Absence of detectable EWS/FLI1 expression after therapy-induced neural differentiation in Ewing sarcoma

Ewing sarcoma and other peripheral primitive neuroectodermal tumors (pPNETs) display limited neural differentiation and are thought to have a neural crest origin Greater than 95% of these tumors share common t(11;22)(q24;q12) ort(21;22)(q22;q12) chromosomal translocations leading to ES/FLI1 or EWS/ERG gene fusions, respectively. The resulting chimeric oncoproteins seem to function as aberrant transcription factors. However, whether these molecules contribute to the limited neural differentiation observed in pPNETs or actually inhibit differentiation remains unclear. We report a Ewing sarcoma case from the forearm of a 10-year-old girl which expressed EWS/FLI1 fusion transcripts. The tumor was treated with surgery, chemotherapy, and local radiation, but residual tumor was detected within a year as a well-differentiated peripheral neural tumor lacking detectable EWS/FLI1 expression. Further studies suggested that the primary and residual tumors were clonally related. This association between apparent therapy-induced differentiation in Ewing sarcoma and absence of detectable fusion transcripts in the residual tumor provides presumptive evidence that EWS/FLI1 expression may inhibit differentiation in tumour cells.