Elsevier

European Urology

Volume 47, Issue 4, April 2005, Pages 463-467
European Urology

P16 Immunoreactivity Is an Independent Predictor of Tumor Progression in Minimally Invasive Urothelial Bladder Carcinoma

https://doi.org/10.1016/j.eururo.2004.12.018Get rights and content

Abstract

Objective:

To evaluate the prognostic impact of p16 immunoreactivity in minimally invasive transitional cell bladder carcinomas (stage T1).

Methods:

Multitissue-arrays containing 73 samples of T1 bladder carcinomas were stained immunohistochemically for p16. Additionally, p53 and Ki-67 antigen expression were examined. A multivariate analysis including other prognostically relevant factors like tumor grade and substage was performed.

Results:

Loss of p16 expression occurred in 54% of cases and was significantly associated with reduced progression-free (p = 0.018 by univariate analysis), but not with recurrence-free survival (p = 0.341). Median Ki-67 antigen and p53 index were 51% (range, 1–93%) and 10% (range, 0–100%), respectively. Both indices correlated significantly (p = 0.041 and p = 0.024, respectively) with recurrence-free, but not with progression-free survival. Also tumor grade was significantly associated with tumor recurrence (p = 0.006). By multivariate analysis, tumor grade (p = 0.008) was identified as an independent predictor of tumor recurrence, whereas p16 expression (p = 0.009) was identified as an independent predictor of tumor progression.

Conclusion:

According to our data, there is a significant correlation between loss of p16 expression and tumor progression in patients with minimally-invasive bladder cancer. Immunohistochemical p16 staining may therefore represent a useful tool of providing additional information on the clinical outcome of these patients.

Introduction

Since its discovery as an inhibitor of cyclin-dependent kinases 4 and 6, the tumor suppressor p16 has attracted high attention in cancer research. Much insight into the role of p16 in carcinogenesis has come from the genetic analysis of precancerous lesions and various tissue culture models. It is now believed that loss of p16 is an early and often critical event in the progression of many tumors [1]. In human papillary transitional cell bladder carcinoma, loss of one or both alleles of the p16 gene, also referred to as CDKN2 or INK4a gene, has been proposed to play a major role in early carcinogenesis [2], [3]. Among several studies investigating immunohistochemical expression of p16 in transitional cell bladder carcinoma, only two [4], [5] reported a significant prognostic impact of p16 immunoreactivity when regarded as a single parameter. To our knowledge, there are no reports describing a correlation between p16 immunoreactivity and the prognosis of patients with bladder carcinomas of stage T1 especially.

The present study aimed to evaluate whether the immunohistochemical p16 status of T1 bladder carcinomas was associated with tumor recurrence or tumor progression. p16 immunoreactivity was also compared with other parameters with known potential prognostic relevance, like immunohistochemical Ki-67 antigen and p53 expression as well as tumor grade, multifocality and substage.

Section snippets

Patients and clinical follow-up

A cohort of 73 patients (60 men, 13 women; median age 68 years) with stage T1 papillary transitional cell carcinoma of the bladder diagnosed at the Department of Urology of the University of Lübeck was included. This cohort represented a consecutive series of patients who had a primary diagnosis of T1 transitional cell bladder carcinoma in the time frame 1987–1999 and met the following inclusion criteria: Endoscopically complete transurethral resection (TUR) of tumor; histological diagnosis of

Results

Immunohistochemical stainings of multitissue arrays were generally successful. In all staining runs, however, on average 12% of cases (range, 11–14%) were not interpretable, mainly because of detachment of chips from the array or because of lack of a representative amount of tumor cells on single tumor chips. Loss of p16 expression was observed in 54% of cases (34/63). No significant relationship between p16 immunoreactivity and clinicopathological variables like tumor grade (p = 0.208 by

Discussion

Papillary bladder carcinomas of stage T1 are characterized by tumor recurrence in approximately 70% of cases [11]. Between 14% [12] and 46% [13] of the tumors progress into a muscle-invasive stage. Tumor grade is an established prognostic factor in T1 bladder carcinomas [12], [14], which is also confirmed by the results of our study. However, there is a need for additional parameters allowing to assess the tumor's biologic behavior more accurately. Thus, patients bearing a high risk of tumor

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