Brain Tumors

• Definition: Brain tumors are intracranial neoplasms arising from neuroepithelial cells (gliomas), meninges, cranial nerve sheaths, pituitary/sellar remnants, or germ cells, plus metastatic deposits from systemic cancer. The 2021 WHO Classification of Tumours of the CNS (CNS5) grades them I–IV using integrated histologic and molecular criteria rather than histology alone.
• Why it matters: The skull is a fixed vault, so even a histologically benign tumor can kill by mass effect, obstructive hydrocephalus, or herniation. Grade, molecular profile, location, patient age, and performance status drive both therapy and prognosis far more than tumor size.

Epidemiology worth recalling

• Metastases outnumber primary tumors in adults; lung, breast, and melanoma dominate (melanoma has the highest per-case propensity to seed brain, lung supplies the most cases by volume).
• Glioblastoma (IDH-wildtype, WHO grade 4) is the most common malignant primary brain tumor of adults, peaking in the 6th–7th decades with a slight male predominance. Median survival with maximal resection plus chemoradiation is roughly 15 months, and 5-year survival remains under 10%.
• Meningioma is the most common primary intracranial tumor overall, is usually benign (grade 1), and shows a clear female predominance — the stem often mentions a middle-aged woman with new seizures or a slowly progressive deficit.
• Medulloblastoma is the classic malignant posterior fossa tumor of childhood, typically presenting before age 10 with a second smaller peak in young adults.
• In children, tumors are more often infratentorial; in adults, supratentorial. This single anatomic rule explains why children present with ataxia and hydrocephalus while adults present with seizures and focal cortical deficits.
• Primary CNS lymphoma is disproportionately seen in the immunosuppressed (advanced HIV, transplant recipients).

Non-modifiable — inherited tumor-predisposition syndromes (high yield)

• Neurofibromatosis type 1 (NF1, neurofibromin, a Ras-GAP): loss of GTPase activity leaves Ras constitutively active → optic pathway glioma, pilocytic astrocytoma.
• Neurofibromatosis type 2 (NF2, merlin): bilateral vestibular schwannomas, plus meningiomas and ependymomas.
• Tuberous sclerosis (TSC1/TSC2): unrestrained mTOR signaling → subependymal giant cell astrocytoma.
• Von Hippel–Lindau: defective HIF degradation → cerebellar hemangioblastoma, which can secrete erythropoietin and cause secondary polycythemia.
• Li-Fraumeni (TP53): gliomas, choroid plexus carcinoma. Turcot: glioma or medulloblastoma with colorectal polyposis. Gorlin (nevoid basal cell) syndrome (PTCH1): SHH-subgroup medulloblastoma.

Non-modifiable — host factors

• Age: glioblastoma and metastases in older adults; medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma in children.
• Sex/hormones: meningiomas are more common in women, are frequently progesterone-receptor positive, and may enlarge in pregnancy.
• Race/ancestry: gliomas are somewhat more common in white patients; meningiomas more common in Black patients.

Modifiable / acquired

• Therapeutic ionizing radiation — the only firmly established environmental cause. Prior cranial irradiation (e.g., childhood leukemia prophylaxis, tinea capitis treatment historically) predisposes to meningioma, glioma, and sarcoma years later.
• Immunosuppression: HIV with low CD4 count or post-transplant immunosuppression permits EBV-driven primary CNS lymphoma.
• Systemic malignancy: an untreated or advanced lung, breast, melanoma, renal, or colorectal primary is the dominant "risk factor" for an intracranial mass in an adult.

• Driver step: acquired or germline mutations in growth-signaling and tumor-suppressor pathways (IDH1/2, TERT promoter, EGFR amplification, chromosome +7/−10 in glioblastoma; *NF2*/merlin loss in meningioma; SHH or WNT pathway activation in medulloblastoma) produce clonal, unregulated proliferation within a rigid vault.

From mass to symptoms — the Monro–Kellie chain

• Cranial contents (brain, blood, CSF) sum to a fixed volume. A growing tumor is initially buffered by displacement of CSF and venous blood, which is why slow-growing meningiomas can reach enormous size while remaining silent.
• Once buffering is exhausted, the intracranial pressure–volume curve turns exponential: small further growth produces large ICP rises and abrupt clinical decompensation.
• Rising ICP lowers cerebral perfusion pressure (MAP − ICP). The brainstem responds with the Cushing reflex — hypertension, bradycardia, irregular respirations — a preterminal sign.

Vasogenic edema

• Tumor-secreted VEGF drives leaky, fenestrated neovasculature and disrupts blood–brain barrier tight junctions. Plasma protein leaks into white matter, dragging water with it. This edema often contributes more mass effect than the tumor itself — and explains why corticosteroids, which restore BBB integrity, relieve symptoms within hours without shrinking tumor.
• BBB breakdown is also why gadolinium enhances high-grade tumors and metastases but not most low-grade gliomas.

Local consequences

• Cortical irritation by tumor or peritumoral gliosis creates a hyperexcitable epileptogenic focus → focal seizures with or without generalization; low-grade, slow-growing cortical tumors are the most epileptogenic.
• CSF pathway obstruction at the aqueduct, fourth ventricle, or foramina (medulloblastoma, ependymoma, pineal tumors, colloid cyst) → non-communicating hydrocephalus with headache, vomiting, and papilledema.
• Herniation syndromes follow the pressure gradient: uncal herniation compresses CN III (ipsilateral blown pupil) and the posterior cerebral artery; subfalcine herniation compresses the anterior cerebral artery; tonsillar herniation crushes the medulla. Stretching of CN VI over the petrous ridge produces a false localizing abducens palsy.
• Glioma infiltration along white matter tracts (across the corpus callosum → butterfly glioma) makes cure by resection impossible even when imaging looks focal.

Increased ICP (classic, generalized)

• Headache: worse on waking and with Valsalva, coughing, or bending. Recumbency and sleep-related hypercapnia cause cerebral vasodilation and a further ICP rise overnight.
• Vomiting, often projectile and without preceding nausea, from posterior fossa/area postrema pressure.
• Papilledema: transmitted pressure along the optic nerve sheath; may cause transient visual obscurations. A late finding in adults, so its absence never excludes a tumor.
• Cushing reflex and depressed consciousness signal impending herniation.

Seizure

• New-onset focal or generalized seizure in an adult over 40 with no prior epilepsy is a tumor until imaged. Postictal focal weakness (Todd paralysis) can be mistaken for stroke.

Localizing findings (mechanism = which tract or nucleus is displaced)

• Frontal: apathy, disinhibition, executive dysfunction, gait apraxia, urinary incontinence; contralateral hemiparesis if precentral gyrus involved.
• Temporal: focal impaired-awareness seizures, olfactory/gustatory auras, superior quadrantanopia (pie in the sky from Meyer loop).
• Posterior fossa/cerebellar (pediatric stem): truncal or appendicular ataxia, nystagmus, head tilt, morning vomiting, and hydrocephalus.
• Cerebellopontine angle: progressive unilateral sensorineural hearing loss with poor speech discrimination, tinnitus, imbalance, then ipsilateral facial numbness (CN V) and facial weakness (CN VII).
• Sellar/suprasellar: bitemporal hemianopia from optic chiasm compression; hyperprolactinemia (amenorrhea-galactorrhea, low libido), acromegaly, or Cushing disease. Craniopharyngioma in a child adds growth failure and diabetes insipidus.
• Pineal region: Parinaud syndrome — upgaze palsy, light–near dissociation, convergence-retraction nystagmus — plus hydrocephalus from aqueductal compression.

Step 1 — imaging

• Non-contrast head CT is the fastest first test in an unstable patient or acute presentation: it detects hemorrhage, hydrocephalus, midline shift, effaced basal cisterns, and calcification (meningioma, oligodendroglioma, craniopharyngioma).
• MRI brain with and without gadolinium is the study of choice for characterization, per NCCN CNS Cancers guidance. Look for enhancement pattern, edema, and location.
• Glioblastoma: irregular ring enhancement with central necrosis, crossing the corpus callosum as a butterfly lesion.
• Metastases: multiple, well-circumscribed, gray–white junction lesions with edema out of proportion to size.
• Meningioma: extra-axial, homogeneously enhancing, with a dural tail.
• Pilocytic astrocytoma: cystic cerebellar lesion with an enhancing mural nodule.
• Primary CNS lymphoma: homogeneously enhancing periventricular mass, often diffusion-restricting.
• Advanced sequences (MR spectroscopy with elevated choline and reduced NAA, perfusion, FDG-PET) help separate recurrent tumor from radiation necrosis and pseudoprogression.

Step 2 — staging/context

• If metastasis is plausible, hunt the primary: CT chest/abdomen/pelvis, mammography, dermatologic exam.
• Craniospinal MRI and, when safe, CSF cytology stage tumors that seed CSF — medulloblastoma (Chang staging), ependymoma, germinoma.
• Lumbar puncture is contraindicated before imaging in suspected posterior fossa mass or any lesion with mass effect: herniation risk.

Step 3 — tissue

• Histopathology from stereotactic biopsy or resection is the gold standard. Diagnosis is now integrated per the WHO CNS5 (2021) classification: IDH mutation status, 1p/19q codeletion (defines oligodendroglioma), ATRX and TP53, TERT promoter, EGFR amplification, +7/−10, and H3 K27M for diffuse midline glioma.
• MGMT promoter methylation in glioblastoma is predictive of temozolomide benefit — always the molecular test the stem wants.
• Classic morphology: pseudopalisading necrosis and microvascular proliferation (glioblastoma), psammoma bodies and whorls (meningioma), fried-egg cells with chicken-wire vasculature (oligodendroglioma), Rosenthal fibers (pilocytic astrocytoma), perivascular pseudorosettes (ependymoma), Homer-Wright rosettes/small round blue cells (medulloblastoma).
• Karnofsky Performance Status is the functional score used to select therapy.

Immediate stabilization (herniation or symptomatic mass effect)

• Elevate the head of bed, ensure normoxia/normocapnia, and obtain emergent neurosurgical consultation.
• Hyperosmolar therapy: mannitol or hypertonic saline creates an osmotic gradient that draws water from intact brain, per Neurocritical Care Society guidance. Brief hyperventilation is a bridge only.
• Corticosteroids: dexamethasone is preferred for vasogenic edema — minimal mineralocorticoid effect, long half-life. It does nothing for cytotoxic edema of stroke.
• Antiseizure medication for a patient who has seized (levetiracetam is favored: no CYP induction, no interaction with chemotherapy). Per the American Academy of Neurology, routine prophylactic antiepileptics are not recommended in brain tumor patients who have never seized.
• Do not give steroids before biopsy if primary CNS lymphoma is suspected — they are lympholytic and can make the lesion vanish, rendering biopsy non-diagnostic.

Definitive management by tumor (NCCN CNS Cancers framework)

• Glioblastoma: maximal safe resection, then involved-field radiotherapy with concurrent daily temozolomide followed by adjuvant temozolomide (Stupp regimen). Tumor-treating fields are an NCCN-listed option for newly diagnosed disease after chemoradiation. Elderly or poor-performance patients receive hypofractionated radiation, with temozolomide favored if MGMT methylated. Recurrence: re-resection, re-irradiation, or bevacizumab (anti-VEGF), which relieves edema and steroid burden without a demonstrated survival benefit.
• IDH-mutant, 1p/19q-codeleted oligodendroglioma: resection followed by radiation plus PCV (procarbazine, lomustine, vincristine) or temozolomide.
• Medulloblastoma: resection, craniospinal irradiation (deferred or dose-modified in very young children), and platinum-based chemotherapy.
• Meningioma: observation with serial MRI for small asymptomatic lesions; resection when symptomatic; stereotactic radiosurgery for surgically inaccessible or residual disease.
• Brain metastases: stereotactic radiosurgery for limited lesions and surgery for a large symptomatic lesion; whole-brain radiation, when needed, with hippocampal avoidance plus memantine to limit neurocognitive toxicity, per ASTRO/ASCO/SNO guidance. CNS-penetrant targeted agents (e.g., osimertinib, tucatinib-based regimens) are increasingly used.
• Prolactinoma: a dopamine agonist (cabergoline) is first-line — surgery is the classic wrong answer.

Emergencies (recognize instantly)

• Herniation: uncal herniation → ipsilateral fixed dilated pupil and contralateral hemiparesis (or ipsilateral weakness from Kernohan notch); tonsillar herniation → neck stiffness, bradycardia, respiratory arrest. Triggered classically by LP performed before imaging.
• Obstructive hydrocephalus from fourth-ventricle or aqueductal compression → rapidly declining consciousness; needs external ventricular drain or shunt.
• Intratumoral hemorrhage: highest with melanoma, renal cell, choriocarcinoma, and thyroid metastases and with glioblastoma; presents as sudden headache and deficit.
• Status epilepticus from a cortical focus.
• Pituitary apoplexy: sudden headache, ophthalmoplegia, vision loss, and hypotension from adrenal insufficiency — give stress-dose hydrocortisone.

Disease-related

• Venous thromboembolism: gliomas express high tissue factor; unexplained dyspnea or leg swelling is a common stem.
• Leptomeningeal carcinomatosis: multifocal cranial neuropathies plus radicular pain; CSF cytology positive.
• Hyponatremia from SIADH or cerebral salt wasting (distinguished by volume status).
• Endocrine failure and diabetes insipidus with sellar/suprasellar lesions.
• Permanent focal deficits, cognitive decline, and poor quality of life.

Treatment-related

• Corticosteroids: hyperglycemia, proximal steroid myopathy (weakness that mimics tumor progression), insomnia, psychosis, osteoporosis, gastric injury, and opportunistic infection.
• Temozolomide: myelosuppression, especially thrombocytopenia and lymphopenia; Pneumocystis jirovecii prophylaxis is given during concurrent chemoradiation.
• Radiation: acute fatigue and edema; pseudoprogression within months of chemoradiation (enhancement that is not tumor — do not abandon therapy prematurely); late radiation necrosis mimicking recurrence on MRI; leukoencephalopathy, hypopituitarism, cataract, hearing loss, and second malignancies (meningioma, sarcoma) years later. Craniospinal irradiation in children causes growth failure and neurocognitive impairment.
• Bevacizumab: hypertension, proteinuria, impaired wound healing, hemorrhage, arterial thrombosis, GI perforation.
• Surgery: CSF leak, meningitis, new deficit, and posterior fossa syndrome (cerebellar mutism) after medulloblastoma resection.

• Best next step, almost always: MRI brain with and without gadolinium. In a crashing patient with a blown pupil, obtain non-contrast CT and start hyperosmolar therapy plus dexamethasone first — imaging never precedes stabilization.
• Never LP before imaging in a suspected intracranial mass. The stem that describes a child with ataxia, morning vomiting, and papilledema is testing whether you will cause tonsillar herniation.
• MGMT promoter methylation predicts temozolomide benefit in glioblastoma; 1p/19q codeletion with IDH mutation defines oligodendroglioma and predicts chemosensitivity and longer survival. IDH-mutant gliomas do better than IDH-wildtype at every grade.
• Ring-enhancing lesion differential: glioblastoma, metastasis, abscess, toxoplasmosis, and CNS lymphoma. In advanced HIV, multiple ring-enhancing lesions favor toxoplasmosis; a solitary periventricular homogeneously enhancing, EBV-positive lesion favors primary CNS lymphoma — and steroids given before biopsy can erase it.
• Dural tail + psammoma bodies + whorls + calcification in a woman = meningioma; it is extra-axial and may enlarge in pregnancy (progesterone receptors).
• Bilateral vestibular schwannomas = NF2, not NF1. NF1 gives optic glioma and pilocytic astrocytoma.
• Do not start prophylactic antiseizure drugs in a brain tumor patient who has never seized — the American Academy of Neurology advises against it. If a drug is needed, prefer levetiracetam over enzyme-inducing agents like phenytoin, which accelerate chemotherapy metabolism.
• Common distractors: assuming a solitary lesion in a smoker is a primary glioma (metastasis is far more likely); calling new enhancement months after chemoradiation "progression" when it may be pseudoprogression or radiation necrosis; and choosing transsphenoidal surgery for a prolactinoma, where the dopamine agonist cabergoline is first-line.

• Most common adult primary brain tumor: glioblastoma (Grade IV astrocytoma); most common pediatric brain tumor: medulloblastoma
• Most common brain metastases: lung, breast, melanoma (remember: "LBM")
• Brain tumors cause symptoms via mass effect, edema, increased ICP, and seizures
• MRI with contrast is imaging of choice; biopsy confirms diagnosis
• Prognosis depends on grade, location, and extent of resection

1. 1.Confusing primary vs. metastatic: Metastases are MORE common than primary tumors in adults; assume solitary lesion with lung/breast history = mets until proven otherwise
2. 2.Ignoring posterior fossa signs: Medulloblastoma/ependymoma present with ataxia + hydrocephalus, not typical supratentorial deficits—easy to miss initially
3. 3.Forgetting seizure as sole presentation: New-onset seizure in patient >40 years = suspect brain tumor/metastasis; don't anchor on "idiopathic epilepsy"

• Surgery: Maximum safe resection (cytoreduction improves prognosis)
• Radiation therapy: Post-op external beam for high-grade tumors
• Chemotherapy: Temozolomide for glioblastoma; cisplatin/etoposide for medulloblastoma
• Supportive: Corticosteroids (dexamethasone) for edema, anticonvulsants for seizure prophylaxis
• Palliative care: Consider in advanced, unresectable disease