Prognostic impact of P53 status in Ewing sarcoma

BAGKGROUND. Disease stage at the time of diagnosis and response to therapy are the main prognostic factors for patients with Ewing sarcoma or peripher al neuroectodermal tumor (ES/PNET). The primary genetic alteration in ES/PN ET, the fusion of the EWS gene with FLI1 or ERG, is diagnostically highly s pecific for these tumors, and molecular variation in the structure of the E WS-FLI1 fusion gene also is of prognostic significance. In contrast, second ary genetic alterations, such as P53 alterations, are relatively uncommon i n ES/PNET, and their prognostic impact has not been extensively studied. METHODS. Prechemotherapy, paraffin embedded, nondecalcified, primary tumor material in a well-characterized series of 55 patients with ES/PNET with de fined EWS-FLI1 fusion transcripts (32 patients with type 1 and 23 patients with other types) was studied retrospectively by immunohistochemical techni ques for cell cycle regulators and proliferative markers, such as P53, p21( WAF1), and Ki-67, as well as by the terminal deoxynucleotidyl transferase-m ediated dUTP nick-end labeling (TUNEL) technique for apoptosis. Nuclear P53 expression in > 20% of tumor cells was scored as aberrant overexpression. Histologic response to neoadjuvant chemotherapy was assessed. RESULTS. Aberrant P53 expression (in > 20% of tumor cells) was present in 6 patients (11%) but showed no statistically significant correlation with di sease stage, tumor size, proliferation rate (Ki-67), apoptotic rate (TUNEL) , or EWS-FLI1 fusion type. By univariate analysis, the P53 > 20% group show ed a significantly poorer overall survival among patients with localized di sease (n = 43 patients) (P = 0.001) and in the entire study group (P = 0.01 ). In multivariate Cox analyses of overall survival, P53 > 20% was the stro ngest negative factor among prognostic factors available at the time of dia gnosis (P = 0.001; relative risk [RR] = 9) and when chemotherapy response w as included in the analysis (P53 > 20%: P = 0.01; RR = 10). CONCLUSIONS. P53 alteration appears to define a small clinical subset of pa tients with ES/PNET with a markedly poor outcome. The current observations warrant a systematic prospective study with comprehensive P53 mutation anal ysis. [See related article on pages 793-9, this issue.] (C) 2000 American C ancer Society.