A 42-year-old Indian male presents with a 3-month history of progressive headaches, morning vomiting, and recent onset focal seizures. MRI brain reveals a well-demarcated, heterogeneous mass in the left frontal lobe with mixed signal intensity, significant peritumoral edema, and mass effect. On histopathology, the tumor shows a mixture of cells with varying nuclear sizes, frequent mitotic figures, and areas of necrosis. Immunohistochemistry is positive for GFAP and negative for IDH1 R132H mutation. What is the most likely diagnosis?

Explanation

## Diagnosis: Glioblastoma Multiforme (WHO Grade IV) ### Clinical Presentation **Key Point:** The constellation of rapidly progressive symptoms (3 months), seizures, morning vomiting (raised intracranial pressure), and focal neurological deficits is classic for a high-grade glioma. ### Imaging Features **High-Yield:** Glioblastoma typically presents with: - Heterogeneous signal intensity (mixed T1/T2 appearance) - Significant peritumoral edema (vasogenic) - Mass effect with midline shift - Ring-like enhancement with central necrosis on contrast-enhanced MRI ### Histopathological Findings **Key Point:** The presence of: 1. Mixed cellularity with marked nuclear pleomorphism 2. Frequent mitotic figures (≥10 per 10 hpf) 3. Areas of necrosis (hallmark of Grade IV) 4. GFAP positivity (astrocytic differentiation) These findings are diagnostic of WHO Grade IV glioblastoma. ### Molecular Marker **Clinical Pearl:** Negative IDH1 R132H mutation indicates a **primary (de novo) glioblastoma** rather than secondary glioblastoma (which would be IDH-mutant). Primary glioblastomas account for ~90% of cases and have worse prognosis. ### Grading Differentiation | Feature | Grade II | Grade III | Grade IV | |---------|----------|-----------|----------| | Mitotic activity | Absent/rare | Present | Frequent (>10/10 hpf) | | Necrosis | Absent | Absent | Present (hallmark) | | Microvascular proliferation | Absent | Absent | Present | | Clinical course | Slow (years) | Intermediate (months) | Rapid (weeks-months) | | Median survival | 5–10 years | 2–3 years | 12–15 months | ### Mnemonic: WHO Grading of Astrocytomas **GFAP-MANIC:** - **G**rade I (Pilocytic): Good prognosis, often cystic - **F**unctional Grade II: Few mitoses, no necrosis - **A**naplastic Grade III: Atypia + mitoses, no necrosis - **P**rimary/secondary Grade IV: Proliferation + necrosis (Glioblastoma) - **M**itoses increase with grade - **A**typia increases with grade - **N**ecrosis = Grade IV (hallmark) - **I**DH mutation = secondary (better prognosis) - **C**ellular pleomorphism increases with grade