Brain Tumors in Adults

Tumorigenesis and Genetic Alterations

• Glioblastoma develops through stepwise accumulation of genetic mutations, including TP53 mutations, EGFR amplification, PTEN loss, and RB pathway inactivation, leading to uncontrolled proliferation and loss of apoptotic mechanisms
• Meningiomas frequently harbor NF2 mutations (chromosome 22q) or activating mutations in TRAF7 and KLF4, resulting in abnormal growth of meningeal fibroblasts
• Pituitary adenomas often involve GNAS mutations (ACTH-secreting) or loss of tumor suppressors, leading to hormone overproduction and mass effect

Cellular Mechanisms of Tumor Growth

• Activation of growth factor signaling pathways (EGFR, PDGFRA, MET) drives proliferation independent of normal growth constraints
• Glioma-derived growth factors stimulate angiogenesis through VEGF secretion, forming abnormal vasculature with increased permeability and blood-brain barrier disruption
• Microglial infiltration and immunosuppressive tumor microenvironment create an immune-privileged niche that resists anti-tumor immunity
• Loss of contact inhibition and cell-cell adhesion molecules (E-cadherin) enables invasive migration into surrounding parenchyma

Organ-Level Effects and Mass Effect

• Space-occupying mass effect causes compression of adjacent neural structures, leading to focal deficits corresponding to tumor location (motor cortex → hemiparesis; temporal lobe → memory impairment)
• Cerebral edema (vasogenic edema predominating) results from disruption of tight junctions in tumor vasculature by VEGF and bradykinin, causing fluid accumulation in white matter
• Increased intracranial pressure (ICP) develops through mass effect combined with edema; elevated ICP decreases cerebral perfusion pressure (CPP = MAP - ICP), precipitating ischemia and hernia syndromes
• Midline shift and herniation occur when unilateral mass expansion exceeds compensatory CSF/blood displacement, forcing brain tissue across dural compartments (uncal or central herniation)
• Seizure genesis results from disruption of normal cortical architecture, altered neurotransmitter balance, and abnormal electrical activity at the tumor-brain interface

Primary Brain Tumors (Non-Metastatic Origin)

• Gliomas (oligodendrogliomas, astrocytomas, glioblastoma): arise from glial lineage cells; glioblastoma constitutes ~45% of malignant primary brain tumors
• Meningiomas: originate from arachnoid cap cells; most common intracranial tumor overall (~35% of primary CNS tumors); typically benign but may be malignant
• Schwannomas (vestibular schwannomas/acoustic neuromas): arise from Schwann cells of CN VIII; second most common benign primary tumor
• Pituitary adenomas: derived from anterior pituitary epithelium; functional adenomas secrete hormones (prolactin, ACTH, GH); most common sellar masses
• Medulloblastomas and embryonal tumors: occur predominantly in children but can present in young adults; cerebellar location typical
• Ependymomas: arise from ependymal lining of ventricles; various grades of malignancy

Secondary (Metastatic) Tumors

• Lung cancer (most common primary source, ~35-40% of cerebral metastases); small cell lung cancer (SCLC) has highest propensity for brain metastasis
• Breast cancer (15-25% of cerebral metastases); HER2-positive and triple-negative subtypes associated with increased CNS involvement
• Melanoma (5-10% of brain metastases); notable for aggressive behavior and higher incidence relative to prevalence
• Colorectal, renal cell, and gastric cancers: less frequent but clinically significant sources

Non-Modifiable Risk Factors

• Age: peak incidence varies by histology (glioblastoma 45-70 years; meningiomas 50-70 years; pituitary adenomas 30-40 years)
• Genetic predisposition syndromes: neurofibromatosis type 1 (NF1) increases glioma and optic pathway tumor risk; NF2 predisposes to bilateral vestibular schwannomas and meningiomas; Li-Fraumeni syndrome (TP53 mutations) increases multiple CNS malignancies; Cowden syndrome (PTEN) increases glioblastoma risk; familial adenomatous polyposis (FAP) increases medulloblastoma risk

Potentially Modifiable Risk Factors

• Prior radiation exposure: cumulative dose and dose rate affect risk; cranial radiation for leukemia, lymphoma, or prior CNS tumors increases secondary malignancy risk (peak latency 15-20 years)
• Immunosuppression: organ transplant recipients and HIV/AIDS patients have increased CNS lymphoma risk (particularly primary CNS lymphoma [PCNSL] in AIDS)
• Environmental factors: controversial associations with electromagnetic fields, mobile phones, and pesticide exposure lack definitive causality in large epidemiologic studies

Cardinal Neurologic Symptoms

• Headache: present in 40-50% of patients; typically progressive, worse in morning, may be associated with nausea/vomiting from elevated ICP; pain characteristics do not reliably distinguish tumor from benign causes
• Seizures: occur in 20-30% of patients as presenting symptom; more common with slow-growing tumors and cortical location (meningiomas, low-grade gliomas); partial seizures with secondary generalization typical
• Focal neurologic deficits: vary by tumor location (motor weakness, visual field defects, speech disturbance, sensory loss); progressive course distinguishes from acute stroke
• Cognitive changes: memory impairment, executive dysfunction, personality change, attention deficit; may be subtle initially
• Visual symptoms: diplopia (CN III/IV involvement), blurred vision, visual field defects (homonymous hemianopia with temporal lobe/optic radiation involvement, bitemporal hemianopia with pituitary/suprasellar compression)
• Vertigo and balance disorders: with posterior fossa/cerebellar tumors

Symptoms from Elevated Intracranial Pressure

• Morning nausea and vomiting (worse supine, improves with head elevation)
• Papilledema on fundoscopy (delayed finding; may be absent in acute presentations)
• Altered mental status, somnolence, declining consciousness

Presentation by Tumor Location

• Frontal lobe: personality change, disinhibition, gait disturbance, motor weakness, abulia
• Temporal lobe: seizures, memory impairment, visual field defects (superior quadrantanopia), language disturbance (if dominant hemisphere)
• Parietal lobe: sensory loss, neglect syndrome, visuospatial disturbance, visual field defects
• Occipital lobe: visual field defects (homonymous hemianopia), visual hallucinations
• Posterior fossa/cerebellum: ataxia, truncal instability, headache, nausea/vomiting (hydrocephalus from aqueductal compression)
• Sellar/suprasellar region (pituitary): endocrine abnormalities (amenorrhea, erectile dysfunction, galactorrhea with prolactinoma; growth failure or Cushing's with ACTH-secreting; hypothyroidism; hypopituitarism), bitemporal hemianopia, headache

Physical Examination Findings

• Neurologic deficits: hemiparesis, hyperreflexia, extensor plantar response (Babinski sign); sensory level or loss; cranial nerve palsies depending on location
• Papilledema: optic disc swelling with blurred margins, loss of spontaneous venous pulsations, elevation of optic disc margins; indicates elevated ICP
• Gaze deviation: ipsilateral gaze deviation toward hemisphere lesion ("the eyes look toward the lesion, away from the paresis")
• Ataxia and nystagmus: cerebellar or brainstem involvement
• Horner's syndrome: with brainstem or spinal involvement
• Endocrine abnormalities: with pituitary adenomas (gynecomastia, hirsutism, hypertension, acne with prolactinoma; moon facies, proximal weakness with Cushing's adenoma)

Asymptomatic Presentation

• Brain tumors discovered incidentally on imaging obtained for unrelated indications; incidence 0.4-1.5% of MRIs; management depends on imaging characteristics and surveillance intervals

Neuroimaging - Foundation of Diagnosis

MRI with Gadolinium (Gold Standard)

• Glioblastoma: heterogeneous enhancement with central necrosis, prominent vasogenic edema (FLAIR hyperintensity), irregular infiltrative borders; restricted diffusion in necrotic/densely cellular regions (elevated diffusion-weighted imaging [DWI] signal, low apparent diffusion coefficient [ADC])
• Low-grade gliomas: minimal or no enhancement, T2/FLAIR hyperintensity with indistinct margins, minimal edema
• Meningiomas: broad dural base ("dural tail"), isointense to hypointense on T1, homogeneous enhancement, minimal surrounding edema (unless malignant), may have calcifications on CT
• Schwannomas: well-circumscribed, enhanced lesions often with eccentric location at cerebellopontine angle; cystic components common; widened internal auditory canal
• Pituitary adenomas: sellar mass, iso/hypointense T1 and T2, variable enhancement; suprasellar extension possible; assess for pituitary apoplexy (hemorrhage)
• Brain metastases: multiple lesions at gray-white matter junction with surrounding edema (vasogenic); "cannonball" lesions on contrast-enhanced MRI; may be solitary; rapid growth
• Advanced MRI techniques: perfusion MRI (relative cerebral blood volume [rCBV] assessment; high rCBV suggests high-grade glioma), MR spectroscopy (elevated choline/creatinine, depressed N-acetylaspartate [NAA] in tumors), diffusion tensor imaging (fiber tract mapping for surgical planning)

CT Imaging

• Role: rapid assessment in acute presentations (subarachnoid hemorrhage, acute hydrocephalus, herniation); better demonstrates calcification (meningiomas, oligodendrogliomas)
• Limitations: less sensitive than MRI for posterior fossa lesions, lower soft tissue contrast

Positron Emission Tomography (PET)

• 18F-FDG-PET: identifies high-metabolic lesions, helps distinguish high-grade from low-grade gliomas; not standard for diagnosis but useful for treatment planning and surveillance
• Amino acid PET (11C-methionine, 18F-DOPA): improved specificity for glioma diagnosis and grading; research modality in many centers

Lumbar Puncture/Cerebrospinal Fluid Analysis

• Indications: suspected leptomeningeal disease, PCNSL, meningeal carcinomatosis
• Findings: elevated protein (often >100 mg/dL), variable glucose (low with malignant infiltration), pleocytosis (lymphocytic predominance in PCNSL, malignant cells on cytology)
• Contraindication: mass effect with herniation risk; must obtain imaging first to exclude papilledema and mass effect
• Flow cytometry: for hematologic malignancies (PCNSL)

Pathologic Diagnosis - Essential for Grading and Prognosis

Stereotactic Brain Biopsy

• Indications: tissue diagnosis when non-diagnostic imaging, deep/eloquent location, or when differential diagnosis includes infection or demyelination
• Approach: framebased or frameless stereotactic navigation; risks include hemorrhage (1-5%), infection, needle tract seeding
• Interpretation: must determine WHO grade (I-IV), histologic type, and molecular markers

Surgical Resection/Craniotomy

• Indications: accessible tumor with mass effect, midline shift, or signs of herniation; therapeutic (cytoreduction) and diagnostic
• Extent of resection: correlates with progression-free survival and overall survival in gliomas; gross total resection (>90%) or subtotal resection attempted when safe
• Intraoperative adjuncts: neuronavigation, intraoperative MRI, awake craniotomy for tumors in eloquent cortex, intraoperative electrocorticography (icECoG), 5-aminolevulinic acid (5-ALA) fluorescence

Histopathologic Grading (WHO 2021 Classification)

For Gliomas

• Grade I: pilocytic astrocytoma (low proliferation, excellent prognosis)
• Grade II: low-grade diffuse glioma (oligodendroglioma, astrocytoma); mitoses rare; can undergo malignant transformation
• Grade III: anaplastic glioma (oligodendroglioma, astrocytoma); increased mitotic activity, nuclear pleomorphism; shorter survival
• Grade IV: glioblastoma (formerly glioblastoma multiforme); mitoses numerous, endothelial proliferation, necrosis; most aggressive

Molecular Testing (Increasingly Important for Prognosis and Treatment)

Critical Molecular Markers in Gliomas

• IDH mutation status (IDH1 R132H or IDH2): strong favorable prognostic factor; present in ~70% of grade II/III gliomas and secondary glioblastomas; mutations confer better prognosis
• 1p/19q codeletion: oligodendrogliomas with codeletion have improved prognosis and better chemotherapy response; critical for distinguishing oligodendroglioma from astrocytoma
• MGMT methylation status: promoter methylation predicts better response to temozolomide and improved survival in glioblastoma; methylated = favorable
• TP53 mutation: common in astrocytomas; associated with lower survival in some contexts
• EGFR amplification and mutation: common in glioblastoma; potential therapeutic target
• TERT promoter mutation: associated with aggressive behavior in gliomas
• PTEN loss: confers worse prognosis
• Immunohistochemistry: P53, Ki-67 proliferation index, IDH1 R132H, ATRX loss (predicts IDH mutation)

Immunophenotyping (For PCNSL and Lymphomas)

• Flow cytometry of CSF or biopsy: B-cell marker expression, CD5/CD10 status
• Epstein-Barr virus (EBV) in situ hybridization: positive in AIDS-associated PCNSL

Laboratory Assessment

Routine Labs

• Complete blood count, metabolic panel, liver function tests (baseline before chemotherapy)
• Coagulation studies: if biopsy/surgery planned

Tumor Markers

• Alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (β-hCG): if germ cell tumor suspected
• CSF tumor markers: in suspected leptomeningeal disease

Endocrine Assessment (Pituitary Tumors)

• Basal hormone levels: morning cortisol, ACTH, TSH, free T4, prolactin, IGF-1,

Immediate stabilisation (symptomatic mass effect / herniation)

• Corticosteroids: dexamethasone is preferred (minimal mineralocorticoid effect, long half-life); it restores tight-junction integrity and reverses VEGF-driven vasogenic edema, often improving deficits within hours. A loading dose followed by divided maintenance dosing is standard practice; taper to the lowest effective dose.
• Hyperosmolar therapy: mannitol or hypertonic saline for impending herniation, plus head-of-bed elevation and short-term controlled ventilation; these are bridges to surgical decompression, not definitive therapy.
• Antiseizure drugs: treat clinical seizures with a non–enzyme-inducing agent such as levetiracetam (avoids CYP induction that lowers chemotherapy levels). The AAN advises against prophylactic antiseizure drugs in patients who have never seized.

Definitive management by histology (NCCN Central Nervous System Cancers guidelines)

• Glioblastoma: maximal safe resection, then concurrent external-beam radiotherapy with the oral alkylator temozolomide, followed by adjuvant temozolomide (Stupp regimen); tumor-treating fields may be added. Benefit is greatest with MGMT promoter methylation. Elderly or poor–performance-status patients receive hypofractionated radiotherapy ± temozolomide.
• IDH-mutant, 1p/19q-codeleted oligodendroglioma: resection plus radiotherapy with PCV (procarbazine, lomustine, vincristine) or temozolomide.
• Meningioma: observe small asymptomatic lesions with serial MRI; resect symptomatic or growing tumors; stereotactic radiosurgery for surgically inaccessible or residual disease.
• Brain metastases: stereotactic radiosurgery for limited intracranial disease, with surgery for large or symptomatic lesions; when whole-brain radiotherapy is used, ASCO/SNO/ASTRO endorse hippocampal avoidance plus memantine to limit neurocognitive decline.
• Prolactinoma: dopamine agonist (cabergoline) is first-line even for macroadenomas — Endocrine Society guidance; surgery is reserved for intolerance, resistance, or apoplexy. Other pituitary adenomas: transsphenoidal resection, with somatostatin analogs (octreotide) as escalation in acromegaly.

Contraindicated / avoid

• Empiric steroids before biopsy in suspected primary CNS lymphoma: lymphocytolysis can render tissue non-diagnostic.
• Lumbar puncture with mass effect or midline shift: risk of downward herniation.

Disease-related — emergencies

• Cerebral herniation (uncal, central, tonsillar): expanding mass plus vasogenic edema exhausts CSF/venous compensation. Signaled by ipsilateral blown pupil with contralateral hemiparesis, declining consciousness, or Cushing reflex (hypertension, bradycardia, irregular respirations). Emergency — hyperosmolar therapy and neurosurgical decompression.
• Obstructive hydrocephalus: posterior fossa or intraventricular tumors compress the aqueduct or fourth ventricle; presents with headache, vomiting, upgaze palsy, and ventriculomegaly. Emergency — external ventricular drain.
• Pituitary apoplexy: hemorrhagic infarction of an adenoma causing sudden thunderclap headache, ophthalmoplegia, visual loss, and secondary adrenal insufficiency. Emergency — stress-dose glucocorticoids before imaging-guided decompression.
• Status epilepticus: cortical irritation at the tumor–brain interface; any seizure lasting beyond a few minutes requires benzodiazepine plus a loading antiseizure drug.
• Intratumoral hemorrhage: fragile neovasculature, classically in melanoma, renal cell, choriocarcinoma, and thyroid metastases and in glioblastoma; abrupt deficit with hyperdense CT lesion.

Disease-related — non-emergent

• Venous thromboembolism: gliomas release tissue factor; unexplained leg swelling or hypoxia. Anticoagulation is generally acceptable despite the intracranial lesion.
• Hyponatremia (SIADH or cerebral salt wasting): worsens edema and lowers seizure threshold.

Treatment-related

• Corticosteroid toxicity: hyperglycemia, proximal myopathy (difficulty rising from a chair), osteonecrosis, psychosis, and opportunistic infection — Pneumocystis prophylaxis is indicated with prolonged steroids plus temozolomide-induced lymphopenia.
• Temozolomide myelosuppression: thrombocytopenia and lymphopenia; monitor counts through each cycle.
• Pseudoprogression: increased enhancement within roughly the first few months after chemoradiation that resolves without treatment change; the distractor is calling it true progression.
• Radiation necrosis: delayed, mimics tumor on MRI; low perfusion (rCBV) favors necrosis. Bevacizumab reduces associated edema.
• Post-transsphenoidal complications: CSF rhinorrhea with meningitis risk, transient central diabetes insipidus, and hypopituitarism/adrenal crisis.
• Post–whole-brain radiotherapy neurocognitive decline and delayed leukoencephalopathy.

• Pseudopalisading necrosis with microvascular proliferation is glioblastoma; a butterfly lesion crossing the corpus callosum on MRI is glioblastoma or primary CNS lymphoma, not metastasis.
• Multiple ring-enhancing lesions at the gray–white junction = metastases until proven otherwise; the single best next step is a search for the primary (CT chest/abdomen/pelvis, skin exam), not immediate craniotomy.
• Dural tail with homogeneous enhancement and psammoma bodies with whorled cells = meningioma; it is extra-axial, often estrogen/progesterone receptor–positive, and may enlarge in pregnancy.
• Prolactinoma is treated medically, not surgically — cabergoline (dopamine agonist) is first-line even for macroadenomas per the Endocrine Society. The classic distractor is transsphenoidal surgery as initial therapy.
• Mild prolactin elevation with a large sellar mass suggests stalk effect from a non-lactotroph tumor, not a prolactinoma.
• Do not give corticosteroids before biopsy when primary CNS lymphoma is suspected (periventricular, homogeneously enhancing, restricted diffusion, immunosuppressed host) — steroids melt the lesion and destroy diagnostic tissue.
• MGMT promoter methylation predicts temozolomide benefit; IDH mutation predicts better overall survival; 1p/19q codeletion defines oligodendroglioma and predicts chemosensitivity. Examiners pair MGMT with treatment response and IDH with prognosis.
• Bilateral vestibular schwannomas = NF2; unilateral hearing loss with tinnitus and a cerebellopontine angle mass is the sporadic form. Do not attribute bilateral schwannomas to NF1 (café-au-lait spots, optic glioma, Lisch nodules).
• Never perform lumbar puncture first when papilledema, focal deficits, or midline shift are present — image the brain before tapping.
• The AAN advises against prophylactic antiseizure drugs in a brain tumor patient who has not had a seizure; levetiracetam is preferred when treatment is needed because it does not induce hepatic enzymes.