astrocytic lineage and rules out oligodendroglioma (which would require 1p/19q codeletion) 1
- p53 mutation not identified: While TP53 mutations are common in IDH-mutant astrocytomas, their absence in IDH-wildtype glioblastoma is not unusual 1
- Ki-67 proliferation rate 10%: This relatively modest proliferation index does not change the grade 4 designation, as the presence of microvascular proliferation and necrosis are sufficient 1
The diagnosis should be: Glioblastoma, IDH-wildtype, WHO grade 4 1
Prognostic Implications
IDH-wildtype status is the single most powerful negative prognostic factor in high-grade gliomas, more significant than histologic grade alone 2:
- IDH-wildtype glioblastomas have median survival of approximately 15 months with standard treatment 1, 3
- Patients with IDH-wildtype anaplastic astrocytomas actually have worse outcomes than patients with IDH-mutant glioblastomas, demonstrating that molecular status supersedes histologic grading for prognosis 2
- The absence of IDH1 mutation in older adults with aggressive imaging features predicts rapid progression characteristic of primary (de novo) glioblastoma 4
MGMT Promoter Methylation—Critical Pending Result
The pending MGMT promoter methylation status is the most important remaining test result, as it directly predicts benefit from temozolomide chemotherapy 1:
- MGMT methylated tumors: Show significantly better response to alkylating chemotherapy (temozolomide) and improved survival 1
- MGMT unmethylated tumors: Derive less benefit from temozolomide, though it remains standard of care 1
- This result should guide discussions about the expected benefit of adjuvant chemotherapy 1
Standard Treatment Approach
The standard treatment for newly diagnosed glioblastoma, IDH-wildtype is the Stupp protocol: maximal safe resection followed by concurrent temozolomide (75 mg/m² daily) with focal radiotherapy (60 Gy in 30 fractions), then maintenance temozolomide (150-200 mg/m² days 1-5 of 28-day cycles) for 6 cycles 3:
- This regimen demonstrated a statistically significant survival benefit with hazard ratio 0.63 (95% CI 0.52-0.75, p<0.0001), increasing median survival by 2.5 months 3
- Pneumocystis pneumonia prophylaxis is required during concurrent chemoradiotherapy and should continue until lymphocyte recovery 3
- The MGMT result will help frame realistic expectations about chemotherapy benefit but does not change the recommendation to proceed with standard treatment 1
Key Clinical Pitfalls
- Do not wait for MGMT results to initiate treatment: Standard chemoradiotherapy should begin regardless of MGMT status 1
- Age matters for prognosis: Much of the poor prognostic effect of advanced age is explained by the predominance of IDH-wildtype tumors in older patients 2
- This is NOT a "secondary glioblastoma": The IDH-wildtype status indicates this is a primary (de novo) glioblastoma, which is biologically distinct from IDH-mutant glioblastoma (formerly called secondary glioblastoma) despite identical histologic appearance 1, 5