A 52-year-old man from Mumbai presents with a 3-month history of progressive weakness in the right arm and leg, followed by generalized tonic-clonic seizures. MRI brain shows a large, ring-enhancing mass in the left motor cortex with significant vasogenic edema and mass effect. The lesion demonstrates high signal on diffusion-weighted imaging (DWI). Histology shows a highly cellular neoplasm with marked nuclear pleomorphism, numerous mitotic figures (>10 per 10 HPF), and areas of necrosis surrounded by pseudopalisading cells. GFAP and p53 immunostains are strongly positive. IDH1 R132H is negative. What is the most likely diagnosis?

Explanation

## Diagnosis: Glioblastoma, IDH-Wildtype (WHO Grade IV) ### Critical Histological Features **Key Point:** The presence of **necrosis with pseudopalisading** is the pathognomonic hallmark that elevates this tumor to WHO Grade IV, regardless of other features. ### Diagnostic Criteria for Glioblastoma (WHO Grade IV) | Criterion | Finding in This Case | | --- | --- | | **Necrosis** | Present (pseudopalisading) | | **Mitotic activity** | High (>10/10 HPF) | | **Nuclear pleomorphism** | Marked | | **Microvascular proliferation** | Implied by ring enhancement | | **GFAP positivity** | Confirms astrocytic origin | | **IDH status** | Wildtype (worse prognosis) | **High-Yield:** Pseudopalisading necrosis — where tumor cells arrange in a fence-like pattern around areas of central necrosis — is the defining feature that distinguishes glioblastoma (Grade IV) from anaplastic astrocytoma (Grade III). Even a single focus of necrosis upgrades the tumor to Grade IV. ### Imaging Correlates - **Ring enhancement:** indicates blood-brain barrier disruption and necrotic core - **High DWI signal:** reflects high cellularity and restricted diffusion in the solid tumor portions - **Vasogenic edema:** due to increased vascular permeability from VEGF secretion - **Mass effect:** indicates aggressive growth and poor prognosis **Mnemonic: GLIOBLASTOMA features = "NECROSIS + PLEOMORPHISM + MITOSIS"** - **N**ecrosis (pseudopalisading) - **E**nhancement (ring pattern) - **C**ellularity (high) - **R**apid growth (mass effect) - **O**ncogenic mutations (TP53, PTEN, EGFR amplification) - **S**urvival poor (median ~14 months with standard therapy) - **I**DH-wildtype (worse than IDH-mutant) - **S**eizures and focal deficits (common presentation) ### Clinical Pearl **Clinical Pearl:** IDH-wildtype glioblastomas (the most common type, ~90% of de novo glioblastomas) have a median overall survival of 12–15 months with standard therapy (surgery + radiotherapy + temozolomide), whereas IDH-mutant glioblastomas have significantly better outcomes (~31 months). This molecular distinction is now incorporated into WHO 2021 prognostic stratification. ### Why Grade IV, Not Grade III? Anaplastic astrocytomas (Grade III) show high cellularity, pleomorphism, and mitotic activity BUT **lack necrosis**. The presence of necrosis with pseudopalisading is the single most important feature that defines Grade IV glioblastoma and mandates more aggressive treatment.