Chapter 454

Ewing sarcoma (ES) is the second most common bone tumor in children and adolescents. It was named for James Ewing, a pathologist who first described the tumor in 1921, emphasizing its distinction from osteosarcoma based upon enhanced radiosensitivity and a propensity to involve flat bones of the axial skeleton.1 In the early 1980s, both Ewing sarcoma and peripheral primitive neuroectodermal tumor (PNET) were found to contain identical t(11;22)(q24;q12) translocations.2,3 Based upon the shared translocation, and similar clinical behaviors, Ewing Sarcoma Family of Tumors (ESFT) is now considered one disease entity that includes classical ES, atypical ES, peripheral primitive neuroectodermal tumor, neuroepithelioma, and Askin tumor (an ESFT of the chest wall). It should be emphasized that peripheral PNETs are entirely different from PNETs arising in the central nervous system which do not bear the t(11;22) translocation and are not considered part of the ESFT category.

### Epidemiology, Pathophysiology, and Genetics

ESFTs occur in approximately 2 to 3 per million/year in persons less than 20 years4 with a peak in the second decade of life, although they have been reported in infants and occur with a substantial incidence in adults, especially prior to age 40. For unknown reasons, ESFT are extremely rare among individuals of African and Asian heritage. This is in contrast to osteogenic sarcoma, which has a relatively equal race distribution.4 Despite this dramatic ethnic predilection, neither specific genetic nor environmental risk factors for the development of ESFT have been identified. For instance, unlike osteosarcoma, which occurs more commonly following irradiation, there is no evidence for an increased incidence of ESFT following irradiation, and there is no evidence that ESFT occurs more frequently in patients with defined cancer predisposition syndromes. Importantly, however, family members of ESFT patients have an increased incidence of neuroectodermal, stomach, and breast malignancies, and survivors of ESFT show a high rate of second malignant neoplasms, suggesting that as yet undefined genetic factors may predispose to ESFT.5

The cell of origin that gives rise to ESFT is also unknown, with primitive neural cells implicated historically, and recent studies suggesting that mesenchymal stem cells may give rise to the disease.6,7 The classic translocation t(11;22)(q24;q12), or another related translocation, occurs in greater than 95% of ESFT.8 ESFT-associated translocations join the Ewing sarcoma (EWS) gene located on chromosome 22 to an ets-family gene, most commonly FLI1 (Friend Leukemia Insertion), located on chromosome 11.9 The 68-kDa protein produced by the EWS-FLI1 fusion transcript functions as an aberrant transcription factor and plays a critical role in initiating and sustaining ESFT. Expression of this molecule can transform mouse fibroblasts,10 and reduction of EWS-FLI1 expression induces death of ESFT cell lines.11-13 Such studies have established the EWS-ets translocation as a compelling therapeutic target. However, clinically applicable therapies to successfully prevent expression of EWS-ets or interfere with downstream oncogenic events induced by the fusion ...

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