Clear Cell Sarcoma of Soft Tissue

Clear cell sarcoma of soft tissue is a rare malignant melanocytic tumour of tendons and aponeuroses, defined by an EWSR1::ATF1 fusion from t(12;22) in about 90% of cases. It was formerly called malignant melanoma of soft parts, and it differs genetically from cutaneous melanoma.

It makes up about 1% of soft tissue sarcomas. Median age is in the 30s, and the foot and ankle account for about 40% of cases, followed by the knee, thigh, hand and wrist.

No predisposing syndrome, ultraviolet exposure or environmental cause is known.

Pathophysiology. The fusion (EWSR1::CREB1 in a minority) drives MITF-dependent melanocytic gene expression. BRAF and NRAS are wild type and CDKN2A is intact, unlike cutaneous melanoma.

Histology. Nests and fascicles of epithelioid to spindle cells with clear to pale eosinophilic cytoplasm and prominent nucleoli. S100, SOX10, HMB-45 and Melan-A are positive, and melanin is present in a minority.

Behaviour. Regional lymph node metastasis occurs in 20% to 40%, and lung and bone metastases follow. Relapse can occur beyond 10 years. Five year survival is about 50% to 70% and ten year survival about 40%. Size over 5 cm, necrosis, local recurrence and metastasis at diagnosis predict worse outcome.

• Slowly growing, deep, firm mass attached to tendon or fascia, painless or mildly tender, often present for months to years and often under 5 cm.
• Foot and ankle lesions are commonly mistaken for ganglion or plantar fibroma.
• Regional lymph nodes may be palpable.

• MRI: well defined mass, iso- to slightly hyperintense on T1 (melanin) and hyperintense on T2, with enhancement.
• Image targeted core biopsy through a planned track. Immunohistochemistry confirms melanocytic markers. Confirm the fusion by EWSR1 break apart FISH or RT-PCR.
• BRAF testing: V600E positivity favours metastatic melanoma. Examine skin, mucosae and eyes for a melanoma primary.
• Staging: CT chest, regional nodal imaging (ultrasound, MRI or FDG-PET, which is usually avid), and consideration of sentinel node biopsy for clinically node negative limb tumours.
• Baseline echocardiography, creatinine and liver tests if chemotherapy is likely.

Differential diagnosis.

• Metastatic or primary melanoma
• Synovial sarcoma
• Epithelioid sarcoma
• Malignant peripheral nerve sheath tumour
• Alveolar soft part sarcoma
• Perivascular epithelioid cell tumour and myoepithelial carcinoma
• Tenosynovial giant cell tumour and ganglion

Localised disease. Wide excision with negative margins by a sarcoma surgeon, with amputation for extensive distal disease when function cannot be preserved.

• Sentinel node biopsy for clinically node negative limb tumours, and therapeutic regional lymph node dissection for involved nodes.
• Radiotherapy: preoperative 50 Gy in 25 fractions, or postoperative 60 Gy in 30 fractions (66 Gy for positive margins), for large, deep or close margin tumours.

Advanced disease. Chemosensitivity is low and response rates to cytotoxic therapy are poor.

• 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.
• Pazopanib: 800 mg orally once daily on an empty stomach until progression; maximum 800 mg daily; monitoring: liver tests at baseline, weeks 3, 5, 7 and 9, then months 3 and 4 and as needed, blood pressure at each visit, ECG and electrolytes, thyroid function, proteinuria; adjustment: reduce in 200 mg steps for toxicity, 200 mg daily in moderate hepatic impairment (bilirubin over 1.5 to 3 times the upper limit), avoid in severe impairment, stop for ALT over 8 times the upper limit, avoid strong CYP3A4 inhibitors.
• Checkpoint inhibitors have rarely produced responses and are not routine.
• Resection or stereotactic radiotherapy for limited lung or nodal metastases.

Monitoring. Examination, regional nodal assessment and MRI every 3 to 4 months for 2 years, then 6 monthly to year 5, then annually. CT chest at the same intervals. Continue lifelong surveillance because of late relapse.

Referral and escalation.

• Sarcoma centre referral before biopsy or excision of any enlarging mass attached to a tendon.
• Re-excision with wide margins when the diagnosis follows an unplanned excision.

Special groups.

• Young adults: discuss fertility before systemic therapy and plan functional reconstruction for foot and ankle surgery.
• Pregnancy: surgery is possible in any trimester. Defer radiotherapy and systemic therapy.