A 38-year-old woman from Delhi presents with a 6-month history of progressive headaches, morning nausea, and recent-onset focal seizures. MRI brain reveals a well-demarcated, non-enhancing intra-axial mass in the left frontal lobe with significant surrounding edema. The tumor shows a heterogeneous signal on T2-weighted imaging. Histopathology demonstrates a diffuse infiltrative neoplasm with moderate cellularity, nuclear pleomorphism, and scattered mitotic figures. Immunohistochemistry is positive for GFAP and negative for IDH1 R132H mutation. What is the most likely diagnosis?

Explanation

## Diagnosis: Diffuse Astrocytoma, IDH-Wildtype (WHO Grade II/III) ### Key Clinical Features **Key Point:** The combination of a diffuse, non-enhancing intra-axial mass with moderate cellularity, nuclear pleomorphism, and mitotic activity in an adult strongly suggests a diffuse glioma. ### Histopathological Clues - GFAP positivity confirms astrocytic differentiation - **Negative IDH1 R132H mutation** is the critical finding — this indicates an IDH-wildtype tumor, which carries a worse prognosis than IDH-mutant variants - Moderate cellularity and mitotic figures rule out low-grade pilocytic astrocytoma - The diffuse infiltrative pattern (not well-circumscribed) is characteristic of diffuse astrocytomas ### WHO Classification Context | Feature | Pilocytic (Gr I) | Diffuse Astro (Gr II/III) | Oligodendro (Gr II) | Ependymoma (Gr II) | | --- | --- | --- | --- | --- | | **Appearance** | Well-circumscribed | Diffuse, infiltrative | Diffuse | Intra-ventricular/spinal | | **Enhancement** | Often enhances | Non-enhancing (Gr II) | Non-enhancing | Variable | | **IDH mutation** | Rare | Common (Gr II), variable (Gr III) | Frequent | Rare | | **GFAP** | Positive | Positive | Negative | Positive | | **Age** | Children/young adults | Adults | Adults | Any age | **High-Yield:** IDH-wildtype diffuse astrocytomas have significantly worse outcomes than IDH-mutant tumors — this molecular distinction is now part of the WHO 2021 classification and has major prognostic and therapeutic implications. ### Why This Diagnosis Fits 1. Adult patient with diffuse, non-enhancing mass → diffuse glioma 2. GFAP+ → astrocytic lineage 3. IDH-wildtype → poor prognostic subtype 4. Moderate cellularity and mitosis → WHO Grade II/III **Clinical Pearl:** IDH-wildtype diffuse astrocytomas often behave more aggressively than their IDH-mutant counterparts and may warrant more intensive adjuvant therapy (radiation ± chemotherapy) even at lower histological grades.