National Cancer Institute
Last Modified: November 26, 2012
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 Ewing sarcoma is derived from a primordial bone marrowderived mesenchymal stem cell. 7 8 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. 9 Data from the 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. 10
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. 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:
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 extraosseous primary sites. 14 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|
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. 38 39 40 41 Female gender and younger age predict a good histologic response to preoperative therapy. 42 For patients who receive preinduction and postinduction chemotherapy positron emission tomography (PET) scans, decreased PET uptake following chemotherapy correlated with good histologic response and better outcome. 43 44 Patients with poor response to presurgical chemotherapy have an increased risk for local recurrence. 45
Ewing sarcoma belongs to the group of neoplasms commonly referred to as small, round, blue-cell tumors of childhood. The individual cells of Ewing sarcoma contain round-to-oval nuclei with fine dispersed chromatin without nucleoli. Occasionally, cells with smaller, more hyperchromatic, and probably degenerative nuclei are present, giving a light cell/dark cell pattern. The cytoplasm varies in amount, but in the classic case, it is clear and contains glycogen, which can be highlighted with a periodic acid-Schiff stain. The tumor cells are tightly packed and grow in a diffuse pattern without evidence of structural organization. Tumors with the requisite translocation that show neuronal differentiation are not considered a separate entity, but rather, part of a continuum of differentiation.
The MIC2 gene product, CD99, is a surface membrane protein that is expressed in most cases of Ewing sarcoma and is useful in suggesting diagnosis of these tumors when the results are interpreted in the context of clinical and pathologic parameters. 1 MIC2 positivity is not unique to Ewing sarcoma, and positivity by immunochemistry is found in several other tumors including synovial sarcoma, non-Hodgkin lymphoma, and gastrointestinal stromal tumors. The detection of a translocation involving the EWSR1 gene on chromosome 22 band q12 and any one of a number of partner chromosomes is the key feature in the diagnosis of Ewing sarcoma. 2
Cytogenetic studies of Ewing sarcoma have identified a consistent alteration of the EWSR1 locus (a member of the TET family [TLS/EWS/TAF15] of RNA binding proteins) on chromosome 22 band q12 that may involve other chromosomes, including 11 or 21. 3 Characteristically, the amino terminus of the EWSR1 gene is juxtaposed with the carboxy terminus of another gene. In most cases (90%), the carboxy terminus is provided by FLI1, a member of the Ets family of transcription factor genes located on chromosome 11 band q24. Other Ets family members that may combine with the EWSR1 gene in order of frequency are ERG, located on chromosome 21; ETV1, located on chromosome 7; and E1AF, located on chromosome 17; these result in the following translocations: t(21;22), 4 t(7;22), and t(17;22), respectively. Rarely, other TET family members can substitute for EWS. 5 Besides these consistent aberrations involving the EWSR1 gene at 22q12, additional numerical and structural aberrations have been observed in Ewing sarcoma, including gains of chromosomes 2, 5, 8, 9, 12, and 15; the nonreciprocal translocation t(1;16)(q12;q11.2); and deletions on the short arm of chromosome 6. Trisomy 20 may be associated with a more aggressive subset of Ewing sarcoma tumors. 6
A molecular test (i.e., reverse transcriptase polymerase chain reaction [PCR] and restriction analysis of PCR products), currently available on a research basis only, now offers the opportunity to markedly simplify the definition of Ewing sarcoma. 7 8 The molecular assay can be performed on relatively small amounts of tissue obtained by minimally invasive biopsies and is capable of providing results faster than cytogenetic analysis.
For patients with confirmed Ewing sarcoma, pretreatment staging studies should include magnetic resonance imaging (MRI) and/or computed tomography (CT) scan, depending on the primary site. Despite the fact that CT and MRI are both equivalent in terms of staging, use of both imaging modalities may help radiation therapy planning. 1 Whole-body MRI may provide additional information that could potentially alter therapy planning. 2 Additional pretreatment staging studies should include bone scan, CT scan of the chest, and bone marrow aspiration and biopsy. A staging modality under evaluation but not required on current clinical trials is molecular analysis of bone marrow for the presence of fusion transcript. In certain studies, determination of pretreatment tumor volume is an important variable.
Although positron emission tomography using fluorodeoxyglucose (FDG-PET) or FDG-PET/CT are optional staging modalities, they have demonstrated high sensitivity and specificity in Ewing sarcoma and may provide additional information that alters therapy planning. FDG-PET/CT is more accurate than FDG-PET alone in Ewing sarcoma. 3 4 5
For Ewing sarcoma, the tumor is defined as localized when, by clinical and imaging techniques, there is no spread beyond the primary site or regional lymph node involvement. Continuous extension into adjacent soft tissue may occur. If there is a question of regional lymph node involvement, an excisional biopsy should be performed.
Patients should be evaluated by specialists from the appropriate disciplines (e.g., radiologist, chemotherapist, pathologist, surgical or orthopedic oncologist, and radiation oncologist) as early as possible. Appropriate imaging studies of the site should be obtained prior to biopsy. The surgical or orthopedic oncologist who will perform the definitive surgery should be involved prior to or during the biopsy so that the incision can be placed in an acceptable location. This is especially important if it is thought that the lesion can be totally excised or if a limb salvage procedure may be attempted. Biopsy should be from soft tissue as often as possible to avoid increasing the risk of fracture. 1 The radiation oncologist and pathologist should be consulted prior to biopsy/surgery in order to be sure that the incision will not compromise the radiation port and so that multiple types of tissue samples are obtained. It is important to obtain fresh tissue, whenever possible, for cytogenetics and molecular pathology. A second option is to perform a needle biopsy as long as adequate tissue for molecular biology and cytogenetics is obtained. 2
The successful treatment of patients with Ewing sarcoma requires systemic chemotherapy 3 4 5 6 7 8 9 in conjunction with either surgery or radiation therapy or both modalities for local tumor control. 10 11 12 13 14 In general, patients receive preoperative chemotherapy prior to instituting local control measures. In patients who undergo surgery, surgical margins and histologic response are considered in planning postoperative therapy. Most patients with metastatic disease have a good initial response to preoperative chemotherapy; however, in most cases, the disease is only partially controlled or recurs. 15 16 17 18 Patients with lung as the sole metastatic site have a better prognosis than patients with metastases to bone and/or bone marrow. Adequate local control for metastatic sites, particularly bone metastases, may be an important issue.
Multidrug chemotherapy for Ewing sarcoma always includes vincristine, doxorubicin, ifosfamide, and etoposide. Most protocols use cyclophosphamide as well. Certain protocols incorporate dactinomycin. The mode of administration and dose intensity of cyclophosphamide within courses differs markedly between protocols. A European Intergroup Cooperative Ewing Sarcoma Study (EICESS) trial suggested that 1.2 grams of cyclophosphamide produced a similar event-free survival (EFS) compared with 6 grams of ifosfamide in patients with lower-risk disease, and identified a trend toward better EFS for patients with localized Ewing sarcoma and higher-risk disease when treatment included etoposide (GER-GPOH-EICESS-92). 19[Level of evidence: 1iiA] Protocols in the United States generally alternate courses of vincristine, cyclophosphamide, and doxorubicin with courses of ifosfamide/etoposide, 7 while European protocols generally combine vincristine, doxorubicin, and an alkylating agent with or without etoposide in a single treatment cycle. 9
The duration of primary chemotherapy ranges from 6 months to approximately 1 year. A randomized clinical trial (COG-AEWS0031 [NCT00006734]) from the Children's Oncology Group showed that for patients presenting without metastases, the administration of cycles of cyclophosphamide, doxorubicin, and vincristine alternating with cycles of ifosfamide and etoposide at 2-week intervals achieved superior EFS (5-year EFS, 73%) than alternating cycles at 3-week intervals (5-year EFS, 65%). 20
Treatment approaches for Ewing sarcoma titrate therapeutic aggressiveness with the goal of maximizing local control while minimizing morbidity.
While surgery is effective and appropriate for patients who can undergo complete resection with acceptable morbidity, children who have unresectable tumors or who would suffer loss of function are treated with radiation therapy alone. Those who undergo gross resections with microscopic residual disease may benefit from adjuvant radiation therapy. Randomized trials that directly compare both modalities do not exist, and their relative roles remain controversial. Although retrospective institutional series suggest superior local control and survival with surgery rather than radiation therapy, most of these studies are compromised by selection bias. Data for patients with pelvic primary Ewing sarcoma from a North American intergroup trial showed no difference in local control or survival based on local-control modalitysurgery alone, radiation therapy alone, or radiation plus surgery. 21
For patients who undergo gross total resection with microscopic residual disease, the value of adjuvant radiation therapy is controversial. Investigations addressing this issue are retrospective and nonrandomized, limiting their value. Investigators from St. Jude Children's Research Hospital reported 39 patients with localized Ewing sarcoma who received both surgery and radiation. Local failure for patients with positive and negative margins was 17% and 5%, respectively, and overall survival (OS) was 71% and 94%, respectively. 13 However, in a large retrospective Italian study, 45 Gy adjuvant radiation therapy for patients with inadequate margins did not appear to improve either local control or disease-free survival. 14 It is not known whether higher doses of radiation therapy could improve outcome. These investigators concluded that patients who are anticipated to have suboptimal surgery should be considered for definitive radiation therapy.
Thus, surgery is chosen as definitive local therapy for suitable patients, but radiation therapy is appropriate for patients with unresectable disease or those who would experience functional compromise by definitive surgery. The possibility of impaired function needs to be measured against the possibility of second tumors in the radiation field (see below). Adjuvant radiation therapy should be considered for patients with residual microscopic disease, inadequate margins, or who have viable tumor in the resected specimen and close margins.
When preoperative assessment has suggested a high probability that surgical margins will be close or positive, preoperative radiation therapy has achieved tumor shrinkage and allowed surgical resection with clear margins. 22
For patients with a high risk of relapse with conventional treatments, certain investigators have utilized high-dose chemotherapy with hematopoietic stem cell transplant (HSCT) as consolidation treatment, in an effort to improve outcome. 23 24 25 26 27 28 29 30 31 32 In a prospective study, patients with bone and/or bone marrow metastases at diagnosis were treated with aggressive chemotherapy, surgery, and/or radiation and HSCT if a good initial response was achieved. The study showed no benefit for HSCT compared with historical controls. 28 A retrospective review using international bone marrow transplant registries compared outcome after treatment with reduced-intensity conditioning to high-intensity conditioning followed by allogeneic stem cell transplant for patients with Ewing sarcoma at high risk for relapse. 33[Level of evidence: 3iiiA] There was no difference in outcome and the authors concluded that this suggested the absence of a clinically relevant graft-versus-tumor effect against Ewing sarcoma tumor cells with current approaches. Multiple small studies that report benefit for HSCT have been published but are difficult to interpret because only patients who have a good initial response to standard chemotherapy are considered for HSCT. The role of high-dose therapy followed by stem cell rescue is being investigated in a Euro-Ewing clinical trial (EURO-EWING-INTERGROUP-EE99) for patients that present with pulmonary metastases.
Extraosseous Ewing sarcoma is biologically similar to Ewing sarcoma arising in bone. Until recently, most children and young adults with extraosseous Ewing sarcoma were treated on protocols designed for the treatment of rhabdomyosarcoma. This is important because many of the treatment regimens for rhabdomyosarcoma do not include an anthracycline, which is a critical component of current treatment regimens for Ewing sarcoma. Currently, patients with extraosseous Ewing sarcoma are eligible for studies that include Ewing sarcoma of bone.
From 1987 to 2004, 111 patients with nonmetastatic extraosseous Ewing sarcoma were enrolled on the RMS-88 and RMS-96 protocols. 52 Patients with initial complete tumor resection received ifosfamide, vincristine, and actinomycin (IVA) while patients with residual tumor received IVA plus doxorubicin (VAIA) or IVA plus carboplatin, epirubicin, and etoposide (CEVAIE). Seventy-six percent of patients received radiation. The 5-year EFS and OS were 59% and 69%, respectively. In a multivariate analysis, independent adverse prognostic factors included axial primary, tumor size greater than 10 cm, Intergroup Rhabdomyosarcoma Studies Group III, and lack of radiation therapy.
Two hundred thirty-six patients with extraosseous Ewing sarcoma were entered on studies of the German Pediatric Oncology Group. 53 The median age at diagnosis was 15 years and 133 patients were male. Primary tumor site was either extremity (n = 62) or central site (n = 174). Sixty of 236 patients had metastases at diagnosis. Chemotherapy consisted of vincristine, doxorubicin, cyclophosphamide, and actinomycin (VACA); CEVAIE; or vincristine, ifosfamide, doxorubicin, and etoposide (VIDE). The 5-year EFS and OS were 49% and 60%, respectively. Five-year survival was 70% for patients with localized disease and 33% for patients with metastasis at diagnosis. OS in patients with localized disease did not seem related to tumor site or size. In a retrospective French study, patients with extraosseous Ewing sarcoma were treated using a rhabdomyosarcoma regimen (no anthracyclines) or a Ewing sarcoma regimen (includes anthracyclines). Patients receiving the anthracycline-containing regimen had a significantly better EFS and OS compared with patients receiving no anthracyclines. 54 55
Cutaneous Ewing sarcoma is a soft tissue tumor in the skin or subcutaneous tissue that seems to behave as a less-aggressive tumor than primary bone or soft tissue Ewing sarcoma. Tumors can form throughout the body, although the extremity is the most common site, and they are almost always localized. In a review of 78 reported cases, some lacking molecular confirmation, the OS was 91%. Adequate local control, defined as a complete resection with negative margins, radiation therapy, or a combination, significantly reduced the incidence of relapse. Standard chemotherapy for Ewing sarcoma should be used for these patients because there are no data to suggest which patients could be treated less aggressively. 56 57
Patients treated for Ewing sarcoma have a significantly higher risk of developing subsequent neoplasms than patients in the general population.
Treatment-related acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have generally been reported to occur in 1% to 2% of survivors of Ewing sarcoma, 58; 59[Level of evidence: 3iiiDi] although some dose-intensive regimens appear to be associated with a higher risk of hematological malignancy. 60 61; 62[Level of evidence: 3ii] Treatment-related AML and MDS arise most commonly at 2 to 5 years following diagnosis.
Survivors of Ewing sarcoma remain at increased risk of developing a subsequent solid tumor throughout their lifetime. Sarcomas usually occur within the prior radiation field. 63 64 The risk of developing a sarcoma following radiation therapy is dose-dependent, with higher doses associated with an increased risk of sarcoma development. 58; 59[Level of evidence: 3iiiDi] The cumulative incidence of subsequent neoplasms in children treated for Ewing sarcoma between 1970 and 1986 at 25 years after diagnosis was 9.0% (confidence interval, 5.812.2). Most of these patients received radiation therapy; comparable long-term data do not yet exist for significant numbers of patients who did not receive radiation therapy. 65
(Refer to the PDQ® summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)