Brain Tumor Overview

Malignant transformation and progression

• Activation of proto-oncogenes: Point mutations, amplifications, and translocations in growth-promoting genes (EGFR, PDGFRA, MET, BRAF) drive proliferation and survival signaling
• Inactivation of tumor suppressors: Loss of TP53, PTEN, RB, and NF1 function removes critical checkpoints controlling cell cycle progression and apoptosis
• Glioma-CIMP phenotype: CpG island methylator phenotype silences tumor suppressors and mismatch repair genes through epigenetic mechanisms

Microenvironmental interactions

• Angiogenesis: Hypoxia-induced upregulation of VEGF and HIF-1α promotes neovascularization to support tumor growth and enables blood-brain barrier (BBB) disruption
• Neuroinflammation: Tumor-associated macrophages and activated microglia secrete immunosuppressive cytokines (IL-10, TGF-β) and create an anti-inflammatory microenvironment promoting immune evasion
• Invasion and migration: Degradation of extracellular matrix by matrix metalloproteinases and acquisition of epithelial-mesenchymal transition (EMT) phenotypes facilitate infiltration into normal brain parenchyma

Mass effect and increased intracranial pressure

• Vasogenic edema: Disrupted BBB permits fluid accumulation in white matter, exacerbated by increased vascular permeability and reduced tight junction integrity
• Hydrocephalus: Obstruction of CSF flow (especially tumors in posterior fossa, lateral/third ventricles) causes increased intracranial pressure (ICP)
• Midline shift and herniation: Large masses cause displacement of brain structures; uncal or transtentorial herniation becomes life-threatening emergency

Seizure pathogenesis

• Aberrant glutamate release, altered GABAergic inhibition, and disrupted potassium homeostasis lower seizure threshold
• Cortical gliomas (low-grade particularly) have high seizure propensity; subcortical tumors less frequently epileptogenic

Primary CNS tumors (intrinsic origin)

• Gliomas (40-50% of primary brain tumors): Glioblastoma (WHO grade IV, highest malignancy), anaplastic glioma (grade III), low-grade diffuse glioma (grade II)
• Meningiomas (30% of primary tumors): Usually benign (WHO grade I); arise from dura mater; female predominance
• Vestibular schwannomas/Acoustic neuromas: Benign nerve sheath tumors on CN VIII; bilateral in neurofibromatosis type 2 (NF2)
• Ependymomas and choroid plexus tumors: Arise from ependymal lining; more common in pediatric population
• Medulloblastomas: Most common malignant pediatric tumor; arise from cerebellar vermis
• Pituitary adenomas: Benign functional or non-functional tumors; prolactin-secreting most common
• CNS Lymphomas: Primary CNS lymphoma (usually diffuse large B-cell lymphoma); increased incidence in immunocompromised hosts

Secondary/metastatic tumors

• Most common sources: Lung cancer (50%), breast cancer (15%), melanoma (10%), colorectal cancer, renal cell carcinoma
• Often multiple lesions at gray-white matter junctions

Molecular/genetic predisposition factors

• TP53 mutations: Li-Fraumeni syndrome increases glioma and other malignancy risk
• NF1 inactivation: Neurofibromatosis type 1 increases optic nerve gliomas and malignant peripheral nerve sheath tumors
• PTEN loss: Cowden syndrome associated with increased CNS tumor risk
• IDH1/IDH2 mutations: Favorable prognostic indicator in gliomas; associated with secondary high-grade gliomas from low-grade precursors
• BRAF V600E mutations: Found in pilocytic astrocytomas and some lower-grade gliomas; target for dabrafenib therapy
• EGFR amplification: Adverse prognostic marker in GBM; potential therapeutic target

Environmental and host factors

• Radiation exposure: Prior head/neck radiation (including therapeutic radiation for other CNS conditions); dose-dependent risk
• Immunosuppression: AIDS/low CD4 count increases primary CNS lymphoma risk (though less common post-HAART era)
• Age: Incidence bimodal—peaks in children (infratentorial tumors) and older adults (supratentorial)
• Female sex: Meningiomas and optic nerve gliomas more common in women; hormone receptor expression may play role

Cardinal symptoms (mass effect and increased ICP)

• Headache: Most common initial symptom (40-50% of patients); often morning headaches worse with Valsalva, progressive over weeks to months; may be associated with nausea/vomiting
• Seizures: Generalized tonic-clonic, focal, or secondarily generalized; low-grade gliomas especially epileptogenic (70% of low-grade glioma patients develop seizures)
• Focal neurologic deficits: Depend on tumor location—hemiparesis, hemisensory loss, visual field defects, aphasia, ataxia, cranial nerve palsies
• Cognitive/behavioral changes: Memory impairment, personality changes, executive dysfunction, depression, apathy (especially frontal tumors)
• Vision disturbances: Bitemporal hemianopsia (suprasellar/pituitary tumors compressing optic chiasm), monocular vision loss (optic nerve compression), diplopia (CN III/IV/VI involvement)

Posterior fossa tumor symptoms

• Ataxia, dysmetria, nystagmus, truncal instability
• Obstructive hydrocephalus with acute ICP elevation
• Cranial nerve deficits (trigeminal, facial, vestibulocochlear, vagal, hypoglossal)

Physical examination findings

• Papilledema: Indicates chronic elevated ICP; occurs late—absence does not exclude increased ICP
• Optic atrophy: Chronic papilledema or direct optic nerve compression
• Visual field defects: Mapping defects helps localize tumor
• Motor weakness: Pyramidal pattern weakness with hyperreflexia, spasticity, positive Babinski sign suggests corticospinal tract involvement
• Cerebellar signs: Ipsilateral ataxia, dysarthria, intention tremor (indicating cerebellar or brainstem involvement)
• Cranial nerve palsies: CN II (vision/pupils), CN III (ptosis, "down and out" eye), CN VI (impaired adduction), CN VII (facial weakness), CN VIII (hearing loss, vertigo), CN XII (tongue deviation)
• Cognitive/speech deficits: Aphasia (dominant hemisphere), neglect (non-dominant parietal), abulia (medial frontal)
• Gait disturbance: Hemiparesis, ataxia, or normal-pressure hydrocephalus-like "magnetic" gait

Endocrinologic manifestations (pituitary/suprasellar tumors)

• Hyperprolactinemia (amenorrhea, galactorrhea, erectile dysfunction)
• Acromegaly/gigantism (GH-secreting adenomas)
• Cushing's syndrome (ACTH-secreting adenomas)
• Central hypothyroidism, hypogonadism, diabetes insipidus (mass effect on pituitary stalk)

Neuroimaging—gold standard

• Magnetic Resonance Imaging (MRI) with gadolinium: Superior soft tissue contrast; T1-weighted with contrast shows enhancement of disrupted BBB (ring enhancement classic for GBM), T2/FLAIR shows edema/infiltration. Diffusion-weighted imaging (DWI) shows restricted diffusion in high-cellularity tumors (high-grade malignancy); perfusion-weighted imaging (PWI) reveals increased relative cerebral blood volume (rCBV) in malignant tumors. MR spectroscopy shows elevated choline (proliferation), reduced N-acetylaspartate (neuronal loss), elevated lactate (anaerobic metabolism).
• Computed Tomography (CT): Less sensitive than MRI; useful for detecting calcification (meningiomas, some gliomas), bone involvement, or when MRI contraindicated. CT perfusion may assess tissue viability.
• Positron Emission Tomography (PET): 18F-FDG PET shows increased metabolic activity in malignant lesions (lower FDG uptake in low-grade tumors); 11C-methionine or 18F-DOPA PET superior for delineating tumor margins and detecting recurrence. Helpful for differentiating tumor recurrence from radiation necrosis.

Histopathology and molecular profiling (essential for primary tumors)

• Stereotactic needle biopsy or open resection with pathologic analysis is gold standard for diagnosis
• WHO classification (2021): Gliomas classified by histology (astrocytic, oligodendroglial, ependymal, etc.) and grade (I-IV). Grading based on mitotic activity, necrosis, microvascular proliferation, cellular atypia.
• Critical molecular markers:
• IDH1/IDH2 mutation status: IDH-wild-type GBM (primary, de novo) vs. IDH-mutant (secondary from low-grade precursor); IDH mutation favorable prognostic factor
• TP53 and ATRX status: Co-mutations define astrocytoma; mutations associated with worse prognosis
• 1p19q co-deletion: Oligodendroglioma marker; highly predictive of chemotherapy responsiveness (PCV or TMZ) and longer survival
• MGMT promoter methylation: GBM; methylation associated with better response to alkylating agents (temozolomide)
• EGFR amplification and EGFRvIII: Adverse prognostic markers in GBM; potential therapeutic targets
• BRAF V600E: Found in pilocytic astrocytomas, pleomorphic xanthoastrocytomas; enables targeted therapy with dabrafenib
• Chromosome 10 loss (monosomy 10): Associated with worse GBM prognosis
• Telomerase reverse transcriptase (TERT) promoter mutations: GBM marker; associated with worse outcomes

Laboratory studies

• Lumbar puncture with CSF analysis: For CNS lymphoma (flow cytometry for malignant cells), meningeal disease, or infection ruling; contraindicated if mass effect/increased ICP (risk of herniation)
• Thyroid function (TSH, free T4): Baseline in pituitary adenomas or if pituitary involvement suspected
• Prolactin, ACTH, cortisol, IGF-1: Endocrine evaluation for functioning pituitary adenomas
• Complete blood count, comprehensive metabolic panel, coagulation studies: Preoperative assessment

Staging and extent-of-disease evaluation

• Spine MRI with gadolinium: For medulloblastomas, ependymomas, spinal cord gliomas to assess leptomeningeal spread
• Chest/abdomen/pelvis imaging: In metastatic workup for secondary brain tumors; identify primary malignancy
• Whole-body PET/CT: Staging metastatic disease or primary CNS lymphoma

Diagnostic criteria (WHO 2021)

• Glioma diagnosis requires histologic confirmation with grading based on mitotic rate, necrosis, and microvascular proliferation, supplemented by molecular markers (IDH, TP53, ATRX, 1p19q, EGFR, TERT)
• GBM: Grade IV malignancy; by definition shows both necrosis AND microvascular proliferation OR meets molecular criteria (IDH-wild-type + additional alterations like EGFR amp, PTEN loss, TP53 mutation)

First-line therapy for primary malignant tumors (glioblastoma model)

Maximal safe surgical resection

• Goal is gross total resection (GTR) when feasible, improving survival and neurologic outcomes vs. biopsy alone
• Intraoperative neuromonitoring (motor/sensory evoked potentials) and awake craniotomy preserve eloquent cortex
• 5-aminolevulinic acid (5-ALA) fluorescence intraoperatively highlights tumor tissue, improving extent of resection in high-grade gliomas
• Extent of resection is independent prognostic factor; each 10% increase in resection volume associated with improved survival

Radiation therapy

• Conformal external beam radiation (focal therapy) with 3D planning: Standard dose 60 Gy in 30 fractions over 6 weeks to tumor plus 1-2 cm margin
• Intensity-modulated radiation therapy (IMRT) reduces dose to normal brain
• Temozolomide (TMZ) concurrent with radiation: Alkylating agent; radiosensitizer given daily during RT, followed by adjuvant TMZ cycles
• Bevacizumab (anti-VEGF monoclonal antibody): Added to RT/TMZ in some protocols; improves progression-free but not overall survival in newly diagnosed GBM
• Tumor treating fields (Optune): Alternating electric fields; FDA-approved for GBM; worn as cap 18+ hours daily; may prolong survival when combined with TMZ

Adjuvant chemotherapy

• Temozolomide: Standard alkylating agent; 5-day cycle each month × 6-12 cycles after concurrent chemoradiation. Requires monitoring for myelosuppression (CBC before each cycle). MGMT promoter methylation predicts better response.
• PCV regimen (procarbazine, CCNU, vincristine): Alternative for oligodendrogliomas with 1p19q co-deletion and anaplastic astrocytomas; superior to TMZ for these histologies in some trials
• Bevacizumab: Anti-VEGF antibody; extends progression-free survival in recurrent GBM; given IV every 2 weeks. Monitor for hypertension, proteinuria, bleeding, thromboembolism.
• Checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab): Under investigation; limited benefit to date in unselected populations but potential in PD-L1-positive or MMR-deficient tumors

Low-grade gliomas (grade II)

• Observation alone often appropriate for asymptomatic, completely resected, IDH-mutant tumors (favorable prognosis)
• RT ± chemotherapy for incompletely resected, symptomatic, or IDH-wild-type tumors
• TMZ or PCV: Chemotherapy for progression; no clear survival benefit in newly diagnosed but delays progression

Meningiomas

• Grade I (benign): Surgical resection alone; adjuvant RT if incompletely resected, recurrent, or high-risk features
• Grade II-III (atypical/malignant): GTR followed by adjuvant IMRT; chemotherapy role limited. Somatostatin receptor antagonists (pasireotide) under investigation for recurrent/progressive disease.

CNS Lymphoma

• High-dose methotrexate (HD-MTX) (3.5-8 g/m²

Neurologic emergencies

• Cerebral herniation: expanding mass plus vasogenic edema exceeds intracranial compliance; uncal herniation signals with an ipsilateral blown pupil (CN III compression) and contralateral hemiparesis, progressing to Cushing reflex (hypertension, bradycardia, irregular respirations). Emergency — head elevation, hyperosmolar therapy (mannitol or hypertonic saline), IV dexamethasone for tumor-related vasogenic edema, and urgent neurosurgical decompression, consistent with Neurocritical Care Society guidance on ICP crisis.
• Obstructive hydrocephalus: posterior fossa or intraventricular tumors block CSF outflow; declining consciousness, upgaze palsy, and ventriculomegaly on imaging. Emergency — external ventricular drain or resection.
• Status epilepticus: cortical irritation and peritumoral gliosis; emergency benzodiazepine (lorazepam IV) then a nonenzyme-inducing antiseizure drug such as levetiracetam, which avoids CYP induction that lowers chemotherapy levels.
• Intratumoral hemorrhage: fragile neovasculature; sudden headache with deficit. Classic in melanoma, renal cell, choriocarcinoma, and thyroid metastases, and in GBM.

Systemic and treatment-related

• Venous thromboembolism: tumor tissue factor release makes high-grade glioma among the most thrombogenic malignancies; unilateral leg swelling or hypoxia. Anticoagulation is generally acceptable per NCCN CNS Cancers guidance even after craniotomy once hemostasis is secure.
• Corticosteroid toxicity: hyperglycemia, proximal steroid myopathy, insomnia, psychosis, and immunosuppression; taper to lowest effective dose.
• Temozolomide myelosuppression and lymphopenia: nadir thrombocytopenia and CD4 depletion; NCCN advises Pneumocystis jirovecii prophylaxis during concurrent chemoradiation.
• Bevacizumab effects: VEGF blockade impairs endothelial repair — hypertension, proteinuria, bleeding, wound dehiscence, GI perforation, and arterial thrombosis.
• Radiation necrosis vs pseudoprogression: delayed enhancing lesion with edema mimicking recurrence; low rCBV on perfusion MRI and low uptake on amino-acid PET favor necrosis.
• Late radiation injury: leukoencephalopathy with cognitive decline, hypopituitarism, cataract, and radiation-induced meningioma or sarcoma years later. For whole-brain radiation, hippocampal avoidance plus memantine is endorsed in the ASCO/SNO/ASTRO brain metastases guideline.
• Leptomeningeal disease: multifocal cranial neuropathies with radiculopathy; enhancing sugar-coating of leptomeninges.

• Metastases outnumber primaries: multiple well-circumscribed enhancing lesions at the gray-white junction are metastatic until proven otherwise; lung is the leading source. The common distractor is calling a solitary ring-enhancing lesion a GBM without imaging the chest.
• Ring enhancement is not specific: GBM, metastasis, abscess, toxoplasmosis, and demyelination all ring-enhance. An abscess restricts diffusion centrally on DWI; tumor necrosis does not. Butterfly enhancement crossing the corpus callosum is the GBM buzzword.
• Single best next step for suspected mass: MRI brain with and without gadolinium. Lumbar puncture is contraindicated with mass effect — herniation risk — even when CNS lymphoma is suspected.
• Withhold steroids before biopsy if primary CNS lymphoma is suspected: glucocorticoids are lympholytic and can transiently vanish the lesion, yielding a nondiagnostic biopsy. This is the classic examiner trap. Think periventricular, homogeneously enhancing lesion in an immunocompromised patient with EBV DNA in CSF.
• Histology one-liners: meningioma — dural tail, psammoma bodies, women, progesterone receptors; oligodendroglioma — fried-egg cells, chicken-wire vasculature, calcification, 1p/19q codeletion predicting chemosensitivity; pilocytic astrocytoma — cystic cerebellar lesion with enhancing mural nodule and Rosenthal fibers; medulloblastoma — small round blue cells with Homer-Wright rosettes and drop metastases; ependymoma — perivascular pseudorosettes; schwannoma — Antoni A/B, S-100 positive, bilateral in NF2; hemangioblastoma — von Hippel-Lindau, erythropoietin-driven polycythemia.
• Molecular associations examiners favor: IDH mutation is favorable, MGMT promoter methylation predicts temozolomide benefit, and IDH-wild-type histology with EGFR amplification or TERT mutation behaves as grade 4 under the WHO 2021 scheme.
• Do not give prophylactic antiseizure drugs to a brain tumor patient who has never seized; the American Academy of Neurology practice parameter found no benefit. Treat after a first seizure, preferring levetiracetam over enzyme-inducing agents.
• Dexamethasone is the steroid of choice for peritumoral vasogenic edema because of minimal mineralocorticoid activity and long half-life; it does not treat cytotoxic edema from stroke.