Approach to Pediatric Thigh Mass: Ewing Sarcoma and Osteosarcoma

Immediate Action: Referral Before Biopsy

Any pediatric patient with radiological findings suggesting a bone sarcoma in the thigh must be referred immediately to a specialized bone sarcoma center BEFORE any biopsy is performed. 1 This prevents contamination of tissue planes that could compromise limb-salvage surgery and worsen outcomes. 1 The biopsy must be performed at the reference center by the surgeon who will perform the definitive tumor resection. 1

Critical Initial Instruction

Instruct the patient to avoid weight-bearing on the affected extremity to prevent pathologic fracture during the evaluation period. 1

Clinical Presentation: Key Distinguishing Features

Osteosarcoma Presentation

Age and demographics: Peak incidence at 10-14 years, male predominance 1
Location: Metaphyseal region of long bones (distal femur most common in thigh) 2
Symptoms: Localized pain and swelling (91.5% present with limb pain) 3
Pain characteristics: Activity-related pain requiring modification or medication use (78.9%), night pain (35.2%), palpable mass (40.8%) 3
Constitutional symptoms: Generally absent (fever in only 2.8%) 3

Ewing Sarcoma Presentation

Age and demographics: Median age 14 years, 90% under 20 years, male predominance 4
Location: Diaphysis of long bones (femur is most common), unlike osteosarcoma 4
Radiographic appearance: Mottled bone with classic "onion skin" periosteal reaction 4
Distinctive features: Large soft tissue component dominates 4
Constitutional symptoms: Unlike osteosarcoma, fever, weight loss, and fatigue may be present 4
Laboratory findings: Elevated serum LDH and leukocytosis may occur 4

Common Pitfall

Twenty percent of patients have negative radiographs at initial presentation, leading to a significantly prolonged interval to diagnosis (54 days vs. 20 days average). 3 In patients with persistent unilateral thigh pain in appropriate age groups, proceed directly to MRI even if plain films are negative. 3

Complete Staging Workup (BEFORE Biopsy)

Imaging Studies Required

The complete staging must be performed BEFORE biopsy to avoid tissue contamination. 4

Chest CT (with or without contrast as clinically indicated; noncontrast preferred for restaging) 4
Contrast-enhanced MRI of primary site (with or without CT) to evaluate entire affected bone 4
Whole-body FDG-PET/CT (preferred) and/or bone scan for metastatic evaluation 4
- PET/CT demonstrates 96% sensitivity and 92% specificity for staging Ewing sarcoma 4
- PET/CT may replace bone marrow biopsy (100% sensitivity, 96% specificity) 4
Bone marrow biopsy and/or screening MRI (with or without contrast) of spine and pelvis 4
Plain radiographs of the primary site 4

Laboratory Studies

Serum LDH: Prognostic marker for both tumors 4
Complete blood count: May show leukocytosis in Ewing sarcoma 4

Fertility Preservation

Fertility consultation should be considered before treatment initiation for all patients 4
Sperm banking should be offered to male patients 4

Biopsy Technique and Molecular Diagnosis

Biopsy Approach

Open biopsy is strongly preferred over percutaneous biopsy. 5 Open biopsy achieves 94.1% diagnostic success vs. 73.1% for percutaneous approach, with odds of successful diagnosis 7.8 times higher. 5 The biopsy must be performed by the surgeon who will do the definitive resection. 1

Essential Molecular Studies for Ewing Sarcoma

Cytogenetic and/or molecular studies to detect EWSR1 translocations 4
EWSR1::FLI1 fusion (chromosome translocation t(11;22)(q24;q12)) present in 85% of cases 4
Alternative fusions: EWSR1 with ERG, ETV1, ETV4, or FEV (5-10% of cases) 4
Rare variants: FUS::ERG or FUS::FEV (no EWSR1 rearrangement) 4
CD99 (MIC2) expression: Strong immunohistochemical marker, though not exclusively specific 4

If Initial Molecular Studies Are Negative

If targeted PCR, FISH, or cytogenetics are negative, comprehensive genomic profiling or other fusion panels should be performed to identify atypical translocations. 4

Prognostic Stratification

Favorable Prognostic Factors

Distal/peripheral location (thigh is more favorable than pelvis) 4
Tumor volume < 100 mL or diameter < 8-10 cm 4
Normal serum LDH at presentation 4
Age < 15 years 4
Absence of metastatic disease 4
Good histologic response to chemotherapy (≥90% necrosis) 4

Adverse Prognostic Factors

Metastatic disease at presentation (most significant adverse factor) 4
Pelvic or axial location 4
Tumor diameter > 8-10 cm 4
Elevated serum LDH 4
Age > 15 years 4
Poor histologic response to chemotherapy 4
Radiotherapy as only local treatment 4

Metastatic Disease Outcomes

Localized disease: 55-60% 5-year survival 4
Metastatic disease: 22% 5-year relapse-free survival 4
Lung metastases only: 30-50% 5-year survival 4
Bone/bone marrow metastases: 10% 5-year survival 4

Treatment Protocol for Localized Disease

Overall Treatment Structure

Treatment consists of 8-12 months of multimodal therapy divided into three phases. 4, 1

Phase 1: Induction Chemotherapy (3-6 Cycles, Minimum 9 Weeks)

Multiagent chemotherapy must be administered for at least 9 weeks prior to local therapy. 4

Standard chemotherapy agents include: 4

Vincristine
Doxorubicin and/or dactinomycin
Cyclophosphamide and/or ifosfamide
Etoposide

The 4-drug VACD regimen (vincristine, dactinomycin, cyclophosphamide, doxorubicin) demonstrated superior relapse-free survival (60%) compared to 3-drug VAC regimen (24%). 4

Restaging After Induction

Mandatory restaging before local therapy includes: 4

Chest CT (noncontrast preferred)
Contrast-enhanced MRI ± CT of primary site
Plain radiographs of primary site
Consider FDG-PET/CT (head-to-toe) or bone scan
Repeat other abnormal studies
Cytogenetics and/or molecular studies (may require re-biopsy) 4

Phase 2: Local Control

Surgery is the strongly preferred method for local control. 4, 1 Wide surgical resection with negative margins should be achieved. 1

Radiotherapy indications: 4

Marginal or intralesional surgical margins
Inoperable tumors
Patient/family refusal of surgery

Radiotherapy dosing: 4

40-45 Gy for microscopic residual disease
50-60 Gy for macroscopic disease

Phase 3: Consolidation Chemotherapy (8-10 Cycles)

Continue multiagent chemotherapy to complete 12-15 total cycles over 8-12 months. 4

Treatment of Metastatic Disease at Presentation

Systemic Chemotherapy

Patients with metastatic disease receive the same standardized chemotherapy as localized disease. 4, 1

Additional Interventions for Lung Metastases

Total lung irradiation should be considered for patients achieving complete remission 4
Thoracotomy should be considered for limited residual macroscopic disease 4
Surgical resection of pulmonary metastases after chemotherapy may confer survival advantage for osteosarcoma 1

Bone Metastases

Supplemental irradiation of bone metastases is usually indicated. 4

Management of Recurrent or Progressive Disease

Patients with systemic or local recurrence should generally be considered for palliative management, with rare exceptions for limited relapse after long disease-free interval. 4, 1

Palliative Chemotherapy Options (in order of preference)

High-dose ifosfamide: Most effective palliative regimen 6
Topotecan and cyclophosphamide: 44% response rate 6
Irinotecan and temozolomide: 63% objective response rate, 8.3 months median time to progression 6
Gemcitabine and docetaxel 1

Long-Term Surveillance Protocol

Intensive long-term follow-up is mandatory due to late relapse risk and treatment-related toxicity. 4, 1, 6

Follow-Up Schedule

Years 0-3: Every 3 months 4, 1, 6
Years 3-5: Every 6 months 4, 1, 6
Years 5-10: Every 8-12 months 4, 1, 6
Beyond 10 years: Continue surveillance due to late complications 4, 6

Rationale for Extended Surveillance

Late relapses: Can occur 5-15 years after treatment 7
Secondary malignancies: 5% risk including acute myelogenous leukemia (regardless of radiotherapy) and secondary sarcomas (within radiation fields) 4, 6
Treatment-related toxicity: Cardiopulmonary complications, renal dysfunction 6, 7

Adaptations for Low-to-Middle Income Countries

Essential Principles That Cannot Be Compromised

Referral to specialized center before biopsy 1
Complete staging before biopsy 4
Multiagent chemotherapy (minimum VACD regimen) 4
Adequate local control (surgery preferred over radiotherapy alone) 4

Potential Modifications When Resources Limited

If PET/CT unavailable, use bone scan plus bone marrow biopsy for metastatic evaluation 4
If comprehensive genomic profiling unavailable, targeted PCR or FISH for EWSR1::FLI1 is acceptable 4
Standard-dose chemotherapy regimens remain effective; dose intensification strategies have not shown consistent benefit 4

Critical Warning

Treatment must be delivered at specialized sarcoma centers to achieve optimal outcomes, as this requires complex multidisciplinary coordination. 7 Survival rates drop significantly when treatment is fragmented across multiple non-specialized facilities.

Expected Outcomes

Localized Disease

5-year survival: 60-75% with modern multimodal therapy 4, 7, 2, 8
10-year survival: 60.2% for osteosarcoma, 54.5% for Ewing sarcoma 8

Metastatic Disease

Isolated lung metastases: 30-50% 5-year survival 4, 7
Bone/bone marrow metastases: 10% 5-year survival 4, 7
Overall metastatic disease: 22% 5-year relapse-free survival 4

Recurrent Disease

Event-free 5-year survival of only 10% for patients with disease relapse. 9

What is the appropriate diagnostic workup and management plan for a pediatric patient with a thigh mass suspected to be Ewing's sarcoma or osteosarcoma?

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