Ewing’s Sarcoma

In 1920, during a meeting of the New York Pathological Society, James Ewing described an unusual tumor in a 14-year-old girl as a “diffuse endothelioma of bone.”1 The tumor had initially been diagnosed as an osteosarcoma, but its architecture, the morphologic features of its cells, and its marked sensitivity to radiation therapy led Ewing to consider it as a distinct entity, going so far as to hypothesize an endothelial-cell origin.1 He later reported similar tumors in other adolescents, which pathologists variously referred to as Ewing’s sarcoma, Askin’s tumor, and peripheral primitive neuroectodermal tumor, on the basis of their shared morphologic and immunohistochemical features. The first landmark discovery toward unequivocally diagnosing Ewing’s sarcoma was made more than 70 years later, when the most frequent of the chromosomal translocations that define the tumor was identified.2 A century after Ewing’s seminal observation, the cancer that bears his name has become a paradigm for solid-tumor development after a single genetic rearrangement. In this review, we discuss the clinical features and pathogenesis of Ewing’s sarcoma, along with current and experimental therapeutic approaches. From the mechanistic point of view, we review the way in which a unique chromosomal translocation harnesses the epigenetic machinery of permissive cells to rewire their transcriptome and initiate a heterogeneous cancer that can elude even the most intensive conventional therapy available.