---

INTRACRANIAL TUMORS - Complete Undergraduate Notes

---

1. DEFINITION

---

2. INCIDENCE AND EPIDEMIOLOGY

• Overall incidence: approximately 15-20 per 100,000 population per year (primary brain tumors)
• Primary vs. secondary: Metastatic tumors are MORE COMMON than primary brain tumors overall; metastases account for ~50% of all intracranial tumors in adults
• Age distribution:
  • Children: peak incidence 5-10 years; posterior fossa tumors predominate (medulloblastoma, ependymoma, pilocytic astrocytoma)
  • Adults: peak incidence in 5th-6th decades; supratentorial tumors predominate (glioblastoma, meningioma, metastases)
• Sex ratio:
  • Glioblastoma: slightly more common in males (M:F = 1.5:1)
  • Meningiomas: more common in females (F:M = 2:1) -- possibly related to progesterone receptor expression
  • Vestibular schwannoma: equal sex distribution
• Race: Glioblastoma more common in Caucasians than in African or Asian populations
• Low-grade glioma: peak incidence in 4th decade; presents with seizures initially

Risk Factors

---

3. COMMON SITES OF INTRACRANIAL TUMORS

Supratentorial (above tentorium cerebelli) - common in adults

Infratentorial (posterior fossa) - common in children

Age-based Distribution (Mnemonic: PEMA for children, GMM for adults)

• Children: Medulloblastoma, Pilocytic Astrocytoma, Ependymoma (posterior fossa predominant)
• Adults: Glioblastoma, Metastases, Meningioma (supratentorial predominant)

---

4. PATHOLOGICAL CLASSIFICATION

WHO Classification of CNS Tumors (2021 update, 5th Edition)

A. Gliomas (neuroepithelial tumors)

• Pilocytic astrocytoma (Grade 1) - children, cerebellum; benign; Rosenthal fibers + biphasic pattern; BRAF fusion
• Diffuse astrocytoma, IDH-mutant (Grade 2) - adults; infiltrating
• Anaplastic astrocytoma, IDH-mutant (Grade 3)
• Glioblastoma, IDH-wildtype (Grade 4) - most malignant; IDH-wildtype = primary GBM; IDH-mutant = secondary GBM

• Necrosis with pseudopalisading (pathognomonic)
• Microvascular proliferation / glomeruloid vessels
• Pleomorphism, mitoses
• "Butterfly glioma" when crossing corpus callosum
• EGFR amplification, PTEN deletion, MGMT promoter methylation (prognostic)

• "Fried-egg" appearance on histology (round nuclei with clear cytoplasm)
• "Chicken-wire" vasculature
• Calcification on CT (characteristic)
• Better prognosis than astrocytoma; responds to chemotherapy (PCV or temozolomide)

• Arises from ependymal lining of ventricles and central canal
• 4th ventricle most common site in children; spinal cord in adults
• Perivascular pseudorosettes (pathognomonic) + true ependymal rosettes
• Myxopapillary ependymoma (Grade 1) - sacral/lumbar spinal cord

B. Neuronal and Mixed Neuronal-Glial Tumors

• Ganglioglioma - temporal lobe; epilepsy in children
• Dysembryoplastic neuroepithelial tumor (DNET) - cortex; drug-resistant seizures
• Central neurocytoma - lateral/3rd ventricle

C. Embryonal Tumors (Grade 4)

• Medulloblastoma - most common malignant brain tumor in children
  • Arises from cerebellar vermis
  • 4 molecular subtypes: WNT-activated (best prognosis), SHH-activated, Group 3, Group 4
  • "Small blue cell tumor" - dense cellularity, Homer-Wright rosettes
  • CSF seeding / "drop metastases" to spinal cord

D. Meningioma

• Most common PRIMARY intracranial tumor (when metastases excluded)
• Arises from arachnoid cap cells (not dura)
• WHO Grade 1 (benign, ~80%), Grade 2 (atypical), Grade 3 (anaplastic/malignant)
• Key pathological features:
  • Psammoma bodies (concentric calcified whorls) - pathognomonic
  • Whorled pattern of meningothelial cells
  • Syncytial, fibrous, transitional histological subtypes
• Sites: parasagittal (most common), sphenoid wing, olfactory groove, cerebellopontine angle, foramen magnum, spinal canal
• Imaging: dural-based, uniformly enhancing, "dural tail" sign on MRI
• NF-2 mutation (chromosome 22) in most sporadic cases

E. Nerve Sheath Tumors

• Vestibular schwannoma (acoustic neuroma) - Grade 1
  • Arises from Schwann cells of CN VIII (vestibular portion)
  • Cerebellopontine angle
  • Antoni A tissue (compact, palisading - Verocay bodies) + Antoni B tissue (loose, myxoid)
  • Bilateral = NF-2

F. Pituitary Region Tumors

• Pituitary adenoma (benign; not WHO graded)
  • Micro (<10 mm) vs. macro (>10 mm)
  • Functioning: prolactinoma (most common), GH-secreting (acromegaly), ACTH-secreting (Cushing's), TSH-secreting
  • Non-functioning: presents with mass effect
• Craniopharyngioma - Grade 1
  • Arises from Rathke's pouch remnants
  • Adamantinomatous (children) vs. papillary (adults)
  • Calcification in suprasellar region ("machine oil" cyst)

G. Pineal Region Tumors

• Germinoma (most common germ cell tumor; radiosensitive)
• Pineocytoma (Grade 1) / Pineoblastoma (Grade 4)
• Teratoma

H. Lymphoma

• Primary CNS lymphoma (PCNSL): diffuse large B-cell lymphoma; periventricular; immunocompromised patients; EBV-associated in AIDS; "ring-enhancing" on MRI
• Secondary CNS lymphoma

I. Metastatic Tumors (most common intracranial tumors overall)

• Primary sources: Lung > Breast > Melanoma > Kidney > Colon
  • Mnemonic: "Let Bronchial Melanoma Kill Colorectal"
• Lung carcinoma: most common source overall
• Melanoma: highest per capita tendency to metastasize to brain
• Multiple lesions favor metastasis; solitary lesion may mimic primary tumor
• Located at grey-white junction (watershed zone) - characteristic
• Leptomeningeal carcinomatosis: seeding of meninges; poor prognosis

J. Vascular Tumors

• Hemangioblastoma - Grade 1; cerebellum; von Hippel-Lindau; produces erythropoietin (polycythemia)

---

5. WHO GRADING SYSTEM

---

6. CLASSIFICATION BASED ON SITE

A. Supratentorial vs. Infratentorial

• Cerebral hemisphere tumors: glioblastoma, astrocytoma, metastases, meningioma, lymphoma
• Midline tumors: pituitary adenoma, craniopharyngioma, colloid cyst (3rd ventricle), pineal tumors, optic nerve glioma

• Medulloblastoma (vermis)
• Pilocytic astrocytoma (cerebellar hemisphere)
• Ependymoma (4th ventricle floor)
• Brainstem glioma / DIPG
• Vestibular schwannoma (CPA)
• Hemangioblastoma (cerebellar hemisphere)

B. Intra-axial vs. Extra-axial

C. Intrinsic vs. Extrinsic

• Intrinsic: within substance of brain = gliomas, metastases
• Extrinsic: compress brain from outside = meningioma, neurofibroma, pituitary adenoma, craniopharyngioma

D. Primary vs. Secondary (Metastatic)

• Primary: arise from cells within CNS
• Secondary: metastasize from elsewhere; lung, breast, melanoma most common

---

7. CLINICAL FEATURES

A. Symptoms/Signs of Raised Intracranial Pressure (ICP)

1. Headache - diffuse, worse in morning (recumbency increases ICP), aggravated by straining/coughing (Valsalva); later persistent
2. Vomiting - often projectile, may be without nausea; due to pressure on vomiting center (area postrema)
3. Papilloedema - blurring of optic disc margins, dilated veins, hemorrhages; indicates chronic raised ICP; may lead to progressive visual loss

• Altered consciousness / personality change (frontal lobe pressure)
• Diplopia - CN VI (abducens) palsy is the most common false-localizing sign; CN VI has a long intracranial course
• Cushing's Triad (life-threatening raised ICP): hypertension + bradycardia + irregular respiration
• Herniation syndromes (see below)

• Uncal (transtentorial) herniation: ipsilateral CN III palsy (dilated, fixed pupil), contralateral hemiplegia; "blown pupil"
• Central herniation: bilateral miosis then dilatation, coma
• Tonsillar herniation: cerebellar tonsils through foramen magnum; cardiorespiratory arrest
• Subfalcine herniation: cingulate gyrus under falx; ipsilateral ACA compression

B. Focal Neurological Deficits (Localizing Signs)

C. Epileptic Seizures

• Occur in 30-50% of patients with brain tumors
• More common with slow-growing tumors (astrocytoma, oligodendroglioma, meningioma) than fast-growing ones
• Focal (partial) seizures suggest cortical involvement
• New-onset seizures in an adult should always raise suspicion of a structural lesion
• Low-grade glioma: seizures may be the ONLY presenting feature for years

D. Psychiatric/Cognitive Changes

• Personality change, depression, memory impairment
• May mislead to psychiatric diagnosis (up to 20% of patients initially seek psychiatric help)

E. Endocrine Manifestations (Pituitary Tumors)

• Prolactinoma: amenorrhoea, galactorrhoea, infertility, hypogonadism
• GH-secreting adenoma: acromegaly (adults), gigantism (children)
• ACTH-secreting: Cushing's disease
• Non-functioning macroadenoma: hypopituitarism, bitemporal hemianopia
• Pituitary apoplexy: sudden headache, visual loss, ophthalmoplegia (haemorrhage/infarction in pituitary tumor); emergency

F. Special Presentations

• Metastases: often present with stroke-like sudden deficit (hemorrhagic metastasis - melanoma, choriocarcinoma, renal cell)
• Medulloblastoma: morning headache, vomiting, truncal ataxia in child
• Craniopharyngioma: visual field defects + growth failure in child; diabetes insipidus

---

8. INVESTIGATIONS

A. Imaging (First-Line)

• Superior tissue contrast, multiplanar
• T1 with contrast: blood-brain barrier breakdown (ring-enhancement in GBM, uniform enhancement in meningioma)
• T2/FLAIR: shows edema, infiltration
• DWI (Diffusion-Weighted Imaging): distinguishes abscess (restricted diffusion) from tumor
• MR Spectroscopy: Choline↑ (cell membrane turnover), NAA↓ (neuronal loss), Lac peak in necrosis; helps distinguish tumor from abscess/radiation necrosis
• Perfusion MRI: rCBV (relative cerebral blood volume) - higher in high-grade tumors
• Functional MRI (fMRI): pre-surgical mapping of eloquent cortex (speech, motor)
• MR Angiography: assess vascular supply before surgery

• Available, fast; identifies hydrocephalus, calcification (oligodendroglioma, craniopharyngioma, meningioma), hemorrhage, bone involvement (skull base tumors)
• CT chest-abdomen-pelvis: exclude extracranial primary when metastasis suspected

B. Blood Tests

• FBC, ESR, CRP (infection, lymphoma)
• LFTs, renal function (for contrast, metastasis work-up)
• Tumor markers: AFP, beta-hCG (pineal germ cell tumors); CEA, PSA (metastasis screening)
• Hormonal profile: prolactin, GH, IGF-1, cortisol, TSH/T4, LH, FSH, testosterone/estradiol (pituitary tumors)
• Serum protein electrophoresis (lymphoma/myeloma)

C. Cerebrospinal Fluid (CSF) Examination

• Contraindicated if raised ICP or space-occupying lesion (risk of herniation)
• Indicated for: lymphoma (cytology, flow cytometry), leptomeningeal carcinomatosis, medulloblastoma (staging)
• Findings: raised protein, normal/low glucose; malignant cells on cytology; oligoclonal bands in lymphoma

D. Histological / Tissue Diagnosis (Gold Standard)

1. Stereotactic biopsy: frameless or frame-based; used for deep/eloquent area lesions, lymphoma diagnosis
2. Open biopsy / surgical resection: provides tissue and debulks tumor
3. Liquid biopsy: circulating tumor DNA in blood/CSF (emerging technique for IDH mutation, MGMT)

• 5-ALA (5-aminolevulinic acid): taken orally pre-op; accumulates in GBM cells; fluoresces pink/violet under UV light, allowing real-time identification of tumor margins
• Intraoperative MRI / neuronavigation
• Awake craniotomy with brain mapping: for tumors near eloquent cortex (speech, motor); patient is awake, responds to commands while surgeon maps cortex with stimulator

E. EEG

• Useful when seizures are present or suspected
• Can help with epilepsy monitoring and guiding antiepileptic therapy

F. Formal Visual Field Testing (Perimetry)

• For pituitary adenomas, optic pathway gliomas, craniopharyngiomas
• Bitemporal hemianopia: chiasmal compression
• Homonymous hemianopia: posterior hemisphere/temporal lesion

---

9. MANAGEMENT

A. General Principles

1. Multidisciplinary Team (MDT): neuro-oncologist, neurosurgeon, radiation oncologist, neuropathologist, neurologist, oncology nurse, palliative care
2. Goals of treatment: reduce tumor burden, alleviate symptoms, provide histological diagnosis, improve/preserve neurological function, extend survival

B. Medical Management

• Immediate role in all symptomatic brain tumors
• Reduces peritumoral vasogenic edema
• Dose: 4-8 mg twice daily (IV or oral)
• Effect seen within 24-48 hours; dramatic neurological improvement
• Always given with proton pump inhibitor (gastric protection)
• NOT effective for radiation necrosis or lymphoma edema

• Indicated when seizures have occurred
• Prophylactic AEDs NOT routinely recommended (except perioperative period)
• Preferred agents: levetiracetam (least drug interactions, no hepatic enzyme induction), sodium valproate
• Avoid phenytoin/carbamazepine in patients on temozolomide (enzyme induction)

• For acute herniation/raised ICP
• Mannitol 0.25-1 g/kg IV bolus

C. Surgical Management

1. Biopsy: stereotactic (frame-based or frameless); for deep lesions, lymphoma, eloquent cortex
2. Craniotomy + tumor excision: primary treatment for most surgically accessible tumors
   • Awake craniotomy: tumor near speech/motor cortex; intraoperative brain mapping
   • Gross total resection (GTR) vs. subtotal resection: extent of resection predicts outcome in glioma and meningioma
3. Endoscopic approaches: transsphenoidal endoscopic surgery (pituitary adenoma, craniopharyngioma) - through nostril/sphenoid sinus; less morbid than open craniotomy
4. CSF diversion:
   • Ventriculoperitoneal (VP) shunt: for obstructive hydrocephalus
   • Endoscopic third ventriculostomy (ETV): alternative to shunt in obstructive hydrocephalus
   • External ventricular drain (EVD): temporary, acute raised ICP

• Neuronavigation systems (GPS for the brain) using pre-operative MRI
• 5-ALA fluorescence-guided surgery for GBM
• Intraoperative MRI to confirm extent of resection
• Cortical mapping (awake or under anaesthesia) to identify eloquent areas

D. Radiotherapy

• Standard for high-grade gliomas (Grades 3-4) after surgery
• Total dose: 60 Gy in 30 fractions over 6 weeks for GBM
• 54 Gy for Grade 3 gliomas
• Whole-brain radiotherapy (WBRT): for multiple metastases
• Craniospinal irradiation: medulloblastoma (whole brain + spine)
• Proton beam therapy: children (reduces dose to normal brain)

• Single high-precision dose to small, well-defined lesion
• Indications: 1-4 brain metastases, vestibular schwannoma, arteriovenous malformation, recurrent meningioma
• Gamma Knife (cobalt-60 sources), CyberKnife (linear accelerator-based)
• Advantage: non-invasive, highly precise, outpatient

• For larger lesions near critical structures
• Pituitary adenoma, large meningioma, optic nerve glioma

E. Chemotherapy

F. Targeted Therapy and Immunotherapy

• Bevacizumab (anti-VEGF): recurrent GBM; reduces edema; improves progression-free survival but not overall survival
• IDH inhibitors: enasidenib, ivosidenib - for IDH-mutant gliomas (emerging)
• Tumor Treating Fields (TTF / Optune): alternating electric fields; scalp electrodes; improves survival in GBM when added to maintenance TMZ
• Checkpoint inhibitors (nivolumab, pembrolizumab): under investigation for GBM; limited efficacy to date
• BRAF inhibitors (dabrafenib + trametinib): BRAF V600E-mutant gliomas, pilocytic astrocytoma

G. Tumor-Specific Management Highlights

• Surgery (maximal safe resection) + RT (60 Gy/30f) + concurrent TMZ + adjuvant TMZ x 6 cycles = "Stupp Protocol" (2005)
• 5-ALA guided surgery improves GTR rates
• Median survival: ~14 months (without MGMT methylation), ~21 months (with MGMT methylation)
• Recurrence is universal

• Small/incidental: watch and wait with serial MRI (especially elderly)
• Surgical resection: curative if complete (Simpson Grade I/II)
• Simpson Grading: Grade I (complete resection + dural excision) = lowest recurrence (9% at 10 years); Grade IV/V (incomplete) = high recurrence
• Adjuvant SRS for subtotal resection or recurrence
• Grade 2/3: adjuvant radiotherapy

• Prolactinoma (FIRST-LINE): medical -- dopamine agonists (cabergoline, bromocriptine); surgery if refractory/intolerant
• Other functioning adenomas + non-functioning macroadenomas: transsphenoidal surgery (endoscopic)
• Pituitary apoplexy: IV dexamethasone + emergency surgery (if visual deterioration)
• Radiotherapy: residual/recurrent adenoma

• Small intracanalicular: surveillance MRI + audiological monitoring
• Intermediate size: radiosurgery (Gamma Knife) -- hearing preservation possible in smaller tumors with intact function
• Large (>4 cm) with brainstem compression: microsurgical excision (translabyrinthine, retrosigmoid, or middle fossa approach)
• Approaches: translabyrinthine (sacrifice hearing, best facial nerve identification), retrosigmoid (hearing preservation possible), middle fossa (hearing preservation, small lateral tumors)
• Bilateral = NF-2: hearing preservation paramount

• Surgery (maximal resection) + craniospinal irradiation + adjuvant PCV/cisplatin-based chemotherapy
• Risk stratification: standard risk vs. high risk (based on extent of resection, CSF dissemination, molecular subtype)
• WNT-activated: best prognosis; SHH-activated: intermediate; Group 3: worst prognosis

• Single/few (1-4) and good performance status: stereotactic radiosurgery (SRS) +/- surgery
• Multiple: WBRT (30 Gy/10f) or SRS
• Surgery: when diagnosis uncertain, single large lesion with mass effect, known chemo-resistant primary
• Systemic therapy: per primary tumor (targeted therapy if driver mutation known)

• No surgery (biopsy only for diagnosis)
• Stop steroids BEFORE biopsy (steroid-induced lysis makes pathology difficult)
• High-dose methotrexate-based chemotherapy +/- rituximab
• WBRT if incomplete response
• Autologous stem cell transplant for relapsed disease

• Surgical excision (transsphenoidal or transcranial)
• RT for residual/unresectable disease
• Intracystic bleomycin or interferon-alpha for cystic lesions
• Complications: hypopituitarism, diabetes insipidus, obesity, visual loss (lifelong endocrine replacement needed)

---

10. PROGNOSIS

---

11. SHORT ANSWER QUESTIONS (SAQ) / EXAM POINTERS

• GBM: pseudopalisading necrosis + microvascular proliferation
• Oligodendroglioma: fried-egg cells + chicken-wire vasculature + calcification
• Meningioma: psammoma bodies + whorled pattern
• Schwannoma: Antoni A (Verocay bodies) + Antoni B
• Ependymoma: perivascular pseudorosettes

---

12. LONG ANSWER QUESTION (LAQ) APPROACH

1. Introduction + incidence (2 marks)
2. Classification: WHO + pathological + site-based (3 marks)
3. Clinical features: raised ICP + focal deficits + seizures (3 marks)
4. Investigations: MRI, CT, biopsy, blood tests (3 marks)
5. Management: medical + surgical + radio/chemo per tumor type (3 marks)
6. Prognosis (1 mark)

---