Ewing's Sarcoma

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).

Molecular Genetics

Driven primarily by epigenetic modifications and hallmark chromosomal translocations resulting in chimeric fusion proteins acting as aberrant transcription factors causing growth deregulation.

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

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 Factors

Note: Translocation fusion type (e.g., EWS-FLI1 vs EWS-ERG) has lost prognostic significance with the advent of modern interval-compressed chemotherapy protocols.