Anaplastic Meningioma

Anaplastic meningioma is a grade 3 meningioma, defined by 20 or more mitoses in 10 high power fields, frank anaplasia, or molecular markers of aggression (TERT promoter mutation, homozygous CDKN2A/B deletion). It behaves like a high grade sarcoma, with frequent recurrence and a median survival of about 2 to 3 years.

It forms about 1% to 3% of meningiomas, with a median age of about 60 to 65. The male to female ratio is about equal. Tumours arise de novo or by progression from grade 1 or 2 meningioma.

Risk factors are previous cranial irradiation, NF2 and progression of earlier meningiomas. Hormonal factors matter less than in grade 1 tumours.

Pathophysiology. Anaplastic tumours show loss of NF2, complex chromosomal loss, TERT promoter mutation, CDKN2A/B deletion, and often loss of H3K27me3. They infiltrate the brain and spread along the dura and through bone and venous sinuses.

Behaviour. Recurrence is frequent (about 70% to 90% within 5 years) and distant metastasis to lung, bone, liver and pleura occurs in a minority (about 10% to 20%). Five year survival is about 30% to 50%.

• Rapidly progressive headache, seizures, focal neurological deficits, visual loss and cognitive change.
• Raised intracranial pressure from large tumours and oedema.
• Skull swelling when bone is invaded and cranial nerve palsies from skull base disease.

Red flags.

• Rapid decline in consciousness or signs of herniation.
• Sudden deficit from haemorrhage, or venous sinus occlusion with infarction.

• MRI brain with gadolinium: irregular heterogeneous enhancing mass with necrosis, brain invasion, marked oedema and bone destruction. Spinal MRI for suspected dissemination.
• DOTATATE PET-CT, CT of the chest, abdomen and pelvis when metastasis is suspected.
• Pathology: frank anaplasia (sarcoma like, carcinoma like or melanoma like morphology), at least 20 mitoses in 10 high power fields, brain invasion, necrosis and proliferation index, with TERT promoter and CDKN2A/B testing.
• Baseline FBC, liver tests, creatinine and visual fields.

Differential diagnosis.

• Atypical meningioma and metastasis (breast, lung, renal)
• Meningeal sarcoma, solitary fibrous tumour and melanocytic tumours
• Glioblastoma with a dural attachment and lymphoma

Surgery. Maximal safe resection, including dura and invaded bone, for diagnosis and decompression.

Radiotherapy. Adjuvant radiotherapy to the resection bed with margin (60 Gy in 30 fractions) is given to nearly all patients after surgery, whatever the extent of resection. Re-irradiation or stereotactic radiosurgery is used for recurrent disease when feasible.

Systemic therapy. Chemotherapy has little proven benefit. Drug therapy is used at recurrence.

• Bevacizumab: bevacizumab 10 mg/kg IV every 2 weeks (first infusion over 90 minutes, then 60 minutes, then 30 minutes if tolerated) until progression or toxicity; maximum 10 mg/kg each dose; monitoring: blood pressure at each visit, urine protein before each dose, FBC, bleeding, thromboembolism, wound healing; adjustment: omit for 28 days before and after major surgery, hold for urine protein over 2 g in 24 hours until it falls under 2 g, stop for gastrointestinal perforation, severe haemorrhage, hypertensive crisis, arterial thromboembolism or posterior reversible encephalopathy

Seizure and oedema control.

• 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

Targeted and experimental options. Somatostatin receptor radionuclide therapy and inhibitors of cell cycle and signalling proteins are used only in specialised centres or clinical studies.

Monitoring. MRI at 4 to 6 weeks after radiotherapy, then every 3 months for 2 years and every 6 months after. Staging of extracranial sites when symptoms arise.

Referral and escalation.

• Neuro oncology referral at diagnosis, with early palliative care.
• Emergency admission for herniation signs, haemorrhage or status epilepticus.

Special groups.

• NF2: radiotherapy increases the risk of new tumours, so decide with a specialist.
• Pregnancy: urgent multidisciplinary decision, with surgery in the second trimester and radiotherapy deferred.
• Older adults: shorter radiotherapy courses.