Pleomorphic Rhabdomyosarcoma

Pleomorphic rhabdomyosarcoma is a high grade sarcoma of adults composed of pleomorphic cells with skeletal muscle differentiation, and no embryonal or alveolar component. It is a diagnosis of exclusion after other pleomorphic sarcomas with rhabdomyoblastic elements are ruled out.

It accounts for under 2% of adult soft tissue sarcomas. Median age is 55 to 65, and it is rare under 30. The deep tissues of the thigh and lower limb are commonest, then trunk, retroperitoneum and head and neck.

No predisposing syndrome is established. A few cases follow radiotherapy.

Pathophysiology. The karyotype is complex, with TP53 and RB1 alterations and no PAX3 or PAX7 fusion to FOXO1. Cells express desmin, with nuclear MyoD1 and myogenin in at least some tumour cells (myogenin is often focal).

Behaviour. Local recurrence occurs in 30% to 50% and metastasis in 40% to 60%, mainly to lung. Five year survival is about 20% to 40%. Size over 10 cm, retroperitoneal site and incomplete resection worsen outcome.

Distinction from paediatric types. Paediatric multi-agent regimens have not shown better outcomes in adults with this subtype. Adult sarcoma regimens are used.

• Rapidly enlarging, painless or painful deep mass, often over 5 cm, sometimes with haemorrhage into the tumour.
• Retroperitoneal tumours produce abdominal symptoms late.
• Metastatic symptoms: cough, dyspnoea, bone pain.

• MRI of the primary site, and CT of the retroperitoneum or trunk. CT of the chest for staging, with abdominal and pelvic imaging for deep tumours.
• Core biopsy through a planned track. Immunohistochemistry: desmin, myogenin, MyoD1 positive. Exclusion panel: cytokeratins and p63 (carcinoma), S100 and SOX10 (melanoma), MDM2 FISH (dedifferentiated liposarcoma), H3K27me3 (loss in malignant peripheral nerve sheath tumour), FOXO1 FISH (alveolar type), and sequencing for MYOD1 L122R.
• In young men with a mediastinal or retroperitoneal mass, AFP and beta-hCG exclude a germ cell tumour with rhabdomyosarcomatous differentiation.
• Baseline echocardiography, creatinine and liver tests.

Differential diagnosis.

• Dedifferentiated liposarcoma with rhabdomyoblastic differentiation
• Malignant peripheral nerve sheath tumour with rhabdomyoblastic differentiation (malignant Triton tumour)
• Embryonal and alveolar rhabdomyosarcoma in adults
• Pleomorphic liposarcoma, leiomyosarcoma and undifferentiated pleomorphic sarcoma
• Carcinosarcoma and sarcomatoid carcinoma
• Melanoma and germ cell tumour with somatic type malignancy

Localised disease. Wide excision with negative margins by a sarcoma surgeon.

• Radiotherapy: preoperative 50 Gy in 25 fractions, or postoperative 60 Gy in 30 fractions (66 Gy for positive margins).
• Chemotherapy with doxorubicin and ifosfamide is considered for tumours over 5 cm in fit patients. Benefit is not proven.

Advanced disease.

• Doxorubicin: 75 mg/m2 IV every 3 weeks for up to 6 cycles; maximum cumulative working ceiling 450 mg/m2; monitoring: echocardiography at baseline and every 2 cycles, FBC before each cycle; adjustment: bilirubin 20 to 51 micromol/L reduce by 50%, 53 to 85 micromol/L reduce by 75%, over 85 micromol/L avoid; consider reduction when eGFR is under 30 mL/min/1.73 m2.
• Doxorubicin with ifosfamide: doxorubicin 75 mg/m2 total each cycle (25 mg/m2 daily on days 1 to 3) with ifosfamide 10 g/m2 total (2.5 g/m2 daily on days 1 to 4) IV, with mesna at a total of 60% to 100% of the ifosfamide dose and pegfilgrastim 6 mg subcutaneously 24 to 72 hours after chemotherapy, every 3 weeks for up to 6 cycles; maximum doxorubicin cumulative working ceiling 450 mg/m2 and ifosfamide 10 g/m2 each cycle; monitoring: FBC, creatinine, urinalysis for haematuria, neurological status (ifosfamide encephalopathy), echocardiography; adjustment: avoid ifosfamide when eGFR is under 30 mL/min/1.73 m2 and reduce by about 25% to 50% when it is 30 to 59, stop for grade 2 neurotoxicity, reduce doxorubicin for hepatic impairment (bilirubin 20 to 51 micromol/L by 50%, 53 to 85 micromol/L by 75%, over 85 micromol/L avoid).
• Gemcitabine with docetaxel (second line): gemcitabine 900 mg/m2 IV over 90 minutes on days 1 and 8 with docetaxel 75 mg/m2 IV on day 8, with pegfilgrastim 6 mg subcutaneously on day 9, every 21 days until progression; maximum gemcitabine 900 mg/m2 and docetaxel 75 mg/m2 each cycle; monitoring: FBC before each dose, liver tests, creatinine, pneumonitis, oedema; adjustment: do not give docetaxel when bilirubin exceeds the upper limit or AST or ALT exceeds 1.5 times the upper limit with alkaline phosphatase over 2.5 times, reduce both agents by 25% for grade 3 to 4 toxicity, caution when creatinine clearance is under 30 mL/min.
• Resection or stereotactic radiotherapy for limited lung metastases.

Monitoring. Examination and MRI of the primary site every 3 to 4 months for 2 years, then 6 monthly to year 5. CT of the chest at the same intervals.

Referral and escalation.

• Sarcoma centre referral before biopsy or excision.
• Urgent assessment for febrile neutropenia, haemorrhage into the tumour or pneumothorax.

Special groups.

• Older adults: surgery and radiotherapy are preferred, with single agent doxorubicin when systemic therapy is needed.
• Young adults: confirm that the tumour is not an alveolar or embryonal rhabdomyosarcoma, since paediatric type regimens apply to those.
• Pregnancy: surgery is possible in any trimester. Defer radiotherapy and systemic therapy.