Atypical Teratoid Rhabdoid Tumour

Atypical teratoid rhabdoid tumour is a highly malignant embryonal tumour of the central nervous system, graded 4, defined by loss of SMARCB1 (INI1) or, rarely, SMARCA4 (BRG1). It occurs mostly in children under 3 years, is aggressive, and requires intensive multimodal treatment.

It forms about 1% to 2% of paediatric brain tumours but 10% to 20% in children under 3 years. Median age at diagnosis is about 2 years. Tumours are found in the posterior fossa (cerebellum and brainstem) in about half and in the cerebral hemispheres, with spinal tumours less often.

Rhabdoid tumour predisposition syndrome (germline SMARCB1 or SMARCA4 variants) is present in about 25% to 35%, with synchronous or later kidney (malignant rhabdoid tumour), liver and other rhabdoid tumours. Parents may be carriers or mosaic.

Pathophysiology. Biallelic loss of SMARCB1 (chromosome 22q11.2) disrupts chromatin remodelling by the SWI/SNF complex. The tumour has very few other mutations. Three molecular groups are described (ATRT-TYR, ATRT-SHH and ATRT-MYC), with differing age, location and outcome.

Histology. Rhabdoid cells with eccentric nuclei and eosinophilic inclusions, with a variable mix of primitive neuroectodermal, epithelial and mesenchymal elements. Immunohistochemistry shows loss of nuclear INI1 staining, with positivity for EMA, vimentin, smooth muscle actin and variably GFAP, synaptophysin and cytokeratin.

Behaviour. Disease is fast growing with early dissemination in the cerebrospinal fluid (about 20% to 30% at diagnosis). Overall survival is about 30% to 50% at 5 years with intensive therapy, and worse in infants and with metastasis.

• Infants: irritability, vomiting, lethargy, failure to thrive, macrocephaly, bulging fontanelle, loss of milestones.
• Posterior fossa tumours: ataxia, head tilt, cranial nerve palsies (especially VI and VII), nystagmus.
• Hemispheric tumours: seizures, hemiparesis, increased intracranial pressure.
• Spinal tumours: weakness, back pain, sphincter loss.
• Renal or abdominal mass, in patients with synchronous rhabdoid tumours.

Red flags.

• Falling consciousness, bradycardia and apnoea (herniation or acute hydrocephalus).
• Acute haemorrhage into the tumour.

• MRI of the brain and whole spine with gadolinium before surgery: large heterogeneous enhancing mass with cysts, haemorrhage and restricted diffusion, with hydrocephalus. CT is used only in emergencies.
• Lumbar CSF cytology 2 or more weeks after surgery, when safe.
• Biopsy or resection with INI1 and BRG1 immunohistochemistry, and molecular classification when available.
• Germline testing for SMARCB1 and SMARCA4 variants, with parental testing and genetic counselling.
• Renal ultrasound and abdominal imaging at diagnosis and during follow up for synchronous rhabdoid tumours.
• Baseline audiometry, echocardiography, renal and liver function, and fertility counselling where relevant.

Differential diagnosis.

• Medulloblastoma and other embryonal tumours (including embryonal tumour with multilayered rosettes)
• Choroid plexus carcinoma
• Primitive neuroectodermal and germ cell tumours
• Ependymoma and high grade glioma

Treatment is multimodal and delivered by a paediatric neuro oncology team, with surgery, intensive multi-agent chemotherapy including intrathecal therapy and high dose consolidation with autologous stem cell rescue, and radiotherapy. Specific drug doses are set by the treating paediatric team because they are weight- and age based and differ between regimens.

Surgery. Maximal safe resection (gross total resection improves survival) after control of hydrocephalus by external drain or third ventriculostomy.

Chemotherapy. Intensive multi-agent therapy begins soon after surgery in all patients, with high dose consolidation and stem cell rescue in most. Intrathecal therapy is included in many regimens.

Radiotherapy. Focal radiotherapy for localised disease, or craniospinal radiotherapy for disseminated disease, in children older than about 18 to 36 months, because of severe neurocognitive effects in younger infants. Proton therapy is preferred where available.

Supportive treatment.

• 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
• Dosing in infants is by weight and surface area, with specialist paediatric pharmacy checking.

Relapse. Early relapse is common, and options are limited to re-resection, further chemotherapy and clinical studies of targeted agents (EZH2 and other epigenetic inhibitors, immunotherapy).

Monitoring. MRI of the brain and spine every 2 to 3 months for 2 years, then every 3 to 4 months. Abdominal ultrasound every 3 months for synchronous or metachronous rhabdoid tumours. Long term neurocognitive, endocrine, hearing and growth surveillance.

Referral and escalation.

• Immediate referral to a paediatric neuro oncology centre.
• Emergency neurosurgery for acute hydrocephalus or herniation.
• Genetic counselling and family testing for germline carriers.

Special groups.

• Infants: avoid or delay radiotherapy, with surgery and intensive chemotherapy as the base.
• Germline carriers: lifelong surveillance and avoidance of unnecessary radiation exposure.
• Adolescents and adults (rare): similar multimodality management at a neuro oncology centre.