Ewing Sarcoma and Primitive Neuroectodermal Tumors 

James Ewing first described Ewing sarcoma in 1921 after observing radiosensitivity in a subgroup of bone tumors. In the early 1980s, Ewing sarcoma and the peripheral primitive neuroectodermal tumor were both 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. These tumors were categorized as the Ewing sarcoma family of tumors because of the shared translocation and the similar cellular physiology. The Ewing sarcoma family of tumors includes Ewing sarcoma, peripheral primitive neuroectodermal tumor, neuroepithelioma, atypical Ewing sarcoma, and Askin tumor (tumor of the chest wall). The tumors in the Ewing sarcoma family are treated similarly on the basis of their clinical presentation (eg, metastatic or localized) rather than their histologic subtype.

Tumors in the Ewing sarcoma family are thought to derive from cells of the neural crest, possibly postganglionic cholinergic neurons. The exact cell of origin of the Ewing sarcoma family of tumors is unknown. Research is ongoing to further characterize the biology of the EWS-FLI1 fusion protein and its role in transformation, cell growth, and chemosensitivity. The focus of most research is the fusion protein generated from t(11;22).

Translocation t(11;22) or one of a series of related translocations occurs in more than 95% of the Ewing sarcoma family of tumors. Some argue that, without a translocation, the tumor does not belong to the Ewing sarcoma family. 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]). The EWS-FLI1 fusion transcript encodes a 68-kDa 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. EWS-FLI1 transforms mouse fibroblasts, and this transformation requires both the EWS and the FLI1 functional domains to be intact. Therefore, the EWS-FLI1 fusion protein is implicated in the pathogenesis of the Ewing sarcoma family of tumors. However, no data regarding the cause of the translocation are available. Downstream targets that are responsible for EWS-FLI1 transformation are currently under study.

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 is EWS exon 7 fused to FLI1 exon 6 (type 1 translocation), which occurs in approximately 50-64% of tumors of the Ewing sarcoma family. Retrospective analyses showed that patients who have localized tumors with the 7/6 fusion have a 4-year survival rate of 70%, whereas patients with the other variants have a 4-year survival rate of 20%. This difference may, at least in part, be due to different potencies among the variants in their ability to activate gene transcription.

Frequency

United States

The annual incidence of Ewing sarcoma family tumors from birth to age 20 years is 2.9 cases per million population. Approximately 10% of patients are aged 20-30 years. Cases occurring later than this are infrequent.

Mortality/Morbidity

The survival of patients with Ewing sarcoma family tumors highly depends 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 survival rate is 60%; however, for patients with localized disease, the survival rate approaches 70%. Patients with metastatic disease have a long-term survival rate of less than 25%.

Race

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

Sex

The incidence of Ewing sarcoma family tumors in female individuals is 2.6 cases per million population. The incidence in male individuals is 3.3 cases per million population.

Age

Incidence 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 of life, and 9% of cases occur in the third decade of life.