Epithelioid Sarcoma

Epithelioid sarcoma is a rare, malignant soft tissue tumour of epithelioid and spindle cells with loss of nuclear INI1 (SMARCB1) expression in over 90%. It has a high rate of local recurrence, regional lymph node metastasis and late distant metastasis.

It makes up under 1% of soft tissue sarcomas. The classic (distal) type occurs in young adults (median age 20s to 30s) on the hand, forearm, wrist and foot. The proximal type affects older adults (median age 40s) in the pelvis, perineum, genital region and proximal limbs and trunk, and is more aggressive.

No predisposing syndrome is well established, and some report a link to prior trauma at the site.

Pathophysiology. Biallelic loss of SMARCB1 disrupts chromatin remodelling and leaves EZH2-driven gene silencing unopposed, which is the rationale for EZH2 inhibition.

Histology. The classic type forms nodules with central necrosis resembling granulomas. The proximal type has large rhabdoid like cells, sheets and high grade features. Cytokeratin and EMA are positive, CD34 in about half, and ERG in a minority. CD31 is negative.

Behaviour. Local recurrence occurs in 30% to 70%. Regional lymph node metastasis (a rare event in sarcomas) occurs in 20% to 40%, and lung metastasis in 40% to 50%. Five year overall survival is about 60% to 70% and ten year survival about 50%. Proximal tumours, large size, deep location, vascular invasion and necrosis worsen prognosis.

• Slowly growing, firm, painless dermal or subcutaneous nodule on the distal limb, often ulcerating and mistaken for a benign lesion for months or years.
• Multiple nodules and ulceration, or recurrent growth after minor excision.
• Proximal type: deep mass in the pelvis, perineum or groin, which can be large.
• Palpable regional lymph nodes in some cases.

• MRI of the primary site and regional nodal basin. CT chest, with nodal imaging (ultrasound, MRI or PET-CT) and consideration of sentinel node biopsy for limb tumours.
• Deep core biopsy or incisional biopsy (excision biopsy is avoided). Immunohistochemistry shows cytokeratin and EMA positivity with INI1 loss.
• Baseline echocardiography, creatinine and liver tests.

Differential diagnosis.

• Squamous cell carcinoma and other carcinoma
• Malignant rhabdoid tumour
• Synovial sarcoma (INI1 retained, SS18::SSX fusion)
• Epithelioid angiosarcoma (CD31 and ERG positive)
• Epithelioid malignant peripheral nerve sheath tumour and myoepithelial carcinoma
• Melanoma
• Granuloma annulare, necrotising granuloma, rheumatoid nodule and ganglion

Localised disease. Wide excision with negative margins by a sarcoma surgeon, including amputation at times for distal tumours with extensive involvement. Sentinel node biopsy or regional lymph node assessment is included given the high rate of nodal spread. Positive nodes need regional lymph node dissection.

Radiotherapy. Preoperative 50 Gy in 25 fractions, or postoperative 60 Gy in 30 fractions (66 Gy for positive margins), to lower local recurrence in tumours with close margins, large or proximal tumours.

Systemic therapy. Chemosensitivity is modest. Chemotherapy is considered for large, proximal, high grade tumours, though evidence is limited.

Advanced disease.

• Tazemetostat (EZH2 inhibitor, for metastatic or locally advanced disease not eligible for complete resection): 800 mg orally twice daily until progression or intolerance; maximum 1600 mg daily; monitoring: FBC and liver tests monthly for 3 months then as needed, surveillance for secondary malignancy (T-cell lymphoma, myelodysplastic syndrome, acute myeloid leukaemia); adjustment: avoid strong CYP3A inhibitors and inducers, reduce by about half (400 mg twice daily) with moderate CYP3A inhibitors, no adjustment for mild to moderate renal or hepatic impairment, reduce stepwise for toxicity.
• 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.
• Gemcitabine with docetaxel: 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 metastases.

Monitoring. Examination, regional lymph node assessment and MRI every 3 months for 2 years, then 6 monthly to year 5, then annually. CT chest at the same intervals, with surveillance for late relapse beyond 5 years.

Referral and escalation.

• Referral to a sarcoma centre for any persistent, ulcerating or recurrent nodule on the distal limb, before further excision.
• Re-excision with wide margins when the diagnosis follows an unplanned excision.

Special groups.

• Young adults: discuss fertility preservation before chemotherapy, and functional reconstruction after distal limb surgery.
• Tazemetostat: contraception during and for 6 months after treatment (3 months for male partners), and counselling about secondary malignancy.