How do I interpret pathology results showing an infiltrative glial neoplasm with negative IDH1 (Isocitrate Dehydrogenase 1) R132H immunoreactivity, no p53 mutation, and a Ki67 (Proliferation Marker) proliferation rate of 10% to discuss treatment options with a patient?

Interpreting Pathology Results: Glioblastoma Multiforme

These pathology results indicate a primary (IDH-wildtype) glioblastoma multiforme (WHO Grade IV), which carries the worst prognosis among high-grade gliomas, with median survival of approximately 15 months and only 27% 2-year survival. 1, 2

Key Pathological Features and Their Significance

Histologic Diagnosis

• Infiltrative growth pattern with microvascular proliferation and palisaded necrosis are defining features of glioblastoma multiforme (WHO Grade IV), the most aggressive primary brain tumor 2
• The presence of both microvascular proliferation and necrosis confirms the highest grade malignancy 1

Critical Molecular Markers

IDH1 R132H Negative:

• This negative result indicates primary (de novo) glioblastoma, which accounts for >90% of cases and carries the worst prognosis 2
• IDH-wildtype glioblastomas have median survival of 13-15 months compared to significantly better outcomes in IDH-mutant tumors 1, 2
• The absence of IDH mutation means this tumor did not evolve from a lower-grade precursor lesion 1, 2

p53 Mutation: Not Identified & ATRX Retained:

• The combination of negative IDH1, absent p53 mutation, and retained ATRX is the classic molecular signature of primary glioblastoma 3, 4
• This molecular profile (ATRX+/p53-/IDH1-) represents the "wild-type protein expression group" seen in 11.4% of glioblastomas and confirms primary rather than secondary glioblastoma 3
• Secondary glioblastomas typically show IDH mutation with p53 mutation and ATRX loss 4

Ki67 Proliferation Rate 10%:

• This proliferation index of 10% indicates moderate proliferative activity 1
• While Ki67 helps assess tumor aggressiveness, it is less prognostically significant than IDH status in glioblastoma 3

MGMT Promoter Methylation (Pending):

• This is the single most important pending result for treatment planning 1, 5
• MGMT methylation is predictive for benefit from temozolomide chemotherapy in glioblastoma 1
• Patients with methylated MGMT have median survival of 23 months (49% 2-year survival) versus 13 months (12% 2-year survival) for unmethylated MGMT 1
• The absence of IDH mutation actually enhances the predictive value of MGMT methylation status for chemotherapy benefit 1

Treatment Implications

Standard Treatment Approach:

• Maximal safe surgical resection followed by concurrent temozolomide (75 mg/m² daily) with radiotherapy (60 Gy in 30 fractions), then adjuvant temozolomide (150-200 mg/m² days 1-5 every 28 days for 6 cycles) 5, 6
• This combined modality approach (TMZ/RT→TMZ) remains standard of care regardless of MGMT status, though benefit is greatest with MGMT methylation 1, 5

MGMT-Guided Modifications:

• If MGMT is methylated: Proceed with full temozolomide-based regimen as this predicts substantial benefit from alkylating chemotherapy 1, 5
• If MGMT is unmethylated: Standard TMZ/RT→TMZ remains recommended, though alternative clinical trial enrollment should be considered given limited chemotherapy benefit 1

Age-Based Considerations:

• For elderly patients (>65-70 years) with unmethylated MGMT, hypofractionated radiotherapy alone (34 Gy/10 fractions or 40.05 Gy/15 fractions) may be preferred over combined modality therapy 1, 5
• For elderly patients with methylated MGMT, temozolomide chemotherapy alone may be considered as an alternative to radiotherapy 1, 5

Prognostic Discussion Points

Expected Outcomes:

• Median survival: 15 months overall; 23 months if MGMT methylated, 13 months if unmethylated 1
• 1-year survival: approximately 33% 2
• 2-year survival: 27% overall; 49% if MGMT methylated, 12% if unmethylated 1
• 5-year survival: <5% 2

Favorable Prognostic Factors to Assess:

• Younger age and good performance status (Karnofsky ≥70) are major therapy-independent favorable factors 1, 5
• Extent of surgical resection significantly impacts survival, with gross total resection superior to subtotal resection 1, 5

Critical Pitfall to Avoid

Do not misinterpret this as oligodendroglioma or a more favorable subtype despite the "small cell" morphology mentioned. The combination of negative IDH1, retained ATRX, absent p53 mutation, plus microvascular proliferation and necrosis definitively establishes this as primary glioblastoma 2, 4. True oligodendrogliomas require IDH mutation AND 1p/19q codeletion, which would show ATRX retention but would be IDH-positive 1, 4.