Pathobiologic markers of the ewing sarcoma family of tumors: state of the art and prediction of behaviour

Abstract

Over the past three decades, the outcome of Ewing sarcoma family tumor (ESFT) patients who are nonmetastatic at presentation has improved considerably. The prognosis of patients with metastatic disease at the time of diagnosis and recurrence after therapy remains dismal. Drug-resistant disease at diagnosis or at relapse remains a major cause of mortality among patients diagnosed with ESFT. In order to improve the outcome for patients with potential relapse, there is an urgent need to find reliable markers that either predict tumor behaviour at diagnosis or identify therapeutic molecular targets at the time of recurrence. An improved understanding of the cell of origin and the molecular pathways that regulate tumorigenicity in ESFT should aid us in the search for novel therapies for ESFT. The purpose of this paper is thus to outline current concepts of sarcomagenesis in ESFT and to discuss ESFT patterns of differentiation and molecular markers that might affect prognosis or direct future therapeutic development.

Figure 1

Classical Ewing's sarcoma, microscopic image of typical histomorphology. The lesion comprises patternless sheets of small blue cells with round, regular nuclei, even nuclear margins, minimal cytoplasm, and indistinct boundaries.

Figure 2

Peripheral primitive neuroectodermal tumor with Homer Wright rosettes. The rosettes contain a circular wreath of oval nuclei that surround a pale eosinophilic, fibrillary core.

Figure 3

Atypical Ewing sarcoma, postchemotherapy and recurrence. This recurrent ESFT displays epithelioid features, such as increased eosinophilic cytoplasm and cohesive nests.

Figure 4

Ewing's sarcoma with FUS translocation. This CD99-positive lesion arose from the femur and had typical Ewing's sarcoma morphology. It was negative for an EWS rearrangement by both RT-PCR and FISH studies. In this interphase nucleus, note that one copy of the FUS locus has been divided, as evidenced by separate centromeric and telomeric gene signals, whereas the other copy has an intact, conjoined signal. Since breakapart FISH only tests a single gene locus, the partner gene in this translocation is unknown (fluorescence in situ hybridization of the FUS locus; courtesy of Dr. Ji-Yun Lee, University of Oklahoma).