A 58-year-old woman from Bangalore presents with a 3-month history of progressive cognitive decline, personality changes, and right-sided weakness. MRI brain reveals a large, heterogeneous mass in the left frontal lobe with marked enhancement, central necrosis, and surrounding vasogenic edema. CSF analysis shows elevated protein (120 mg/dL) and normal glucose. Histopathology demonstrates high cellularity with marked nuclear pleomorphism, abundant mitotic figures, areas of necrosis, and prominent microvascular proliferation. Immunohistochemistry shows GFAP positivity and IDH1 R132H mutation is negative. What is the most likely diagnosis?

Explanation

## Clinical and Radiological Features The patient presents with acute neurological decline (cognitive, behavioral, focal motor deficit) — typical of a rapidly growing intracranial mass. The MRI shows hallmark features of glioblastoma: - **Large heterogeneous mass** - **Ring-like enhancement** (indicating blood-brain barrier disruption) - **Central necrosis** (pathognomonic for high-grade glioma) - **Vasogenic edema** (from increased vascular permeability) ## Histopathological Diagnosis: WHO Grade IV Glioblastoma **Key Point:** The presence of **BOTH necrosis AND microvascular proliferation** is the defining criterion for WHO Grade IV glioblastoma. These two features are not seen in Grade II or III gliomas. | Criterion | Grade II | Grade III | Grade IV | |-----------|----------|-----------|----------| | Necrosis | Absent | Absent | **Present** | | Microvascular proliferation | Absent | Absent | **Present** | | Mitotic activity | Rare | Brisk | Abundant | | Nuclear pleomorphism | Mild | Moderate | **Marked** | | Enhancement on MRI | No | Variable | Yes (ring-like) | ## Molecular Classification: IDH-Wildtype (Primary) vs. IDH-Mutant (Secondary) **High-Yield:** The **negative IDH1 R132H mutation** is the critical distinguishing feature. | Feature | Primary GBM (IDH-WT) | Secondary GBM (IDH-Mutant) | |---------|----------------------|----------------------------| | IDH1/IDH2 mutation | Absent (wildtype) | Present (R132H or R172K) | | Age at presentation | Older (>55 years) | Younger (<45 years) | | Prior lower-grade tumor | No | Yes (Grade II→III→IV) | | TP53 mutation | Common (65%) | Common (65%) | | EGFR amplification | Common (45%) | Rare | | Prognosis | Slightly worse | Slightly better | | Median OS | ~12 months | ~15 months | **Clinical Pearl:** IDH-wildtype GBM accounts for ~90% of all glioblastomas and typically arises de novo in older patients. IDH-mutant GBM (secondary) arises from prior lower-grade diffuse gliomas in younger patients — this patient has no history of prior tumor. ## Why This Is Primary GBM 1. **Age 58** — typical for primary GBM (older population) 2. **No history of prior glioma** — excludes secondary progression 3. **IDH1 R132H negative** — primary GBM is IDH-wildtype 4. **De novo presentation** with rapid clinical course — characteristic of primary GBM **Mnemonic: PIG** — **P**rimary GBM = **I**DH-**G**wildtype (older, de novo).