Expressions of P-Glycoprotein, Multidrug Resistance Protein 1 and Annexin A2 as Predictive Factors for Intravesical Recurrence of Bladder Cancer after the Initial Transurethral Resection and Immediate Single Intravesical Instillation of Adriamycin

Abstract

Objective: Immediate single instillation of chemotherapy following transurethral resection of bladder tumor (TURBT) is suggested for non-muscle invasive bladder cancer (NMIBC) patients. However, no study has evaluated molecular marker that was involved in intravesical recurrence (IVR) after single instillation of chemotherapy. Therefore, this study aimed to evaluate whether P-glycoprotein, multidrug resistance protein 1 (MRP1), Annexin A2 (ANXA2) or nucleophosmin (NPM) expression predicts IVR after initial TURBT and immediate single intravesical adriamycin instillation.

Methods: We retrospectively reviewed consecutive 443 patients who underwent TURBT. Of these, 54 patients who underwent initial TURBT and single instillation of adriamycin for NMIBC were included. The expressions of P-glycoprotein, MRP1, ANXA2 and NPM were evaluated immunohistochemically and were divided into 2 groups (low or high) according to the staining intensity and/or proportion of positive cells. IVR was assessed by Kaplan-Meier method. Cox`s multivaritate analyses were performed to identify independent predictors for IVR.

Results: Nineteen patients (35.1%) had IVR. High P-glycoprotein expression was significantly correlated with multiplicity, pT stage and high grade. High ANXA2 expression was significantly correlated with high grade. MRP1 and NPM were not correlated with any clinicopathological variables. MRP1 expression and ANXA2 expression were significantly correlated with P-glycoprotein expression. Patients with high P-glycoprotein expression had significantly worse IVR-free survival (IVRFS) than those with low P-glycoprotein expression (P =0.015). The difference in IVRFS rates between patients with high ANXA2 expression and those with low ANXA2 expression was nearly significant (P =0.057). Univariate analyses indicated multiplicity, high grade and high P-glycoprotein expression were significant predictors for IVR. Multivariate analysis indicated high grade was an independent predictor for IVR.

Conclusions: High P-glycoprotein expression was associated with IVR. Further study was needed to determine significance of P-glycoprotein expression in IVR after single intravesical adriamycin instillation.

Keywords: adriamycin; bladder cancer; intravesical recurrence; p-glycoprotein.

Figure 1

Results of Immunohistochemistry in Paraffin Embedded Bladder Cancer Specimens for P-glycoprotein (A and B), multidrug resistance protein 1 (MRP1) (C and D), annexin A2 (ANXA2) (E and F), and nucleophosmin (NPM) (G and H). (A) Faint cytoplasmic staining for P-glycoprotein. (B) Strong staining of membrane and cytoplasm for P-glycoprotein. (C) Weak cytoplasmic staining for MRP1. (D) Strong cytoplasmic staining for MRP1. (E) Weak cytoplasmic staining for ANXA2. (F) Strong cytolpasmic staining for ANXA2. (G) Weak nuclear staining for NPM. (H) Strong nuclear staining for NPM. Magnification ×100

Figure 2

Intravesical Recurrence-Free Survival Curves of the Patients with Bladder Cancer after the Initial TURBT and Immediate Single Intravesial Adriamycin Instillation. (A) Curves stratified by P-glycoprotein expression status. (B) Curves stratified by MRP1 expression status. (C) Curves stratified by ANXA2 expression status. (D) Curves stratified by NPM expression status. Two curves differ significantly between high and low P-glycoprotein expression groups (P = 0.015) in (A). Two curves tend to differ between high and low ANXA2 expression groups but the difference was not significant (P = 0.057) in (C). Two curves did not differ in (B) and (D). Pgp, P-glycoprotein; MRP1, multidrug resistance protein 1; ANXA2, Annexin A2; NPM, nucleophosmin

Figure 3

Kaplan-Meier Curves for Intravesical Recurrence-Free Survival of NMIBC Patients after Immediate Single Intravesial Adriamycin Instillation. Curves stratified by risk stratification (B) Curves stratified by P-glycoprotein expression status in high-risk patients. Pgp, P-glycoprotein