BIPHENOTYPIC SARCOMAS WITH MYOGENIC AND NEURAL DIFFERENTIATION EXPRESS THE EWINGS-SARCOMA EWS FLI1 FUSION GENE/

Accurate diagnosis of primitive childhood sarcomas continues to be a f ormidable problem because these malignancies generally demonstrate ver y little morphological evidence of their tissue of origin. One of thes e tumor classes, the Ewing's sarcoma family of peripheral primitive ne uroectodermal tumors (pPNETs), are thought to have a neural histogenes is based on evidence of neuroectodermal differentiation. Greater than 95% of pPNETs carry t(11;22) or t(21;22) chromosomal translocations wh ich fuse the EWS gene from chromosome 22q12 in-frame with either FLI1 from chromosome 11q24 or ERG from chromosome 21q22. The pPNETs are con sidered to be histogenetically distinct from rhabdomyosarcomas, myogen ic tumors lacking these EWS gene fusions and hypothesized to derive fr om immature skeletal muscle precursors. In the present study, we descr ibe a unique set of childhood soft tissue sarcomas that show both neur al and myogenic differentiation. These biphenotypic tumors express myo genic regulatory factors and muscle-specific antigens and also show ne uroectodermal differentiation with ultrastructural evidence of neurose cretory granules and expression of neural-associated genes. Northern a nalysis and reverse transcriptase PCR reveal expression of EWS/FLI1 ge ne fusions in all biphenotypic sarcomas analyzed. Chimeric EWS/FLI1 tr anscripts and fusion proteins in these tumors are identical to those d escribed for pPNETs. Our results provide evidence for a class of biphe notypic childhood sarcomas with myogenic and neural differentiation an d suggest that these tumors mag be related to the Ewing's sarcoma fami ly of pPNETs.