Ewing Sarcoma Family of Tumors

The Ewing sarcoma family of tumors (ESFT) consists of a group of tumors characterized by morphologically similar round-cell neoplasm and by the presence of a common chromosomal translocation. Although rare, such tumors constitute the third most frequent primary sarcoma of bone after osteosarcoma and chondrosarcoma. ESFT most commonly affects young children and adolescents. Because most patients with clinically apparent localized disease at diagnosis may also have occult metastatic (ie, systemic) disease, multidrug chemotherapy as well as local disease control with surgery and/or radiation therapy are indicated for all patients. Despite marked improvements in survival during the past 40 years for patients with localized disease, lesser improvements have been seen in patients with metastatic or recurrent disease. A better understanding of the complex biology of ESFT may lead to the successful development of biologically targeted therapies. As the regulatory pathways responsible for transformation, growth, and metastasis of ESFT become more refined, the number of potential therapeutic targets will expand. Tumors of the Ewing sarcoma family of tumors (ESFT) are characterized by morphologically similar roundcell neoplasms as well as by the presence of common chromosomal translocation. In 1918, Stout reported a case of an ulnar nerve tumor composed of undifferentiated round cells that formed rosettes; this lesion was subsequently defined as primitive neuroectodermal tumor (PNET) of soft tissue. In 1921, Ewing reported a case of round-cell tumor in the radius of a 14-year-old girl as a “diffuse endothelioma of bone,” proposing an endothelial derivation (Ewing sarcoma [ES]). Angervall and Enzinger reported the first case of an ES arising in soft tissue (ie, extraskeletal ES) in 1975. In 1979, Askin et alreported a “malignant small-cell tumor of the thoracopulmonary region” (ie, Askin tumor) with histologic features similar to those in PNET. In 1984, Jaffe et al described a neuroectodermal tumor of bone, calling it a PNET of bone. Initially, ESFT were believed to be biologically distinct. However, based on their wide spectrum of neural differentiation (PNET being the most differentiated); their immunohistochemical, cytogenetic, and molecular uniformity; and their identical response to Ewing-based chemotherapy regimens, it was determined that these sarcomas are related and that they originate from unique mesenchymal stem cells capable of multilineage differentiation. A common chromosomal translocation that results in EWS-ETS fusion (between the EWS gene on chromosome 22 and an ETS-type gene, most commonly the FLI1 gene on chromosome 11) has been implicated in 80% to 95% of cases of ES, PNET, and Askin tumor. Thus, these leAditya V. Maheshwari, MD