Neuro-Oncology
Neuro-Oncology
What Do You Need to Know?
- 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: Do NOT give steroids before biopsy — “ghost tumor” (transient regression obscures diagnosis)
- 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
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
Adult Diffuse Gliomas
Three-Type Classification
| Feature | Astrocytoma IDH-Mutant | Oligodendroglioma | Glioblastoma IDH-Wildtype |
|---|---|---|---|
| IDH status | Mutant | Mutant | Wildtype |
| 1p/19q | Intact (NO codeletion) | Codeleted (REQUIRED) | Intact |
| ATRX | Lost | Retained | Variable |
| p53 | Mutated | Usually wildtype | Variable |
| TERT promoter | Usually wildtype | Mutated | Mutated |
| Other molecular | CDKN2A/B homozygous deletion → grade 4 | — | EGFR amplification, +7/−10 |
| WHO grade | 2, 3, or 4 | 2 or 3 | 4 only |
| Histology | Fibrillary; gemistocytic variant | “Fried egg” cells, chicken-wire vasculature, calcification | Necrosis (palisading), microvascular proliferation |
| Median survival | Grade 2: >10 yr; Grade 4: ~3–5 yr | Grade 2: >12 yr; Grade 3: ~10 yr | ~15 months |
| Treatment | Surgery + RT + TMZ (grade 3–4); observation if low-grade, young, gross total resection | Surgery + RT + PCV (grade 3); PCV superior to TMZ for oligo | Stupp protocol: maximal safe resection + RT (60 Gy/30 fx) + concurrent & adjuvant TMZ |
Key Treatment Protocols
| Protocol | Regimen | Indication |
|---|---|---|
| Stupp protocol | RT 60 Gy (30 fractions) + concurrent TMZ daily → adjuvant TMZ (6 cycles, 5/28 days) | Glioblastoma IDH-wildtype (standard of care) |
| PCV | Procarbazine + CCNU (lomustine) + vincristine | Oligodendroglioma (grade 2–3); shown to prolong OS vs. RT alone |
| TMZ alone | Temozolomide monotherapy | Elderly GBM or poor performance status; especially if MGMT methylated |
| Tumor treating fields (TTFields) | Alternating electric fields via scalp transducers + TMZ | GBM maintenance; modest OS benefit (~5 months) |
💎 Board Pearl
- MGMT methylation predicts TMZ response. MGMT promoter methylation silences DNA repair enzyme → TMZ-induced DNA damage cannot be repaired → tumor cell death. Unmethylated = poor TMZ response
- PCV is superior to TMZ for oligodendroglioma (RTOG 9402, EORTC 26951 trials). For GBM, TMZ (Stupp) is standard
- CDKN2A/B homozygous deletion upgrades IDH-mutant astrocytoma to grade 4 regardless of histology
Other Primary Brain Tumors
Key Tumor Types
| Tumor | Location | Key Features | Histology/Markers | Treatment |
|---|---|---|---|---|
| Meningioma | Dural-based; convexity, parasagittal, sphenoid wing, olfactory groove, CPA | Most common primary brain tumor; extra-axial; calcification (psammoma bodies); en plaque variant; NF2 association; “dural tail” on MRI | EMA+; WHO grade I (80%), II (atypical), III (anaplastic); NF2/merlin loss | Surgery ± RT; observation if small/asymptomatic |
| Schwannoma | CN VIII (vestibular); CPA; spinal nerve roots | Bilateral vestibular schwannomas = NF2; unilateral = sporadic; hearing loss, tinnitus | S100+; Antoni A (compact, Verocay bodies) & Antoni B (loose, myxoid) | Surgery or SRS (Gamma Knife) |
| Ependymoma | 4th ventricle (children); spinal cord (adults, especially with NF2) | Perivascular pseudorosettes; may cause hydrocephalus; spinal myxopapillary variant (conus/filum) | EMA+ (dot-like); GFAP+; perivascular pseudorosettes | Surgery + focal RT; chemotherapy limited role |
| Medulloblastoma | Posterior fossa (cerebellar vermis → 4th ventricle) | Most common malignant pediatric brain tumor; drop metastases (leptomeningeal spread); 4 molecular groups | Synaptophysin+; Homer-Wright rosettes | Surgery + craniospinal RT + chemotherapy |
| Hemangioblastoma | Posterior fossa (cerebellum); spinal cord | Cyst + mural nodule (enhancing); VHL association (multiple); erythropoietin → polycythemia | Inhibin A+; lipid-laden stromal cells; highly vascular | Surgery (curative for sporadic) |
| Craniopharyngioma | Suprasellar | Bimodal: children (5–14) + adults (50–70); calcification; visual field deficits; endocrinopathy | Adamantinomatous: calcification, cholesterol crystals, “wet keratin”, craniopharyngeal duct origin. Papillary: BRAF V600E, adults only | Surgery ± RT; BRAF inhibitors for papillary type |
| DNET | Cortical (temporal lobe) | “Bubbly” multicystic MRI; seizures (often drug-resistant); benign — NO chemo/RT | Specific glioneuronal element; cortical dysplasia | Surgery (curative for seizures) |
| Central neurocytoma | Lateral ventricle (foramen of Monro) | Young adults; may cause hydrocephalus; “fried egg” cells (can mimic oligo on histology) | Synaptophysin+ (key distinction from oligo); neuronal differentiation | Surgery ± RT |
Medulloblastoma Molecular Groups
| Group | Pathway | Demographics | Prognosis | Key Features |
|---|---|---|---|---|
| WNT | WNT/β-catenin | Children & young adults | Best (>90% OS) | Nuclear β-catenin+; monosomy 6; rarely metastatic |
| SHH | Sonic hedgehog | Bimodal (infants + adults) | Intermediate | Cerebellar hemispheres (not vermis); targetable with vismodegib (smoothened inhibitor) |
| Group 3 | MYC amplification | Infants/children; male | Worst (<50% OS) | Large cell/anaplastic; high rate of leptomeningeal dissemination |
| Group 4 | Isochromosome 17q | Children; male predominant | Intermediate | Most common subgroup (~35%); mechanisms still being characterized |
💎 Board Pearl
- Central neurocytoma is synaptophysin+ and intraventricular — this distinguishes it from oligodendroglioma (both have “fried egg” cells, but oligo is synaptophysin− and intraparenchymal)
- Hemangioblastoma + polycythemia + family history = VHL. Screen for renal cell carcinoma and pheochromocytoma
- DNET = benign. Cortical “bubbly” lesion + seizures in a young patient — surgery cures seizures; do NOT treat with chemotherapy or radiation
Pituitary Tumors
Classification
| Type | Hormone | Frequency | Key Clinical Features | Treatment |
|---|---|---|---|---|
| Prolactinoma | Prolactin | Most common functioning (~40%) | Galactorrhea, amenorrhea, infertility, decreased libido | Medical first: cabergoline (D2 agonist) — NOT surgery |
| GH adenoma | Growth hormone | ~20% | Acromegaly (adults): coarse features, enlarged hands/feet, prognathism; gigantism (children) | Surgery (transsphenoidal); octreotide (somatostatin analog); pegvisomant (GH receptor antagonist) |
| ACTH adenoma | ACTH | ~10% | Cushing disease: central obesity, moon facies, striae, proximal myopathy, hypertension, diabetes | Surgery; ketoconazole/metyrapone (adrenal enzyme inhibitors); bilateral adrenalectomy (last resort → risk of Nelson syndrome) |
| TSH adenoma | TSH | Rare (<1%) | Hyperthyroidism with inappropriately normal/elevated TSH | Surgery; octreotide |
| Non-functioning | None (or FSH/LH) | ~30% | Mass effect: bitemporal hemianopia, headache, hypopituitarism | Surgery if symptomatic; observation if incidental |
Pituitary Apoplexy
- Hemorrhage or infarction of a pituitary adenoma (often previously undiagnosed)
- Presentation: sudden severe headache (“thunderclap”), visual loss (chiasmal compression), ophthalmoplegia (cavernous sinus, CN III/IV/VI), altered consciousness
- Endocrine emergency: acute adrenal insufficiency — can be fatal
- Treatment: IV corticosteroids immediately (hydrocortisone 100 mg bolus) → urgent transsphenoidal surgery if visual deterioration
Rathke Cleft Cyst vs. Craniopharyngioma
| Feature | Rathke Cleft Cyst | Craniopharyngioma |
|---|---|---|
| Origin | Rathke pouch remnant | Rathke pouch / craniopharyngeal duct |
| Location | Intrasellar (between anterior & posterior pituitary) | Suprasellar (± intrasellar) |
| Calcification | Rare | Common (adamantinomatous) |
| Enhancement | Thin rim only (no solid enhancement) | Solid + cystic with enhancement |
| Size | Usually small, often incidental | Often large; compresses chiasm |
| Treatment | Observation; surgery if symptomatic | Surgery ± RT |
💎 Board Pearl
- Prolactinoma = MEDICAL treatment first. Cabergoline (or bromocriptine) shrinks the tumor. Surgery only if medical therapy fails or acute visual threat. This is unique among pituitary adenomas
- Pituitary apoplexy = give steroids before anything else. Acute adrenal crisis is the immediate life-threatening concern. Hydrocortisone 100 mg IV bolus, then surgical decompression
- Mild hyperprolactinemia (<200 ng/mL) with a large sellar mass = “stalk effect” (compression of infundibulum blocks dopamine delivery), NOT a prolactinoma. True prolactinomas: prolactin level usually correlates with tumor size (macroadenoma >200 ng/mL)
Brain Metastases
Epidemiology & Sources
- Most common brain tumors overall (10× more common than primary brain tumors)
- Located at gray-white junction (hematogenous spread); 80% supratentorial
| Primary Cancer | Frequency | Key Features |
|---|---|---|
| Lung | #1 source (~40–50%) | Most common overall; both NSCLC and SCLC |
| Breast | #2 | HER2+ and triple-negative subtypes highest risk |
| Melanoma | #3 | Highest propensity per case; often hemorrhagic |
| Renal cell | #4 | Highly vascular; hemorrhagic; may present years after nephrectomy |
| Colorectal | #5 | Usually posterior fossa |
Hemorrhagic Brain Metastases
- Mnemonic: “MR CT” — Melanoma, Renal, Choriocarcinoma, Thyroid
- Melanoma and renal cell are the most likely to hemorrhage on boards
Treatment by Number/Size
| Scenario | Treatment | Notes |
|---|---|---|
| Single metastasis | Surgery + postop SRS or SRS alone | Surgery preferred if large (>3 cm), causing mass effect, or tissue needed for diagnosis |
| Limited (2–4) metastases | SRS (stereotactic radiosurgery) | Each lesion ≤3 cm; avoids neurocognitive effects of WBRT |
| Multiple (>4) metastases | WBRT or SRS | WBRT associated with neurocognitive decline; SRS increasingly used for >4 lesions |
| Leptomeningeal disease | Intrathecal chemotherapy; systemic therapy; RT to symptomatic areas | Poor prognosis (weeks to months) |
Leptomeningeal Carcinomatosis (Carcinomatous Meningitis)
- Primary sources: breast, lung, melanoma (most common solid tumors); leukemia/lymphoma (hematologic)
- Presentation: multifocal cranial neuropathies, radiculopathies, headache, hydrocephalus, cauda equina syndrome
- Diagnosis: CSF cytology (may need ≥3 LPs for sensitivity); MRI with gadolinium (enhancing meninges, nerve roots, nodules)
- CSF findings: elevated protein, low glucose, lymphocytic pleocytosis, positive cytology
- Treatment: intrathecal methotrexate or cytarabine; systemic therapy; prognosis dismal (median survival 2–4 months)
💎 Board Pearl
- Hemorrhagic brain metastasis in a patient with unknown primary = think melanoma, renal, choriocarcinoma, or thyroid. Melanoma is the highest-yield answer on boards
- Single brain metastasis + controlled systemic disease = surgery + SRS, NOT WBRT (cognitive preservation)
- Multiple cranial neuropathies + positive CSF cytology = leptomeningeal carcinomatosis. Repeat LP if first cytology is negative (sensitivity ~50% on first LP, ~90% after three)
CNS Lymphoma
Primary CNS Lymphoma (PCNSL)
| Feature | Details |
|---|---|
| Histology | Diffuse large B-cell lymphoma (DLBCL) in >95% |
| Location | Periventricular white matter; often deep (basal ganglia, corpus callosum); frequently multifocal |
| MRI | Homogeneously enhancing (immunocompetent); ring-enhancing (immunocompromised/HIV) |
| Immunocompromised | HIV/AIDS (CD4 <50); EBV-driven; ring enhancement mimics toxoplasmosis |
| CSF | Elevated protein; positive cytology/flow cytometry (~25%); elevated IL-10; IL-10:IL-6 ratio >1 |
| Eye involvement | Vitreous/retinal infiltration in 15–25%; slit-lamp exam mandatory |
Diagnosis
- Stereotactic brain biopsy — definitive diagnosis
- Do NOT give steroids before biopsy — steroids cause lymphoma regression (“ghost tumor” / “vanishing tumor”) → non-diagnostic biopsy
- Slit-lamp examination and vitreous biopsy (if ocular symptoms)
- Lumbar puncture: cytology, flow cytometry, IL-10
- Whole-body PET/CT to exclude systemic lymphoma
Treatment
- High-dose methotrexate–based chemotherapy = first-line (crosses BBB at high doses)
- Often combined with rituximab (anti-CD20), cytarabine
- NOT surgery (resection does not improve outcome; biopsy only)
- NOT WBRT alone (high neurotoxicity, short remission; now consolidation only)
- Consolidation: high-dose chemotherapy + autologous stem cell transplant OR reduced-dose WBRT
- HIV-PCNSL: ART (immune reconstitution) + high-dose MTX; EBV-directed therapy considered
Intravascular Lymphoma
- Rare aggressive B-cell lymphoma confined to blood vessel lumina
- Presentation: multifocal strokes + cognitive decline + skin lesions + B symptoms + elevated LDH
- Diagnosis: random skin biopsy (even normal-appearing skin) — shows intraluminal lymphoma cells
- Brain biopsy often needed; CSF usually non-diagnostic
- Treatment: R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone)
💎 Board Pearl
- “Ghost tumor”: Periventricular homogeneously enhancing lesion that disappears after steroids = PCNSL. Wait for steroids to wash out (~2 weeks), then re-biopsy
- PCNSL vs. toxoplasmosis in HIV: both ring-enhance. Toxo = multiple, basal ganglia, responds to empiric treatment in 2 weeks; PCNSL = single/periventricular, EBV+ in CSF, thallium/PET avid. If no response to 2 weeks empiric anti-toxo → biopsy
- Unexplained strokes + skin lesions + cognitive decline = intravascular lymphoma. Diagnose with random skin biopsy
Neurocutaneous Syndromes (Phakomatoses)
Master Comparison Table
| Feature | NF1 | NF2 | TSC | VHL |
|---|---|---|---|---|
| Gene | NF1 (neurofibromin) | NF2 (merlin/schwannomin) | TSC1 (hamartin) / TSC2 (tuberin) | VHL |
| Chromosome | 17q11 | 22q12 | 9q34 / 16p13 | 3p25 |
| Inheritance | AD (50% de novo) | AD | AD (2/3 de novo) | AD |
| CNS tumors | Optic pathway glioma (pilocytic astrocytoma); neurofibromas; rare: brainstem glioma | Bilateral vestibular schwannomas; meningiomas (multiple); ependymomas | Cortical tubers; SEGA; subependymal nodules (“candle drippings”) | Hemangioblastomas (cerebellum, spinal cord, retina) |
| Skin findings | Café-au-lait spots (≥6), axillary/inguinal freckling, neurofibromas (dermal, plexiform) | Few skin schwannomas; café-au-lait (fewer than NF1) | Ash-leaf spots (hypomelanotic macules, use Wood lamp), shagreen patch, facial angiofibromas, periungual fibromas | None characteristic |
| Eye findings | Lisch nodules (iris hamartomas) — pathognomonic | Posterior subcapsular cataracts; retinal hamartomas | Retinal astrocytic hamartomas | Retinal hemangioblastomas |
| Other features | Sphenoid wing dysplasia; tibial pseudoarthrosis; learning disability; MPNST risk (8–13%) | — | Cardiac rhabdomyoma (neonatal); renal AML; LAM (lungs); seizures (infantile spasms); autism | Clear cell renal carcinoma; pheochromocytoma; pancreatic cysts/NETs; endolymphatic sac tumors |
| Diagnostic criteria | ≥2 of 7 criteria (NIH) | Bilateral VS OR family hx + unilateral VS/meningioma/schwannoma | Major + minor criteria (clinical/genetic) | Clinical (hemangioblastoma + 1 other) or genetic |
| Targeted therapy | Selumetinib (MEK inhibitor) for plexiform neurofibromas | Bevacizumab for growing schwannomas | Everolimus (mTOR inhibitor) for SEGA and renal AML | Belzutifan (HIF-2α inhibitor) for renal/CNS tumors |
Sturge-Weber Syndrome
| Feature | Details |
|---|---|
| Genetics | Somatic (NOT inherited) GNAQ mutation; sporadic |
| Skin | Port-wine stain (nevus flammeus) in V1 distribution (forehead/upper eyelid) |
| CNS | Ipsilateral leptomeningeal angioma → cortical atrophy, calcification |
| Imaging | “Tram-track” calcification (parallel cortical lines) on CT; leptomeningeal enhancement on MRI |
| Seizures | Contralateral focal seizures (onset usually in first year of life); often refractory |
| Eye | Ipsilateral glaucoma (choroidal angioma); buphthalmos |
| Treatment | AEDs for seizures; laser therapy for port-wine stain; surgery for refractory epilepsy; glaucoma management |
💎 Board Pearl
- NF1 = chromosome 17 = neurofibromas + optic glioma + café-au-lait + Lisch nodules. NF2 = chromosome 22 = bilateral vestibular schwannomas + meningiomas. Remember: NF “1” = 17 (has a “7”); NF “2” = 22 (both “2”s)
- TSC + SEGA = everolimus (mTOR pathway). Cardiac rhabdomyoma in a neonate → think TSC. Infantile spasms + ash-leaf spots = TSC
- Sturge-Weber is NOT inherited — somatic GNAQ mutation. Port-wine stain must involve V1 (forehead) for leptomeningeal involvement risk
- MPNST (malignant peripheral nerve sheath tumor) is the most feared complication of NF1 (8–13% lifetime risk). Rapid growth of a plexiform neurofibroma or new pain = suspect MPNST
Paraneoplastic Neurological Syndromes
Cell-Surface vs. Intracellular Antibodies
| Feature | Cell-Surface Antibodies | Intracellular (Onconeural) Antibodies |
|---|---|---|
| Mechanism | Directly pathogenic — receptor blockade/internalization | Biomarker only — CD8+ T-cell cytotoxicity causes neuronal death |
| Immunotherapy response | Good (reversible dysfunction) | Poor (irreversible neuronal destruction) |
| Primary treatment | Immunotherapy (IVIg, PLEX, rituximab) | Tumor removal |
| Prognosis | Favorable if treated early | Guarded to poor |
High-Yield Antibody–Syndrome–Tumor Associations
| Antibody | Type | Syndrome | Associated Tumor | Board Clue |
|---|---|---|---|---|
| Anti-NMDAR | Cell-surface | Psychiatric → seizures → dyskinesias → autonomic → coma | Ovarian teratoma | Young woman + psychiatric onset; extreme delta brush on EEG |
| Anti-LGI1 | Cell-surface | Limbic encephalitis; FBDS; hyponatremia | Rarely paraneoplastic | Faciobrachial dystonic seizures; SIADH |
| Anti-CASPR2 | Cell-surface | Morvan syndrome (insomnia + neuromyotonia + encephalopathy) | Thymoma | Older male; peripheral nerve hyperexcitability |
| Anti-GABA-B | Cell-surface | Limbic encephalitis with early seizures | SCLC (~50%) | Seizures dominant; status epilepticus |
| Anti-AMPAR | Cell-surface | Limbic encephalitis (relapsing) | SCLC, breast, thymoma (~70%) | Highest paraneoplastic rate among cell-surface Ab |
| Anti-Hu (ANNA-1) | Intracellular | Sensory neuropathy (ganglionopathy); encephalomyelitis | SCLC | Asymmetric painful sensory ataxia + smoker |
| Anti-Yo (PCA-1) | Intracellular | Cerebellar degeneration | Ovary, breast | Woman + subacute ataxia + normal MRI |
| Anti-Ri (ANNA-2) | Intracellular | Opsoclonus-myoclonus | Breast, SCLC | “Dancing eyes–dancing feet” |
| Anti-CV2/CRMP5 | Intracellular | Chorea; optic neuritis; neuropathy | SCLC, thymoma | Chorea + optic neuritis combination |
| Anti-amphiphysin | Intracellular | Stiff-person syndrome (paraneoplastic) | Breast, SCLC | SPS + cancer = amphiphysin (not GAD65) |
| Anti-Ma2 | Intracellular | Limbic/diencephalic encephalitis; hypersomnia | Testicular germ cell (young); lung (older) | Young male + limbic encephalitis → testicular US |
Anti-NMDAR Encephalitis
- Demographics: Young women (but any age/sex); most common autoimmune encephalitis
- Stages: Prodrome (viral-like) → psychiatric (psychosis, agitation) → seizures → movement disorder (orofacial dyskinesias) → autonomic instability → decreased consciousness
- EEG: Extreme delta brush (pathognomonic but not always present)
- Tumor: Ovarian teratoma in 20–50% of women; pelvic imaging mandatory in ALL women
- Treatment: Tumor removal + first-line immunotherapy (steroids, IVIg, PLEX) → second-line (rituximab, cyclophosphamide)
💎 Board Pearl
- Intracellular antibody = poor response to immunotherapy. Neuronal death has already occurred. Treat the tumor — that is the most effective intervention
- Mnemonic: “Yo-Ovary, Hu-Lung, Ri-Breast, Ma-Testis”
- Anti-NMDAR encephalitis: Young woman with new-onset “psychiatric illness” + seizures + movement disorder → check NMDAR antibodies + pelvic imaging for teratoma
Neurotoxicity of Cancer Therapies
Chemotherapy Neurotoxicity
| Drug | Neurologic Toxicity | Mechanism / Key Notes |
|---|---|---|
| Cisplatin | Sensory neuropathy (large fiber); ototoxicity (high-frequency hearing loss) | DRG toxicity (ganglionopathy); cumulative, dose-dependent; irreversible |
| Oxaliplatin | Acute cold-induced paresthesias; chronic sensory neuropathy | Acute: Na+ channel dysfunction; chronic: DRG toxicity |
| Vincristine | Peripheral neuropathy (axonal, sensorimotor); autonomic neuropathy (constipation); SIADH | Microtubule disruption → axonal transport failure; dose-limiting toxicity |
| Methotrexate | Acute: aseptic meningitis (intrathecal). Subacute: transverse myelopathy (intrathecal). Chronic: leukoencephalopathy | Intrathecal + RT combination greatly ↑ risk of leukoencephalopathy; folate antagonist |
| 5-Fluorouracil (5-FU) | Cerebellar syndrome (ataxia, dysarthria, nystagmus) | Dihydropyrimidine dehydrogenase (DPD) deficiency → severe toxicity; check DPD before starting |
| Cytarabine (Ara-C) | Cerebellar toxicity (high-dose); myelopathy (intrathecal) | High-dose (>3 g/m2); risk ↑ with age >50, renal insufficiency |
| Ifosfamide | Encephalopathy (confusion, hallucinations, seizures, coma) | Treat with methylene blue (restores mitochondrial electron transport); chloroacetaldehyde metabolite |
| Bevacizumab | PRES (posterior reversible encephalopathy syndrome); intracranial hemorrhage | Anti-VEGF → endothelial dysfunction; also paradoxically used to treat radiation necrosis |
| Taxanes (paclitaxel, docetaxel) | Sensory-predominant peripheral neuropathy | Microtubule stabilization; length-dependent “stocking-glove” |
| Bortezomib | Painful small-fiber neuropathy | Proteasome inhibitor; reversible after discontinuation in many cases |
Immune Checkpoint Inhibitor (ICI) Neurotoxicity
| Neurologic irAE | Features | Key Notes |
|---|---|---|
| Myasthenia gravis | Ptosis, diplopia, bulbar weakness, respiratory failure | Can be de novo or flare of subclinical MG; anti-AChR Ab+; often overlaps with myositis/myocarditis — fatal triad |
| Encephalitis | Confusion, seizures, altered behavior | Autoimmune mechanism; may be antibody-mediated or T-cell–mediated |
| Peripheral neuropathy | GBS-like (AIDP); CIDP-like | Can be rapidly progressive; check CSF (albuminocytologic dissociation) |
| Myositis | Proximal weakness, elevated CK, myalgia | May overlap with myocarditis — check troponin |
| Hypophysitis | Headache, fatigue, adrenal insufficiency | Most common with anti-CTLA-4 (ipilimumab); pituitary enlargement on MRI |
Radiation Neurotoxicity
| Timing | Syndrome | Features |
|---|---|---|
| Acute (days–weeks) | Cerebral edema | Headache, worsening neurologic deficits; responds to steroids |
| Early-delayed (1–6 months) | Pseudoprogression; somnolence syndrome | Pseudoprogression: ↑ enhancement on MRI mimicking tumor growth (inflammation/edema, NOT tumor); somnolence syndrome: fatigue, drowsiness (children after WBRT) |
| Late-delayed (>6 months–years) | Radiation necrosis; leukoencephalopathy; secondary tumors; moyamoya; cognitive decline | Radiation necrosis: permanent; leukoencephalopathy: progressive white matter damage (especially with MTX); secondary meningiomas/gliomas decades later |
Radiation Necrosis vs. Tumor Recurrence
| Modality | Radiation Necrosis | Tumor Recurrence |
|---|---|---|
| MR spectroscopy | High lipid/lactate peak; low choline | Elevated choline; elevated choline:NAA ratio |
| MR perfusion (rCBV) | Low rCBV | High rCBV |
| PET (FDG) | Hypometabolic | Hypermetabolic |
| Treatment | Bevacizumab; steroids; surgical debulking | Re-resection; re-irradiation; salvage chemotherapy |
💎 Board Pearl
- Ifosfamide encephalopathy = methylene blue. This is the only chemotherapy neurotoxicity with a specific antidote
- 5-FU cerebellar toxicity: Ataxia + dysarthria during 5-FU treatment — stop drug, check DPD deficiency
- Pseudoprogression: Increased MRI enhancement within 3 months of completing RT, especially in MGMT-methylated GBM. Do NOT mistake for true progression — continue treatment and reimage in 4–8 weeks
- Radiation necrosis vs. recurrence: Low rCBV on perfusion + high lipid/lactate on spectroscopy = necrosis. High rCBV + high choline = tumor
Pediatric Brain Tumors & Special Topics
Most Common Pediatric Brain Tumors
- Posterior fossa predominance (unlike adults where most tumors are supratentorial)
- Brain tumors are the most common solid tumor in children (second most common cancer after leukemia)
| Tumor | Location | Key Features | Molecular | Prognosis |
|---|---|---|---|---|
| Pilocytic astrocytoma | Cerebellum (posterior fossa); optic pathway (NF1) | Most common pediatric brain tumor; cystic + enhancing mural nodule; WHO grade 1 | BRAF::KIAA1549 fusion | Excellent (>95% 10-yr OS); surgery often curative |
| Medulloblastoma | Cerebellar vermis → 4th ventricle | Most common malignant pediatric brain tumor; drop metastases; Homer-Wright rosettes | 4 molecular groups (WNT best, Group 3 worst) | Variable by molecular group (40–>90% OS) |
| Ependymoma | Floor of 4th ventricle (posterior fossa) | Perivascular pseudorosettes; may extend through foramina of Luschka (“plastic”); hydrocephalus | RELA fusion (supratentorial); PFA (posterior fossa A, worst prognosis in children) | Variable; depends on extent of resection |
| DIPG / Diffuse midline glioma H3 K27-altered | Pons (diffusely expanding) | Devastating prognosis (<10% 2-yr OS); NO surgery (diagnosis often clinical + MRI); diffuse pontine enlargement | H3 K27M mutation (or H3 K27 trimethylation loss) | Worst (median survival ~11 months); RT only (temporarily stabilizes) |
| AT/RT | Posterior fossa; supratentorial in infants | Age <3 years; aggressive; mimics medulloblastoma | INI1 (SMARCB1) loss (or rarely BRG1/SMARCA4) | Poor (but improving with intensive protocols) |
| Choroid plexus papilloma | Lateral ventricle (children); 4th ventricle (adults) | Hydrocephalus from CSF overproduction; papillary fronds | — | Papilloma (WHO 1) = excellent; carcinoma (WHO 3) = poor, TP53 association |
Pseudoprogression vs. True Progression
| Feature | Pseudoprogression | True Progression |
|---|---|---|
| Timing | Within 3 months of completing RT (peak at 1–2 months) | Any time; more likely >3 months post-RT |
| MRI | ↑ Enhancement + edema mimicking tumor growth | Progressive enhancement with mass effect |
| MGMT status | More common in MGMT-methylated tumors (~30%) | — |
| Mechanism | Treatment-induced inflammation, BBB disruption, demyelination | Actual tumor growth |
| Perfusion MRI | Low rCBV | High rCBV |
| Management | Continue treatment; reimage in 4–8 weeks | Change therapy |
⚠ Warning
- DIPG: Do NOT attempt surgical resection — the tumor is diffusely infiltrating the pons. Biopsy only if molecular confirmation needed. Radiation therapy is the sole standard treatment (provides transient improvement)
💎 Board Pearl
- Pilocytic astrocytoma = most common pediatric brain tumor (benign, BRAF fusion, cystic + nodule, grade 1). Medulloblastoma = most common malignant pediatric brain tumor (posterior fossa, drop mets, craniospinal RT)
- AT/RT: Posterior fossa tumor in an infant (<3 yr) = check INI1/SMARCB1. Loss of INI1 on immunohistochemistry is diagnostic
- Pseudoprogression is more common in MGMT-methylated GBM (paradoxically, a good prognostic sign) — do NOT change therapy based on imaging alone within 3 months post-RT. Use perfusion MRI or spectroscopy to differentiate
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