Diffuse Hemispheric Glioma, H3 G34-Mutant

Diffuse hemispheric glioma, H3 G34-mutant, is a high grade (grade 4) infiltrating glioma of the cerebral hemispheres, defined by a missense mutation at glycine 34 of histone H3.3. It mainly affects adolescents and young adults, and median survival is about 18 to 24 months.

It is rare, with a median age at diagnosis of about 15 to 30 years, and slight male predominance. Tumours arise in the cerebral hemispheres, most often the parietal, temporal and frontal lobes, and are rare in the midline.

Risk factors are not established. Germline TP53 variants (Li-Fraumeni syndrome) should be considered.

Pathophysiology. H3-3A (H3F3A) G34R (most often) or G34V mutations alter histone methylation and gene regulation. Almost all tumours show TP53 mutation and ATRX loss, often with PDGFRA alterations. MGMT promoter methylation is frequent (over 70%). IDH is wild type, and OLIG2 is usually not expressed.

Histology. Highly cellular tumour with brisk mitoses, necrosis and microvascular proliferation, often resembling a primitive neuroectodermal tumour in younger patients.

Behaviour. Local recurrence is frequent, and spread along the cerebrospinal fluid spaces occurs in a minority. Survival is longer than in H3 K27-altered midline glioma and similar to glioblastoma.

• Headache, vomiting and papilloedema from raised intracranial pressure.
• Seizures, focal weakness, visual field defects, language or cognitive disturbance by site.
• Symptoms progress over weeks.

Red flags.

• Falling consciousness, new focal deficit or signs of herniation.
• Status epilepticus.
• Spinal symptoms suggesting drop metastases.

• MRI of the brain with gadolinium: large infiltrating hemispheric mass, often enhancing, with necrosis and mass effect. MRI of the whole spine when leptomeningeal spread is suspected.
• Resection or biopsy with molecular testing: H3 G34R/V immunohistochemistry and sequencing (H3-3A), ATRX and p53 staining, IDH1/2 (wildtype), MGMT promoter methylation, PDGFRA and EGFR, and OLIG2.
• Lumbar puncture with cytology only when surgery and imaging are complete and no mass effect is present.
• Germline testing for TP53 in young patients.
• Baseline FBC, liver tests, creatinine and neurocognitive assessment.

Differential diagnosis.

• IDH-wildtype glioblastoma
• Diffuse midline glioma, H3 K27-altered
• CNS embryonal tumours (including CNS neuroblastoma FOXR2-activated)
• IDH-mutant astrocytoma and ependymoma
• Pleomorphic xanthoastrocytoma and infant type hemispheric glioma
• Brain abscess, tumefactive demyelination and metastasis

Management follows treatment of glioblastoma, with maximal safe resection, radiotherapy and temozolomide. Paediatric patients are treated at a paediatric neuro oncology centre.

Surgery. Maximal safe resection (preferably gross total resection) with mapping near eloquent cortex.

Radiotherapy with temozolomide. Radiotherapy 60 Gy in 30 fractions (54 Gy in 30 fractions in children), beginning 3 to 6 weeks after surgery, with concurrent and adjuvant temozolomide.

• Temozolomide: during radiotherapy temozolomide 75 mg/m2 orally once daily at the same time each day on an empty stomach for 42 to 49 days, then after a 4-week break 150 mg/m2 orally once daily on days 1 to 5 of a 28-day cycle for cycle 1, increased to 200 mg/m2 on days 1 to 5 from cycle 2 when neutrophils and platelets allow, for 6 cycles; maximum 75 mg/m2 daily during radiotherapy and 200 mg/m2 daily in adjuvant cycles; monitoring: FBC weekly during radiotherapy and on day 22 of each adjuvant cycle, liver tests, antiemetic cover; adjustment: during radiotherapy hold for neutrophils under 1.5 x 10^9/L or platelets under 100 x 10^9/L and stop for neutrophils under 0.5 x 10^9/L or platelets under 10 x 10^9/L, in adjuvant cycles reduce by 50 mg/m2 for neutrophils under 1.0 x 10^9/L or platelets under 50 x 10^9/L and stop if 100 mg/m2 is not tolerated, no change when creatinine clearance is 36 mL/min or more and caution when it is lower, caution in severe hepatic impairment
• Pneumocystis prophylaxis: co-trimoxazole 960 mg orally three times weekly (for example Monday, Wednesday and Friday) throughout concurrent temozolomide and radiotherapy, continued while corticosteroids are used and until lymphocytes recover above 0.5 x 10^9/L; maximum 960 mg daily; monitoring: FBC, potassium, creatinine, rash; adjustment: halve the dose when creatinine clearance is 15 to 30 mL/min and avoid under 15 mL/min, stop for rash or severe cytopenia and use a non-sulfonamide agent

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

Recurrence. Re-resection when feasible, re-irradiation in selected cases, and chemotherapy.

• Lomustine: lomustine 110 mg/m2 orally as a single dose on day 1 of a 6-week cycle, on an empty stomach at bedtime with an antiemetic, for up to 6 cycles; maximum 110 mg/m2 each cycle and cumulative 1000 mg/m2; monitoring: FBC before each cycle and weekly for 6 weeks after each dose, liver tests, lung function (pulmonary fibrosis rises with cumulative dose); adjustment: reduce to 90 mg/m2 then 70 mg/m2 for neutrophil nadir under 1.0 x 10^9/L or platelets under 50 x 10^9/L, delay until neutrophils reach 1.5 x 10^9/L and platelets 100 x 10^9/L, avoid when creatinine clearance is under 30 mL/min, caution in hepatic impairment, prescribe one dose each cycle only to avoid overdose
• Bevacizumab (for symptomatic oedema or refractory disease): 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

Clinical studies. Enrolment in a study of targeted agents (PDGFRA and other kinase inhibitors) is advised where available.

Monitoring. MRI 4 weeks after radiotherapy and then every 2 to 3 months for 2 years, then every 3 to 6 months. Neurocognitive, endocrine and psychological follow up.

Referral and escalation.

• Neuro oncology multidisciplinary referral at diagnosis.
• Urgent admission for herniation signs, status epilepticus or rapid decline.
• Early palliative care.

Special groups.

• Children and adolescents: weight adjusted therapy at a paediatric centre, with fertility counselling and school support.
• Li-Fraumeni carriers: avoid radiotherapy where possible, and offer family screening.
• Pregnancy: surgery in the second trimester, with radiotherapy and chemotherapy deferred if possible.