What is the approach to diagnosis and management of a pediatric patient presenting with a thigh mass suspected to be Ewing's (Ewing sarcoma) or osteosarcoma?

Approach to Diagnosis and Management of Pediatric Thigh Mass Suspicious for Ewing Sarcoma or Osteosarcoma

Immediate Referral Protocol

Any pediatric patient with radiological findings suggesting a bone sarcoma must be referred immediately to a specialized bone sarcoma reference center BEFORE any biopsy is performed. 1

• The biopsy must be performed at the reference center by the surgeon who will perform the definitive tumor resection 1
• This prevents contamination of tissue planes and improves limb-salvage outcomes 1
• Instruct the patient to avoid weight-bearing on the affected extremity to prevent pathologic fracture during evaluation 2

Initial Diagnostic Workup at Specialized Center

Clinical Presentation Features to Document

Osteosarcoma typically presents with:

• Pain and swelling in the metaphyseal region of long bones (most commonly distal femur, proximal tibia) 3, 4
• Peak age 10-14 years, with second peak in 7th-8th decades 1, 3
• Male predominance (1.4:1) 1
• Occasional pathologic fracture at presentation 3, 5

Ewing sarcoma typically presents with:

• Large soft tissue component often dominating the clinical picture 1
• Median age 14 years (90% of patients <20 years) 1
• Male predominance (1.5:1) 1
• 50% involve extremities, 20% involve pelvis 1

Imaging Protocol Before Biopsy

Complete the following imaging studies before any tissue sampling: 1

• Plain radiographs of entire affected bone: Osteosarcoma shows mixed sclerotic/lytic lesion in metaphyseal region; Ewing sarcoma shows permeative destruction with soft tissue mass 3, 2
• Chest CT scan: To detect pulmonary metastases (present in ~20% at diagnosis) 1
• Bone scintigraphy: To rule out bone metastases 1
• MRI of primary site: To define local extent and soft tissue involvement 3

Biopsy Technique and Pathologic Confirmation

Open surgical biopsy is strongly preferred over percutaneous approaches 6

• Open biopsy has 94.1% diagnostic success rate versus 73.1% for percutaneous biopsy (7.8 times higher odds of success) 6
• The biopsy tract must be planned for en-bloc resection with the definitive specimen 1

For Ewing sarcoma diagnosis, confirm: 1

• MIC2 gene expression by immunohistochemistry (distinguishes from other "blue tumors") 1
• Translocation t(11;22)(q24;q12) by cytogenetics or PCR (present in >90%) 1
• Alternative translocations include t(21;22)(q22;q12) 1

For osteosarcoma diagnosis, confirm: 3

• Spindle cells producing osteoid on histology 3
• High-grade features in conventional osteosarcoma 1

Mandatory Staging Studies

Complete the following additional staging before treatment initiation: 1

• Bone marrow aspirates for light microscopy (mandatory for Ewing sarcoma) 1
• Serum LDH level (elevated LDH is adverse prognostic factor) 1
• Sperm banking should be offered to post-pubertal males 1

Risk Stratification

Adverse Prognostic Factors (Both Tumor Types)

The following factors predict worse outcomes: 1

• Metastatic disease at presentation (20% of patients) 1
• Tumor diameter >8-10 cm 1
• Age >15 years 1
• Pelvic or axial location 1
• Elevated serum LDH 1
• Poor histological response to preoperative chemotherapy (<90% necrosis) 1, 5
• Radiotherapy as only local treatment 1

Metastatic Disease Prognosis

Survival varies dramatically by metastatic site: 1, 7

• Isolated lung metastases: 30-50% 5-year survival 1, 7
• Bone or bone marrow metastases: 10% 5-year survival 1, 7
• Localized disease: 60-75% 5-year survival 7, 3, 4

Treatment Protocol for Localized Disease

Ewing Sarcoma Treatment Algorithm

Standard treatment consists of 8-12 months of multimodal therapy: 1, 7

1. Induction chemotherapy (3-6 cycles): 1, 7

   • VAC/IE regimen: vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide 8
   • Dactinomycin may be included in some protocols 1
   • Total of 12-15 courses over treatment period 1

2. Local control (after induction): 1, 8

   • Surgery is preferred: Wide surgical resection with negative margins 1, 8
   • Radiotherapy indications: Marginal/intralesional surgery or inoperable tumors 1
   • Radiation doses: 40-45 Gy for microscopic residual disease; 50-60 Gy for macroscopic disease 1, 8
   • Hyperfractionated regimens may optimize integration with chemotherapy 1

3. Consolidation chemotherapy (8-10 cycles): 1, 7

   • Continue same agents to eradicate micrometastatic disease 7

Osteosarcoma Treatment Algorithm

Standard treatment follows similar timeline with different chemotherapy: 3, 4

1. Neoadjuvant chemotherapy: 8, 3

   • MAP regimen: high-dose methotrexate, cisplatin, doxorubicin 8
   • Allows assessment of tumor response and facilitates limb-salvage 3, 4

2. Surgical resection: 8, 3, 4

   • Wide or radical resection margins required 5
   • 90-95% of patients can undergo limb-sparing resection with reconstruction 8, 3, 4
   • Inadequate surgical margins are a significant adverse prognostic factor 8, 5

3. Adjuvant chemotherapy: 3, 4

   • Continue MAP protocol based on histologic response 3
   • Poor responders (<90% necrosis) may require intensification 8

Treatment of Metastatic Disease at Presentation

Ewing Sarcoma with Metastases

Patients with metastatic disease receive the same standardized chemotherapy as localized disease 1

Additional interventions for lung metastases: 1, 8

• Total lung irradiation for patients achieving complete remission 1
• Thoracotomy for limited residual macroscopic disease 1

For bone metastases: 1, 9

• Supplemental irradiation of symptomatic bone sites is usually indicated 1, 9

Osteosarcoma with Metastases

Surgical resection of pulmonary metastases after chemotherapy may confer survival advantage 8

Pulmonary irradiation may be considered for unresectable lung metastases 8

Management of Recurrent Disease

Patients with systemic or local recurrence should be considered palliative, with rare exceptions 1, 9

For recurrent Ewing sarcoma, chemotherapy options in order of efficacy: 9

1. High-dose ifosfamide 9
2. Topotecan and cyclophosphamide 9
3. Irinotecan and temozolomide 9
4. Gemcitabine and docetaxel 9

Multi-targeted tyrosine kinase inhibitors (pazopanib, cabozantinib, regorafenib) have shown single-agent activity 9

Palliative radiotherapy should be considered for symptomatic sites 9

Quality of life becomes paramount given median overall survival of approximately one year 9

Critical Follow-Up Protocol

Long-term surveillance is mandatory due to late relapse risk and treatment toxicity: 1, 7

• Years 0-3: Every 3 months 1
• Years 3-5: Every 6 months 1
• Years 5-10: Every 8-12 months 1
• Beyond 10 years: Continue surveillance for late relapses (can occur 5-15 years post-treatment) and secondary malignancies 1, 7

Common Pitfalls to Avoid

Never perform biopsy before referral to specialized center - This contaminates tissue planes and compromises limb-salvage surgery 1

Never treat outside specialized sarcoma centers - Complex multidisciplinary coordination is essential for optimal outcomes 1, 7

Never use radiotherapy alone when surgical resection is feasible - Surgery provides superior local control despite radiosensitivity of Ewing sarcoma 1, 8

Never assume cure at 5 years - Late relapses occur, and treatment-related complications (secondary malignancies, cardiopulmonary toxicity) emerge years later 7

Avoid inadequate surgical margins - This is a significant adverse prognostic factor that dramatically reduces survival 8, 5