By Nita Sharma Das, PhD, MD
Ewing's sarcoma (ES) is a rare cancerous tumor that grows in bone or in soft tissue. This type of malignant tumor possesses heterogeneous morphological characteristics.
Any bony structure present in the arms, feet, legs, hands, spine, skull, and pelvis may be affected by ES, as well as the soft tissues connected to these bony structures such as the head, neck, arm, leg, trunk and the abdominal cavity. However, among all skeletal structures, ES is most frequently found in the femur (20%) and pelvic bones (26%). The disease was named after James Ewing, the American pathologist who was the first to define the radiosensitive nature of this tumor.
The clinical presentation of ES typically begins with pain at the affected site. The intensity of pain varies from individual to individual and depends on the location of the tumor. Some affected patients also experience paresthesia along with pain. ES is often characterized by a palpable mass attached to a bony structure, accompanied by a fever of unknown origin and brittleness of the involved bone. ES is often characterized by sporadic pain in growing children, and this should not be confused with similar pain due to bone growth. As a result, any bone pain of frequent occurrence along with other clinical features should not be neglected. The aggressive nature of ES is associated with a correspondingly poor survival rate.
ES may go by different names depending upon the place of origin. Thus ES of the neural tube epithelium (neuroectodermal ES) is also called primitive neuroectodermal tumor; ES in the chest is called Askin tumor; and ES in soft tissues without bone involvement is called extraosseous ES. Altogether, these tumors may be grouped as the ES family of tumors.
ES is primarily considered as a pediatric tumor. This tumor typically contains small round blue cells. Different biomarkers of ES include CD99 which is expressed in a chain-mail pattern, and negativity for CD45 representing immunoreactive lymphoma as well as for other biomarkers such as MYOG gene, DES gene, and actin which are found in rhabdomyosarcoma, and neurofilament (NF) protein found in patients with neuroblastoma.
Familial transmission of this condition has not been established by epidemiological studies, but siblings are known in rare cases to have developed ES. The prevalence of this disease is low, since it makes up only 5 to 10 percent of all primary bone tumors. However, the incidence of this tumor is high in children and its prevalence is second among children and adolescents. Male children are slightly more likely to develop ES. ES typically develops between 10 years to19 years (the second decade of life).
A massive increase in the incidence rate of ES has been observed over the last two decades. Experts assume that this is primarily due to mutations. However, the detailed pathophysiological description is unknown as of now. Nonrandom chromosomal translocations are considered to cause the cellular heterogeneity of tumor cells. Pathological findings suggest that the heterogeneity of the tumor cell may be due to the non-uniform cellular composition, with a larger cell size being due to a varying percentage of differentiated neuroectodermal cells. On the other hand, it may be a nominal morphological alteration of the same type of smaller cells.
The chromosomal translocation found in Ewing's sarcoma is t(11;22)(q24;q12) and is responsible for the production of the EWS-FLI1 fusion protein. The formation of ES primarily involves the cloning of the EWS-FLI1 fusion oncogene which contributes to the pathogenesis of the disease. The EWS-FLI1 fusion protein is primarily localized in the primitive neuroectodermal tumor cells, and it modulates the genetic expression of the targeted gene to result in ES.
FLI-1 contains a carboxyl domain and is a member of the Ets transcription factor family. Therefore, like other Ets proteins, the FLI-1 interferes specifically with sequence-specific DNA binding. Moreover, the amino-terminal structure of FLI-1 is thought to carry a transcription activation domain that can interact with other transcription factors on the protein-protein binding site.
The genetic structure is determined by such binding specificity, which is transcriptionally modulated by FLI-1. Therefore, the genetic rearrangement in Ewing's sarcoma takes place in t(11;22)(q24;q12), and also in the amino-terminal domain of FLI-1 which is replaced by the EWS sequence. This results in the presence of a series of degenerate repeats with high glutamine content. This further helps in the total formation of the EWS-FLI1 fusion protein.
This is not only a structural fusion but the development of a chimeric gene which results in a linkage between the EWS activation domain and the FLI-1 DNA-binding domain, leading to malignant transformation of the cell.