Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 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. 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. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. For Ewing sarcoma, the 5-year survival rate has increased over the same time from 59% to 78% for children younger than 15 years and from 20% to 60% for adolescents aged 15 to 19 years. 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.
Origin and Incidence of Ewing Sarcoma
Studies using immunohistochemical markers, cytogenetics,[5,6] molecular genetics, and tissue culture  indicate that Ewing sarcoma is derived from a primordial bone marrow–derived mesenchymal stem cell.[8,9] Older terms such as primitive neuroectodermal tumor, Askin tumor (Ewing sarcoma of chest wall), and extraosseous Ewing sarcoma (often combined in the term Ewing sarcoma family of tumors) refer to this same tumor.
The incidence of Ewing sarcoma is approximately three cases per 1 million per year and has remained unchanged for 30 years. Data from the U.S. National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) registries report an overall incidence of Ewing sarcoma of one case per 1 million in the U.S. population. The incidence in patients aged 10 to 19 years is between nine and ten cases per 1 million. The same analysis suggests that the incidence of Ewing sarcoma in the United States is nine times greater in Caucasians than in African Americans.
The median age of patients with Ewing sarcoma is 15 years, and more than 50% of patients are adolescents. Well-characterized cases of Ewing sarcoma in neonates and infants have been described.[12,13] 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:
For extraosseous primary tumors, the most common primary sites of disease include the following:
The median time from first symptom to diagnosis of Ewing sarcoma is often long, with a median interval reported from 2 to 5 months. Longer times are associated with older age and pelvic primary sites. This has not been associated with metastasis, surgical outcome, or survival. Approximately 25% of patients will have metastatic disease at diagnosis.
The SEER database was used to compare patients younger than 40 years with Ewing sarcoma who presented with skeletal and extraosseous primary sites. Patients with extraosseous Ewing sarcoma were more likely to be older, female, nonwhite, and have axial primary sites and were less likely to have pelvic primary sites when compared with patients with skeletal Ewing sarcoma.
|Characteristic||Extraosseous Ewing Sarcoma||Skeletal Ewing Sarcoma||P Value|
|Mean age (range), years||20 (0–39)||16 (0–39)||<.001|
|White (nonwhite race)||85% (15%)||93% (8%)||<.001|
|Axial primary sites (non-axial primary)||73% (27%)||54% (46%)||<.001|
|Pelvic primary sites (nonpelvic primary)||20% (80%)||27% (73%)||.001|
Prognostic Factors for Ewing Sarcoma
The two major types of prognostic factors for patients with Ewing sarcoma are as follows:
- Site of tumor: 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.[19-21] Patients with tumors of the sacrum have a very poor prognosis.
- Tumor size or volume: Tumor size or volume has been shown to be an important prognostic factor in most studies. Cutoffs of a volume of 100 mL or 200 mL and/or single dimension greater than 8 cm are used to define larger tumors. Larger tumors tend to occur in unfavorable sites.[21,23]
- Age: Infants and younger patients (aged <15 years) have a better prognosis than adolescents aged 15 years or older, young adults, or adults.[13,19-21,24] In North American studies, patients younger than 10 years have a better outcome than those aged 10 to 17 years at diagnosis (relative risk [RR], 1.4). Patients older than 18 years have an inferior outcome (RR, 2.5). A retrospective review of two consecutive German trials for Ewing sarcoma identified 47 patients older than 40 years. With adequate multimodal therapy, survival was comparable to the survival observed in adolescents treated on the same trials.
- Gender: Girls with Ewing sarcoma have a better prognosis than boys.[11,20]
- Serum lactate dehydrogenase (LDH): Increased serum LDH levels before treatment are associated with inferior prognosis. Increased LDH levels are also correlated with large primary tumors and metastatic disease.
- 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. Metastases at diagnosis are detected in about 25% of patients. Patients with metastatic disease confined to lung have a better prognosis than patients with extrapulmonary metastatic sites.[19,21,27] 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. Patients with metastasis to bone only seem to have a better outcome than patients with metastases to both bone and lung. Based on an analysis from the SEER database, regional lymph node involvement in patients is associated with an inferior overall outcome when compared with patients without regional lymph node involvement.
- Prior treatment for cancer: Fifty-eight patients with Ewing sarcoma who were diagnosed after treatment for a prior malignancy (2.1% of patients with Ewing sarcoma in the SEER database) were compared with 2,756 patients in the SEER database with Ewing sarcoma as a first cancer over the same period. Patients with Ewing sarcoma as a second malignant neoplasm were older (secondary Ewing sarcoma, mean age of 47.8 years; primary Ewing sarcoma, mean age of 22.5 years), more likely to have a primary tumor in an axial or extraskeletal site, and had a worse prognosis (5-year overall survival for patients with secondary Ewing sarcoma, 43.5%; patients with primary Ewing sarcoma, 64.2%).
- 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.
- Detectable fusion transcripts in morphologically normal marrow: Reverse transcriptase 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.
Other biological factors: Overexpression of the p53 protein, Ki67 expression, and loss of 16q may be adverse prognostic factors.[34-36] High expression of microsomal glutathione S-transferase, an enzyme associated with resistance to doxorubicin, is associated with inferior outcome for Ewing sarcoma.
The Children's Oncology Group performed a prospective analysis of TP53 mutations and/or CDKN2A deletions in patients with Ewing sarcoma; no correlation was found with event-free survival.
The following are not considered to be adverse prognostic factors for Ewing sarcoma:
- Pathologic fracture: Pathologic fractures do not appear to be a prognostic factor.
- Histopathology: The degree of neural differentiation is not a prognostic factor in Ewing sarcoma.[40,41]
- Molecular pathology: The EWS-FLI1 translocation associated with Ewing sarcoma 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, two large series have shown the EWS-FLI1 translocation breakpoint site is not an adverse prognostic factor.[43,44]
Treatment response factors to preoperative therapy
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.[45-48] Female gender and younger age predict a good histologic response to preoperative therapy. For patients who receive preinduction and postinduction chemotherapy positron emission tomography (PET) scans, decreased PET uptake after chemotherapy correlated with good histologic response and better outcome.[50,51] Patients with poor response to presurgical chemotherapy have an increased risk for local recurrence.
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