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 metadiaphysis of long bones (~50%) femur tibia humerus pelvis (~25%) scapula 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 found in 85-95% of cases leads to the formation of a fusion protein (EWS-FLI1) can be identified with PCR/FISH and useful to differentiate Ewing sarcoma from other round cell lesions 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 acute myeloid leukemia myelodysplastic syndrome solid secondary tumors sarcoma carcinoma 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 occur in 10% of cases findings will show very "hot" lesion MRI indications used to identify: soft-tissue extension marrow involvement relationship of lesion to adjacent neurovascular structures 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 useful for staging and detecting macrometastases 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 CD99 (in 95%) MIC2 CD45 vimentin PAS positive (intracellular glycogen) neuron specific enolase (NSE) S100 Leu7 (CD57) negative cytokeratin reticulin (positive in lymphoma) neurofilament (positive in neuroblastoma) myoglobin (positive in embryonal rhabdomyosarcoma) see complete immunostaining chart 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 non-resectable tumors (e.g. large spinal/pelvic tumors) sites where functional deficit is unacceptable outcomes higher rates of local recurrence (35%) without surgical resection (5-10%) high rates of radiation related complications (>60%) limb-length discrepancies, joint contracture, muscle atrophy, pathologic fracture, secondary malignancy trend is towards surgical resection and away from radiation therapy because of associated morbidity Operative chemotherapy + surgical resection ± adjuvant radiation indications standard of care in most patients where primary tumor can be completely removed (expendable and surgically reconstructible sites) techniques chemotherapy neoadjuvant (8-12 weeks) + adjuvant (6-12 months) surgical resection goal is to obtain local control and prevent late recurrence of chemoresistant cells when wide margins are obtained, 5-year survival rates are improved adjuvant radiation not necessary if margins are adequate and there is good response to chemotherapy indications positive post-resection surgical margins patients who present with widely metastatic disease all patients with pulmonary metastases should undergo radiation where chemotherapeutic response has been poor outcomes 5-year survival rate of 39% and 82% in those with and without metastases at diagnosis, respectively 10-year survival rate of 32% and 63% in those with and without metastases at diagnosis, respectively Techniques Chemotherapy technique standard regimen includes vincristine, doxorubicin, cyclophosphamide some studies have suggested addition of ifosfamide and etoposide improve survival and decrease failure rates neoadjuvant chemotherapy for 8-12 weeks followed by surgical resection neoadjuvant therapy helps to eradicate micrometastases and reduce size of primary tumor 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 5-year survival improves by over 10% with negative margins if positive margins identified, re-resection should be performed +/- radiation therapy technique vascularized and nonvascularized autograft reconstruction fibular, scapula, iliac crest, rib, clavicle allograft reconstruction allograft-prosthetic composites endoprosthetic reconstruction rotationplasty complications failure to maintain functional limb recurrence of disease amputation more likely in following cases: extremely large tumors involving vital structures (nerves/vessels) unmanageable/displaced pathologic fractures lesion of foot/ankle difficult to obtain negative margins and maintain functional limb Complications Secondary neoplasms bone sarcoma incidence previously described as 20% at 20 years risk factors prior radiation therapy sarcoma arises in prior radiation treatment field thought to be dose dependent <60 Gy confers <5% risk treatment wide resection +/- chemotherapy/radiation hematologic malignancy (acute myeloid leukemia/myelodysplasia) incidence 1-2% of survivors affected arises 2-5 years following diagnosis most commonly risk factors prior chemotherapy dose-intensive regimens may increase risk treatment chemotherapy, stem-cell transplantation, targeted drug therapy 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 <10% 5-year survival rate 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 30% cure rate for lung mets alone 20% cure rate for bone mets alone <15% cure rate for combined bone and lung mets 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