Background:
Disease stage at the time of diagnosis and response to therapy are the main prognostic factors for patients with ewing sarcoma or peripheral neuroectodermal tumor (es/pnet). the primary genetic alteration in es/pnet, the fusion of the ews gene with fli1 or erg, is diagnostically highly specific for these tumors, and molecular variation in the structure of the ews-fli1 fusion gene also is of prognostic significance. in contrast, secondary genetic alterations, such as p53 alterations, are relatively uncommon in 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 defined ews-fli1 fusion transcripts (32 patients with type 1 and 23 patients with other types) was studied retrospectively by immunohistochemical techniques for cell cycle regulators and proliferative markers, such as p53, p21(waf1), and ki-67, as well as by the terminal deoxynucleotidyl transferase-mediated 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 disease stage, tumor size, proliferation rate (ki-67), apoptotic rate (tunel), or ews-fli1 fusion type. by univariate analysis, the p53 > 20% group showed a significantly poorer overall survival among patients with localized disease (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 strongest negative factor among prognostic factors available at the time of diagnosis (p = 0.001; relative risk [rr] = 9) and when chemotherapy response was included in the analysis (p53 > 20%: p = 0.01; rr = 10).
Conclusions:
P53 alteration appears to define a small clinical subset of patients with es/pnet with a markedly poor outcome. the current observations warrant a systematic prospective study with comprehensive p53 mutation analysis. [see related article on pages 793-9, this issue.]