Original article
Expression of cell cycle-associated proteins in non-muscle-invasive bladder cancer: Correlation with intravesical recurrence following transurethral resection

https://doi.org/10.1016/j.urolonc.2009.08.002Get rights and content

Abstract

The objective of this study was to evaluate the expression patterns of cell cycle-associated proteins in newly diagnosed non-muscle-invasive bladder cancer (NMIBC) to clarify the significance of these proteins as prognostic predictors in 161 consecutive patients undergoing transurethral resection (TUR). Expression levels of 7 cell cycle-associated proteins, including Aurora-A, c-erbB2, cyclin-D1, Ki-67, p21, p27, and p53, in TUR specimens were measured by immunohistochemical staining. Of the 7 proteins, weak expression of p21 was significantly associated with the incidence of intravesical recurrence (P = 0.012). Univariate analysis identified expression level of p21, tumor size, T stage, and concomitant carcinoma in situ (CIS) as significant predictors for intravesical recurrence (P = 0.0053, 0.0014, 0.024, and 0.035, respectively). Of these, p21 expression, tumor size, and concomitant CIS appeared to be independently related to intravesical recurrence (P = 0.029, 0.025, and 0.016, respectively). Furthermore, there were significant differences in intravesical recurrence-free survival according to positive patterns of these 3 independent factors; that is, intravesical recurrence occurred in 17 of 72 patients who were negative for risk factor (23.6%), 30 of 57 positive for a single risk factor (52.6%), and 24 of 32 positive for 2 or 3 risk factors (75.0%). These findings suggest that consideration of expression levels of cell cycle-associated proteins, in addition to conventional parameters, would contribute to accurate prediction of intravesical recurrence following TUR of NMIBC. Moreover, combined evaluation of p21 expression, tumor size, and concomitant CIS might be particularly useful for further refinement of the outcome in predicting intravesical recurrence following TUR of NMIBC.

Introduction

Approximately 80% of newly diagnosed bladder cancers are non-muscle-invasive tumors that are limited to the urothelium or infiltrate no deeper than the lamina propria. Complete transurethral resection (TUR) of the visible tumor burden is the current standard of care in patients with non-muscle-invasive bladder cancer (NMIBC), and the prognosis of such patients is generally favorable, achieving survival rates at 5 years greater than 80% [1]. However, intravesical recurrence following TUR has been reported in 30% to 80% of patients with NMIBC [1], [2], [3]. Intensive efforts, therefore, have been made for the development of systems precisely predicting the outcome of TUR, which are of great utility in planning both postoperative adjuvant therapy and follow-up schedule in an individual patient.

Although a number of investigators have identified risk factors associated with intravesical recurrence of NMIBC, including tumor multiplicity, maximal tumor size, grade, stage, growth pattern, and microvascular invasion [3], [4], [5], [6], [7], the outcomes of these studies are not consistent. Hence, in order to provide more reliable information regarding the probability of intravesical recurrence in patients with NMIBC following TUR, several studies have investigated the value of a wide variety of molecular markers, and some of these molecules were shown to be significantly related to postoperative prognostic outcomes [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. For example, Choi et al. performed cDNA microarray analysis and identified metalloproteinase-1 and -12, transforming growth factor-β1, vascular endothelial growth factor, and fos as useful predictors of recurrence in patients with low grade NMIBC [13]. We also previously reported the significantly higher intravesical recurrence rate in patients with strong clusterin expression in resected NMIBC specimens than in those with weak expression [14]. However, to date, there are no established systems for predicting clinical outcomes in patients with NMIBC who were treated with TUR; therefore, it would be an attractive approach to incorporate the profile of molecular markers into currently available clinicopathologic information of NMIBC to accurately predict the postoperative recurrence of NMIBC.

Considering these findings, we focused on the significance of markers involved in cell cycle regulation, which has been shown to be a key event in determining the biological behavior of NMIBC [19], evaluated the expression level of 7 potential cell cycle-associated proteins, including Aurora-A, c-erbB2, cyclin-D1, Ki-67, p21, p27, and p53, in TUR specimens with immunohistochemical staining, and analyzed these outcomes according to several clinicopathologic parameters.

Section snippets

Patients and methods

This study included a total of 161 consecutive patients who were treated with TUR of newly diagnosed primary urothelial carcinoma of the bladder between January 2000 and December 2007, and were subsequently diagnosed as having NMIBC (i.e., stage Ta or T1 tumor). Tumor size is defined as the largest tumor measured with a resection loop that is 1 cm long. The growth pattern was macroscopically classified into either papillary or non-papillary type. Complete resection of all visible tumors was

Results

During the observation period of this study (median, 47 months; range, 13–93 months), 71 of the 161 patients (44.1%) developed disease recurrence, and 1-, 3-, and 5-year recurrence-free survival rates were 67.7%, 53.9%, and 45.2%, respectively (Fig. 1). In addition, progression to muscle-invasive disease was detected in 5 of the 161 patients (3.1%), who subsequently underwent radical cystectomy. Table 1 summarizes the characteristics of 161 patients included in this study according to whether

Discussion

Despite a number of studies that evaluated the factors predicting intravesical recurrence following TUR of NMIBC, these studies are sometimes difficult to compare, resulting in a failure to show consistent findings [3], [4], [5], [6], [7]. This could be due to several factors as follows: (1) indications of intravesical therapy after TUR differed at each institution; (2) the same variable has been evaluated according to different cut off points; (3) the study designs varied from small

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