Ewing Sarcoma

Updated: Sep 12, 2016
  • Author: Jeffrey A Toretsky, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP  more...
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Overview

Practice Essentials

Ewing sarcoma tumors include Ewing sarcoma, Askin tumor, and peripheral primitive neuroectodermal tumors. These tumors have a similar cellular physiology, as well as a shared chromosomal translocation. In the early 1980s, Ewing sarcoma and the peripheral primitive neuroectodermal tumor were found to contain the same reciprocal translocation between chromosomes 11 and 22, t(11;22). Later that decade, similar patterns of biochemical and oncogene expression were observed. (See Etiology.)

In any individual patient, t(11;22) fuses one of many observed combinations of exons from EWS and FLI1 to form the fusion message. The most common combination— EWS exon 7 fused to FLI1 exon 6 (type 1 translocation)—occurs in approximately 50-64% of tumors of Ewing sarcomas. Data currently do not support outcome differences based on translocation exon combination when patients are prospectively evaluated. [1, 2]

See the image below.

Radiograph of an 11-year-old boy with a large Ewin Radiograph of an 11-year-old boy with a large Ewing sarcoma in the right pelvic area. Destruction of the bone structure resulted from tumor involvement.

Signs and symptoms

Signs and symptoms of Ewing sarcoma may include the following:

  • Localized pain
  • Back pain, which may indicate a paraspinal, retroperitoneal, or deep pelvic tumor
  • Palpable mass
  • Systemic symptoms of fever and weight loss, which often indicate metastatic disease

Examination for Ewing sarcoma includes the following:

  • Careful inspection and palpation of painful sites, as tumors of Ewing sarcoma can occur in almost any location; lesions of the long bones can present with a pathologic fracture
  • Comprehensive neurologic examination to evaluate asymmetrical weakness, numbness, or pain; tumors close to bone can result in neuropathic pain
  • Skin inspection for petechiae or purpura that may be caused by thrombocytopenia due to clinically significant bone marrow metastases
  • Pulmonary auscultation for asymmetrical breath sounds, pleural signs, or rales that may indicate lung metastases

See Clinical Presentation for more specific information on the signs, symptoms, patient history, and physical examination for Ewing sarcoma.

Diagnosis

Testing

No specific blood tests are diagnostic for Ewing sarcoma. However, the following studies may be useful in identifying or excluding other disorders:

  • Complete blood count
  • Blood cultures
  • C-reactive protein levels
  • Erythrocyte sedimentation rate
  • Lactate dehydrogenase [3]
  • Cytogenetic and molecular studies [4]
  • Histology
  • Imaging of the suspected primary lesion or of any region with symptoms
  • Plain radiography in areas where a bony mass is palpated
  • Magnetic resonance imaging
  • Computed tomography

If metastasis is suspected, the following studies are important for evaluation of the tumor extent and for distant metastases:

  • Bilateral bone marrow biopsies
  • Chest CT scanning
  • Radioisotopic bone scanning
  • Whole-body MRI
  • Fluorodeoxyglucose positron emission tomography (FDG-PET) scanning

See Workup for more specific information on testing and imaging modalities for Ewing sarcoma.

Management

Treatment for Ewing sarcoma includes the following:

  • Chemotherapy with alternating courses of 2 regimens: (1) vincristine, doxorubicin, and cyclophosphamide; and (2) ifosfamide and etoposide [5]
  • Neutrophil support
  • Red blood cell and platelet support
  • Surgery and/or radiotherapy

See Treatment and Medication for more specific information regarding pharmacologic and other therapies for Ewing sarcoma.

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Etiology

Ewing sarcomas are thought to derive from cells of the neural crest, possibly mesenchymal stem cells, via a pathway that might include postganglionic cholinergic neurons. However, the exact cell of origin of the Ewing sarcomas is unknown.

Translocation of EWSR1 (Ewing sarcoma breakpoint region 1) with an ETS (E26 transformation-specific) transcription factor gene occurs in more than 95% of Ewing sarcomas. (Some argue that without a translocation, the tumor does not belong to Ewing sarcoma). The most common translocation seen in about 85% of all Ewing tumor is the t(11;22) translocation. This translocation joins the Ewing sarcoma gene EWS on chromosome 22 to a gene of the ETS family, friend leukemia insertion (FLI1), on chromosome 11 (ie, t[11;22]). Alternative translocations include EWS-ERG t(21;22), EWS-ETV t(7;22), and EWS-FEV t(2;22), all of which involve the ETS family protein. Recently, approximately 4% of Ewing sarcoma were identified as having an intrachromosomal X-fusion leading to BCOR (encoding the BCL6co-repressor) and CCNB3 (encoding the testis-specific cyclin B3). [6]

No data regarding the cause of the chromosomal translocation are available. Downstream targets and protein partners responsible for EWS-FLI1 transformation of cells are numerous; however, any one of these downstream pathways is neither adequate to create a Ewing sarcoma nor is its inhibition adequate to lead to Ewing sarcoma cell death. [7]

Fusion protein

The EWS-FLI1 fusion transcript encodes a 68-kd protein with 2 primary domains. The EWS domain is a potent transcriptional activator, whereas the FLI1 domain contains a highly conserved ETS DNA-binding domain. The EWS-FLI1 fusion protein thus acts as an aberrant transcription factor and has been found to transform mouse fibroblasts if both the EWS and the FLI1 functional domains are intact. The protein has consequently been implicated in the pathogenesis of Ewing sarcoma.

EWS-FLI1 remains the singular most direct target to eliminating Ewing sarcoma tumor cells. A small molecule that binds to EWS-FLI1, YK-4-279, blocks its interaction with a key partner protein, RNA Helicase A (RHA), leading to apoptotic cell death. [8] Other approaches to target EWS-FLI1 have been developed by functional screening assays. While agents identified from these assays may lead to Ewing sarcoma cell death, evidence is inadequate to describe the agents as directly targeting the activity of EWS-FLI1. [9] This distinction is important when considering the potential of nonspecific toxicities and off-target effects of novel agents.

Causes

The cause of tumors in Ewing sarcoma is unknown. Cases are thought to be sporadic, although it has been found that relatives of patients with Ewing sarcoma have an increased incidence of neuroectodermal and stomach malignancies. In rare cases, Ewing sarcomas have been reported as a second malignancy, being found after a patient has been treated for another neoplasm.

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Epidemiology

Occurrence in the United States

The overall annual incidence of Ewing sarcoma is approximately 1 case per 1 million per year in the United States. The incidence from birth to age 20 years is 2.9 cases per million population. Approximately half of all patients are aged 10-20 years at the time of first diagnosis, making this the second most common primarily malignant bone tumor in children and adolescents. Cases have been reported from birth through 80 years, although very infrequently.

Race-, sex-, and age-related demographics

The incidence of these tumors in whites is at least 9 times higher than it is in blacks. This finding contrasts with that observed in osteosarcoma, which has a relatively equal racial distribution. African countries report similar incidences, with a paucity Ewing sarcoma.

The incidence of Ewing sarcoma in females is 2.6 cases per million population, compared with 3.3 cases per million population in males.

The incidence of these tumors peaks in the late teenage years. Overall, 27% of cases occur in the first decade of life, 64% of cases occur in the second decade, and 9% of cases occur in the third decade.

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Prognosis

The most significant factor currently known to determine the prognosis in patients with Ewing sarcoma is the presence or absence of metastatic disease. Primary site of the tumor also is a prognostic factor, with distal extremities being more favorable than those with central or pelvic sites. [10] Age younger than 15 years also seems to be a more favorable prognosis. [10, 11]

Treatment complications

Complications of chemotherapy can include the following:

  • Vincristine - Primarily causes neuropathy, including constipation, myalgias, arthralgias, and cholestasis
  • Doxorubicin - Causes myocardial dysfunction and pancytopenia
  • Cyclophosphamide - Causes pancytopenia and a dosage-dependent hemorrhagic cystitis
  • Ifosfamide - Similar to cyclophosphamide, although it is associated with an increased incidence of hemorrhagic cystitis, which requires the use of mesna; patients near the end of therapy occasionally develop the Fanconi syndrome of electrolyte wasting.
  • Etoposide - Can result in pancytopenia, as well as anaphylactic reactions, and it is implicated in the development of second malignancies, particularly acute myelogenous leukemia
  • Combination chemotherapy - Results, in general, in alopecia, nausea, vomiting, and occasionally diarrhea; increased risk of infection from immune suppression; the nutritional and psychological status of patients undergoing this therapy must be closely monitored; effects of chemotherapy such as organ damage, infertility, and risk of secondary malignancy

Surgical complications generally include infection and bleeding. Specific complications are related to the site of the operation and to the patient's overall condition at the time of surgery.

Similarly, the complications of radiation therapy are a direct result of the sites of radiation. Patients who receive large pelvic doses of radiation often have increased problems with pancytopenia, malnutrition, and diarrhea. In addition, radiation increases the likelihood of second malignancies, particularly in the radiation field.

Mortality

The survival of patients with Ewing sarcoma depends highly on the initial manifestation of the disease. Approximately 80% of patients present with localized disease, whereas 20% present with clinically detectable metastatic disease, most often to the lungs, bone, and/or bone marrow. The overall patient survival rate is 60%; for patients with localized disease, however, the survival rate approaches 70%. Patients with metastatic disease have a long-term survival rate of less than 25%.

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Patient Education

For the patient, education includes age- and developmentally appropriate information about his or her disease, its therapy, and its prognosis. Education also includes information about expected complications, particularly fever and its management. (See Prognosis, Treatment, and Medication.)

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