Alveolar Rhabdomyosarcoma

Alveolar rhabdomyosarcoma is a high grade primitive skeletal muscle sarcoma, defined by a PAX3::FOXO1 fusion (about 60%) or PAX7::FOXO1 fusion (about 20%). Tumours with the same histology but no fusion behave like embryonal rhabdomyosarcoma and are managed accordingly.

It accounts for about 20% to 30% of rhabdomyosarcoma. Median age is 10 to 15 years, with a male excess, and it is the commonest subtype in adolescents and young adults. Sites are the extremities, trunk, parameningeal head and neck and perineum.

No predisposing syndrome is clearly associated.

Pathophysiology. The fusion transcription factor drives proliferation and blocks differentiation. PAX3::FOXO1 is associated with more aggressive disease than PAX7::FOXO1, which is more often localised. MYCN amplification and CDK4 amplification are common.

Behaviour. Lymph node involvement (30% to 40%) and bone marrow involvement are frequent, and about 30% to 40% have metastases at diagnosis (lung, bone, bone marrow). Five year survival is about 65% to 75% for localised fusion positive disease and under 20% for metastatic disease.

• Rapidly enlarging, painless mass in an extremity, trunk or perineum.
• Parameningeal: nasal obstruction, epistaxis, cranial nerve palsies, otitis media.
• Systemic symptoms with bone marrow disease: pallor, bruising, bone pain, fever.

• MRI of the primary site and regional nodes. CT chest. FDG-PET or whole body MRI, bone scintigraphy, and bone marrow aspirates and trephines from two sites.
• Lumbar puncture for parameningeal disease.
• Biopsy: nests with a fibrovascular alveolar pattern (or solid variant), desmin positive, and strong diffuse nuclear myogenin and MyoD1. FOXO1 FISH or RT-PCR defines fusion status (PAX3::FOXO1 or PAX7::FOXO1).
• Regional lymph node assessment: sentinel node biopsy or imaging for extremity tumours.
• Baseline FBC, creatinine, liver tests, audiometry, echocardiography and fertility preservation.

Differential diagnosis.

• Embryonal rhabdomyosarcoma (fusion negative)
• Ewing sarcoma, CIC-rearranged sarcoma and desmoplastic small round cell tumour
• Neuroblastoma and lymphoma (including lymphoblastic)
• Synovial sarcoma and small cell carcinoma
• Mesenchymal chondrosarcoma and melanoma (alveolar like)

Treatment is intensive and multimodal, with risk grouping by fusion status, stage and site.

Chemotherapy (vincristine, dactinomycin and cyclophosphamide with intensification).

• Vincristine, dactinomycin and cyclophosphamide: vincristine 1.5 mg/m2 IV (maximum 2 mg) weekly for the first 12 weeks then on day 1 of each cycle; dactinomycin 0.045 mg/kg IV (maximum 2.5 mg) on day 1 (0.025 mg/kg for infants under 1 year or under 10 kg); cyclophosphamide 1.2 g/m2 IV on day 1 with mesna and hydration; every 3 weeks for about 42 weeks (14 cycles); maximum cyclophosphamide cumulative about 16.8 g/m2; monitoring: FBC, liver tests and bilirubin (dactinomycin veno occlusive disease), neuropathy and constipation, sodium, urinalysis, fertility; adjustment: vincristine reduce by 50% when bilirubin is 26 to 51 micromol/L and avoid over 51, avoid strong CYP3A inhibitors (azole antifungals), omit dactinomycin during radiotherapy to the same field, cyclophosphamide reduce by about 25% to 50% when eGFR is under 30 mL/min/1.73 m2.
• Intensification: alternating irinotecan cycles (irinotecan 50 mg/m2 IV daily on days 1 to 5 with vincristine 1.5 mg/m2 on day 1) in intermediate risk and high risk disease; maximum irinotecan 50 mg/m2 each day and vincristine 2 mg each dose; monitoring: diarrhoea (loperamide, antibiotic prophylaxis), FBC, liver tests; adjustment: reduce irinotecan by about 25% for grade 3 diarrhoea or neutropenia, lower starting dose in UGT1A1*28 homozygotes, avoid when bilirubin exceeds 34 micromol/L.
• Maintenance for high risk disease after induction (6 cycles of 28 days): vinorelbine 25 mg/m2 IV on days 1, 8 and 15 with cyclophosphamide 25 mg/m2 orally daily on days 1 to 28; maximum vinorelbine 25 mg/m2 each dose and cyclophosphamide 25 mg/m2 daily; monitoring: FBC before each dose, constipation, neuropathy, urinalysis; adjustment: reduce vinorelbine for hepatic impairment (50% when bilirubin is 35 to 51 micromol/L, avoid over 51), reduce cyclophosphamide when eGFR is under 30 mL/min/1.73 m2, hold for grade 3 to 4 neutropenia.

Local control.

• Surgery when complete resection preserves function. Alveolar tumours need radiotherapy even after complete resection.
• Radiotherapy begins at week 13 of chemotherapy (week 4 for parameningeal disease with intracranial extension). Doses are about 36 Gy for completely resected primary tumours, 41.4 to 50.4 Gy for microscopic residual disease, and 50.4 Gy for gross residual disease or involved nodes, set by site and tissue tolerance.
• Nodal disease: radiotherapy to involved nodes, with lymph node dissection or sampling for extremity primaries.

Metastatic disease. Intensified chemotherapy, radiotherapy to the primary tumour and metastases, and maintenance therapy.

Relapse. Irinotecan with temozolomide, or re-irradiation, in specialist centres.

Irinotecan 50 mg/m2 IV daily on days 1 to 5 with temozolomide 100 mg/m2 orally daily on days 1 to 5, every 21 days until progression or intolerance. Maximum irinotecan 50 mg/m2 and temozolomide 100 mg/m2 each day.

Monitoring: FBC, diarrhoea (loperamide and antibiotic prophylaxis for early diarrhoea), liver tests. Adjustment:

• reduce irinotecan by about 25% for grade 3 diarrhoea or neutropenia
• lower starting dose in UGT1A1*28 homozygotes
• avoid irinotecan when bilirubin exceeds 34 micromol/L
• caution with temozolomide when creatinine clearance is under 36 mL/min

Monitoring. MRI of the primary site and CT of the chest every 3 months for 2 years, then every 6 months to year 5. Late effects: growth, fertility, bladder and sexual function, secondary malignancy, cardiac and neurological effects.

Referral and escalation.

• Urgent paediatric or adolescent and young adult sarcoma centre referral on suspicion.
• Same day assessment for cord compression, cranial nerve deficit, pancytopenia or febrile neutropenia.

Special groups.

• Adolescents and adults: paediatric type regimens are used, with fertility preservation and intensive supportive care.
• Pregnancy: urgent multidisciplinary review. Multi-agent chemotherapy is teratogenic.