Ewing’s Sarcoma — Protocols

Ewing sarcoma is the second most common primary malignant bone tumour in children and adolescents after osteosarcoma, and the most common in the first decade of life. It is a highly aggressive malignancy arising from primitive mesenchymal stem cells and characterised by a specific chromosomal translocation. Without treatment, survival is measured in months; with modern multimodal treatment (chemotherapy + surgery ± radiotherapy), five-year survival for localised disease approaches 70–80%, making Ewing sarcoma one of the most chemotherapy-sensitive solid tumours in paediatric oncology.

• Epidemiology: incidence approximately 3 per million per year; peak age 10–15 years (first decade and early second decade); rare below age 5 and above age 30; male:female ratio approximately 1.5:1; strong predilection for White/Caucasian patients (rare in Black and Asian populations — possibly related to EWS-FLI1 translocation frequency differences); approximately 25% of patients have metastatic disease at diagnosis; most common sites — pelvis and sacrum (25%), femur (20%), tibia (10%), humerus (10%), ribs and vertebrae (15%); unlike osteosarcoma (which is predominantly metaphyseal), Ewing sarcoma has a DIAPHYSEAL predilection
• Molecular pathology — the translocation: Ewing sarcoma is defined by a specific chromosomal translocation in almost all cases; the most common is t(11;22)(q24;q12) — present in approximately 85% of cases; this fuses the EWSR1 gene (chromosome 22) with the FLI1 gene (chromosome 11) to produce the EWS-FLI1 fusion protein; this oncogenic fusion protein is an aberrant transcription factor that drives tumour cell proliferation and inhibits differentiation; other less common translocations include t(21;22)(q22;q12) — EWS-ERG fusion (5–10%); detection of this translocation by FISH (fluorescence in situ hybridisation) or RT-PCR on tumour tissue is confirmatory of Ewing sarcoma; the translocation is the diagnostic hallmark that distinguishes it from other small round blue cell tumours

• Clinical features: pain (most common presenting symptom — typically intermittent initially, then constant); soft tissue swelling (large extraosseous mass component is characteristic of Ewing sarcoma and helps distinguish it from osteosarcoma which tends to have a smaller soft tissue component); local warmth and erythema (may mimic osteomyelitis — the `masquerader` diagnosis); systemic features — fever, malaise, elevated ESR, elevated LDH, elevated WBC; these systemic inflammatory features make Ewing sarcoma the bone tumour most commonly mistaken for osteomyelitis (this is a classic exam scenario — differentiating Ewing sarcoma from osteomyelitis); in a child with a diaphyseal bone lesion + fever + raised inflammatory markers, biopsy before treating as infection
• Plain radiographic features of Ewing sarcoma: diaphyseal location; permeative `moth-eaten` pattern of bone destruction — diffuse permeation through cancellous bone giving an indistinct margin; laminated (onion-skin) periosteal reaction — multiple concentric layers of periosteal new bone; sunburst periosteal reaction (less common but recognised); Codman`s triangle (reactive periosteum lifted by tumour); soft tissue mass (often disproportionately large compared to the bony destruction)
• MRI features: MRI is mandatory for local staging; T1 — low signal in the medullary canal; T2/STIR — high signal in the marrow (replacing normal fatty marrow signal) with an extensive extraosseous soft tissue mass of high T2 signal; the soft tissue component is often dramatic and extends well beyond the visible bony lesion; MRI of the entire bone is required to exclude skip lesions; gadolinium enhances the viable tumour periphery and heterogeneous enhancement reflects central necrosis (which may be pronounced after neoadjuvant chemotherapy)
• Staging investigations: MRI of the primary bone (entire bone); CT chest for pulmonary metastases; bone scan (Tc-99m MDP) or PET-CT for distant osseous metastases; PET-CT is increasingly preferred over bone scan for initial staging and response assessment; bilateral bone marrow trephine biopsies (to assess bone marrow metastases — present in ~20% of patients at diagnosis); LDH, FBC, CRP, ESR

• Histological response to neoadjuvant chemotherapy — the most important prognostic factor: the proportion of viable tumour cells in the resected specimen after neoadjuvant chemotherapy predicts outcome; good histological response (<10% viable tumour — equivalent to Huvos III–IV in osteosarcoma) is associated with ~70–75% event-free survival at 5 years; poor histological response (>10% viable tumour) is associated with ~25–35% event-free survival; histological response is the single most powerful predictor of survival in Ewing sarcoma
• Other prognostic factors: absence of metastases at diagnosis (the most important clinical factor — localised disease 5-year survival ~70–80% vs metastatic disease ~20–30%); tumour site — pelvis and sacral tumours have significantly worse outcomes than appendicular tumours (due to large tumour volume, proximity to critical structures, often unresectable, and delayed diagnosis); tumour size (>8 cm or >200 mL volume = poor prognosis); LDH (elevated LDH = worse prognosis); age (>15 years = worse prognosis); EWS-ERG translocation (slightly worse prognosis than EWS-FLI1)
• Pelvic Ewing sarcoma: particularly challenging; large volume at diagnosis; adjacent to rectum, bladder, iliac vessels, sacral nerve roots; surgical resection is often incomplete; RT + chemotherapy frequently used as primary local control; outcomes significantly worse than extremity tumours; 5-year survival for pelvic Ewing sarcoma approximately 40–50%

• Ewing sarcoma: most common bone sarcoma in 1st decade; 2nd most common overall; diaphyseal; flat bones (pelvis, ribs) also common; peak age 10–15 years; White patients predominantly; EWS-FLI1 fusion (85%) from t(11;22)
• Classic imaging triad: permeative (moth-eaten) medullary destruction + laminated (onion-skin) periosteal reaction + large soft tissue mass; diaphyseal location; no tumour matrix (unlike osteosarcoma)
• Ewing vs osteomyelitis: clinical mimic — both cause fever, swelling, raised ESR/WBC; distinguish by MRI (Ewing has massive extraosseous soft tissue mass) and biopsy; NEVER treat as osteomyelitis without biopsy if Ewing is suspected
• CD99 (MIC2) strongly positive: the immunohistochemical hallmark of ESFT; membranous staining; confirms diagnosis; confirm with molecular testing (FISH for EWS-FLI1 or RT-PCR)
• VIDE protocol (EuroEWING neoadjuvant): Vincristine, Ifosfamide, Doxorubicin, Etoposide; 6 cycles × 3 weeks = 18 weeks; followed by local control (surgery ± RT) then consolidation chemo; total ~12–14 months
• Radiotherapy: Ewing sarcoma is THE most radiosensitive primary bone sarcoma; RT used for axial/unresectable tumours, inadequate margins, or pelvic disease; 45–54 Gy; proton beam for axial
• Histological response: best prognostic indicator; <10% viable tumour after neoadjuvant chemo = good response → ~70–75% EFS; >10% viable = poor response → ~25–35% EFS
• Worst prognosis: metastatic disease (20–30% 5-year survival vs 70–80% localised); pelvic/sacral tumours (~40–50% 5-year); large tumour volume; elevated LDH; poor histological response; age >15 years
• Bone marrow trephines: bilateral trephine biopsies for staging (marrow metastases in ~20% at diagnosis); staging also requires PET-CT or bone scan + CT chest
• EWS-ERG translocation t(21;22): second most common (5–10%); slightly worse prognosis than EWS-FLI1; all ESFT family share EWS gene rearrangement on chromosome 22