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