Pilocytic Astrocytoma

Pilocytic astrocytoma is a slow growing, well circumscribed grade 1 glioma, often cystic, that mainly affects children and young adults. It is the commonest paediatric glioma, is often cured by complete resection, and has a 10-year survival of over 95% in resected cases.

It accounts for about 15% of paediatric brain tumours, with an incidence of about 3 to 5 cases in 1,000,000 children each year, and it is rarer in adults. The peak age is 5 to 15 years. Locations are the cerebellum (most common), optic nerve and chiasm and hypothalamus, brainstem and cerebral hemispheres.

Neurofibromatosis type 1 is the main association, and optic nerve and chiasm gliomas develop in 15% to 20% of affected children. Most other cases are sporadic.

Pathophysiology. Constitutive activation of the MAPK signalling cascade is nearly universal. The commonest change is a KIAA1549::BRAF fusion (about 70% of cerebellar tumours), then BRAF V600E, NF1 loss and FGFR1 variants.

Histology. Biphasic pattern of compact fibrillary areas with Rosenthal fibres and loose areas with microcysts and eosinophilic granular bodies. Mitoses are rare, and atypical features do not change grade 1. Leptomeningeal spread occurs without worsening prognosis in most cases.

Behaviour. Tumours may stop growing or even regress, especially in NF1 optic nerve and chiasm disease. Anaplastic progression is rare and mostly follows radiotherapy.

• Cerebellar tumours: headache, vomiting and ataxia from obstructive hydrocephalus, head tilt and nystagmus.
• Optic nerve and chiasm tumours: reduced visual acuity, visual field loss, proptosis, strabismus and optic atrophy.
• Hypothalamic tumours: diencephalic syndrome in infants (marked emaciation despite normal intake), precocious puberty, endocrine dysfunction.
• Brainstem tumours: cranial nerve palsies and long tract signs, usually slowly progressive.
• Cerebral tumours: seizures and focal signs.

Red flags.

• Signs of raised intracranial pressure (morning vomiting, papilloedema, drowsiness).
• Rapid visual loss.
• Acute intracystic haemorrhage with sudden deterioration.

• MRI of the brain and whole spine with gadolinium: cystic mass with an enhancing mural nodule (cerebellar), or enhancing solid mass of the optic nerve and chiasm. Optic nerve and chiasm tumours in NF1 may be diagnosed on imaging without biopsy.
• Biopsy or resection when the diagnosis is uncertain or the tumour is symptomatic, with BRAF fusion and V600E testing, NF1 and FGFR1 testing as indicated.
• Ophthalmological examination with visual fields and acuity, endocrine assessment (growth, puberty, thyroid, cortisol, IGF-1, prolactin) for optic nerve and chiasm and hypothalamic tumours.
• Assessment for NF1 (café-au-lait macules, axillary freckling, neurofibromas, Lisch nodules).
• Baseline FBC, creatinine and liver tests before chemotherapy.

Differential diagnosis.

• Medulloblastoma, ependymoma and haemangioblastoma
• Pilomyxoid astrocytoma and diffuse low grade glioma
• Craniopharyngioma, germinoma and pituitary tumour (suprasellar tumours)
• Ganglioglioma, dysembryoplastic neuroepithelial tumour and pleomorphic xanthoastrocytoma
• Brain abscess and metastasis
• Optic neuritis and optic nerve sheath meningioma

Surgery. Gross total resection is curative and is the treatment of choice for accessible tumours, especially cerebellar. Hydrocephalus is treated by endoscopic third ventriculostomy or an external drain, before or at resection. Observation after complete resection with serial MRI.

Observation. Asymptomatic and stable optic nerve and chiasm tumours (especially in NF1) are observed with MRI and visual assessment every 3 to 6 months.

Chemotherapy for progressive or unresectable tumours, especially in young children (to delay radiotherapy).

• Carboplatin with vincristine: carboplatin 175 mg/m2 IV once weekly for 4 weeks followed by a 2-week rest, with vincristine 1.5 mg/m2 IV (maximum 2 mg) once weekly for 10 weeks, then 8 maintenance cycles of 6 weeks (carboplatin 175 mg/m2 weeks 1 to 4, vincristine 1.5 mg/m2 weeks 1 to 3), about 58 weeks in all; maximum carboplatin 175 mg/m2 each dose and vincristine 2 mg each dose; monitoring: FBC weekly, creatinine, audiometry, neuropathy and constipation, hypersensitivity to carboplatin after repeated doses; adjustment: reduce carboplatin by 25% for neutrophils under 0.5 x 10^9/L or platelets under 50 x 10^9/L, reduce vincristine by 50% when bilirubin is 26 to 51 micromol/L and avoid it over 51 micromol/L, avoid strong CYP3A inhibitors (azole antifungals), reduce carboplatin in renal impairment by the creatinine clearance formula

Targeted therapy for BRAF V600E tumours.

• Dabrafenib with trametinib: dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily until progression or unacceptable toxicity, for BRAF V600E tumours in adults and in adolescents weighing 51 kg or more (weight banded doses set by a paediatric oncology pharmacist below 51 kg); maximum dabrafenib 300 mg daily and trametinib 2 mg daily; monitoring: left ventricular ejection fraction at baseline, 1 month and then every 2 to 3 months, skin and eye examination, blood pressure, liver tests, glucose, temperature; adjustment: reduce dabrafenib stepwise to 100 mg then 75 mg twice daily and trametinib to 1.5 mg then 1 mg daily, hold both for fever of 38.5 C or more, stop for a fall in ejection fraction of over 10 points to under the lower limit of normal, avoid strong CYP3A4 or CYP2C8 inducers and inhibitors, no renal adjustment for mild to moderate impairment

Radiotherapy. Reserved for progressive disease after chemotherapy in older children and adults (50.4 to 54 Gy in 28 to 30 fractions, with proton therapy preferred). It is avoided in children under 5 and in NF1 because of risk of moyamoya, second tumours and neurocognitive loss.

Seizure and oedema control (cerebral tumours).

• Antiseizure therapy: levetiracetam 500 mg orally twice daily, increased by 500 mg twice daily every 1 to 2 weeks to a usual 1000 to 1500 mg twice daily after a seizure (it is not continued as prophylaxis in seizure free patients after the early postoperative period); maximum 3000 mg daily; monitoring: mood, irritability, somnolence, renal function; adjustment: creatinine clearance 50 to 79 mL/min 500 to 1000 mg twice daily, 30 to 49 mL/min 250 to 750 mg twice daily, under 30 mL/min 250 to 500 mg twice daily; avoid enzyme inducing antiseizure drugs because they lower temozolomide and lomustine exposure
• Corticosteroid for symptomatic oedema: dexamethasone 4 mg orally or IV once or twice daily for mild symptoms and up to 4 mg four times daily for marked oedema or raised intracranial pressure, for the shortest period, tapered over 1 to 2 weeks once symptoms settle; maximum 16 mg daily; monitoring: glucose, blood pressure, mood and sleep, gastric symptoms (gastric protection when combined with other risk factors), opportunistic infection, myopathy; adjustment: use the lowest effective dose, avoid prolonged courses because of myopathy, osteoporosis and infection, use lower doses in hepatic impairment

Monitoring. MRI 24 to 72 hours after surgery to define residual tumour, then every 3 to 6 months for 2 years and every 6 to 12 months to year 5. Visual, endocrine, growth and neurodevelopmental review. Late surveillance in survivors of radiotherapy.

Referral and escalation.

• Paediatric neuro oncology referral at diagnosis.
• Emergency neurosurgery for hydrocephalus with falling consciousness.
• Ophthalmology review for any visual decline.

Special groups.

• NF1: avoid radiotherapy, observe optic nerve and chiasm tumours, and screen for other tumours.
• Infants with diencephalic syndrome: nutritional rehabilitation and early chemotherapy.
• Adults: tumours behave more aggressively, and complete resection is more often followed by recurrence.
• Pregnancy: surgery in the second trimester when needed.