Ewing Sarcoma: Diagnostic Workup and Multimodal Treatment
Overview
Ewing sarcoma requires immediate referral to a specialized bone sarcoma center before any biopsy is performed, followed by complete staging with FDG-PET/CT, contrast-enhanced MRI of the primary site, chest CT, and consideration of bone marrow biopsy, then treatment with 8-12 months of multiagent chemotherapy combined with surgical resection or radiotherapy for local control. 1, 2
Clinical Presentation
Ewing sarcoma typically presents in adolescents and young adults (median age 15 years) with a male predominance of 1.5:1, occurring almost exclusively in white Caucasians (incidence 0.3/100,000/year in those under 25) but is very rare in African and Asian populations. 1
Key presenting features include:
- Localized pain or swelling at the affected site, often mistakenly attributed to trauma 1
- Constitutional symptoms (fever, weight loss, fatigue) may be present—unlike other bone sarcomas 1
- Laboratory abnormalities: elevated serum LDH and leukocytosis 1
Most common anatomic sites:
- Pelvic bones (20-25% of cases) 1
- Femur and long bones (50% extremity tumors) 1
- Chest wall and ribs 1
- When arising in long bones, the diaphysis is most frequently affected 1, 3
Diagnostic Workup
Immediate Referral Protocol
Critical first step: Any patient with radiographic findings suggesting Ewing sarcoma must be referred immediately to a specialized bone sarcoma center before biopsy to prevent tissue plane contamination and optimize limb-salvage outcomes. 2, 3 The biopsy must be performed at the reference center by the surgeon who will perform definitive resection. 2
Complete Staging Before Biopsy
The NCCN 2025 guidelines mandate the following staging studies: 1
- Chest CT with or without contrast (noncontrast preferred for restaging) 1
- Contrast-enhanced MRI of the primary site (with or without CT) to define precise bone, bone marrow, and soft tissue involvement including relationship to neurovascular structures 1
- Whole body FDG-PET/CT (preferred) and/or bone scan—PET/CT demonstrates 96% sensitivity and 92% specificity for staging 1
- Bone marrow biopsy and/or aspiration from sites distant from the primary tumor (though FDG-PET alone may be considered, showing 100% sensitivity and 96% specificity) 1
- Screening MRI with or without contrast of spine and pelvis (as clinically indicated) 1
Biopsy and Pathologic Diagnosis
Biopsy must provide sufficient material for: 1
- Conventional histology: small round blue cells, PAS-positive, CD99 (MIC2)-positive 1
- Molecular biology testing (fresh, unfixated material): detection of characteristic translocations 1
Molecular characteristics: 1
- EWSR1::FLI1 fusion from t(11;22)(q24;q12) in ~85% of cases 1
- EWSR1 fused with other ETS family members (ERG, ETV1, ETV4, FEV) in 5-10% 1
- Rare FUS::ERG or FUS::FEV fusions without EWSR1 rearrangement 1
- Overall, 90% have one of four cytogenetic translocations 1
Confirmation by an expert bone tumor pathologist is mandatory. 1
Radiographic Features
Classic imaging findings: 1, 3
- Mottled bone appearance 1, 3
- "Onion skin" periosteal reaction (lamellated pattern) 1, 3
- Large soft tissue component often present 1
Prognostic Stratification
Favorable Prognostic Factors
- Distal/peripheral site of primary disease
- Tumor volume < 100 mL
- Normal LDH at presentation
- Absence of metastatic disease at presentation (most important)
Adverse Prognostic Factors
- Metastatic disease at presentation (20-25% of patients)—most significant adverse factor
- Tumor diameter > 8 cm
- Axial location (spine, sacrum, pelvis)
- Age > 15 years
- Elevated serum LDH
- Poor histologic response to preoperative chemotherapy (< 90% necrosis)
- Radiotherapy as only local treatment
Metastatic disease outcomes: 1
- 5-year relapse-free survival: 22% with metastases vs. 55% without metastases 1
- Bone metastases: < 20% 5-year survival 1
- Lung/pleura metastases alone: 20-40% 5-year survival 1
Multimodal Treatment Plan
Localized Disease
Standard treatment consists of 8-12 months of therapy with three components: 1, 2, 4
1. Induction Chemotherapy (3-6 cycles)
The most effective regimens include: 1, 2, 4
- Alternating cycles of VDC (vincristine/doxorubicin/cyclophosphamide) and IE (ifosfamide/etoposide) given every 2 weeks with growth factor support 5, 4
- All active protocols must include at least one alkylating agent (ifosfamide or cyclophosphamide) and doxorubicin 1
- Six-drug combinations incorporating doxorubicin, vincristine, cyclophosphamide, ifosfamide, dactinomycin, and etoposide 1, 4
The incorporation of ifosfamide and etoposide significantly improved outcomes. 1
2. Local Control
Surgical resection is preferred when feasible: 2
Radiotherapy indications: 1
- When complete surgical resection not achievable
- For axial/pelvic tumors where surgery would cause unacceptable morbidity
- Must be administered at the same specialized center providing surgical and systemic interventions 1
Critical timing: Local therapy is performed after induction chemotherapy to assess histologic response. 1, 2
3. Consolidation Chemotherapy (6-10 additional cycles)
Continue multiagent chemotherapy for total treatment duration of 8-12 months. 1, 2
Metastatic Disease at Presentation
- Same standardized chemotherapy regimen as localized disease 2
- Aggressive local control of primary tumor 2, 4
- Consider surgical resection of pulmonary metastases after chemotherapy 2
- 5-year overall survival < 30% (except isolated pulmonary metastases ~50%) 4
Recurrent Disease
Prognosis is dismal for recurrent disease. 4 Chemotherapy options include: 2
- High-dose ifosfamide
- Topotecan and cyclophosphamide
- Irinotecan and temozolomide
- Gemcitabine and docetaxel
Most patients with recurrence are considered palliative. 2
Follow-Up Protocol
Long-term surveillance is mandatory due to late relapse risk and treatment-related toxicity: 2
Surveillance should monitor for late relapses and secondary malignancies. 2
Critical Pitfalls to Avoid
- Never perform biopsy before referral to specialized center—this contaminates tissue planes and compromises limb-salvage surgery 2, 3
- Do not delay staging workup—complete staging must precede biopsy 1
- Radiographic features alone are insufficient—molecular confirmation with EWSR1 rearrangement is essential 3
- Do not underestimate constitutional symptoms—fever and weight loss at presentation distinguish Ewing sarcoma from other bone sarcomas 1
- Recognize racial epidemiology—extremely rare in African and Asian populations; reconsider diagnosis if patient is not white Caucasian 1, 6