CNS Tumors
CNS Tumors
What Do You Need to Know?
- Most common brain tumor overall = metastasis; most common primary malignant brain tumor = glioblastoma (IDH-wildtype, grade 4); most common primary brain tumor (benign + malignant) = meningioma
- Most common pediatric brain tumor = pilocytic astrocytoma (grade 1, cerebellar, BRAF fusion, excellent prognosis); most common malignant pediatric brain tumor = medulloblastoma
- 2021 WHO CNS5 classification integrates molecular markers into tumor diagnosis — key classification-defining markers include IDH mutation status, 1p/19q codeletion, H3 K27-altered status, CDKN2A/B, TERT/EGFR/+7/−10, BRAF, and INI1/SMARCB1. MGMT promoter methylation is a key predictive marker for temozolomide response in glioblastoma but is NOT itself a WHO CNS5 classification-defining marker.
- IDH mutation = better prognosis in diffuse gliomas; IDH-wildtype diffuse astrocytic tumor in adults is classified as glioblastoma regardless of histologic grade if molecular criteria are met
- 1p/19q codeletion defines oligodendroglioma and predicts chemosensitivity (PCV regimen); MGMT promoter methylation predicts temozolomide response in glioblastoma
- Hemorrhagic metastases mnemonic “MR CT”: Melanoma, Renal cell carcinoma, Choriocarcinoma, Thyroid — gray-white junction predilection
- Genetic syndromes: NF1 → optic glioma; NF2 → bilateral vestibular schwannomas + meningiomas; VHL → hemangioblastoma; TSC → SEGA
- Pseudopalisading necrosis + microvascular proliferation = glioblastoma; psammoma bodies = meningioma; Rosenthal fibers = pilocytic astrocytoma; Homer Wright rosettes = medulloblastoma
🚩 Don’t Miss — Test-Day Priorities
- WHO 2021 = molecular > histology: integrated molecular-histologic diagnosis — IDH, 1p/19q, H3 K27-altered (includes K27M and non-K27M mechanisms in diffuse midline glioma), CDKN2A/B, TERT/EGFR/+7−10, BRAF, and INI1/SMARCB1 drive classification, not microscope alone. MGMT methylation is predictive (TMZ response) rather than classification-defining.
- CDKN2A/B homozygous deletion in IDH-mutant astrocytoma → grade 4 even without necrosis or microvascular proliferation; IDH-WT diffuse astrocytic tumor + TERT promoter mutation OR EGFR amplification OR +7/−10 → glioblastoma grade 4 regardless of histology
- Oligodendroglioma requires BOTH IDH-mutant AND 1p/19q codeletion (ATRX retained); 1p/19q codeletion predicts chemosensitivity to PCV; frontal predominance, fried-egg cells, chicken-wire vasculature
- Medulloblastoma 4 molecular groups: WNT (best prognosis, β-catenin nuclear, monosomy 6) > SHH (PTCH1/SUFU; TP53-WT better than TP53-mut) > Group 4 (most common) > Group 3 (MYC amp, worst); all get craniospinal RT + chemo
- Ependymoma molecular subgroups: supratentorial ZFTA (RELA) fusion (worse) vs YAP1 fusion; posterior fossa Group A (high methylation, infants, worse) vs Group B (older, better); perivascular pseudorosettes + true ependymal rosettes
- AT/RT = SMARCB1 (INI1) loss on IHC — pediatric, rhabdoid cells, highly aggressive; germline INI1 = rhabdoid predisposition syndrome; ETMR = LIN28A+ with C19MC alteration (infantile)
- Pilocytic astrocytoma: KIAA1549-BRAF fusion (NOT V600E); cerebellar cyst + enhancing mural nodule; Rosenthal fibers + eosinophilic granular bodies; grade 1, excellent prognosis. PXA, ganglioglioma, papillary craniopharyngioma = BRAF V600E
- NF2-related schwannomatosis (merlin/22q) → bilateral vestibular schwannomas + meningiomas + ependymomas; meningioma brain invasion alone OR atypical histologic features (including necrosis) upgrades to grade 2; grade 3 (anaplastic) requires frank anaplasia, very high mitotic activity, OR molecular criteria (TERT promoter mutation or CDKN2A/B homozygous deletion)
- Hemorrhagic mets mnemonic “MR CT”: Melanoma, RCC, Choriocarcinoma, Thyroid (+ lung) — gray-white junction; PCNSL = periventricular, homogeneously enhancing, restricted diffusion, CD20+ large B-cell, HD-MTX
- Bifocal pineal + suprasellar mass = synchronous germinomas; germinoma is PLAP+/OCT3/4+ and radiosensitive; NGGCTs use serum/CSF AFP (yolk sac) and β-hCG (choriocarcinoma) markers
🔍 Buzzwords & Pathognomonic FindingsHistology · Molecular · Imaging / location
Histology / immunohistochemistry
- Pseudopalisading necrosis + microvascular proliferation → Glioblastoma (astrocytoma grade 4, IDH-wildtype)
- Fried-egg cells + chicken-wire vasculature → Oligodendroglioma
- Perivascular pseudorosettes (radial tumor cells around vessel) + true ependymal rosettes → Ependymoma
- Rosenthal fibers + eosinophilic granular bodies (EGB) → Pilocytic astrocytoma (also PXA, ganglioglioma)
- Homer Wright pseudorosettes + small blue round cells → Medulloblastoma
- Rhabdoid cells with eccentric nuclei + INI1/SMARCB1 loss on IHC → AT/RT (atypical teratoid/rhabdoid tumor)
- Psammoma bodies + whorls + spindle/syncytial cells + EMA+ → Meningioma
- Antoni A (Verocay bodies — palisading nuclei around acellular zone) + Antoni B (loose myxoid) + S100+ → Schwannoma
- Schwann cells + axons + fibroblasts + mast cells (admixed) → Neurofibroma (plexiform variant pathognomonic for NF1)
- Stromal cells with foamy/vacuolated cytoplasm + rich capillary network + inhibin+ → Hemangioblastoma
- Wet keratin nodules + “machine oil” cyst fluid → Adamantinomatous craniopharyngioma
- Lymphocyte-rich infiltrate + PLAP+ + OCT3/4+ large cells → Germinoma
- CD20+ large B-cell perivascular infiltrate → PCNSL
- Reticulin loss (vs normal acinar pattern) + monomorphic cells → Pituitary adenoma
- Brachyury (T)+ physaliphorous (bubbly) cells → Chordoma
- Floating neurons in mucin pools + cortical bubbly nodules → DNET (dysembryoplastic neuroepithelial tumor)
- Pleomorphic + xanthomatous (lipid-laden) cells + reticulin + EGB → PXA (pleomorphic xanthoastrocytoma)
Molecular markers
- IDH-wildtype + TERT promoter mutation / EGFR amplification / +7/−10 → Glioblastoma grade 4 (regardless of histology)
- CDKN2A/B homozygous deletion (in IDH-mutant astrocytoma) → Grade 4 upgrade even without histologic features
- IDH-mutant + 1p/19q codeletion + ATRX-retained (both required) → Oligodendroglioma (PCV-chemosensitive)
- MGMT promoter methylation → Temozolomide response in glioblastoma
- H3K27M / H3 K27-altered → Diffuse midline glioma, grade 4 (DIPG, thalamus, spinal cord)
- KIAA1549-BRAF fusion → Pilocytic astrocytoma (NOT V600E)
- BRAF V600E → PXA, ganglioglioma, papillary craniopharyngioma (adamantinomatous = NOT V600E)
- ZFTA (RELA) fusion → Supratentorial ependymoma (worse) vs YAP1 fusion (better)
- WNT-activated (nuclear β-catenin, monosomy 6) → Medulloblastoma WNT (best prognosis); MYC amplification → Group 3 (worst); PTCH1/SUFU → SHH
- SMARCB1 (INI1) loss → AT/RT; germline = rhabdoid predisposition syndrome
- LIN28A+ with C19MC alteration → ETMR (embryonal tumor with multilayered rosettes)
- NF2 / merlin (22q) loss → Schwannoma, meningioma, ependymoma
- VHL (3p) inactivation → Hemangioblastoma (cerebellum + spinal) + RCC + pheo
- AFP elevation → Yolk sac tumor; β-hCG elevation → Choriocarcinoma (NGGCTs)
Imaging / location / clinical
- Cystic cerebellar mass with enhancing mural nodule (child) → Pilocytic astrocytoma
- Cystic mass with enhancing mural nodule (adult, cerebellum/spinal) → Hemangioblastoma (VHL; polycythemia from EPO)
- Midline posterior fossa mass in child + hydrocephalus → Medulloblastoma
- 4th ventricle mass in child / spinal cord mass in adult → Ependymoma
- Butterfly lesion crossing corpus callosum → Glioblastoma (or PCNSL)
- Extra-axial dural-based mass + dural tail + intense homogeneous enhancement → Meningioma
- Bilateral CN VIII (cerebellopontine angle) masses → NF2 vestibular schwannomas
- Calcified suprasellar mass with cysts (child) → Adamantinomatous craniopharyngioma
- Periventricular homogeneously enhancing mass + restricted diffusion (immunocompromised) → PCNSL
- Multiple gray-white junction lesions → Brain metastases (lung, breast, melanoma, RCC, colon)
- Bifocal pineal + suprasellar enhancing mass → Synchronous germinomas
- Clival or sacral midline destructive mass → Chordoma (notochordal remnant; brachyury+)
- Superficial temporal cystic mass + epilepsy (young adult) → PXA or ganglioglioma
- Drug-resistant focal epilepsy + cortical bubbly multinodular lesion → DNET
- Olfactory groove mass with intracranial + sinonasal extension → Esthesioneuroblastoma
- Frontal lobe tumor with calcifications (adult) → Oligodendroglioma
- Cardiac myxomas + spotty pigmentation + pigmented schwannoma → Carney complex
WHO Grading Overview
WHO CNS5 Classification (2021)
- The 5th edition of the WHO Classification of CNS Tumors fundamentally shifted from a purely histologic system to an integrated molecular-histologic approach
- Molecular markers are now required for accurate classification of many tumor types
- Key principle: tumors with identical histology but different molecular profiles are now classified as distinct entities with different prognoses and treatment responses
Grading System
| WHO Grade | Biologic Behavior | Examples |
|---|---|---|
| Grade 1 | Low proliferative potential; possible cure with surgery alone | Pilocytic astrocytoma, schwannoma, most meningiomas |
| Grade 2 | Infiltrative, low mitotic activity; tendency to recur and progress | Astrocytoma IDH-mutant (grade 2), oligodendroglioma (grade 2) |
| Grade 3 | Histologic evidence of malignancy (anaplasia, high mitotic activity) | Astrocytoma IDH-mutant, grade 3; Oligodendroglioma IDH-mutant and 1p/19q-codeleted, grade 3 |
| Grade 4 | Highly malignant; rapid growth, necrosis, microvascular proliferation | Glioblastoma IDH-wildtype, diffuse midline glioma H3K27-altered, medulloblastoma |
IDH Mutation — The Central Dividing Line
- IDH-mutant gliomas: Younger patients (20s–40s), frontal lobe predilection, better prognosis, longer survival
- IDH-wildtype gliomas: Older patients (>55), aggressive behavior; diffuse astrocytic gliomas with IDH-wildtype status are classified as glioblastoma if they carry TERT promoter mutation, EGFR amplification, or +7/−10
- IDH1 R132H is the most common mutation (~90% of IDH-mutant gliomas) — detectable by immunohistochemistry
- IDH mutations produce 2-hydroxyglutarate (2-HG) — an oncometabolite detectable by MR spectroscopy
- Adult-type vs pediatric-type distinction: The TERT/EGFR/+7−10 reclassification rule (IDH-wildtype astrocytic tumor → glioblastoma) applies only to adult-type diffuse gliomas. Pediatric-type diffuse high-grade glioma H3-wildtype/IDH-wildtype is a separate CNS5 family with distinct biology and classification
- IHC interpretation pearl (cIMPACT-NOW): IDH1 R132H IHC-negative cases in patients <55 should undergo sequencing for non-canonical IDH1 (R132C/G/L/S) and IDH2 mutations before classifying as IDH-wildtype
Board Pearl
IDH status is the single most important molecular marker in diffuse gliomas. IDH-mutant = better prognosis across all grades. Under WHO CNS5, a histologically low-grade diffuse astrocytic tumor that is IDH-wildtype is reclassified as glioblastoma (grade 4) if it has TERT promoter mutation, EGFR amplification, or +7/−10 chromosomal changes — regardless of the absence of necrosis or microvascular proliferation.
Adult Tumors — Diffuse Gliomas
Classification of Adult-Type Diffuse Gliomas
| Tumor | WHO Grade | Key Molecular Features | Histology | Prognosis |
|---|---|---|---|---|
| Astrocytoma, IDH-mutant | 2, 3, or 4 | IDH1/2 mutation, ATRX loss, TP53 mutation; NO 1p/19q codeletion | Diffusely infiltrating fibrillary astrocytes; anaplasia and necrosis in higher grades | Better than IDH-wildtype GBM; grade-dependent (median ~5–10 yrs grade 2; ~3–5 yrs grade 3; ~2–3 yrs grade 4) |
| Oligodendroglioma, IDH-mutant & 1p/19q-codeleted | 2 or 3 | IDH1/2 mutation + 1p/19q codeletion (both required); TERT promoter mutation common | “Fried egg” cells (perinuclear halo, artifact), chicken-wire vasculature, frequent calcifications | Best prognosis among diffuse gliomas; highly chemosensitive (PCV regimen); median survival >10–15 yrs |
| Glioblastoma, IDH-wildtype | 4 | IDH-wildtype; EGFR amplification, TERT promoter mutation, +7/−10 chromosome changes; MGMT methylation in ~40% | Pseudopalisading necrosis, microvascular proliferation (glomeruloid vessels); highly pleomorphic | Worst prognosis; median survival ~14–16 months with standard treatment (Stupp protocol: surgery + RT + temozolomide) |
| Diffuse midline glioma, H3K27-altered | 4 | Defined by loss of H3 K27 trimethylation; mechanisms include H3K27M mutation (most common), EZHIP overexpression, and EGFR-mutant bithalamic variants | Diffusely infiltrating; variable histology | Very poor prognosis; median survival <1 year; includes DIPG (pediatric pontine), thalamic, and spinal cord gliomas |
Board Pearl
Oligodendroglioma requires BOTH IDH mutation AND 1p/19q codeletion for diagnosis under WHO CNS5. The 1p/19q codeletion results from an unbalanced translocation t(1;19)(q10;p10). If a tumor has IDH mutation but retains 1p/19q → it is an astrocytoma, IDH-mutant (check for ATRX loss and TP53 mutation). The presence of 1p/19q codeletion predicts excellent response to PCV chemotherapy (procarbazine, CCNU/lomustine, vincristine).
Glioblastoma — Key Details
- Most common malignant primary brain tumor in adults (~50% of all gliomas)
- Demographics: Peak age 55–70 years; male predominance (M:F ~1.6:1)
- Location: Hemispheric white matter; frontal and temporal lobes most common; can cross corpus callosum → “butterfly glioma”
- Imaging: Ring-enhancing mass with central necrosis, irregular borders, surrounding edema, mass effect
- MGMT promoter methylation: Present in ~40% of GBM; silences DNA repair enzyme → tumor cannot repair temozolomide-induced DNA damage → better response to temozolomide and improved survival
- Stupp protocol (standard of care): Maximal safe resection → concurrent radiation (60 Gy/30 fractions) + daily temozolomide → adjuvant temozolomide (6 cycles)
- Tumor treating fields (TTFields / Optune): Alternating electric fields disrupt mitosis; shown to improve survival when added to maintenance temozolomide
- Pseudoprogression: Transient increase in enhancement on MRI 2–6 months after chemoradiation (especially with MGMT methylation) — mimics tumor recurrence but is a treatment effect; do NOT change therapy prematurely
Clinical Pearl
Pseudoprogression vs. true progression in GBM: Pseudoprogression occurs in up to 30% of GBM patients (more common with MGMT methylation) at 2–6 months post-chemoradiation. MR perfusion (low rCBV) and MR spectroscopy (no elevated choline) can help distinguish from true recurrence. Updated RANO criteria require confirmation of progression on follow-up imaging or clinical deterioration. Premature treatment changes based on a single MRI can deprive patients of effective therapy.
IDH-Mutant Glioma — Vorasidenib (INDIGO Trial)
- Vorasidenib — oral, brain-penetrant IDH1/2 inhibitor; FDA approved August 2024
- Indication: Residual or recurrent grade 2 IDH-mutant astrocytoma or oligodendroglioma after surgery (when RT/chemo can be deferred)
- INDIGO trial: Doubled progression-free survival vs placebo (27.7 vs 11.1 months); first targeted therapy approved for IDH-mutant low-grade glioma
Oligodendroglioma — RT + PCV (RTOG 9802 / 9402 / EORTC 26951)
- RTOG 9802 — high-risk grade 2 glioma (age >40 OR subtotal resection) → RT + PCV improved median OS from 7.8 to 13.3 years vs RT alone
- Grade 3 oligodendroglioma: RT + PCV is standard per RTOG 9402 and EORTC 26951; long-term survival benefit driven largely by the 1p/19q-codeleted subset
- PCV = procarbazine + CCNU (lomustine) + vincristine; some centers substitute temozolomide for tolerability
Adult Tumors — Other Types
Non-Glial and Extra-Axial Tumors
| Tumor | Key Features | Histology / Markers | Associations |
|---|---|---|---|
| Meningioma | Most common extra-axial tumor; dura-based, well-circumscribed; most are WHO grade 1 (benign); “dural tail” sign on MRI; calcifications common; parasagittal, convexity, and sphenoid wing most common sites | Psammoma bodies (concentric calcified whorls); EMA+, vimentin+; whorled pattern of meningothelial cells | NF2 (merlin/schwannomin loss); chromosome 22q deletion; prior radiation; female predominance (hormonal receptors); progesterone-receptor positive |
| Schwannoma | Vestibular schwannoma (CN VIII) is most common; arises from Schwann cells; well-encapsulated; cerebellopontine angle mass | Antoni A (compact, palisading nuclei) + Antoni B (loose, myxoid); Verocay bodies (nuclear palisades); S100+ | NF2 → bilateral vestibular schwannomas (pathognomonic); sporadic cases are unilateral |
| Primary CNS Lymphoma (PCNSL) | Diffuse large B-cell lymphoma (DLBCL); periventricular location; homogeneous enhancement; “ghost tumor” (melts away with steroids, then recurs); multifocal in 50% | B-cell markers (CD20+, CD79a+); perivascular cuffing (angiocentric growth); high Ki-67 | EBV-associated in immunocompromised (HIV/AIDS, transplant); avoid steroids before biopsy (can cause false-negative); treat with high-dose methotrexate-based regimen, NOT whole-brain RT alone |
| Hemangioblastoma | Highly vascular; cerebellar (most common posterior fossa tumor in adults); cystic with vividly enhancing mural nodule | Stromal cells with lipid-laden vacuoles; rich capillary network; inhibin-A+ (vs metastatic RCC, which is EMA+ / CD10+); not a metastatic tumor | VHL syndrome (chromosome 3p deletion); can produce EPO → secondary polycythemia; also retinal angiomas, pheochromocytoma, renal cell carcinoma. DDx pearl: both hemangioblastoma and metastatic RCC are cerebellar/vascular and VHL-associated — inhibin-A distinguishes |
| Pituitary adenoma (WHO 2022: PitNET — pituitary neuroendocrine tumor) | Most common sellar mass; functional (hormone-secreting) vs. nonfunctional; macroadenoma (>1 cm) can compress optic chiasm → bitemporal hemianopia. Functional subtypes: lactotroph (prolactinoma — most common functional), somatotroph (GH → acromegaly/gigantism), corticotroph (ACTH → Cushing disease), thyrotroph (TSH — rare), gonadotroph (usually nonfunctional — most common nonfunctional macroadenoma) | Uniform cells; immunohistochemistry for hormones (prolactin, GH, ACTH, etc.) and transcription factors (PIT1, TPIT, SF1) | Prolactinoma = most common functional type (treat with dopamine agonists: cabergoline, bromocriptine); macroprolactinoma typically >200 ng/mL with hook-effect potential (falsely low result on undiluted assay — require serial dilution); pituitary apoplexy = acute hemorrhage into adenoma → sudden headache, visual loss, hypopituitarism |
Board Pearl
PCNSL “ghost tumor”: Steroids cause rapid lympholysis → dramatic shrinkage of enhancement on MRI. This is why steroids must be withheld before biopsy whenever possible — administering steroids can render the biopsy non-diagnostic. If steroids were already given, wait for the tumor to regrow before biopsy. PCNSL is treated with high-dose IV methotrexate-based chemotherapy, NOT standard CHOP (cannot cross BBB effectively).
PCNSL — Molecular and Immunophenotype
- MYD88 L265P mutation in ~75% of PCNSL; CD79B mutations also characteristic — both activate NF-κB signaling
- ABC (activated B-cell) subtype of DLBCL (more aggressive than germinal-center DLBCL)
- Immunophenotype: BCL6+, MUM1+, CD10 typically negative — distinguishes from systemic germinal-center DLBCL (which is CD10+, BCL6+, MUM1−)
Intravascular (Angiotropic) Large B-Cell Lymphoma
- Rare DLBCL variant in which lymphoma cells are confined to the lumina of small/medium vessels (no extravascular mass).
- Presents as a cryptogenic multi-territory stroke / encephalopathy mimicking CNS vasculitis — subacute cognitive decline, fluctuating focal deficits, fever, weight loss, B-symptoms.
- Labs: very elevated LDH, pancytopenia, hemophagocytic features; ESR/CRP up; renal/adrenal involvement common.
- Imaging: multiple small DWI-bright infarcts in many vascular territories without a discrete mass; enhancement variable.
- Diagnosis: random skin biopsy (deep dermis — high yield even without skin lesions); brain biopsy if skin negative.
- Treat as systemic DLBCL: R-CHOP ± CNS prophylaxis with high-dose methotrexate.
💎 Board Pearl
Subacute encephalopathy + multi-territory small DWI infarcts + very high LDH + B-symptoms → intravascular lymphoma until proven otherwise. Random skin biopsy first.
Sellar / Parasellar / Ventricular Cysts — Quick Reference
| Lesion | Key Features |
|---|---|
| Colloid cyst | Hyperdense non-enhancing cyst at foramen of Monro; intermittent positional headaches ± sudden obstructive hydrocephalus and drop attacks/sudden death; 3rd–4th decade peak |
| Epidermoid cyst | CSF-density on T1/T2 but restricts on DWI and stays bright on FLAIR (lipid/keratin contents); “pearly tumor”; commonly cerebellopontine angle |
| Arachnoid cyst | Truly CSF-equivalent on all sequences; does NOT restrict on DWI; middle fossa most common; usually incidental |
| Rathke cleft cyst | Non-calcified sellar/suprasellar cyst with intracystic nodule; “claw sign” of pituitary draped around it; rarely apoplexy |
| Hypothalamic hamartoma | Non-enhancing tuber-cinereum mass → gelastic seizures + central precocious puberty ± cognitive decline; treat with focal laser ablation |
| Dermoid cyst | Fat signal (T1 bright); rupture → chemical meningitis with scattered subarachnoid fat droplets |
💎 Board Pearl — Epidermoid vs Arachnoid
Both look like CSF on T1/T2. Epidermoid restricts on DWI (the discriminator) and is bright on FLAIR; arachnoid cyst follows CSF on every sequence.
Meningioma — WHO 2021 Grading
| WHO Grade | Diagnostic Criteria |
|---|---|
| Grade 1 | Benign meningioma; most common; lacks atypical/anaplastic features |
| Grade 2 (atypical) | Brain invasion OR ≥4 mitoses/10 HPF OR 3 of 5 minor criteria (sheeting/loss of architecture, hypercellularity, prominent nucleoli, small-cell change, spontaneous necrosis); also chordoid and clear-cell histologic variants |
| Grade 3 (anaplastic) | ≥20 mitoses/10 HPF OR frank anaplasia (sarcoma/carcinoma/melanoma-like) OR TERT promoter mutation OR CDKN2A/B homozygous deletion; also rhabdoid and papillary variants |
Meningioma — Simpson Grade (Extent of Resection)
| Simpson Grade | Resection Extent | Recurrence Risk |
|---|---|---|
| I | Gross-total resection + dural attachment + abnormal bone | Lowest |
| II | Gross-total resection + coagulation of dural attachment | Low |
| III | Gross-total resection without coagulation or excision of dural attachment | Intermediate |
| IV | Subtotal (partial) resection | High |
| V | Decompression only (biopsy) | Highest |
Additional Entities — Glioneuronal, Embryonal, Mesenchymal & Sellar
Board-Relevant Additional Tumors
| Tumor | Location / Demographics | Histology / Markers | Key Pearls |
|---|---|---|---|
| Pleomorphic xanthoastrocytoma (PXA) | Superficial temporal lobe; children/young adults; seizures | Pleomorphic spindled cells with eosinophilic granular bodies; lipidized (xanthomatous) cells; reticulin network | BRAF V600E in ~60%; usually grade 2; PXA grade 3 if ≥5 mitoses/10 HPF; BRAF inhibitors targetable |
| Ganglioglioma | Temporal lobe; children/young adults; chronic epilepsy | Dysplastic neurons + neoplastic glia (biphasic); eosinophilic granular bodies; CD34+ often | BRAF V600E in ~30%; grade 1 usually; surgery often curative for seizures |
| Central neurocytoma | Intraventricular (foramen of Monro), young adults; obstructive hydrocephalus | Uniform round cells with perinuclear halos — “fried egg” appearance (DDx oligodendroglioma); synaptophysin+ (key distinction from oligo) | Benign; surgery typically curative; grade 2 |
| Lhermitte-Duclos (dysplastic gangliocytoma of cerebellum) | Cerebellum; adults | Enlarged dysplastic cerebellar folia (“tiger-striped” on MRI); abnormal granular/molecular layer architecture | PTEN germline mutation — Cowden syndrome (breast, thyroid, endometrial cancers, mucocutaneous lesions) |
| ETMR (embryonal tumor with multilayered rosettes) | Infants/young children; supratentorial | Multilayered (ependymoblastic) rosettes; primitive neuroectodermal cells | C19MC amplification (chromosome 19q13.42); replaces older entities ependymoblastoma and medulloepithelioma in WHO CNS5; very poor prognosis |
| Chordoma | Clivus (sphenooccipital) or sacrum; adults; midline | Physaliphorous cells (vacuolated “bubble” cells); lobulated, myxoid; brachyury (TBXT)+, cytokeratin+, S100+ | Arises from notochordal remnants; locally aggressive; high recurrence; proton-beam RT often used |
| Choroid plexus tumors | Intraventricular; children (lateral ventricle), adults (4th ventricle) | Papillary fronds; transthyretin (TTR)+, cytokeratin+; papilloma (grade 1), atypical papilloma (grade 2), carcinoma (grade 3) | Li-Fraumeni (TP53) association for choroid plexus carcinoma; can cause CSF overproduction → hydrocephalus |
| Neurofibroma | Peripheral nerves; skin; can be plexiform | Mixed cellularity: Schwann cells + fibroblasts + perineurial cells + axons + mast cells; non-encapsulated (vs schwannoma); S100+ (focal/patchy) | Plexiform neurofibroma is pathognomonic for NF1; MPNST transformation risk (~10% lifetime in NF1) |
Pediatric Tumors
Overview
- Brain tumors are the most common solid tumors in children and the leading cause of cancer-related death in pediatrics
- Posterior fossa tumors predominate in children (unlike adults where supratentorial tumors are more common)
- Key posterior fossa tumors: pilocytic astrocytoma (cerebellum), medulloblastoma (4th ventricle), ependymoma (4th ventricle)
Major Pediatric Brain Tumors
| Tumor | Grade | Location / Features | Histology / Molecular | Prognosis |
|---|---|---|---|---|
| Pilocytic astrocytoma | 1 | Most common pediatric brain tumor; cerebellum (most common), optic pathway; cystic with enhancing mural nodule | Rosenthal fibers (corkscrew eosinophilic fibers), eosinophilic granular bodies; biphasic (compact + loose); BRAF-KIAA1549 fusion | Excellent (>95% 10-year survival); surgical cure often possible |
| Medulloblastoma | 4 | Most common malignant pediatric brain tumor; posterior fossa / 4th ventricle (midline); drop metastases via CSF (requires craniospinal MRI and CSF cytology for staging) | Homer Wright rosettes (tumor cells around central neuropil); small round blue cells; synaptophysin+ | Molecular subgroup-dependent (see below) |
| Ependymoma | 2–3 | 4th ventricle (posterior fossa most common in children); can cause obstructive hydrocephalus; tends to extend through foramina of Luschka/Magendie | Perivascular pseudorosettes (GFAP+ processes radiating around vessels — most characteristic); true ependymal rosettes (less common); see CNS5 subgroups below | Depends on anatomic compartment and molecular subgroup (see table below); gross total resection improves outcomes |
| Craniopharyngioma | 1 | Suprasellar; arises from Rathke pouch remnants; can compress chiasm → bitemporal hemianopia; can cause hypothalamic dysfunction and panhypopituitarism | Adamantinomatous (children): calcifications, “motor oil” cyst fluid, wet keratin, CTNNB1 (β-catenin) mutation Papillary (adults): rarely calcifies, solid, BRAF V600E mutation |
Benign but locally aggressive; recurrence common after incomplete resection; significant endocrine morbidity |
| ATRT (Atypical Teratoid/Rhabdoid Tumor) | 4 | Age <3 years; posterior fossa most common; highly aggressive; can mimic medulloblastoma on imaging | INI1 (SMARCB1) loss on immunohistochemistry (diagnostic); rhabdoid cells with eccentric nuclei | Very poor (median survival <1 year without aggressive multimodal therapy) |
| Diffuse midline glioma (DIPG) | 4 | Pontine (classic DIPG); also thalamic, spinal cord; diffusely expands the pons; historically diagnosed clinically + MRI without biopsy; current practice increasingly favors stereotactic biopsy for molecular profiling (H3K27M, ACVR1, TP53) and trial eligibility | H3K27M mutation; now classified as diffuse midline glioma, H3K27-altered | Dismal; median survival ~9–11 months; radiation provides temporary improvement; no effective chemotherapy to date |
Ependymoma — WHO CNS5 Molecular Subgroups
| Compartment | Subgroup | Key Features | Prognosis |
|---|---|---|---|
| Supratentorial | ZFTA-fusion (formerly RELA) | Most common supratentorial subtype; ZFTA (C11orf95)-RELA fusion activates NF-κB | Worse prognosis |
| YAP1-fusion | Younger children; YAP1-MAMLD1 fusion most common | Better prognosis | |
| Posterior fossa | PFA | H3K27me3 loss on IHC (EZHIP overexpression or H3K27M); infants/young children; lateral location | Poor prognosis |
| PFB | Older children/adults; retains H3K27me3; chromosomal instability | Better prognosis | |
| Spinal | MYCN-amplified spinal ependymoma | Aggressive; arises in spinal cord (NOT posterior fossa); recently recognized distinct entity | Poor; high recurrence/dissemination risk |
Medulloblastoma Molecular Subgroups
| Subgroup | Key Features | Prognosis |
|---|---|---|
| WNT-activated | ~10% of cases; monosomy 6; nuclear β-catenin; often older children; rarely metastatic | Best prognosis (>90% 5-year survival); clinical trials exploring treatment de-escalation |
| SHH-activated & TP53-wildtype | Sonic hedgehog pathway; bimodal age (infants and adults); lateral cerebellar (hemispheric); PTCH1, SMO, SUFU mutations | Intermediate; targeted therapies (vismodegib/sonidegib) for SHH-driven tumors |
| SHH-activated & TP53-mutant | Distinct CNS5 entity from SHH/TP53-wildtype; often Li-Fraumeni-associated; large-cell/anaplastic histology common | Poor prognosis |
| Group 3 | MYC amplification in ~25%; isochromosome 17q common; predominantly male infants/children; frequently metastatic at diagnosis | Worst prognosis (~50% 5-year survival); high rate of leptomeningeal dissemination |
| Group 4 | Most common subgroup (~35%); MYCN amplification in ~35% (vs MYC in Group 3); isochromosome 17q very common; male predominance | Intermediate prognosis |
Board Pearl
Medulloblastoma molecular subgroups for boards: WNT = best prognosis (monosomy 6, nuclear β-catenin). Group 3 = worst prognosis (MYC amplification, disseminated disease). SHH = targetable with hedgehog pathway inhibitors (vismodegib). Always stage medulloblastoma with craniospinal MRI + CSF cytology because of high risk of drop metastases through the CSF (leptomeningeal spread).
Metastatic Brain Tumors
Overview
- Most common brain tumor overall — outnumber primary brain tumors ~10:1
- Occur in 20–40% of systemic cancer patients
- Predilection for the gray-white matter junction (watershed zone where blood vessels narrow, trapping embolic tumor cells)
- Usually well-circumscribed, round, multiple; surrounded by vasogenic edema disproportionate to tumor size
Primary Sources (by Frequency)
- Lung — #1 source overall (~40–50%); both small cell and non-small cell
- Breast — #2 overall; HER2+ and triple-negative subtypes have highest CNS tropism
- Melanoma — highest per-capita propensity to metastasize to the brain; frequently hemorrhagic
- Renal cell carcinoma — hypervascular, hemorrhagic; can present as solitary metastasis years after nephrectomy
- Colorectal — less common but increasing with improved systemic disease control
Hemorrhagic Metastases
- Mnemonic: “MR CT”
- Melanoma
- Renal cell carcinoma
- Choriocarcinoma
- Thyroid carcinoma
- Hemorrhagic brain metastasis can be the presenting manifestation of occult systemic malignancy
- Any lobar hemorrhage in a cancer patient → consider hemorrhagic metastasis
Leptomeningeal Carcinomatosis (Leptomeningeal Metastasis)
- Tumor cells disseminate through the CSF and coat the leptomeninges
- Most common primaries: breast, lung, melanoma, hematologic malignancies
- Presentation: Multifocal cranial neuropathies, radiculopathies, headache, communicating hydrocephalus, cognitive decline
- Diagnosis: CSF cytology (may need repeated LPs; sensitivity ~50% on first tap, ~80% with three taps); MRI with gadolinium shows leptomeningeal enhancement
- Prognosis: Very poor (median survival 6–8 weeks untreated; 3–6 months with treatment)
Clinical Pearl
Solitary brain metastasis vs. solitary cerebral metastasis: “Solitary” means the brain lesion is the only known site of metastatic disease (including no other extracranial metastases). “Single” means one brain lesion but may have other systemic metastases. This distinction matters because a truly solitary brain metastasis may benefit from surgical resection followed by radiation, with potentially longer survival.
Board Pearl
Gray-white junction predilection of brain metastases: Tumor emboli travel through progressively smaller arteries and become trapped at the gray-white junction where vessel caliber narrows. Multiple ring-enhancing lesions at the gray-white junction with surrounding edema in a cancer patient = metastatic disease until proven otherwise. Melanoma has the highest per-capita brain metastasis rate but lung cancer causes the most brain metastases overall due to higher incidence.
Molecular Markers Summary
Key Molecular Markers in CNS Tumors
| Marker | Associated Tumor(s) | Clinical Significance |
|---|---|---|
| IDH1/2 mutation | Astrocytoma, oligodendroglioma | Better prognosis in diffuse gliomas; IDH-wildtype in adults = glioblastoma (with additional molecular criteria) |
| 1p/19q codeletion | Oligodendroglioma (defining feature) | Required for oligodendroglioma diagnosis; predicts chemosensitivity (PCV); better prognosis |
| MGMT promoter methylation | Glioblastoma | Predicts temozolomide response; silences DNA repair → tumor cannot repair alkylating agent damage; improved survival |
| EGFR amplification | Glioblastoma IDH-wildtype | Common (~40%); EGFRvIII variant is a therapeutic target; diagnostic criterion for GBM if IDH-wildtype |
| BRAF V600E mutation | Pleomorphic xanthoastrocytoma, ganglioglioma, papillary craniopharyngioma | Targetable with BRAF inhibitors (vemurafenib, dabrafenib); also seen in some pilocytic astrocytomas |
| BRAF-KIAA1549 fusion | Pilocytic astrocytoma | Most common alteration in pilocytic astrocytoma; activates MAPK pathway; diagnostic marker |
| H3K27M mutation | Diffuse midline glioma | Defines the entity; grade 4 regardless of histology; very poor prognosis |
| INI1 (SMARCB1) loss | ATRT | Loss of INI1 expression on IHC is diagnostic; distinguishes ATRT from medulloblastoma in young children |
| TERT promoter mutation | Glioblastoma, oligodendroglioma | Telomerase activation → immortalization; diagnostic criterion for GBM (if IDH-wildtype); seen in both GBM and oligodendroglioma |
| Ki-67 / MIB-1 | All CNS tumors | Proliferation index; higher = more aggressive; supports grading but not diagnostic alone |
Genetic Syndromes & Associated Tumors
Tumor Predisposition Syndromes
| Syndrome | Gene / Chromosome | Inheritance | Associated CNS Tumors | Other Features |
|---|---|---|---|---|
| Neurofibromatosis Type 1 (NF1) | NF1 (17q11.2) — neurofibromin (RAS-GAP) | AD | Optic pathway glioma (pilocytic astrocytoma), brainstem glioma, other astrocytomas | Café-au-lait spots (≥6), neurofibromas, Lisch nodules, axillary/inguinal freckling, UBOs on MRI |
| Neurofibromatosis Type 2 (NF2) | NF2 (22q12) — merlin/schwannomin | AD | Bilateral vestibular schwannomas (hallmark), meningiomas (multiple), ependymomas | Posterior subcapsular cataracts; fewer skin lesions than NF1 |
| Von Hippel-Lindau (VHL) | VHL (3p25) — VHL protein (ubiquitin ligase) | AD | Hemangioblastoma (cerebellar, spinal, retinal) | Renal cell carcinoma (clear cell), pheochromocytoma, pancreatic cysts/NETs, EPO-producing hemangioblastoma → polycythemia |
| Tuberous Sclerosis Complex (TSC) | TSC1 (9q34, hamartin) or TSC2 (16p13, tuberin) — mTOR pathway | AD | Subependymal giant cell astrocytoma (SEGA) — near foramen of Monro → can cause hydrocephalus; treat with mTOR inhibitor (everolimus) | Cortical tubers, subependymal nodules, cardiac rhabdomyomas, renal angiomyolipomas, facial angiofibromas, ash-leaf spots, seizures (infantile spasms), intellectual disability |
| Sturge-Weber syndrome | GNAQ (R183Q) — somatic mosaic, chromosome 9q21 (NOT inherited) | Sporadic (post-zygotic mosaic) | Leptomeningeal angiomatosis (capillary-venous malformation); cortical calcifications; secondary atrophy — not a true neoplasm | Port-wine stain in V1 distribution + ipsilateral “tram-track” gyriform calcifications on CT, glaucoma, seizures, hemiparesis, cognitive decline. Board trap: not Mendelian. |
| Li-Fraumeni | TP53 (17p13) | AD | Gliomas (especially astrocytomas), choroid plexus carcinoma | Breast cancer, sarcomas, adrenocortical carcinoma, leukemia — multiple cancers at young age |
| Turcot syndrome (APC type) | APC (5q21) | AD | Medulloblastoma | Familial adenomatous polyposis (FAP); colon polyps/cancer |
| Turcot syndrome (MMR type) | MLH1, MSH2, MSH6, PMS2 (mismatch repair) | AD | Glioblastoma | Hereditary nonpolyposis colorectal cancer (Lynch syndrome) |
| Gorlin syndrome (Nevoid basal cell carcinoma) | PTCH1 (9q22) — Hedgehog pathway | AD | Medulloblastoma (desmoplastic/SHH subtype) | Multiple basal cell carcinomas at young age, odontogenic keratocysts, skeletal anomalies, calcified falx cerebri |
Board Pearl
NF1 vs. NF2 tumor associations: NF1 (chromosome 17) = optic glioma + neurofibromas + café-au-lait spots. NF2 (chromosome 22) = bilateral vestibular schwannomas + meningiomas + ependymomas. Remember: NF2 = 2 schwannomas (bilateral). A unilateral vestibular schwannoma is sporadic; bilateral = NF2 until proven otherwise. Turcot syndrome has two types: APC → medulloblastoma, MMR → glioblastoma (mnemonic: APC-MB, MMR-GBM).
Quick Reference Table
CNS Tumors at a Glance
| Tumor | Classic Location | Hallmark Histology | Key Molecular Marker | Must-Know Pearl |
|---|---|---|---|---|
| Glioblastoma | Cerebral hemispheres; crosses corpus callosum | Pseudopalisading necrosis, microvascular proliferation | IDH-wildtype, EGFR amp, TERT, +7/−10 | Most common malignant primary; MGMT methylation predicts TMZ response |
| Oligodendroglioma | Frontal lobe (cortex) | Fried egg cells, chicken-wire vessels, calcifications | IDH-mutant + 1p/19q codeletion | Best prognosis among diffuse gliomas; PCV-sensitive |
| Meningioma | Convexity, parasagittal, sphenoid wing | Psammoma bodies, whorled cells, EMA+ | NF2 / chromosome 22q loss | Most common extra-axial tumor; dural tail sign |
| Schwannoma | Cerebellopontine angle (CN VIII) | Antoni A & B, Verocay bodies, S100+ | NF2 mutation | Bilateral = NF2; unilateral = sporadic |
| PCNSL | Periventricular | B-cell lymphoma, perivascular cuffing | CD20+ | Ghost tumor; avoid steroids before biopsy |
| Pilocytic astrocytoma | Cerebellum (children) | Rosenthal fibers, biphasic pattern | BRAF fusion | Most common pediatric brain tumor; excellent prognosis |
| Medulloblastoma | 4th ventricle / posterior fossa | Homer Wright rosettes, small blue cells | WNT, SHH, Group 3, Group 4 | Drop metastases; WNT = best, Group 3 = worst prognosis |
| Ependymoma | 4th ventricle (children); spinal cord (adults) | Perivascular pseudorosettes | ZFTA-fusion (supratentorial, worse); YAP1-fusion (supratentorial, better); PFA/PFB (posterior fossa); MYCN-amp (spinal) | Can cause obstructive hydrocephalus |
| Craniopharyngioma | Suprasellar | Adamantinomatous (calcifications, motor oil fluid) vs. papillary | CTNNB1 (adam.) / BRAF V600E (papillary) | Rathke pouch remnant; bitemporal hemianopia |
| Hemangioblastoma | Cerebellum | Stromal cells, lipid vacuoles, rich capillary network | VHL (3p25) | VHL-associated; EPO → polycythemia |
| ATRT | Posterior fossa (age <3) | Rhabdoid cells; INI1 loss on IHC | SMARCB1 (INI1) loss | Must distinguish from medulloblastoma; very aggressive |
| Diffuse midline glioma | Pons (DIPG), thalamus, spinal cord | Diffuse infiltration | H3K27M | Grade 4 by definition; dismal prognosis |
| Metastatic tumor | Gray-white junction; multiple | Matches primary tumor | N/A | Most common brain tumor overall; lung = #1 source |
Clinical Pearl
Posterior fossa tumors in children — quick differentiation: Midline cerebellar mass in a child = pilocytic astrocytoma (cystic, mural nodule) vs. medulloblastoma (solid, 4th ventricle, enhancing). A 4th ventricle mass extending through foramina = ependymoma. Age <3 with aggressive posterior fossa mass = think ATRT (check INI1). Diffuse pontine expansion = DIPG / diffuse midline glioma, H3K27-altered.
References
- Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231-1251.
- Weller M, van den Bent M, Preusser M, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021;18(3):170-186.
- Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996.
- Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003.
- Taylor MD, Northcott PA, Korshunov A, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123(4):465-472.
- Ostrom QT, Price M, Neff C, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015–2019. Neuro Oncol. 2022;24(Suppl 5):v1-v95.
- Ropper AH, Samuels MA, Klein JP, Prasad S. Adams and Victor's Principles of Neurology. 12th ed. McGraw-Hill; 2023.
- Brat DJ, Aldape K, Colman H, et al. cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol. 2020;139(3):603-608.
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