Brain Tumors

Brain metastases are the commonest intracranial tumours in adults, outnumbering primary tumours roughly ten to one. They arise from lung (about half), breast, melanoma, renal and colorectal cancer. Primary CNS tumours have an incidence of about 20 to 25 per 100,000 including benign lesions, with malignant forms near 7 per 100,000.

Classification integrates histology, molecular markers and a grade of 1 to 4. Key entities:

• Adult-type diffuse gliomas: IDH-mutant astrocytoma (grades 2 to 4), IDH-mutant oligodendroglioma with 1p/19q codeletion (grades 2 and 3), and IDH-wildtype glioblastoma (grade 4).
• Circumscribed gliomas: pilocytic astrocytoma (BRAF alterations), ependymoma.
• Embryonal: medulloblastoma, subdivided by WNT, SHH, group 3 and group 4.
• Others: meningioma, schwannoma, pituitary adenoma, primary CNS lymphoma, germ cell tumours, haemangioblastoma, and diffuse midline glioma with H3 K27 alteration.

Distribution differs by age. In adults most primary tumours are supratentorial. In children most are infratentorial (medulloblastoma, pilocytic astrocytoma, ependymoma, diffuse midline glioma).

Risk factors and associations

• Ionising radiation.
• NF1 (optic glioma, astrocytoma), NF2 (schwannoma, meningioma, ependymoma), tuberous sclerosis (subependymal giant cell astrocytoma), von Hippel-Lindau disease (haemangioblastoma), Li-Fraumeni syndrome, Lynch syndrome.
• Immunosuppression, particularly HIV, for primary CNS lymphoma.

Neurological effects arise from direct tissue destruction, vasogenic oedema, mass effect, hydrocephalus, haemorrhage and cortical irritation.

Prognosis varies widely. Glioblastoma has a median survival of about 14 to 16 months with standard treatment, while IDH-mutant lower grade gliomas have survival measured in many years. Pilocytic astrocytoma is often cured by resection.

Presentation is by raised ICP, seizures or focal deficit

• Headache in about half at presentation. It is progressive, worse in the morning or on lying flat, and accompanied by vomiting.
• Seizures in 25 to 30% at presentation and more often with low grade or cortical tumours. In low grade glioma the lifetime frequency exceeds 70%.
• Progressive focal deficit over weeks (hemiparesis, aphasia, visual field loss).
• Cognitive and personality change with frontal lesions.

By location

• Frontal: apathy, disinhibition, anosmia, contralateral weakness, expressive aphasia.
• Temporal: complex partial seizures, memory loss, superior quadrantanopia, receptive aphasia.
• Parietal: sensory loss, neglect, apraxia, Gerstmann syndrome, inferior quadrantanopia.
• Occipital: homonymous hemianopia.
• Cerebellar: truncal ataxia, nystagmus, early hydrocephalus. Vermian tumours give a broad based gait.
• Brainstem: cranial neuropathies, long tract signs, hydrocephalus.
• Pineal region: Parinaud syndrome (upgaze palsy, convergence retraction nystagmus) and hydrocephalus.
• Sellar and suprasellar: bitemporal hemianopia and endocrine dysfunction.

Children may show vomiting, head tilt, ataxia, macrocephaly, developmental regression, and the diencephalic syndrome of failure to thrive with preserved alertness.

Red flags are a new headache after 50 years, a new seizure in an adult, progressive deficits, papilloedema, early morning vomiting, a Cushing response, and a known extracranial primary cancer.

MRI brain with and without gadolinium is the investigation of choice

• Glioblastoma shows irregular ring enhancement with central necrosis, peritumoral FLAIR change, restricted diffusion in the solid rim, and raised relative cerebral blood volume.
• Oligodendroglioma shows cortical involvement and calcification (best seen on CT).
• Lymphoma shows homogeneous enhancement, marked diffusion restriction, and periventricular location.
• Metastases show well circumscribed enhancing lesions at the grey-white junction with disproportionate oedema.
• Abscess shows a thin smooth wall and strongly restricted diffusion in the cavity.

Advanced MRI (perfusion, spectroscopy with raised choline and reduced N-acetylaspartate) assists in separating tumour from radiation necrosis, abscess or demyelination.

Further evaluation

• Whole spine MRI for medulloblastoma, ependymoma, germ cell tumour, lymphoma and leptomeningeal disease.
• CT chest, abdomen and pelvis for suspected metastasis or unknown primary.
• Serum and CSF alpha-fetoprotein and beta hCG for germ cell tumours. CSF cytology and flow cytometry for lymphoma, taken only when imaging shows no obstruction.
• HIV test in suspected lymphoma. Avoid corticosteroids before biopsy when lymphoma is possible, as they can obscure the diagnosis.
• Pituitary hormone profile for sellar masses.

Tissue diagnosis is by resection or stereotactic biopsy, with molecular testing

• IDH1/2, ATRX, TP53, 1p/19q codeletion, TERT promoter, EGFR amplification, CDKN2A/B, MGMT promoter methylation.
• H3 K27M in midline tumours, BRAF V600E in paediatric and pleomorphic tumours, and the medulloblastoma methylation group.

Response is assessed with serial MRI. Pseudoprogression, which is increased enhancement within about 12 weeks of chemoradiation without true progression, must be distinguished from true recurrence.

Symptom control

• Vasogenic oedema: dexamethasone 10 mg IV or orally loading, then 4 mg every 6 hours, tapered to the lowest effective dose. Add a proton pump inhibitor, monitor glucose, and give co-trimoxazole 960 mg three times weekly for Pneumocystis prophylaxis if steroids are prolonged.
• Seizures: treat only after a seizure. Levetiracetam 500 to 1500 mg twice daily, lacosamide 100 to 200 mg twice daily, or valproate. Avoid enzyme inducing drugs (phenytoin, carbamazepine, phenobarbital) because they lower chemotherapy levels.
• Venous thromboembolism prophylaxis, and therapeutic anticoagulation (LMWH preferred) when thrombosis occurs.
• Hydrocephalus: EVD, shunt or endoscopic third ventriculostomy.

Surgery

• Maximal safe resection, using awake mapping and intraoperative MRI or 5-aminolevulinic acid (20 mg/kg orally 3 hours before surgery) fluorescence guidance in high grade glioma.
• Biopsy alone for deep, eloquent or multifocal lesions and lymphoma.

Glioblastoma and IDH-wildtype grade 4

• Radiotherapy 60 Gy in 30 fractions with concurrent temozolomide 75 mg/m2 daily for 42 days, then adjuvant temozolomide 150 mg/m2 on days 1 to 5 of a 28 day cycle, escalated to 200 mg/m2 from cycle 2 if tolerated, for 6 cycles. Tumour treating fields can be added.
• Patients aged 65 to 70 and above, or with poor performance status: 40 Gy in 15 fractions with temozolomide, or 25 Gy in 5 fractions alone.
• MGMT unmethylated tumours derive less benefit from temozolomide.
• Recurrence: re-resection if feasible, lomustine 110 mg/m2 every 6 weeks, bevacizumab 10 mg/kg every 2 weeks, or re-irradiation. Targeted therapy for BRAF V600E mutation (dabrafenib with trametinib).

IDH-mutant and lower grade gliomas

• Grade 2: resection, with observation after complete resection of low risk disease. High risk features (age 40 or above, incomplete resection) call for radiotherapy 54 Gy in 30 fractions followed by PCV (procarbazine 60 mg/m2 days 8 to 21, lomustine 110 mg/m2 day 1, vincristine 1.4 mg/m2 days 8 and 29, every 6 weeks for 6 cycles) or temozolomide.
• Vorasidenib 40 mg daily is an option after surgery for IDH-mutant grade 2 tumours not yet needing radiotherapy.
• Grade 3 oligodendroglioma: radiotherapy followed by PCV or temozolomide. Grade 3 and 4 IDH-mutant astrocytoma: radiotherapy with adjuvant temozolomide.

Primary CNS lymphoma

• No resection. High dose methotrexate 3.5 to 8 g/m2 IV over 2 to 4 hours every 2 weeks with leucovorin rescue, urinary alkalinisation and renal monitoring, combined with rituximab and often cytarabine and thiotepa. Consolidation with autologous stem cell transplant or whole brain radiotherapy.

Paediatric and embryonal tumours

• Medulloblastoma: maximal resection, craniospinal irradiation (23.4 Gy for average risk disease), and adjuvant chemotherapy with vincristine, cisplatin and cyclophosphamide or lomustine. Reduced intensity regimens suit WNT tumours.
• Pilocytic astrocytoma: surgery alone is often curative.
• Ependymoma: resection with focal radiotherapy.
• Germ cell tumours: platinum based chemotherapy with radiotherapy.

Brain metastases

• Single lesion or symptomatic large lesion: resection followed by cavity stereotactic radiosurgery.
• One to four lesions (up to about ten): stereotactic radiosurgery alone.
• Many lesions: whole brain radiotherapy 30 Gy in 10 fractions with hippocampal avoidance and memantine (5 mg daily titrated to 10 mg twice daily over 4 weeks).
• Systemic therapy with CNS activity: osimertinib 80 mg daily for EGFR mutant lung cancer, alectinib 600 mg twice daily for ALK positive disease, dabrafenib with trametinib for BRAF melanoma, ipilimumab 3 mg/kg with nivolumab 1 mg/kg for 4 doses then nivolumab maintenance for melanoma.

Supportive and long term care

• Palliative care involvement early in high grade disease.
• Driving restrictions after seizures, neurorehabilitation, neurocognitive support, and monitoring for steroid myopathy and osteoporosis.
• Surveillance MRI every 2 to 3 months in the first 2 years for high grade tumours.