Extraskeletal Ewing Sarcoma

Extraskeletal Ewing sarcoma is a small round cell sarcoma of soft tissue with an EWSR1 fusion to an ETS family gene, most often EWSR1::FLI1 from t(11;22) (about 85%) or EWSR1::ERG (about 10%). It has the same biology, regimens and prognosis as Ewing sarcoma of bone.

It accounts for about 15% to 20% of Ewing sarcoma. Median age is in the late teens to 20s, with a range through adult life, and a slight male predominance. It is rare in people of African ancestry. Sites are the paravertebral region, chest wall (Askin tumour), lower limb, retroperitoneum and pelvis.

No hereditary predisposition is established.

Pathophysiology. The fusion oncoprotein reprogrammes chromatin and transcription. Diffuse membranous CD99 and nuclear NKX2-2 expression are typical. STAG2 and TP53 mutations carry a worse prognosis.

Behaviour. About 25% have metastases at diagnosis (lung, bone, bone marrow). Five year survival is about 70% to 80% in localised disease, 40% to 50% with lung only metastases and 20% to 30% with bone or marrow metastases. Survival after relapse is about 10% to 15%.

Prognostic features. Tumour size over 8 cm (or volume over 200 mL), pelvic or axial site, age over 15 years, poor response to chemotherapy (under 90% necrosis) and metastases.

• Rapidly enlarging, painful or painless soft tissue mass, with warmth and tenderness in some.
• Paravertebral tumours: back pain, radicular pain, weakness, sensory loss and sphincter disturbance. Chest wall tumours: pain, dyspnoea and pleural effusion.
• Fever, weight loss and anaemia with advanced disease.

Red flags.

• Back pain with limb weakness, sensory level or sphincter disturbance (cord compression from a paravertebral tumour).
• Superior vena cava obstruction or respiratory compromise from a large chest wall or mediastinal mass.
• Fever or bone pain with pancytopenia (marrow involvement).

• MRI of the primary site and adjacent spine for paravertebral tumours.
• Core biopsy: small blue round cells with diffuse CD99 membranous staining and NKX2-2. Confirm EWSR1 rearrangement by break apart FISH, RT-PCR or sequencing, to separate it from other round cell sarcomas.
• Staging: CT chest, FDG-PET or whole body MRI, bone scan if PET is unavailable, and bone marrow aspirate and biopsy (or PET with a negative marrow).
• Baseline FBC, creatinine and eGFR, liver tests, lactate dehydrogenase, echocardiography, pregnancy test, and fertility preservation (sperm banking) before chemotherapy.

Differential diagnosis.

• Alveolar rhabdomyosarcoma
• Desmoplastic small round cell tumour (EWSR1::WT1)
• Synovial sarcoma
• CIC-rearranged and BCOR-rearranged sarcoma
• Neuroblastoma and lymphoblastic lymphoma
• Mesenchymal chondrosarcoma and small cell osteosarcoma
• Merkel cell and small cell carcinoma

Treatment is multimodal: induction chemotherapy, local control, then consolidation chemotherapy. Alternating regimens are given every 2 weeks (interval compressed) with growth factor support.

Induction and consolidation chemotherapy (about 14 to 17 cycles in total over about 30 weeks, alternating the two regimens):

• Vincristine, doxorubicin and cyclophosphamide: vincristine 2 mg/m2 IV (maximum 2 mg) on day 1, doxorubicin 75 mg/m2 IV in total each cycle (37.5 mg/m2 on days 1 and 2), and cyclophosphamide 1200 mg/m2 IV on day 1 with mesna and hydration; maximum cumulative doxorubicin 375 mg/m2 within this regimen (inside the working ceiling of 450 mg/m2); monitoring: FBC before each cycle, echocardiography at baseline and every 4 cycles, neuropathy and constipation, liver tests, urinalysis; adjustment: vincristine reduce by 50% when bilirubin is 26 to 51 micromol/L and avoid over 51, avoid strong CYP3A inhibitors, doxorubicin reduce by 50% when bilirubin is 20 to 51 micromol/L and by 75% when 53 to 85, cyclophosphamide reduce by about 25% to 50% when eGFR is under 30 mL/min/1.73 m2.
• Ifosfamide and etoposide: ifosfamide 1800 mg/m2 IV daily on days 1 to 5 with mesna at 60% to 100% of the ifosfamide dose and hydration, and etoposide 100 mg/m2 IV daily on days 1 to 5; maximum ifosfamide 9 g/m2 and etoposide 500 mg/m2 each cycle; monitoring: FBC, creatinine and electrolytes (including phosphate and magnesium for tubulopathy), urinalysis, neurological status, blood pressure during etoposide infusion; 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, etoposide 75% of the dose when creatinine clearance is 15 to 50 mL/min and 50% when under 15, reduce for hepatic impairment.
• Pegfilgrastim 6 mg subcutaneously 24 to 72 hours after chemotherapy.

Local control.

• Wide excision with negative margins when feasible, after about 12 weeks of induction.
• Radiotherapy 55.8 Gy (45 Gy to the initial volume plus a boost of 10.8 Gy) for unresectable disease, and 50.4 Gy for microscopic residual disease or poor response after surgery, with the dose adjusted to normal tissue tolerance (spinal cord).
• Surgery for paravertebral tumours with cord compression (decompression), or urgent radiotherapy with dexamethasone.

Metastatic disease. Whole lung radiotherapy 15 Gy in 10 fractions for lung metastases, local therapy to bone metastases, and the same chemotherapy. High dose consolidation with stem cell rescue is used in selected high risk patients in specialist centres.

Relapse.

• 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.

Monitoring. MRI of the primary site and CT chest every 3 months for 2 years, then every 4 to 6 months to year 3 to 5, then annually. Late effects: echocardiography, fertility, secondary leukaemia (etoposide, alkylators) and second sarcoma in the radiotherapy field.

Referral and escalation.

• Urgent referral to a sarcoma centre (adolescent and young adult or paediatric) on suspicion, before biopsy.
• Same day spinal team review for cord compression.
• Febrile neutropenia needs same day admission and an intravenous antipseudomonal beta lactam within 1 hour.

Special groups.

• Adolescents and young adults: fertility preservation, psychosocial support and long term cardiac surveillance.
• Pregnancy: terminate or delay systemic therapy by specialist decision, since multi-agent chemotherapy is highly teratogenic.
• Adults over 40: lower tolerance of intensive therapy, with dose adjustment by the multidisciplinary team.