Alterations Affecting the p 53 Control Pathway in Bilharzial-related Bladder Cancer 1

Bilharzial-related bladder carcinoma (BBC) is the most common malignant neoplasm in Egypt, also occurring with a high incidence in other regions of the Middle East and East Africa. The clinical and pathological features of BBC are different than those described for the conventional transitional cell carcinoma of the bladder, including the high incidence of squamous cell carcinoma reported in BBC and the fact that over 90% of BBC cases at presentation are advanced-stage tumors (P3 and P4). This study was conducted to better define the phenotypic alterations associated with BBC affecting the p53 cell cycle control pathway, including altered patterns of expression of downstream effector proteins such as mdm2 and p21/WAF1. A well-characterized cohort of 125 patients affected with bilharzialrelated bladder tumors was studied. Tumors were classified as squamous carcinomas (n 68), transitional cell carcinomas (n = 55), or adenocarcinomas (n 2). The products encoded by TP53, mdm2, and p21/WAFJ genes were analyzed by immunohistochemistry. Furthermore, the patterns of expression of these molecules were correlated with the Ki67 proliferative index. In addition, the microanatomical distribution of programmed cell death was assessed in a subset of tumors, using the so-called terminal deoxynucleotidyl transferase-mediated nick end labeling method. p53 nuclear overexpression was identified in 25 (20%) of 125 cases. Nuclear overexpression of mdm2 was detected in 74 (59.2%) of 125 cases. There was a statistically significant association between coexpression of both p53 and mdm2 and detection of lymph node metastases (P = 0.04). p21/WAF1 expression was detected in 87 (72%) of 121 evaluable cases. A high Ki67 proliferative index was observed in 99 (86%) of Received 10/1 1/96; revised 12/1 1/96; accepted 12/27/96. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. I Supported in part by NIH Grants CA-47538 (to C. C-C.) and ES067 1 8 (to Z-F. Z.). I. 0. is a Molecular Pathology Fellow recipient of a fellowship from National Cancer Institute Training Program CA-60376. 2 To whom requests for reprints should be addressed, at Department of Pathology, Memorial Sloan-Kettering Cancer Center, I 275 York Ayenue, New York, NY 10021. Phone: (212) 639-7746; Fax: (212) 7943186. 115 evaluable cases. There was a statistically significant association between high Ki67 proliferative index and mdm2-positive phenotype (P = 0.005) and deep muscle invasion (P3b; P = 0.026) as well as lymph node metastases (P = 0.039). Apoptosis was observed in terminally differentiated tumor cells identified in the superficial layers of welldifferentiated squamous carcinoma or exfoliating cells in transitional lesions. However, only rare apoptotic tumor cells were found in basal or suprabasal layers as well as in the invasive elements of the neoplasms studied. These results suggest that the frequency of p53 nuclear overexpression in BBC is lower than that reported for conventional transitional cell carcinoma. Nevertheless, tumors with p53 alterations have a greater propensity to progress. The prominent number of cases displaying an mdm2-positive phenotype suggests that this may be an early incident in BBC and should be regarded as a potential oncogenic phenomenon. This is supported by the significant correlation between high Ki67 proliferative index and mdm2 overexpression. The association of an aggressive clinical course with the coexpression of both p53 and mdm2 products might be viewed as a cooperative effect that develops in tumor progression.