Invasion of the bladder by transitional cell carcinoma: Its relation to histologic grade and expression of p53, MIB-1, c-erb B-2, epidermal growth factor receptor, and bcl-2

Although pathologic level of invasion and histologic grade are helpful in predicting the clinical outcome of transitional cell carcinoma of the bladder, they also create uncertainty. Immunohistochemical staining for p53, MIB-1, epidermal growth factor receptor (EGFR), c-erb B-2, and bcl-2 have shown promise as prognostic factors when evaluated singly, although multivariate analyses that include histologic grade and the interactive effects of these markers have not been studied extensively. The authors have initiated a prospective study to determine whether these markers add prognostic information to that provided by level of invasion and histologic grade. This initial report details how these five markers relate to invasion of the bladder after controlling for the effects of histologic grade. The authors evaluated 229 transitional cell carcinomas in 229 patients using the World Health Organization grading schema and immunohistochemical staining with antigen retrieval for p53, MIB-1, EGFR, c-erb B-2, and bcl-2, and they related these markers to invasion after controlling for grade with a multivariate logistic regression model. Although Grades 2 and 3 were the most important for predicting invasion, Grade 2 tumors that stained for either MIB-1 or p53 indicated a significantly greater probability of invasion than suggested by grade alone. bcl-2 and p53 had an opposing and interactive effect: when p53 was absent, the presence of bcl-2 implied less probability of invasion; but when both bcl-2 and p53 were present, the protective effect of bcl-2 was no longer observed. Although neither EGFR nor c-erb B-2 were as important as the other three markers in determining the risk of invasion, Grade 3 tumors that stained for one, and especially both, of these markers were less likely to be invasive. These five markers sort into three interactive pairs: MIB-1 and p53, bcl-2 and p53, and EGFR and c-erb B-2. MIB-1 and p53 together imply a greater probability of invasion. bcl-2 appears to have a dual role, which depends on the presence of accumulated p53. Finally, EGFR and c-erb B-2 related closely to each other and in Grade 3 tumors imply a lesser probability of invasion. It is likely that combinations of markers, or correlations between markers and grades, will yield prognostic information that is more powerful than what histologic grade alone can provide.