Neuro-Oncology
Neuro-Oncology
What You'll Learn
- WHO 2021: Molecular markers now trump histology — adult diffuse gliomas are classified into 3 types only: astrocytoma (IDH-mutant), oligodendroglioma (IDH-mutant + 1p/19q codeleted), glioblastoma (IDH-wildtype)
- IDH mutation = better prognosis: IDH-mutant astrocytoma (even grade 4) has better outcomes than IDH-wildtype glioblastoma
- 1p/19q codeletion is REQUIRED for oligodendroglioma diagnosis — no codeletion = not an oligodendroglioma regardless of histology
- Brain metastases are the most common brain tumors overall; lung is #1 primary source; melanoma and renal most likely to hemorrhage
- PCNSL: Avoid steroids before diagnostic biopsy when clinically safe — cause transient regression / nondiagnostic tissue (“ghost tumor”). Emergency exception: life-threatening mass effect/edema requires stabilization first (biopsy strategy may need adjustment).
- Neurocutaneous syndromes: NF1 = chr 17, neurofibromas, optic glioma; NF2 = chr 22, bilateral vestibular schwannomas; TSC = mTOR, SEGA, treat with everolimus; VHL = chr 3, hemangioblastomas
- Paraneoplastic: Cell-surface antibodies = treatable; intracellular antibodies = find the tumor, poor immunotherapy response
HighYield Pearls
- WHO 2021 rule: molecular > histology — 3 adult diffuse gliomas only (astrocytoma IDH-mut, oligodendroglioma IDH-mut + 1p/19q, GBM IDH-WT)
- GBM = grade 4 IDH-wildtype astrocytoma; TERT promoter mutation OR EGFR amplification OR +7/−10 qualifies as GBM even without necrosis
- Oligodendroglioma REQUIRES both IDH mutation + 1p/19q codeletion — missing either = not oligo regardless of “fried egg” histology
- CDKN2A/B homozygous deletion upgrades IDH-mutant astrocytoma to grade 4 even without histologic grade 4 features
- Diffuse midline glioma, H3 K27-altered (incl DIPG) = grade 4 by definition; includes K27M mutation AND other mechanisms (H3 K27 trimethylation loss / EZHIP); thalamus/brainstem/spinal cord
- Stupp protocol for GBM: max safe resection + concurrent TMZ/RT 6 wk + adjuvant TMZ (6–12 cycles) ± TTFields (Optune); MGMT methylation predicts TMZ response
- PCNSL: Avoid steroids before biopsy when clinically safe (lymphocytolysis → “ghost tumor”); exception is life-threatening mass effect/edema (stabilize first). High-dose methotrexate backbone ± rituximab/cytarabine; avoid WBRT in elderly (neurotoxicity)
- Prolactinoma: prolactin >200 ng/mL → cabergoline (dopamine agonist) first-line, NOT surgery
- Brain mets at grey-white junction — lung #1 source, melanoma/RCC most likely to hemorrhage. ASTRO 2022: SRS for 1–4 lesions with reasonable PS; conditionally for selected 5–10; resect large symptomatic or diagnostic solitary lesions → postoperative cavity SRS preferred over WBRT for resected limited mets; reserve WBRT for diffuse/miliary, leptomeningeal, SCLC, or SRS-infeasible disease (use hippocampal-avoidance + memantine when WBRT is given)
- Anti-epileptic choice in tumors: LEV/LCM/BRV (non-enzyme-inducing); avoid VPA with chemo (thrombocytopenia, hepatotoxicity)
- Spinal drop mets screen entire spine: medulloblastoma, ependymoma, germ cell, CNS lymphoma
- Bilateral vestibular schwannomas = NF2 until proven otherwise
🔍 Quick ReferenceClinical / imaging · Molecular / pathology · Treatment
Clinical / imaging
- Ring-enhancing mass + central necrosis + edema, “butterfly” across corpus callosum → GBM
- Frontal lobe + calcification + chicken-wire vasculature → oligodendroglioma
- Extra-axial dural-based mass + dural tail + homogeneous enhancement → meningioma
- Sellar mass + bitemporal hemianopia → pituitary adenoma
- Asymmetric sensorineural hearing loss + IAC mass → vestibular schwannoma (bilateral = NF2)
- Pediatric posterior fossa midline mass → medulloblastoma
- Pediatric cerebellar cyst with mural nodule → pilocytic astrocytoma
- Cortical “bubbly”/pseudocystic temporal lesion + drug-resistant focal epilepsy → DNET
- Temporal cystic + nodular enhancing lesion + chronic epilepsy → ganglioglioma
- Periventricular homogeneously enhancing mass + restricted diffusion in HIV/immunocompromised → PCNSL
- Ring-enhancing lesion(s) at grey-white junction → brain metastasis
- Nodular leptomeningeal/dural enhancement + cranial neuropathies + radiculopathies → leptomeningeal carcinomatosis
Molecular / pathology
- “Fried egg” cells + chicken-wire vessels + calcification → oligodendroglioma (IDH-mut + 1p/19q)
- Palisading necrosis + microvascular proliferation → GBM
- Psammoma bodies + whorls + EMA+ → meningioma
- True ependymal rosettes + perivascular pseudorosettes → ependymoma
- RELA fusion (supratentorial) or YAP1 fusion → ependymoma
- Rosenthal fibers + eosinophilic granular bodies + BRAF::KIAA1549 fusion → pilocytic astrocytoma
- BRAF V600E + temporal epilepsy lesion → ganglioglioma (also PXA)
- Diffuse midline glioma, H3 K27-altered (K27M mutation OR H3 K27 trimethylation loss / EZHIP) → grade 4 by definition (includes DIPG)
- CDKN2A/B homozygous deletion in IDH-mut astrocytoma → grade 4 prognosis
- TERT promoter mutation / EGFR amplification / +7−10 in IDH-WT glioma → GBM
- MGMT promoter methylation → better TMZ response + improved survival
- ATRX loss + p53 mutation → astrocytoma IDH-mutant
Treatment / pearls
- Stupp protocol (surgery + concurrent TMZ/RT + adjuvant TMZ ± TTFields) → newly diagnosed GBM
- PCV (procarbazine/CCNU/vincristine) + RT → oligodendroglioma (RTOG 9402/9802)
- Vorasidenib (IDH1/2 inhibitor) → grade 2 IDH-mutant glioma post-resection (INDIGO 2024)
- Bevacizumab → recurrent GBM + symptomatic edema (watch for PRES, hemorrhage, thromboembolism)
- Cabergoline / bromocriptine (dopamine agonist) → prolactinoma (first-line, even macroadenoma)
- Octreotide / lanreotide / pegvisomant → GH-secreting acromegaly (post-transsphenoidal)
- High-dose methotrexate ± rituximab + cytarabine → PCNSL (avoid steroids before biopsy when clinically safe; emergency mass effect / edema is the exception)
- Intrathecal methotrexate or cytarabine → leptomeningeal carcinomatosis
- SRS for 1–4 lesions (and selected 5–10); resect large symptomatic/diagnostic solitary lesions then postop cavity SRS; WBRT (+ HA + memantine) only for diffuse/miliary, leptomeningeal, SCLC, or SRS-infeasible → brain metastases (ASTRO 2022)
- LEV / LCM / BRV (non-enzyme-inducing AEDs) → seizures in brain tumor patients
- Methotrexate → leukoencephalopathy + stroke-like syndrome; cisplatin → neuropathy + ototoxicity + PRES; vincristine → neuropathy + SIADH
- Immune-checkpoint inhibitors → encephalitis / neuropathy / myositis / myasthenia overlap
WHO 2021 CNS Tumor Classification — Key Changes
Core Principles
- Molecular over histology: Molecular markers override histologic appearance for classification
- Grading is now within tumor type — NOT across types (e.g., grade 4 astrocytoma ≠ glioblastoma)
- Three adult-type diffuse gliomas only: astrocytoma IDH-mutant, oligodendroglioma IDH-mutant + 1p/19q codeleted, glioblastoma IDH-wildtype
- New entity: diffuse midline glioma, H3 K27-altered (replaces DIPG)
Key Molecular Markers
| Marker | What It Defines | Clinical Significance |
|---|---|---|
| IDH1/2 mutation | Astrocytoma vs. glioblastoma | IDH-mutant = better prognosis; IDH-wildtype = glioblastoma |
| 1p/19q codeletion | Oligodendroglioma (required) | Must have IDH mutation + 1p/19q codeletion; best prognosis among diffuse gliomas |
| ATRX loss | Astrocytoma IDH-mutant | Mutually exclusive with 1p/19q codeletion |
| p53 mutation | Astrocytoma IDH-mutant | Commonly co-occurs with ATRX loss |
| TERT promoter mutation | Glioblastoma IDH-wildtype | One of three sufficient molecular criteria for GBM diagnosis (even without necrosis) |
| EGFR amplification | Glioblastoma IDH-wildtype | Sufficient for GBM diagnosis regardless of grade |
| +7/−10 | Glioblastoma IDH-wildtype | Combined gain of chr 7 + loss of chr 10; sufficient for GBM diagnosis |
| MGMT methylation | Predictive (not diagnostic) | Predicts temozolomide response; methylated = better TMZ response |
| H3 K27M mutation | Diffuse midline glioma | Thalamus, brainstem, spinal cord; grade 4; devastating prognosis |
| BRAF V600E | Pleomorphic xanthoastrocytoma, papillary craniopharyngioma, some low-grade gliomas | Targetable with BRAF inhibitors (vemurafenib, dabrafenib) |
| BRAF::KIAA1549 fusion | Pilocytic astrocytoma | Most common pediatric brain tumor; WHO grade 1; benign |
💎 Board Pearl
- IDH-wildtype diffuse astrocytoma no longer exists. If a diffuse glioma is IDH-wildtype, it is classified as glioblastoma (grade 4) if it has ANY of: TERT promoter mutation, EGFR amplification, or +7/−10 — even without necrosis or microvascular proliferation
- Grade 4 astrocytoma IDH-mutant ≠ glioblastoma. They are separate entities with different biology and prognosis
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