Atypical Meningioma

Atypical meningioma is a grade 2 meningioma defined by 4 to 19 mitoses in 10 high power fields, or brain invasion, or at least 3 of 5 atypical features (hypercellularity, small cells with high nuclear to cytoplasmic ratio, prominent nucleoli, sheet like growth, spontaneous necrosis). It recurs more often than benign meningioma and needs closer follow up.

Meningiomas are the commonest primary intracranial tumour, about 40% of the total, and atypical tumours form 20% to 35% of them. Incidence rises with age, with a median age of about 60 to 65, and women are affected about 2 to 3 times more often than men for grade 1 tumours (the female excess is smaller in higher grades).

Risk factors are previous cranial irradiation (including low dose radiotherapy in childhood), neurofibromatosis type 2 (NF2), prior head trauma (weak), and exogenous progestogens in high doses (cyproterone, medroxyprogesterone). Obesity and breast cancer are weakly associated.

Pathophysiology. NF2 loss on chromosome 22q is the commonest change in convexity and posterior fossa meningiomas. Other drivers (AKT1, TRAF7, KLF4, SMO) occur mainly in grade 1 tumours of skull base. Loss of 1p, 6q and 14q, CDKN2A/B loss and TERT promoter mutation indicate aggressive behaviour. Brain invasion alone upgrades the tumour.

Behaviour. Recurrence at 5 years is about 40% after gross total resection of an atypical meningioma, and about 50% to 60% after subtotal resection. Five year survival is about 80% to 90%.

• Headache, seizures (30% to 40%), focal deficits by site, cognitive or personality change (frontal), visual loss and proptosis (sphenoid wing, optic sheath), anosmia.
• Slowly progressive symptoms over months to years, faster than in grade 1 tumours.
• Raised intracranial pressure from oedema or mass effect.

Red flags.

• Rapid visual loss from optic apparatus compression.
• Seizures that do not stop, or signs of herniation.
• Sudden neurological decline from haemorrhage.

• MRI brain with gadolinium: extra-axial dural based enhancing mass with a dural tail, broad dural base, possible bone hyperostosis, peritumoural oedema, heterogeneous enhancement, bone or brain invasion and mushrooming. CT shows calcification and hyperostosis.
• DOTATATE PET-CT can define residual or recurrent tumour and skull base extent.
• Pathology: mitotic count (counted in 10 consecutive high power fields), brain invasion, atypical features, Ki-67, and molecular markers (CDKN2A/B, TERT, NF2) when available.
• Formal visual fields, and neuroendocrine assessment for skull base tumours.
• NF2 assessment (vestibular schwannoma, family history, multiple meningiomas).

Differential diagnosis.

• Benign (grade 1) meningioma and anaplastic meningioma
• Solitary fibrous tumour and haemangiopericytoma like lesions
• Dural metastasis and lymphoma
• Sarcoidosis and other dural inflammatory disease

Surgery. Maximal safe resection, including involved dura and bone, aims for Simpson grade 1 or 2 resection (complete removal with dural attachment and abnormal bone). Preoperative embolisation is used for large vascular tumours at selected centres.

Radiotherapy. Adjuvant radiotherapy 54 to 60 Gy in 30 fractions is given after subtotal resection and for recurrence. After gross total resection, radiotherapy or close observation is chosen by the team, since evidence is still evolving. Stereotactic radiosurgery treats small residual or recurrent tumours.

Seizure and oedema control.

• Antiseizure therapy (only after seizures, and not as routine prophylaxis): 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

Recurrent disease. Re-resection, re-irradiation and drug therapy.

• 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
• Somatostatin receptor radionuclide therapy and other targeted treatments are used at specialised centres.

Monitoring. MRI at 3 to 6 months after treatment, then every 6 months for 5 years, then yearly for at least 10 years. Visual and endocrine review.

Referral and escalation.

• Neurosurgical and neuro oncology referral at diagnosis.
• Emergency admission for herniation signs, haemorrhage or rapidly falling vision.

Special groups.

• NF2: multiple tumours need individualised surgery, and radiotherapy increases second tumour risk.
• Pregnancy: tumours may enlarge, since meningiomas express progesterone receptors, so manage with a multidisciplinary team and defer radiotherapy.
• Women on high dose progestogens: stop the drug.
• Older adults: observation for small asymptomatic tumours, with surgery or radiosurgery for growth.