glioblastoma

**Definition/Classification:** Diffuse astrocytic glioma, IDH-wildtype, WHO CNS grade 4 (2021 WHO classification). Tumors previously called "secondary GBM" with IDH mutation are now classified as astrocytoma, IDH-mutant, grade 4. A diffuse astrocytic glioma that is IDH-wildtype is classified as GBM if it has microvascular proliferation, necrosis, TERT promoter mutation, EGFR amplification, or +7/-10 chromosome copy number changes.

**Epidemiology:** Most common primary malignant brain tumor in adults, peak age 55-65, slight male predominance. Usually supratentorial (frontal, temporal lobes). Risk factors: prior ionizing radiation and rare syndromes (Li-Fraumeni, neurofibromatosis type 1, Turcot).

**Pathophysiology/Molecular:** Arises from astrocytes or neural stem/progenitor cells. Common alterations: EGFR amplification/mutation (EGFRvIII), PTEN loss, TERT promoter mutation, CDKN2A/B deletion, +7/-10, TP53 mutation. MGMT promoter methylation predicts better response to temozolomide. IDH1 mutation is associated with younger age, better prognosis, and the astrocytoma, IDH-mutant category.

**Pathology:** - Gross: Poorly demarcated mass with central necrosis, hemorrhage, and a variegated appearance. It can cross the corpus callosum ("butterfly glioma"). - Microscopy: Pleomorphic, hyperchromatic astrocytes with high mitotic activity. Characteristic findings are **pseudopalisading necrosis** (tumor cells lined up around necrotic foci) and **microvascular (endothelial) proliferation**. - IHC: GFAP positive.

**Clinical presentation:** Headache, seizures, focal neurologic deficits, personality or cognitive change, and signs of raised ICP (papilledema, vomiting, altered mental status). Progression is often rapid over weeks to months. Frontal lobe involvement can cause personality change and abulia. Temporal lobe involvement can cause seizures.

**Imaging:** MRI with gadolinium shows an irregular **ring-enhancing** lesion with central necrosis and surrounding vasogenic edema. The differential for ring-enhancing lesions includes abscess, metastasis, toxoplasmosis (in HIV), primary CNS lymphoma, and demyelination (tumefactive MS). Biopsy is needed for diagnosis.

**Management:** Maximal safe resection, then radiation plus concurrent and adjuvant temozolomide (the Stupp protocol). Tumor-treating fields (TTFields) can be added. Dexamethasone reduces vasogenic edema. Antiepileptics are used only if seizures occur, not prophylactically. Bevacizumab (anti-VEGF) is used for recurrence. Median survival is ~12-18 months, and recurrence is nearly universal because the tumor infiltrates diffusely.

**Boards pearls:** - "Butterfly" lesion crossing the corpus callosum = GBM. - Pseudopalisading necrosis plus GFAP positive = GBM. - Most common primary adult brain tumor is GBM overall, though meningioma is the most common primary benign/extra-axial tumor. Metastases are the most common brain tumors overall. - Pediatric counterparts: pilocytic astrocytoma (cerebellum, Rosenthal fibers, good prognosis) and medulloblastoma. - Contrast with oligodendroglioma ("fried egg" cells, chicken-wire capillaries, 1p/19q codeletion, calcifications).