Clinical Pearls & Morning Reports
Published January 13, 2021
An aggressive bone and soft-tissue cancer, Ewing’s sarcoma arises predominantly in children and young adults, with an incidence of 1 case per 1.5 million population, a frequency among persons of European ancestry that is almost 10 times as high as the frequency among those of African ancestry, a slight predilection for males, and a peak incidence at 15 years of age. Read the NEJM Review Article here.
Q: Describe some of the features of Ewing’s sarcoma.
A: Ewing’s sarcoma accounts for about 2% of cancers in children, is the second most common bone cancer in children, and can occur in any part of the body but most commonly involves the pelvis and proximal long bones. In approximately 20% of patients, tumors are extraosseous and can arise in numerous organs; extraosseous Ewing’s sarcoma occurs much more frequently in adults than in children. The discovery of an undifferentiated round-cell tumor in the soft tissues of an adult warrants inclusion of Ewing’s sarcoma in the differential diagnosis.
Q: How specific are the clinical and radiographic findings in cases of Ewing’s sarcoma?
A: The clinical features of Ewing’s sarcoma are largely nonspecific. Patients may report localized pain, which may be accompanied by swelling that can be mistaken for a minor injury. The pain is often mild, sometimes increasing at night or after exercise, although some patients do not have pain at all. In the absence of pain, the only sign may be the fortuitous palpation of a firm mass. Nevertheless, a pathological fracture is reported in 10 to 15% of cases, and in cases of advanced disease, nonspecific constitutive symptoms may appear, including fever, night sweats, fatigue, and weight loss. Radiologic analysis is usually more strongly suggestive, with the typical multiple, confluent, lytic bone lesions giving rise to images described as “moth eaten” on standard films. Subperiosteal growth may translate into two other classic images — Codman’s triangle and the “onion peel” — which, respectively, represent the displaced periosteum and the resulting proliferative reaction.
A: Ewing’s sarcoma carries a low mutational burden and, at 0.15 mutations per megabase, has one of the lower mutational rates of all cancers. The defining genetic alteration is one of several possible reciprocal chromosomal translocations that generate the fusion between the gene encoding Ewing’s sarcoma breakpoint region 1 (EWSR1) and a gene encoding a member of the E-twenty-six (ETS) family of transcription factors. About 85 to 90% of cases bear the chromosomal translocation t(11;22)(q24;q12), which leads to the fusion of EWSR1 to the gene encoding Friend leukemia virus integration 1 (FLI1). Shortly after its discovery, the EWS-FLI1 fusion protein was observed to act as an aberrant transcription factor, inducing the expression of genes with oncogenic properties but also repressing numerous genes through mechanisms that remained obscure. Regardless of its mechanism of action, it became clear that EWS-FLI1 plays a central role in the pathogenesis of Ewing’s sarcoma.
A: By far the most important prognostic factor is the presence of metastasis at the time of diagnosis. Patients with local disease that responds to multimodal therapy currently have a 5-year survival rate of more than 70%. In contrast, less than 30% of patients presenting with metastases survive for 5 years. Patients with metastasis limited to the lung have a better prognosis than those with metastasis to the bone or bone marrow. In the absence of metastasis, the tumor site constitutes the single most important prognostic factor, with a worse outcome for patients with proximal primary tumors (i.e., in the pelvis and sacrum) than for patients with distal tumors.