Cerebral neoplasia
Description
- Metastases are the commonest intracranial tumour overall - roughly 10x the incidence of primary brain tumours
- Primary brain tumours essentially never metastasise outside the CNS - they kill by local progression
Vestibular schwannoma - the classic exam lesion
- Arises from the vestibular division of CN VIII in the internal auditory meatus, growing into the cerebellopontine angle
- As it enlarges it compresses, in order:
- CN VIII - unilateral sensorineural hearing loss and tinnitus (speech discrimination worse than the audiogram predicts), imbalance rather than true vertigo
- CN V - loss of the corneal reflex (the earliest trigeminal sign), facial numbness
- Cerebellum - ipsilateral ataxia, nystagmus
- Brainstem - long tract signs, hydrocephalus
- *CN VII is remarkably resistant - facial weakness is late. A facial palsy early in a CPA mass suggests a facial nerve schwannoma or malignancy*
- Bilateral vestibular schwannomas = neurofibromatosis type 2
Other CPA masses
- Meningioma, epidermoid cyst, facial nerve schwannoma, metastasis, glomus jugulare
Epidemiology
Primary brain tumours - proportions
| Tumour | ~% of primary brain tumours |
|---|---|
| Meningioma | ~37% - the commonest non-malignant and the commonest primary brain tumour overall |
| Pituitary tumours | ~16% |
| Glioblastoma | ~15% - the commonest MALIGNANT primary brain tumour |
| Nerve sheath tumours (vestibular schwannoma) | ~8% |
| Astrocytoma (excluding glioblastoma) | ~5% |
| Oligodendroglioma | ~1% |
- Primary CNS lymphoma ~2% (rising in the immunocompetent elderly)
Other
- Brain metastases in ~20-40% of all cancer patients
- Meningioma F>M ~2:1; glioblastoma M>F ~1.6:1, peak 55-75 yrs
- Vestibular schwannoma peak 40-60 yrs; ~95% sporadic and unilateral
- Overall incidence of primary CNS tumours ~7 per 100,000/yr in Australia
Aetiopathogenesis
Sources of brain metastases
- Lung (~40-50%), breast (~15-20%), melanoma (~10%, and the most likely to bleed), renal, colorectal
- Haemorrhagic metastases: melanoma, renal cell, choriocarcinoma, thyroid ("MR CT")
- Distribution follows blood flow: ~80% supratentorial, at the grey-white junction and arterial watershed zones
Risk factors for primary brain tumours
- Ionising radiation - the only firmly established environmental risk factor (meningioma, glioma after cranial irradiation)
- Immunosuppression / HIV -> EBV-driven primary CNS lymphoma
- Genetic syndromes
- Neurofibromatosis 1 - optic pathway glioma, astrocytoma
- Neurofibromatosis 2 - bilateral vestibular schwannomas, meningiomas, ependymomas
- Tuberous sclerosis - subependymal giant cell astrocytoma
- Li-Fraumeni (TP53), Turcot, von Hippel-Lindau (haemangioblastoma), Gorlin
- Mobile phone use is not an established risk factor
Molecular classification (WHO CNS5, 2021) - molecular now overrides histology
- Glioblastoma is now defined as IDH-WILDTYPE only
- Diagnosed in an adult IDH-wildtype diffuse astrocytic glioma with *microvascular proliferation OR necrosis OR TERT promoter mutation OR EGFR amplification OR +7/-10 chromosome copy number change*
- *Molecular features alone are now sufficient - the tumour no longer needs necrosis or microvascular proliferation on histology*
- Tumours formerly called "glioblastoma, IDH-mutant" are now astrocytoma, IDH-mutant, CNS WHO grade 4 - a different disease with a much better prognosis
- Oligodendroglioma = IDH-mutant AND 1p/19q co-deleted - both are required by definition
- MGMT promoter methylation - predicts temozolomide benefit
Diagnosis
Presentations - four patterns
1. Progressive focal deficit - over weeks to months
2. Seizure - first presentation in ~30-50% of gliomas; any new adult-onset seizure needs an MRI
3. Raised intracranial pressure - morning headache, worse on lying flat, coughing or straining, with vomiting; papilloedema; VI nerve palsy as a false localising sign
4. Cognitive or personality change - frontal tumours; often attributed to depression or dementia for months
Red flags in a headache
- New headache >50 yrs, progressive over weeks, worse in the morning or on Valsalva
- Papilloedema; new seizure; focal deficit; personality change
- Known malignancy; immunosuppression
Imaging
- MRI brain with gadolinium is the test (CT only for the acute/emergency setting)
| Appearance | Suggests |
|---|---|
| Ring-enhancing with central necrosis, thick irregular wall, crossing the corpus callosum ("butterfly") | Glioblastoma |
| Multiple ring-enhancing lesions at the grey-white junction with disproportionate oedema | Metastases |
| Extra-axial, dural-based, homogeneously enhancing with a "dural tail", CSF cleft | Meningioma |
| Periventricular, homogeneously and avidly enhancing, restricted diffusion, in an immunosuppressed patient | Primary CNS lymphoma (melts away with steroid - the "ghost tumour") |
| Non-enhancing T2/FLAIR hyperintensity, little mass effect | Low-grade (IDH-mutant) glioma |
| Enhancing lesion in the internal auditory meatus/CPA, "ice cream cone" | Vestibular schwannoma |
| Cystic with an enhancing mural nodule (posterior fossa) | Haemangioblastoma, pilocytic astrocytoma |
- Ring-enhancing lesion differential: metastasis, glioblastoma, abscess, lymphoma, demyelination (incomplete ring), toxoplasmosis, radiation necrosis, resolving haematoma
- Abscess restricts on DWI centrally; tumour usually does not - the key sequence
- Advanced: MR spectroscopy, perfusion, PET (to separate recurrence from radiation necrosis/pseudoprogression)
Tissue and staging
- Histology + molecular profiling (IDH, 1p/19q, MGMT, ATRX, TERT, EGFR) is required - stereotactic biopsy or resection
- *Do NOT give corticosteroid before biopsy if primary CNS lymphoma is possible* - it causes the lesion to disappear and renders the biopsy non-diagnostic
- If metastases are suspected: CT chest/abdomen/pelvis, PET, and examine the skin, breasts and testes - find an accessible primary to biopsy instead
- Primary CNS lymphoma work-up: HIV, slit-lamp examination (vitreoretinal involvement), CSF cytology and flow cytometry, testicular ultrasound, bone marrow
Management
A. Immediate symptom control
- Dexamethasone 4-16 mg/day for symptomatic vasogenic oedema - dramatic effect within 24-48 h
- Give the dose in the morning; add a PPI; monitor glucose; PJP prophylaxis if prolonged
- *Withhold if primary CNS lymphoma is in the differential and the biopsy has not been done*
- Taper as soon as possible - steroid myopathy, hyperglycaemia and psychiatric effects accrue fast
- Antiseizure medication only after a seizure - not prophylactically
- Levetiracetam is preferred - no enzyme induction, so it does not interfere with chemotherapy or targeted agents; avoid enzyme-inducing agents such as carbamazepine and phenytoin
- VTE prophylaxis - brain tumour patients have a very high VTE risk; anticoagulation is generally safe even with brain metastases (except melanoma and other haemorrhagic types - individualise)
B. Glioblastoma (IDH-wildtype)
- Maximal safe resection (awake mapping, 5-ALA fluorescence guidance) - extent of resection correlates with survival
- Stupp protocol: radiotherapy 60 Gy in 30 fractions with concurrent daily temozolomide, then 6 cycles of adjuvant temozolomide
- MGMT promoter methylation predicts temozolomide benefit - unmethylated tumours derive much less
- Elderly or poor performance status: hypofractionated radiotherapy (40 Gy/15) +/- temozolomide; temozolomide alone if MGMT-methylated and unfit for RT
- Tumour treating fields (TTFields) add survival benefit in selected patients - not funded in Australia
- Recurrence: re-resection, re-irradiation, bevacizumab for symptomatic oedema (improves symptoms and steroid requirement, not survival), clinical trial
C. IDH-mutant glioma (grade 2-3)
- Maximal safe resection; radiotherapy + PCV or temozolomide in higher-risk disease
- Vorasidenib (IDH1/2 inhibitor) significantly prolongs progression-free survival in residual or recurrent grade 2 IDH-mutant glioma after surgery, delaying the need for chemoradiation (INDIGO) - the first targeted therapy to change practice in low-grade glioma
- 1p/19q co-deleted oligodendroglioma is the most chemosensitive glioma - median survival >14 years with RT + PCV
D. Brain metastases
- Determined by number, size, symptoms, control of the primary, performance status and available systemic options
- Stereotactic radiosurgery - preferred for a limited number of metastases; better neurocognitive preservation than whole-brain radiotherapy
- Surgery - single large symptomatic lesion, posterior fossa lesion causing hydrocephalus, or when tissue is needed
- Whole-brain radiotherapy - now reserved for diffuse or miliary disease; use hippocampal avoidance + memantine to reduce cognitive toxicity
- WBRT for a limited number of metastases is no longer standard - it worsens cognition without improving survival
- CNS-penetrant systemic therapy has changed the picture entirely - osimertinib (EGFR), alectinib/lorlatinib (ALK), tucatinib + trastuzumab (HER2), BRAF/MEK inhibitors and immunotherapy in melanoma all produce intracranial responses
- Leptomeningeal disease: intrathecal chemotherapy, craniospinal or focal RT, systemic therapy; prognosis poor
E. Meningioma
- Incidental, small and asymptomatic -> serial MRI observation (many never grow)
- Symptomatic or growing -> surgical resection; Simpson grade of resection predicts recurrence
- Radiosurgery for skull base or residual/recurrent disease
- Atypical (grade 2) and anaplastic (grade 3) - adjuvant radiotherapy
F. Vestibular schwannoma
- Observation with serial MRI for small tumours (many grow slowly or not at all)
- Stereotactic radiosurgery for small-to-medium tumours - excellent control, better hearing preservation
- Microsurgery for large tumours or brainstem compression - retrosigmoid, translabyrinthine or middle fossa approach
- Bevacizumab for NF2-related tumours
- Hearing rehabilitation; facial nerve function is the key surgical outcome measure
G. Primary CNS lymphoma
- High-dose methotrexate-based induction (usually with rituximab, cytarabine); consolidation with autologous stem cell transplant or reduced-dose WBRT in fit patients
- Highly responsive but relapses frequently; treat HIV if present
H. Supportive and palliative
- Early palliative care involvement; advance care planning while capacity is retained
- Driving cessation and reporting (Austroads criteria - seizure and visual field requirements)
- Neuro-rehabilitation, OT, speech pathology; cognitive and mood assessment
- Carer support; corticosteroid education; fertility preservation in younger patients
Associations
- Neurofibromatosis type 1 - optic pathway glioma, astrocytoma, malignant peripheral nerve sheath tumour
- Neurofibromatosis type 2 - bilateral vestibular schwannomas, multiple meningiomas, ependymomas, juvenile cataract
- Tuberous sclerosis - subependymal giant cell astrocytoma (everolimus)
- Von Hippel-Lindau - cerebellar and spinal haemangioblastoma, retinal angioma, renal cell carcinoma, phaeochromocytoma
- Li-Fraumeni (TP53), Turcot (colorectal polyposis + glioma/medulloblastoma), Gorlin, Cowden
- Prior cranial irradiation - meningioma, glioma, sarcoma
- Immunosuppression and HIV - EBV-driven primary CNS lymphoma
- Meningioma: female sex, progesterone receptor expression - may enlarge in pregnancy and with high-dose cyproterone acetate
- Epilepsy, VTE, depression and cognitive impairment as consequences
Natural history & complications
| Tumour | Prognosis |
|---|---|
| Glioblastoma, IDH-wildtype | Median survival ~15 months with full Stupp therapy; ~5% alive at 5 years. Better if MGMT-methylated, younger, good performance status, gross total resection |
| Astrocytoma, IDH-mutant grade 4 | Median ~3-5 years - substantially better than glioblastoma, which is why the reclassification matters |
| Oligodendroglioma (IDH-mutant, 1p/19q co-deleted) | Median >14 years |
| Meningioma grade 1 | Excellent; 10-year survival >80%. Recurrence depends on Simpson grade |
| Vestibular schwannoma | Benign; average growth ~1-2 mm/year, and many do not grow at all |
| Brain metastases | Median 3-12 months untreated by histology; far longer with targeted therapy and SRS in selected primaries |
| Primary CNS lymphoma | Median 3-5 years with high-dose methotrexate; poor without treatment (weeks-months) |
Complications
- Raised intracranial pressure -> herniation (uncal, tonsillar) - the terminal event in many
- Hydrocephalus - posterior fossa and intraventricular tumours
- Seizures and status epilepticus
- Intratumoural haemorrhage - melanoma, renal, choriocarcinoma, thyroid metastases; also glioblastoma
- VTE - very high risk
- Corticosteroid toxicity - myopathy, hyperglycaemia, psychosis, infection, osteoporosis (often the dominant morbidity)
- Radiation toxicity - pseudoprogression (within 3 months, mimics progression on MRI and needs no change of therapy), radiation necrosis (months-years), cognitive decline, hypopituitarism
- Cognitive impairment, personality change, loss of independence, carer burden
Monitor
- MRI at defined intervals - and know pseudoprogression before you declare failure
- FBE weekly-fortnightly on temozolomide (thrombocytopenia, lymphopenia); PJP prophylaxis during concurrent chemoradiation
- Glucose, weight, proximal power (steroid myopathy), mood and cognition
- Seizure frequency, driving status, functional and carer needs
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