Embryonal Rhabdomyosarcoma

Embryonal rhabdomyosarcoma is a fusion negative primitive malignant tumour of skeletal muscle lineage, and it is the commonest rhabdomyosarcoma subtype. It mainly affects young children, arises in the head and neck, genitourinary tract, retroperitoneum and extremities, and is treated with multi-agent chemotherapy, surgery and radiotherapy.

It accounts for about 60% of paediatric rhabdomyosarcoma. Overall incidence of rhabdomyosarcoma is about 4 to 5 cases in 1,000,000 children each year. Median age is about 5 years, with a second smaller peak in adolescence. It is uncommon in adults, where outcomes are worse.

Associations are DICER1 syndrome (uterine cervix, lung, thyroid), Li-Fraumeni syndrome, neurofibromatosis type 1, Costello syndrome (HRAS), Noonan syndrome and Beckwith-Wiedemann syndrome.

Pathophysiology. Loss of heterozygosity at 11p15.5 raises IGF2 expression. Mutations in RAS cascade genes (NRAS, KRAS, HRAS), PIK3CA, FGFR4, MYOD1 and TP53 are frequent. There is no PAX3 or PAX7 fusion to FOXO1.

Histological variants. Botryoid (grape like polyp beneath a mucosa, in vagina, bladder and nasopharynx) and spindle cell variants have a favourable prognosis. Anaplasia (TP53-associated) carries a worse prognosis.

Staging and risk. Risk grouping uses pretreatment tumour site, size, nodal status and metastasis, with the extent of surgical resection. Low risk, intermediate risk and high risk groups predict outcome. Event free survival is about 85% to 90% in low risk, 60% to 70% in intermediate risk and under 30% in metastatic disease.

• Depends on site.
• Orbit: proptosis, ptosis, periorbital swelling.
• Parameningeal head and neck: nasal obstruction, epistaxis, chronic otitis media or ear discharge, cranial nerve palsies.
• Bladder or prostate: haematuria, retention, constipation.
• Vagina: grape like mass and bloody discharge.
• Paratesticular: painless scrotal mass.
• Extremity or trunk: painless enlarging mass.

• MRI of the primary site with contrast. CT of the chest. FDG-PET or whole body MRI with bone scintigraphy. Bone marrow aspirates and trephines from two sites.
• Regional lymph node assessment: imaging, with sentinel node biopsy or lymph node sampling for extremity tumours and for paratesticular tumours in age 10 or over.
• Lumbar puncture for parameningeal tumours with intracranial extension.
• Biopsy: small round blue cells, with desmin positive, myogenin patchy or weak, and MyoD1 positive. FOXO1 FISH is negative. Germline testing (TP53, DICER1, NF1) in selected children.
• Baseline FBC, creatinine, liver tests, audiometry, echocardiography if anthracyclines are considered, and fertility preservation.

Differential diagnosis.

• Alveolar rhabdomyosarcoma
• Ewing sarcoma, CIC-rearranged sarcoma and other small round cell tumours
• Neuroblastoma and lymphoma
• Synovial sarcoma and infantile fibrosarcoma
• Nasopharyngeal carcinoma and cervical carcinoma in adolescents
• Benign vaginal polyp, urethral prolapse, orbital cellulitis and haemangioma

Treatment is multimodal and risk adapted, given at a paediatric oncology centre.

Chemotherapy backbone (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 3-week cycle; maximum 2 mg for each dose; monitoring: neuropathy, constipation, jaw pain, hyponatraemia; adjustment: reduce by 50% when bilirubin is 26 to 51 micromol/L and avoid over 51 micromol/L, avoid strong CYP3A inhibitors (azole antifungals), reduce for infants under 1 year by body weight rules.
• Dactinomycin: 0.045 mg/kg IV (maximum 2.5 mg) on day 1 of each 3-week cycle (0.025 mg/kg for infants under 1 year or under 10 kg); maximum 2.5 mg for each dose; monitoring: liver tests and bilirubin (veno occlusive disease), FBC, extravasation; adjustment: omit during radiotherapy to the same field and reduce for hepatic impairment.
• Cyclophosphamide: 1.2 g/m2 IV on day 1 of each 3-week cycle with mesna and hydration; maximum cumulative about 16.8 g/m2 over 14 cycles; monitoring: FBC, urinalysis, sodium, fertility; adjustment: reduce by about 25% to 50% when eGFR is under 30 mL/min/1.73 m2, caution in hepatic impairment.
• Duration is about 24 weeks for low risk disease (vincristine and dactinomycin, with cyclophosphamide in some) and about 42 weeks (14 cycles) for intermediate risk disease. Alternating irinotecan containing cycles are used in some regimens.
• Irinotecan with temozolomide (relapse): 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.

Local control.

• Primary resection when complete excision is possible without mutilation. Organ preserving approaches for bladder, prostate and vagina.
• Orbital tumours: chemotherapy then radiotherapy 45 Gy, without surgery.
• Paratesticular tumours: radical inguinal orchidectomy with high ligation of the cord (no scrotal approach), with retroperitoneal lymph node assessment from age 10.
• Radiotherapy begins at week 13 of chemotherapy (week 4 for parameningeal tumours with intracranial extension or cranial nerve palsy). Doses are about 36 to 41.4 Gy for microscopic residual disease and 45 to 50.4 Gy for gross residual disease or involved nodes, set by site and normal tissue tolerance.

Metastatic disease. The same chemotherapy with intensification, radiotherapy to the primary and metastatic sites, and oral metronomic maintenance therapy after induction. Outcomes remain poor.

Monitoring. Imaging of the primary site and chest every 3 months for 1 to 2 years, then every 6 months to year 5. Late effects: growth, bladder and sexual function, infertility, second malignancy, and neuropathy.

Referral and escalation.

• Urgent paediatric oncology referral for any child with persistent proptosis, haematuria, vaginal mass or a rapidly growing mass.
• Same day assessment for febrile neutropenia, cranial nerve deficit, urinary retention or cord compression.

Special groups.

• Infants: dose reduce chemotherapy and avoid radiotherapy where possible.
• Adolescents and adults: paediatric type regimens with intensive supportive care, and fertility preservation. Outcomes are worse than in young children.
• DICER1 carriers: lung cyst and thyroid surveillance, and family counselling.
• Africa and low resource settings: late presentation and limited radiotherapy access are common, so chemotherapy and surgery are prioritised.