# CIM Case: Ewing's Sarcoma - Adolescent Femur ## Clinical Scenario **Patient:** 14-year-old male **Presentation:** 6-week history of progressive right thigh pain and swelling, worse at night, associated with low-grade fevers and night sweats **Relevant history:** Previously fit and active, no prior bone problems, no trauma, no family history of malignancy, 3kg weight loss over 6 weeks, decreased appetite, fatigue **Examination findings:** - Unwell-appearing adolescent, pale - Temperature 37.8°C - Palpable warm, tender mass over distal right thigh (8cm × 6cm) - Firm, fixed to underlying bone - Visible distension of superficial veins over mass - Range of motion at knee limited by pain - No knee effusion - Neurovascularly intact distally - No palpable lymphadenopathy - Chest clear --- ## Investigations Provided ### Laboratory Results | Test | Result | Normal Range | Interpretation | |------|--------|--------------|----------------| | Hb | 98 g/L | 130-160 g/L | ↓ Anaemia | | WCC | 12.5 ×10⁹/L | 4-11 ×10⁹/L | ↑ Leucocytosis | | Platelets | 485 ×10⁹/L | 150-400 ×10⁹/L | ↑ Reactive thrombocytosis | | CRP | 65 mg/L | <5 mg/L | ↑ Elevated | | ESR | 85 mm/hr | <15 mm/hr | ↑ Markedly elevated | | LDH | 580 U/L | 120-250 U/L | ↑ Elevated (prognostic marker) | | ALP | 245 U/L | 150-420 U/L | Normal (bone turnover) | | Uric acid | 0.48 mmol/L | 0.15-0.45 mmol/L | ↑ Slightly elevated | ### Imaging **Image 1: AP and Lateral Radiographs of Right Femur** **Radiological features:** - Large permeative/moth-eaten lesion in femoral diaphysis - "Onion skin" periosteal reaction (lamellated) - Codman triangle at proximal margin - Lytic destruction without matrix mineralisation - No sclerotic rim (aggressive lesion) - Soft tissue mass extending from bone - Lesion extends approximately 12cm in longitudinal axis **Image 2: MRI Right Femur with Contrast** **MRI findings:** - Large intramedullary tumour with extensive marrow replacement - Low T1 signal, high T2 signal, heterogeneous enhancement - Large extraosseous soft tissue mass (8 × 6 × 10 cm) - Tumour extends into adjacent muscle compartments - No skip lesions identified on whole bone imaging - Neurovascular bundle displaced but not encased - No knee joint involvement **Image 3: CT Chest** **Findings:** - Two small pulmonary nodules (4mm and 6mm) in right lower lobe - Concerning for pulmonary metastases - No mediastinal lymphadenopathy --- ## Questions & Model Answers **Differential Diagnosis by Age (Second Decade):** | Diagnosis | Supporting Features | Against | |-----------|--------------------|---------| | **Ewing sarcoma** | Age (5-25), diaphyseal, permeative, onion skin, systemic symptoms | - | | Osteomyelitis | Fever, elevated inflammatory markers, diaphyseal | No sequestrum, periosteal pattern atypical | | Osteosarcoma | Age group, bone-forming tumour | Typically metaphyseal, usually has matrix | | Lymphoma of bone | Permeative pattern, systemic symptoms | Usually older (>30 years) | | Eosinophilic granuloma | Permeative lesion | Usually younger (5-10 years), typically skull/spine | **Most Likely Diagnosis: Ewing Sarcoma** **Key Supporting Features:** - Age 14 (peak incidence 10-20 years) - Diaphyseal location (Ewing favours diaphysis/metadiaphysis) - Permeative/moth-eaten destruction pattern - "Onion skin" lamellated periosteal reaction (classic) - Large soft tissue mass - Systemic symptoms (fever, weight loss, night sweats) - Elevated LDH (prognostic marker) > **Consultant Tip:** Ewing sarcoma can mimic osteomyelitis clinically and radiographically - both cause fever, elevated inflammatory markers, and periosteal reaction. Always biopsy before treating as infection. **Epidemiology:** - Second most common primary bone malignancy in children/adolescents - Peak age: 10-20 years (95% under 30) - Male predominance (1.5:1) - Rare in African populations **Molecular Pathology:** - **t(11;22)(q24;q12) translocation** - 85% of cases - Creates EWSR1-FLI1 fusion gene - Variant translocations: t(21;22), t(7;22) - Defines the "Ewing sarcoma family of tumours" **Histological Features:** - **Small round blue cell tumour** - uniform appearance - Sheets of small cells with scant cytoplasm - Round nuclei with fine chromatin - PAS-positive (glycogen in cytoplasm) - **CD99 (MIC2) positive** - highly characteristic - Negative for lymphoid markers **Radiographic Features:** - Permeative/moth-eaten destruction (aggressive) - Diaphyseal or metadiaphyseal location - "Onion skin" periosteal reaction (lamellated) - Codman triangle - Large soft tissue mass (often > bone component) - No matrix mineralisation (unlike osteosarcoma) **Common Locations:** - Pelvis (most common overall) - Femur (most common long bone) - Tibia, humerus, ribs > **Consultant Tip:** CD99 positivity + small round blue cells + t(11;22) = Ewing sarcoma. CD99 is sensitive but not specific (also positive in lymphoma, synovial sarcoma). **Complete Staging Protocol:** | Investigation | Purpose | Key Findings to Seek | |---------------|---------|----------------------| | **MRI whole bone** | Local staging | Skip lesions, soft tissue extent, NV involvement | | **CT chest** | Lung metastases | Pulmonary nodules (25% at diagnosis) | | **Bone scan or PET-CT** | Skeletal staging | Other bone metastases (10% at diagnosis) | | **Bone marrow biopsy** | Marrow involvement | Bilateral iliac crest (25% have involvement) | | **CT-guided biopsy** | Tissue diagnosis | Planned along definitive surgical approach | **Essential Blood Tests:** - LDH - prognostic marker (elevated = worse) - FBC - baseline for chemotherapy - Renal/liver function - chemotherapy planning - ESR/CRP - monitor response **Biopsy Principles:** - Discuss with sarcoma surgeon BEFORE biopsy - Plan tract along future surgical approach - Biopsy tract must be excised with definitive resection - Send for molecular studies (FISH for translocation) - Avoid contaminating multiple compartments **Staging (Enneking/MSTS):** - Stage IIB: High grade, extracompartmental (most Ewing at diagnosis) - Stage III: Any grade with metastases **This Patient's Staging:** - Pulmonary nodules on CT chest = Stage III (metastatic) - Bone marrow biopsy required > **Consultant Tip:** Always image the whole bone - skip lesions in 10-15% of Ewing sarcoma. Missing a skip lesion means inadequate resection. **Multimodal Treatment Protocol:** **Phase 1: Neoadjuvant Chemotherapy (12-16 weeks)** | Protocol | Drugs | Duration | |----------|-------|----------| | **VIDE** (European) | Vincristine, Ifosfamide, Doxorubicin, Etoposide | 6 cycles | | **VDC/IE** (North American) | Alternating VDC and IE | 4 cycles | **Phase 2: Restaging** - MRI to assess tumour response - PET-CT for metabolic response - CT chest for pulmonary disease **Phase 3: Local Control** | Option | Indication | Considerations | |--------|------------|----------------| | **Wide surgical excision** | Resectable with acceptable morbidity | Preferred - better local control | | **Radiotherapy** | Unresectable, pelvic, axial, marginal margins | 45-55 Gy | | **Combined surgery + RT** | Marginal resection, poor histological response | | **Phase 4: Adjuvant Chemotherapy** - Continue to complete 12-14 total cycles - Total treatment duration approximately 12 months **Histological Response Assessment:** - **>90% necrosis** - good response, favourable prognosis - **<90% necrosis** - poor response, worse outcomes **Surgical Reconstruction Options:** - Endoprosthetic replacement (most common for diaphyseal femur) - Rotationplasty (Van Nes procedure) - young patients - Expandable prostheses - skeletally immature - Allograft reconstruction - Amputation - rarely needed, last resort > **Consultant Tip:** Ewing sarcoma is chemosensitive. Surgery is preferred for local control when achievable, but radiotherapy is effective (unlike osteosarcoma). **Metastatic Ewing Sarcoma Management:** **Prognosis with Metastases:** - Lung-only metastases: 5-year survival 20-30% - Bone/bone marrow metastases: 5-year survival <20% - Combined metastases: worst prognosis **Treatment Approach (Still Curative Intent):** - Intensive chemotherapy protocols - Whole lung irradiation (12-15 Gy) if lung-only disease - Surgical resection of pulmonary metastases if limited - Local control of primary tumour still indicated **Specific Considerations for This Patient:** - Two small pulmonary nodules (resectable if disease controlled) - If good response to chemotherapy: - Primary tumour resection - Thoracoscopic resection of pulmonary nodules - Whole lung irradiation - Bone marrow transplant may be considered in poor responders **Monitoring During Treatment:** - Serial imaging every 2-3 cycles - LDH trending (response marker) - PET-CT for metabolic response - Watch for treatment-related toxicity **Treatment Toxicity Monitoring:** - Cardiotoxicity (doxorubicin) - echo monitoring - Nephrotoxicity (ifosfamide) - Secondary malignancy risk (long-term) - Growth disturbance (radiation, surgery) > **Consultant Tip:** Don't abandon curative intent for lung-only metastases in Ewing sarcoma. Aggressive multimodal treatment can still achieve long-term survival in 20-30%. **Comparison Table:** | Feature | Ewing Sarcoma | Osteosarcoma | |---------|---------------|--------------| | **Peak age** | 10-20 years | 10-25 years (second peak >60) | | **Location** | Diaphysis/metadiaphysis | Metaphysis | | **Common sites** | Pelvis, femur, ribs | Distal femur, proximal tibia, proximal humerus | | **Radiograph** | Permeative, onion skin, no matrix | Mixed lytic/sclerotic, sunburst, matrix | | **Histology** | Small round blue cells | Pleomorphic cells with osteoid | | **Immunohistochemistry** | CD99 positive | SATB2 positive | | **Genetics** | t(11;22) EWSR1-FLI1 | Complex karyotype | | **Chemosensitivity** | High | Moderate | | **Radiosensitivity** | Yes | No (resistant) | | **Chemotherapy** | VIDE or VDC/IE | MAP (Methotrexate, Adriamycin, Cisplatin) | | **5-year survival (localised)** | 70-75% | 60-70% | | **5-year survival (metastatic)** | 20-30% | <20% | **Key Differentiating Points:** - Ewing: diaphyseal, no matrix, radiosensitive - Osteosarcoma: metaphyseal, bone-forming matrix, radioresistant > **Consultant Tip:** Both require neoadjuvant chemotherapy and MDT management. Key difference: Ewing responds to radiotherapy, osteosarcoma does not. --- ## Key Teaching Points ### Pattern Recognition **This pattern suggests Ewing Sarcoma:** - Adolescent (10-20 years) with bone pain and systemic symptoms - Diaphyseal or metadiaphyseal location - Permeative/moth-eaten destruction on X-ray - "Onion skin" lamellated periosteal reaction - Large soft tissue mass disproportionate to bone lesion - Elevated LDH and inflammatory markers **Age-Based Differential for Round Cell Tumours:** | Age | Most Likely Round Cell Tumour | |-----|-------------------------------| | 0-5 years | Neuroblastoma metastasis, leukaemia | | 5-10 years | Eosinophilic granuloma (LCH) | | 10-25 years | **Ewing sarcoma** | | 25-40 years | Lymphoma | | >40 years | Myeloma, metastases | **Small Round Blue Cell Tumours (Differential):** - Ewing sarcoma (CD99+, t(11;22)) - Lymphoma (CD45+, CD20/CD3+) - Neuroblastoma (NSE+, NB84+) - Rhabdomyosarcoma (desmin+, myogenin+) - Small cell osteosarcoma (SATB2+, osteoid) ### Critical Management Points 1. **Don't treat as infection without biopsy** - Ewing mimics osteomyelitis 2. **Whole bone MRI** - skip lesions change surgical planning 3. **Biopsy tract planning** - must be excised with tumour 4. **Neoadjuvant chemotherapy first** - don't proceed directly to surgery 5. **MDT essential** - sarcoma surgeon, oncologist, radiologist, pathologist 6. **Histological response matters** - >90% necrosis = good prognosis --- ## Common Examiner Follow-ups **Q: "What is the difference between 'onion skin' and 'sunburst' periosteal reaction?"** | Feature | Onion Skin | Sunburst | |---------|------------|----------| | Appearance | Concentric lamellated layers | Radiating spicules | | Mechanism | Slow, intermittent periosteal elevation | Rapid, continuous tumour growth | | Classic tumour | Ewing sarcoma | Osteosarcoma | | Implication | Moderately aggressive | Highly aggressive | --- **Q: "What is the role of radiotherapy in Ewing sarcoma?"** Radiotherapy indications: - Unresectable tumours (pelvis, spine, skull base) - Marginal surgical margins - Poor histological response to chemotherapy - Lung metastases (whole lung irradiation) Dose: 45-55 Gy for definitive treatment, 40-45 Gy if combined with surgery Key point: Unlike osteosarcoma, Ewing sarcoma IS radiosensitive. This makes radiotherapy a viable option for local control when surgery would cause unacceptable morbidity. --- **Q: "What is a skip lesion and why is it important?"** Skip lesion definition: Separate tumour deposit in the same bone, not contiguous with primary lesion. - Occurs in 10-15% of Ewing sarcoma - Must image ENTIRE bone with MRI - Skip lesion = worse prognosis - Surgical resection must include skip lesion - May require whole bone resection or diaphyseal resection Missing a skip lesion leads to local recurrence and treatment failure. --- **Q: "How would you counsel this patient and family about prognosis?"** For metastatic Ewing sarcoma (this patient): - Honest discussion about seriousness of diagnosis - 5-year survival approximately 20-30% with lung-only metastases - Treatment is intensive (12+ months) - Significant side effects (nausea, hair loss, infection risk) - Fertility preservation discussion before starting chemotherapy - Need for long-term surveillance even if cured - Involvement of paediatric oncology nurse, psychologist, social worker - Family support resources, youth cancer support groups --- ## Related Topics - Osteosarcoma - Primary Bone Tumours - Bone Tumour Staging (Enneking) - Endoprosthetic Reconstruction - Chemotherapy Protocols in Bone Sarcoma - Rotationplasty