What is the recommended treatment approach for a patient with a high-grade glioma, OLIG2 (Oligodendrocyte Transcription Factor 2)-positive, IDH1 (Isocitrate Dehydrogenase 1) R132H-negative, and EMA (Epithelial Membrane Antigen)-negative tumor?

Treatment Approach for IDH-Wildtype Glioblastoma

This molecular profile (OLIG2-positive, IDH1 R132H-negative, EMA-negative) is diagnostic of IDH-wildtype glioblastoma (WHO grade 4), and the patient should receive maximal safe surgical resection followed immediately by the Stupp protocol: concurrent temozolomide (75 mg/m² daily) with focal radiotherapy (60 Gy in 30 fractions), then maintenance temozolomide (150-200 mg/m² for 5 days every 28 days for 6 cycles). 1, 2, 3

Molecular Diagnosis Interpretation

The immunohistochemical profile confirms a high-grade astrocytic glioma:

• OLIG2 positivity indicates astrocytic or oligodendroglial lineage, but when combined with the other markers, confirms astrocytic differentiation 4
• IDH1 R132H negativity is the critical finding—this represents IDH-wildtype disease, which accounts for ~90% of glioblastomas and carries the worst prognosis among high-grade gliomas 5, 2
• EMA negativity excludes ependymoma, further supporting the astrocytic diagnosis 5, 4

This constellation definitively indicates glioblastoma, IDH-wildtype, WHO grade 4 (primary/de novo glioblastoma), not a transformed lower-grade lesion. 5, 2

Prognostic Implications

The IDH-wildtype status is the single most powerful negative prognostic factor:

• Median survival: 15 months with standard treatment (2-year survival only 27%) 5, 1
• This is dramatically worse than IDH-mutant glioblastomas, which have median survival exceeding 30 months 5, 2
• The tumor did not evolve from a lower-grade precursor, representing aggressive de novo disease 5, 2

Critical Next Step: MGMT Promoter Methylation Testing

Before initiating treatment, MGMT promoter methylation status MUST be determined, as this is the strongest predictive biomarker for temozolomide benefit:

• MGMT methylated tumors: median survival 23 months (49% 2-year survival) 5, 1
• MGMT unmethylated tumors: median survival 13 months (12% 2-year survival) 5, 1

However, do NOT delay treatment initiation while awaiting MGMT results—standard chemoradiotherapy should begin regardless, as temozolomide remains standard of care even in unmethylated tumors. 2

Standard Treatment Protocol

Phase 1: Maximal Safe Surgical Resection

• Gross total resection significantly improves survival compared to subtotal resection or biopsy alone 5, 6
• Use 5-aminolevulinic acid (5-ALA) fluorescence guidance when available to maximize extent of resection 5
• Obtain sufficient tissue for complete molecular profiling including MGMT status 5

Phase 2: Concurrent Chemoradiotherapy (Stupp Protocol)

Temozolomide 75 mg/m² daily for 42 days concurrent with focal radiotherapy: 3

• Radiotherapy: 60 Gy in 30 fractions over 6 weeks, targeting tumor bed/resection site with 2-3 cm margin 5, 3
• No dose reductions during concurrent phase; only interruptions for toxicity 3
• Continue treatment if ANC ≥1.5 × 10⁹/L, platelets ≥100 × 10⁹/L, and non-hematologic toxicity ≤Grade 1 3

Critical supportive care: Pneumocystis jirovecii pneumonia (PCP) prophylaxis is mandatory during concurrent therapy and must continue until lymphocyte recovery to Grade ≤1. 3

Phase 3: Maintenance Temozolomide (6 Cycles)

Begin 4 weeks after completing concurrent phase: 3

• Cycle 1: 150 mg/m² daily for 5 days, then 23 days rest 3
• Cycles 2-6: Escalate to 200 mg/m² daily for 5 days if Cycle 1 toxicity ≤Grade 2, ANC ≥1.5 × 10⁹/L, and platelets ≥100 × 10⁹/L 3
• Check complete blood count on Day 22 of each cycle 3

Additional Molecular Testing Considerations

While not immediately treatment-altering, complete molecular profiling should include:

• TERT promoter mutation (common in IDH-wildtype glioblastoma) 5
• EGFR amplification (present in ~40% of IDH-wildtype glioblastomas) 5
• +7/-10 cytogenetic signature (chromosome 7 gain/chromosome 10 loss) 5
• CDKN2A/B homozygous deletion (confirms WHO grade 4 status) 5

These markers provide additional prognostic information and may guide future treatment decisions at recurrence. 5

Common Pitfalls to Avoid

• Do not wait for MGMT results to start treatment—begin standard chemoradiotherapy immediately after adequate recovery from surgery 2
• Do not use enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine, phenobarbital) as they interfere with chemotherapy; use levetiracetam, lamotrigine, or valproic acid instead 5
• Do not omit PCP prophylaxis—lymphocytopenia is common and PCP can be fatal 3
• Do not reduce temozolomide dose during concurrent phase—only interrupt or discontinue for severe toxicity 3

Expected Outcomes Based on MGMT Status

If MGMT methylated: Expect substantial benefit from full temozolomide-based regimen with median survival approaching 23 months. 5, 1

If MGMT unmethylated: Temozolomide still provides benefit over radiotherapy alone, though more modest (median survival ~13 months vs. ~12 months with RT alone). 5, 1

Prognostic Factors Beyond Molecular Markers

Additional favorable prognostic factors include:

• Younger age (particularly <50 years) 1
• Good performance status (Karnofsky ≥70) 1
• Extent of resection (gross total > subtotal > biopsy) 1, 6