Spindle Cell Rhabdomyosarcoma

Spindle cell rhabdomyosarcoma, grouped with sclerosing rhabdomyosarcoma, is a rhabdomyosarcoma of fascicular spindle cells with, in some tumours, a hyalinised sclerosing matrix. It contains three molecular subtypes of very different behaviour, and subtype determines management.

It accounts for about 3% to 10% of rhabdomyosarcoma. The congenital and infantile form occurs under 1 year to 5 years of age, mainly in the paratesticular region and trunk. The MYOD1-mutant form affects older children, adolescents and adults (head and neck, extremities). The intraosseous form affects young adults.

Pathophysiology. The subtypes are:

• Congenital and infantile type with VGLL2, NCOA2, TEAD1 or SRF fusions, with an excellent prognosis (over 90% survival).
• MYOD1 L122R mutated type, often with PIK3CA mutation, aggressive, with 5-year survival of about 30% to 50%.
• Intraosseous type with TFCP2 fusion (FUS::TFCP2 or EWSR1::TFCP2), in craniofacial and other bones, very aggressive.

Histology. Desmin is positive, with myogenin variable (diffuse and strong in MYOD1-mutant tumours) and MyoD1 positive. Cytokeratin is expressed in intraosseous tumours.

Behaviour. Infantile tumours rarely metastasise. MYOD1-mutant and TFCP2-rearranged tumours recur locally and metastasise early (lung, bone).

• Infantile type: painless paratesticular or trunk mass in a young child.
• MYOD1-mutant type: enlarging mass in the head and neck, limb or trunk of an adolescent or adult.
• Intraosseous type: bone pain, swelling and bone destruction of facial or other bones.

• MRI of the primary site and CT of the chest. FDG-PET or whole body MRI and bone scintigraphy for older patients.
• Biopsy with desmin, myogenin and MyoD1, then molecular testing: MYOD1 L122R sequencing, and a fusion panel (VGLL2, NCOA2, TEAD1, SRF, TFCP2). FOXO1 FISH excludes alveolar rhabdomyosarcoma.
• Bone marrow assessment for older patients with MYOD1 or TFCP2 tumours, regional node assessment, and baseline echocardiography, creatinine and liver tests.

Differential diagnosis.

• Embryonal and alveolar rhabdomyosarcoma
• Infantile fibrosarcoma and fibromatosis
• Leiomyosarcoma and synovial sarcoma
• Malignant peripheral nerve sheath tumour
• Spindle cell carcinoma and melanoma
• Osteosarcoma and Ewing sarcoma (intraosseous tumours)

Infantile VGLL2-type tumours. Complete excision alone is often sufficient. Residual disease or unresectable tumours are treated with vincristine and dactinomycin, and radiotherapy is avoided. Paratesticular tumours need radical inguinal orchidectomy with high ligation of the cord.

MYOD1-mutant and TFCP2-rearranged tumours. Intensive therapy, with wide excision, radiotherapy and chemotherapy based on vincristine, dactinomycin and cyclophosphamide.

• 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.
• Vincristine with dactinomycin (for infants and low risk disease): 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); every 3 weeks for 24 weeks, without cyclophosphamide; maximum vincristine 2 mg and dactinomycin 2.5 mg each dose; monitoring: FBC, liver tests and bilirubin (dactinomycin veno occlusive disease), neuropathy and constipation, sodium; adjustment: vincristine reduce by 50% when bilirubin is 26 to 51 micromol/L and avoid over 51, avoid strong CYP3A inhibitors, omit dactinomycin during radiotherapy to the same field.
• Radiotherapy to the primary site is about 36 to 50.4 Gy by residual disease and site, since local control in MYOD1-mutant tumours depends on it.
• Relapsed or refractory disease: irinotecan with temozolomide (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.)

Intraosseous (TFCP2) tumours. Multimodal therapy with surgery when feasible, but prognosis is poor, and enrolment in a sarcoma study is advised.

Monitoring. MRI of the primary site and CT of the chest every 3 months for 2 years, then every 6 months to year 5.

Referral and escalation.

• Paediatric or sarcoma centre referral before biopsy.
• Molecular pathology review, since subtype directs treatment intensity.

Special groups.

• Infants: avoid radiotherapy and reduce chemotherapy doses by weight.
• Adolescents and adults with MYOD1-mutant tumours: treat intensively and discuss fertility preservation.
• Pregnancy: urgent multidisciplinary review.