General Information

Origin and Incidence of Ewing Sarcoma Family of Tumors
Prognostic Factors for Ewing Sarcoma
        Pretreatment factors
        Treatment response factors to preoperative therapy

The National Cancer Institute (NCI) provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For Ewing sarcoma, the 5-year survival rate has increased over the same time from 59% to 76% for children younger than 15 years and from 20% to 49% for adolescents aged 15 to 19 years.[1] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.

Studies using immunohistochemical markers,[3] cytogenetics,[4,5] molecular genetics, and tissue culture [6] indicate that classic Ewing sarcoma, primitive neuroectodermal tumor, and Askin tumor (chest wall), as well as extraosseous Ewing sarcoma (EOE) are all derived from the same primordial bone marrow-derived mesenchymal stem cell.[7,8] The incidence of Ewing sarcoma family of tumors (ESFTs) is approximately three per 1,000,000 per year and remained unchanged for 30 years.[9] Data from the Surveillance, Epidemiology, and End Results (SEER) registries reports an overall incidence of ESFT of one per 1,000,000 in the U.S. population. The incidence in patients aged 10 to 19 years is between nine and ten per 1,000,000. The same analysis suggests that the incidence of Ewing sarcoma is nine times greater in U.S. Caucasians than African Americans.[10]

The median age of patients with ESFT is 15 years, and more than 50% of patients are adolescents. Well-characterized cases of ESFT in neonates and infants have been described.[11,12] Based on data from 1,426 patients entered on European Intergroup Cooperative Ewing Sarcoma Studies (EI-CESS), 59% of patients are male and 41% are female. Primary sites of bone disease include the following:

• Lower extremity (41%).
• Pelvis (26%).
• Chest wall (16%).
• Upper extremity (9%).
• Spine (6%).
• Skull (2%).[13]

For EOE, the most common primary sites of disease are the following:

• Trunk (32%).
• Extremity (26%).
• Head and neck (18%).
• Retroperitoneum (16%).
• Other sites (9%).[13]

Approximately 25% of patients will have metastatic disease at diagnosis.[9]

The U.S. NCI SEER database was used to compare patients younger than 40 years with Ewing sarcoma who presented with skeletal and extraskeletal primary sites.[14] Patients with extraskeletal Ewing sarcoma were more likely to be older, female, non-white, and have axial primary sites, and they were less likely to have pelvic primary sites, compared with patients with skeletal Ewing sarcoma.

There are two major types of prognostic factors for patients with Ewing sarcoma: pretreatment factors and treatment response factors.

• Site: Patients with Ewing sarcoma in the distal extremities have the best prognosis. Patients with Ewing sarcoma in the proximal extremities have an intermediate prognosis, followed by patients with central or pelvic sites.[15-17] Patients with tumors of the sacrum have a very poor prognosis.[18]

• Size: Tumor volume has been shown to be an important prognostic factor in most studies. Cutoffs of either 100 mL or 200 mL are used to define larger tumors. Larger tumors tend to occur in unfavorable sites.[17,19]

• Age: Infants and younger patients (<15 years) have a better prognosis than adolescents aged 15 years or older, young adults, or adults.[12,15-17]

• Gender: Girls with Ewing sarcoma have a better prognosis than boys.[10,16]

• Serum lactate dehydrogenase: Increased serum lactate dehydrogenase (LDH) levels prior to treatment are associated with inferior prognosis. Increased LDH levels are also correlated with large primary tumors and metastatic disease.[16]

• Metastases: Any metastatic disease defined by standard imaging techniques or bone marrow aspirate/biopsy by morphology is an adverse prognostic factor. The presence or absence of metastatic disease is the single most powerful predictor of outcome. Patients with metastatic disease confined to lung have a better prognosis than patients with extrapulmonary metastatic sites.[15,17,20] The number of pulmonary lesions does not seem to correlate with outcome, but patients with unilateral lung involvement do better than patients with bilateral lung involvement.[21] Patients with metastasis to bone only seem to have a better outcome than patients with metastases to both bone and lung.[22] Positron emission tomography (PET) scans using fluorine-18-fluorodeoxyglucose (FDG) are under investigation as a staging tool that may provide additional information and alter therapy planning.[23] Whole body MRI may provide additional information which could potentially alter therapy planning.[24]

• Standard cytogenetics: Complex karyotype (defined as the presence of 5 or more independent chromosome abnormalities at diagnosis) and modal chromosome numbers lower than 50 appear to have adverse prognostic significance.[25]

• Detectable fusion transcripts in morphologically normal marrow: Reverse transcription polymerase chain reaction can be used to detect fusion transcripts in bone marrow. In a single retrospective study utilizing patients with normal marrow morphology and no other metastatic site, fusion transcript detection in marrow was associated with an increased risk of relapse.[26]

• Other biological factors: Overexpression of the p53 protein, Ki67 expression, and loss of 16q may be adverse prognostic factors.[27-29] High expression of microsomal glutathione S-transferase, an enzyme associated with resistance to doxorubicin, is associated with inferior outcome for Ewing sarcoma.[30]

The following are not considered to be adverse prognostic factors for ESFT:

• Pathologic fracture: Pathologic fractures do not appear to be a prognostic factor for ETB.[31]

• Histopathology: The degree of neural differentiation is not a prognostic factor in Ewing sarcoma.[32,33]

• Molecular pathology: The EWS-FL1 translocation associated with ESFT can occur at several potential breakpoints in each of the genes which join to form the novel segment of DNA. Once thought to be significant,[34] two large series have shown the EWS-FL1 translocation is not an adverse prognostic factor.[35,36]

Multiple studies have shown that patients with minimal or no residual viable tumor after presurgical chemotherapy have a significantly better event-free survival compared with patients with larger amounts of viable tumor.[21,37-39] Female gender and younger age predict a good histologic response to preoperative therapy.[40] Patients with poor response to presurgical chemotherapy have an increased risk for local recurrence.[41] For patients who receive preinduction and postinduction chemotherapy PET scans, decreased PET uptake following chemotherapy correlated with good histologic response.[42,43]

References

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