Introduction
Ewing sarcoma family of tumors (EFT) comprises a group of undifferentiated, highly malignant small round blue cell tumors (SRBCT). EFT includes:
- Ewing sarcoma of bone (osseous)
- Extraosseous (extraskeletal) Ewing tumor
- Peripheral primitive neuroectodermal tumor (PNET)
- Askin tumors (EFT of the thoracopulmonary region/chest wall).
Accounts for 34% of malignant bone tumors, representing the second most common malignant primary bone tumor of childhood.
Epidemiology And Risk Factors
- Incidence: 3.1 cases per 1 million children (ages 0-19 years) in the United States.
- Age: Peak incidence in second decade of life (adolescence); 80% diagnosed <20 years of age. Rare in adults.
- Gender: Male predominance (Male:Female ratio 1.5:1).
- Ethnicity: High incidence in Caucasians (9-fold higher than Black children). Low incidence in Black and Asian populations.
- Predisposition: Unknown etiology. No association with familial cancer syndromes. Not associated with prior radiation exposure (unlike osteosarcoma).
Pathogenesis And Pathology
Histopathology
- Undifferentiated SRBCT of unknown histogenesis.
- Highly cellular aggregates of small round cells compartmentalized by strands of fibrous tissue.
- Nuclei: Round or oval, finely dispersed chromatin (ground-glass appearance), indistinct nucleoli.
- Mitotic figures: <2 per high-power field.
Immunohistochemistry
Differentiates EFT from other SRBCTs (lymphoma, rhabdomyosarcoma, neuroblastoma, osteomyelitis).
| Marker | EFT Profile | Diagnostic Utility |
|---|---|---|
| CD99 (MIC2) | Positive (Strong) | Pathognomonic honeycomb membranous staining pattern. |
| Vimentin | Positive | Supports mesenchymal origin. |
| Neuron-Specific Enolase (NSE) | Positive (Variable) | Suggests neuroectodermal differentiation. |
| S-100 | Positive (Variable) | Suggests neural differentiation (especially in PNET). |
| Desmin / Actin | Negative | Differentiates from rhabdomyosarcoma. |
| Leukocyte Common Antigen (LCA) | Negative | Differentiates from lymphoma. |
Molecular Genetics
Driven primarily by epigenetic modifications and hallmark chromosomal translocations resulting in chimeric fusion proteins acting as aberrant transcription factors causing growth deregulation.
| Chromosomal Translocation | Fusion Gene | Frequency |
|---|---|---|
| t(11;22)(q24;q12) | EWS-FLI1 | 90-95% |
| t(21;22)(q22;q12) | EWS-ERG | 5-10% |
| t(7;22)(p22;q12) | EWS-ETV1 | <1% |
| t(17;22)(q12;q12) | EWS-ETV4 | <1% |
| t(2;22)(q33;q12) | EWS-FEV | <1% |
Detection: Reverse transcription polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH).
Clinical Features
Symptoms often present 3-6 months prior to diagnosis. Delay does not necessarily correlate with metastatic rate.
- Pain: Most common symptom (96%); intermittent, worsens over time.
- Swelling/Mass: Palpable local mass or soft tissue swelling (61%).
- Fever & Systemic Symptoms: Present in 21%; weight loss, elevated inflammatory markers. Often misdiagnosed as osteomyelitis or fever of unknown origin (FUO).
- Pathologic Fracture: Occurs in 16%.
- Neurologic Deficits: Paraspinal or vertebral primary tumors present with cord compression.
- Respiratory Distress: Large chest wall primaries (Askin tumors).
Anatomic Distribution
Originates evenly between extremities and central axis. Diaphyseal origin in long bones, with extension toward metaphysis.
- Lower Extremity: 45.6% (Femur 20.8%, Fibula 12.2%, Tibia 10.6%).
- Pelvis: 20.0% (Ilium 12.5%, Sacrum/Ischium/Pubis).
- Upper Extremity: 12.9% (Humerus 10.6%).
- Axial Skeleton / Ribs: 12.9%.
Diagnostic Evaluation
Imaging Studies
- Plain Radiographs: Lytic, destructive lesions of the diaphysis. “Moth-eaten” or “permeative” appearance. Characteristic multilayered/lamellated (“onion-skin”) periosteal reaction. Codman triangle may be present. Associated soft-tissue extension (64%).
- Magnetic Resonance Imaging (MRI): Imaging of choice with gadolinium contrast. Evaluates soft-tissue mass, marrow extent, proximity to neurovascular structures, and aids surgical planning.
- Computed Tomography (CT): Chest CT mandatory to rule out pulmonary metastases.
- Nuclear Medicine: 18F-FDG PET/CT scan superior to Technetium-99 bone scan for detecting osseous and bone marrow metastases and monitoring therapy response.
Laboratory And Pathologic Workup
- Biopsy: Open or CT-guided percutaneous core needle biopsy. Surgeon performing definitive resection must perform/plan biopsy to prevent track contamination.
- Bone Marrow: Bilateral bone marrow aspiration and trephine biopsy mandatory for staging.
- Blood Tests: Complete blood count, BUN, Creatinine, Liver function tests. Elevated Lactate Dehydrogenase (LDH) correlates with tumor burden and poor prognosis.
Metastatic Spread
Metastases present in 10-30% at diagnosis. Central/pelvic primaries have higher metastatic rates (40%) compared to distal extremity primaries (15%).
- Lungs: 38%.
- Bone: 31%.
- Bone Marrow: 11%.
Differential Diagnosis
| Tumor/Condition | Differentiating Features |
|---|---|
| Osteosarcoma | Metaphyseal, blastic/sclerotic (“sunburst”), osteoid matrix production, mostly CD99 negative. |
| Osteomyelitis | Febrile presentation similar, requires biopsy/culture. Lacks EWS translocation. |
| Langerhans Cell Histiocytosis | Eosinophilic granuloma; lytic bone lesions without massive soft tissue component. |
| Lymphoma (Primary Bone) | LCA positive, different clinical demographics. |
| Metastatic Neuroblastoma | NSE (+), Urine VMA/HVA (+), <5 years age. |
Treatment Modalities
Comprehensive multidisciplinary approach (chemotherapy, surgery, radiation). Systemic chemotherapy is essential for microscopic and macroscopic disease control.
Chemotherapy
- Neoadjuvant & Adjuvant: Induces rapid tumor necrosis, facilitates limb-sparing local control.
- Standard Regimen (North America): VDC (Vincristine, Doxorubicin, Cyclophosphamide) alternating with IE (Ifosfamide, Etoposide).
- Schedule: Administered every 2 weeks (interval-compressed 14-day schedule yields better outcomes than 21-day schedule) for 12 weeks of induction.
- Metastatic Disease: Myeloablative high-dose chemotherapy (busulfan, melphalan) with autologous stem cell rescue evaluated but did not demonstrate significant overall survival improvement over standard regimens.
Local Control
- Surgery: Complete wide excision with negative margins is preferred for resectable tumors (e.g., distal extremities). Preserves function, avoids radiation-induced secondary malignancies (e.g., osteosarcoma) and growth plate arrest.
- Radiation Therapy: EFT is highly radiosensitive.
- Indications: Unresectable tumors (large sacral/pelvic masses), inadequate surgical margins, or palliative control.
- Dosing: 45 Gy for microscopic residual; 55.8-60 Gy for gross residual/definitive control.
- Whole Lung Radiation: 12-21 Gy standard for patients with pulmonary metastases.
Relapsed Disease
- Early relapse (<2 years) carries an extremely poor prognosis.
- Salvage Chemotherapy Regimens: Irinotecan + Temozolomide; Topotecan + Cyclophosphamide +/- Vincristine; High-dose Ifosfamide.
- Targeted Therapies (Investigational): IGF-1R monoclonal antibodies, PARP inhibitors, EWS-FLI complex targeted agents (LSD1 inhibitors).
Prognosis And Survival
| Prognostic Group | 5-Year Survival Rate |
|---|---|
| Localized (Non-metastatic) | 65-75% |
| Metastatic (At diagnosis) | 20-30% |
| Relapsed / Recurrent | <20% (Very poor) |
Prognostic Factors
| Favorable Factors | Adverse Factors |
|---|---|
| Distal extremity location | Metastatic disease at diagnosis (most critical) |
| Small tumor size | Axial, pelvic, or sacral tumor location |
| Good histologic response to chemotherapy | Older age |
| Complete surgical resectability | Elevated serum LDH levels, fever, anemia |
| Early relapse (<2 years post-treatment) |
Note: Translocation fusion type (e.g., EWS-FLI1 vs EWS-ERG) has lost prognostic significance with the advent of modern interval-compressed chemotherapy protocols.