summary Ewing's Sarcoma is a malignant, distinctive small round cell sarcoma associated with a t(11:22) translocation which most commonly occurs in the diaphysis of long bones in patients <25 with regional pain, swelling and fevers. Diagnosis is made with a biopsy showing sheets of monotonous small round blue cells with prominent nuclei and minimal cytoplasm and immunostaining positive for CD99. Treatment is usually neo-adjuvant chemotherapy and limb salvage surgical resection, followed by adjuvant chemotherapy +/- radiation. Epidemiology Incidence 3/1,000,000 (rare) second most common primary malignant bone tumor in children accounts for 3% of all pediatric malignancies and 10% of all primary malignant bone tumors Demographics male:female ratio = 1.5:1 5-25 years of age most common 80-90% of patients are <20 years of age with peak incidence between 10-15 years old uncommon in African Americans and Asian populations Location bone split evenly between axial skeleton and long bones of appendicular skeleton login to view 6 more bullets soft tissue rare Etiology Pathophysiology cell biology cell of origin in Ewing's Sarcoma unknown, however, thought to be of neuroectodermal origin Genetics mutations t(11:22) translocation login to view 3 more bullets less common translocations including t(21:22) with fusion protein EWS-ERG comprise remaining 10-15% Associated conditions metastatic disease lungs (50%), bone (25%), bone marrow (20%) are common sites 26-28% present with distant macrometastases secondary malignant neoplasm secondary to treatment with chemotherapy +/- radiation hematologic secondary malignancy login to view 2 more bullets solid secondary tumors login to view 2 more bullets Classification Staging almost all tumors are MSTS stage IIB or III (see table below) presence of macrometastases has prognostic significance MSTS staging MSTS Staging for Malignant tumors Stage Grade Site Metastasis IA Low Grade T1 - intracompartmental M0 (none) IB Low Grade T2 - extracompartmental M0 (none) IIA High Grade T1 - intracompartmental M0 (none) IIB High Grade T2 - extracompartmental M0 (none) III Metastatic T1 or T2 - intra or extra-compartmental M1 (regional or distant) Presentation History >50% have symptoms for over 6 months before diagnosis delayed diagnosis more common in pelvis, axial skeleton Symptoms pain most common presenting symptom often worsens at night swelling, erythema often mimics an infection mass may not be palpable until it is quite large fever (25%) weight loss Physical exam inspection swelling local tenderness motion limp and decreased range of motion possible depending on location of tumor Imaging Radiographs recommended views AP and lateral of affected and surrounding areas findings large destructive lesion in the diaphysis or metaphysis with an ill-defined, permeative, moth-eaten appearance lesion may be purely lytic or have variable amounts of reactive new bone formation periosteal reaction may give an "onion skin" or "sunburst" appearance large, associated soft tissue mass appreciated in >80% of cases Bone scan indications used as part of staging workup to detect skip or distant metastases login to view 1 more bullet findings will show very "hot" lesion MRI indications used to identify: login to view 3 more bullets can be used to assess response to neoadjuvant chemotherapy and radiation findings defines local extent of tumor demonstrates large soft tissue component T1: low to intermediate signal T1 w/ contrast: prominent enhancement with heterogeneity T2: high signal w/ heterogeneity CT chest indications required as initial staging workup to look for pulmonary metastasis login to view 1 more bullet Studies Labs ESR is elevated WBC is elevated anemia is common lactic dehydrogenase (LDH) is elevated Tissue biopsy/histology gross appearance gray/white with variable amount of necrosis, hemorrhage or cyst formation may have liquid consistency mimicking pus findings sheets of monotonous small round blue cells high nuclei: cytoplasm ratio may have pseudo-rosettes (circle of cells with necrosis in center) immunostaining positive login to view 8 more bullets negative login to view 5 more bullets Bone marrow biopsy required as part of workup for Ewing's to rule out metastasis to the marrow Differential Small-round-cell tumor differential (by age) < 5 yrs: neuroblastoma or leukemia 5-10 yrs: eosinophilic granuloma 5-30 yrs: ewing's sarcoma >30 yrs: lymphoma > 50 yrs: myeloma Osteosarcoma Osteomyelitis Differential of Ewing's Sarcoma Destructive lesion in young patients Small round cell tumors Treatment is Wide Resection & Chemotherapy Ewing's Sarcoma o o o Osteosarcoma o o Lymphoma o o Leukemia o o Eosinophilic Granuloma o o Osteomyelitis o Desmoplastic fibroma o Metastatic disease Neuroblastoma (soft tissue) o Rhabdomyosarcoma (soft tissue) Secondary Sarcoma Dediff. Chondrosarcoma o MFH/Fibrosarcoma Multiple Myeloma o Treatment Nonoperative chemotherapy + radiation therapy indications login to view 2 more bullets outcomes login to view 4 more bullets Operative chemotherapy + surgical resection ± adjuvant radiation login to view 19 more bullets Techniques Chemotherapy technique standard regimen includes vincristine, doxorubicin, cyclophosphamide login to view 1 more bullet neoadjuvant chemotherapy for 8-12 weeks followed by surgical resection login to view 1 more bullet adjuvant chemotherapy for 6-12 months after resection modes of administration and dose intensity vary between protocols Radiation therapy technique radiation field should include pretreatment tumor volume plus a 2-3 cm margin dose is 56-60 Gy no difference in standard fractionation (5 days a week) vs. hyperfractionation (twice daily at lower dose) Surgical resection limb salvage must obtain negative surgical margins login to view 2 more bullets technique login to view 6 more bullets complications login to view 2 more bullets amputation more likely in following cases: login to view 4 more bullets Complications Secondary neoplasms bone sarcoma incidence login to view 1 more bullet risk factors login to view 4 more bullets treatment login to view 1 more bullet hematologic malignancy (acute myeloid leukemia/myelodysplasia) incidence login to view 2 more bullets risk factors login to view 2 more bullets treatment login to view 1 more bullet Recurrence/progression incidence ~20% rate in those without metastases at initial presentation and >60% rate in those with metastases at initial presentation risk factors (see prognosis) treatment extremely poor prognosis after recurrence login to view 1 more bullet options are limited but may attempt radiation, further radical resection or additional chemotherapy agents Metastases incidence 26-28% have macrometastases on presentation (lungs, bone, bone marrow) treatment cure rates with chemotherapy login to view 3 more bullets Radiation therapy complications incidence >60% of patients undergoing radiation have some complication complications limb length discrepancy (especially in skeletally immature) joint contracture muscle atrophy secondary sarcoma pathologic fracture Venous thromboembolism high rate of venous thromboembolic events in patients with sarcoma tumor activation of factor X to factor Xa Prognosis Survival 5 yr survival 65-82% for localized disease 25-40% for metastatic disease 10 yr survival 60-65% for localized disease 30-35% for metastatic disease Poor prognostic factors metastases (most important prognostic indicator) lung metastases better prognosis than bone/bone marrow mets skip metastases (same bone) better prognosis than metastases to another site amount of bone marrow involvement tumor size/location tumors greater than >8cm in size spine and pelvic tumors (worst) > proximal extremities > distal extremities (best prognosis) age and gender older age (>14) worse prognosis male worse prognosis chemotherapy response < 90% tumor necrosis with chemotherapy laboratory parameters elevated lactic dehydrogenase levels (>200 IU/L) indicates large tumors/metastatic disease anemia and elevated WBC indicates extensive disease molecular pathology p53 mutation in addition to t(11:22) translocation overexpression of cell proliferation antigen Ki-67 overexpression of HER-2/neu