Altered expression of the retinoblastoma gene product: prognostic indicator in bladder cancer

Abstract

Background: It has been reported that 50%-70% of patients with bladder cancer experience recurrence after initial successful treatment and about 10%-20% of these patients die of the disease. Despite precise pathologic staging and grading, we are unable to predict clinical outcome in all patients. The retinoblastoma-susceptibility (RB) gene, a prototype of tumor suppressor genes, has recently been associated with development and/or progression of bladder cancer, as well as sarcoma and small-cell lung cancer. In transitional cell carcinomas of the bladder, we have observed altered expression of the Rb gene product--a nuclear phosphoprotein thought to function as a cell cycle regulator.

Purpose: The aim of this study was to investigate the hypothesis that altered patterns of Rb expression correlate with prognosis in bladder cancer.

Methods: Expression of the RB gene was evaluated in specimens from 48 primary bladder tumors obtained by cystectomy or transurethral resection. Rb protein expression was correlated with disease outcome in these patients. Rb expression was examined by immunohistochemistry, using the mouse monoclonal antibody Rb-PMG3-245 on frozen tissue sections. Computerized image analysis was used to quantify the level of Rb protein in individual tumor cells.

Results: The overall 5-year disease-free survival was 66%, with a median follow-up of 42 months. Normal levels of Rb protein expression were found in 34 patients (Rb-positive group). A spectrum of altered patterns of expression from undetectable levels to heterogeneous expression, however, was observed in 14 patients (altered Rb group). Of the 38 patients with muscle-invasive tumors, 13 were categorized as having altered expression of Rb protein. Only one of 10 patients with superficial carcinomas had altered expression of Rb protein. The 5-year survival was significantly decreased in patients with altered Rb protein compared with the survival in patients with positive Rb expression (P less than .001).

Conclusions: The results suggest that tumors exhibiting decreased expression of the RB gene-coded product (Rb protein) had a more aggressive biological behavior than those that expressed the Rb protein in the majority of their tumor cells.

Implications: This study demonstrates that altered patterns of Rb protein expression may be an important prognostic variable in patients presenting with invasive bladder cancer.