ALTERATIONS AFFECTING THE P53 CONTROL PATHWAY IN BILHARZIAL-RELATED BLADDER-CANCER

Bilharzial-related bladder carcinoma (BBC) is the most common malignan t neoplasm in Egypt, also occurring with a high incidence in other reg ions of the Middle East and East Africa. The clinical and pathological features of BBC are different than those described for the convention al transitional cell carcinoma of the bladder, including the high inci dence of squamous cell carcinoma reported in BBC and the fact that ove r 90% of BBC cases at presentation are advanced-stage tumors (P3 and P 4), This study was conducted to better define the phenotypic alteratio ns associated with BBC affecting the p53 cell cycle control pathway, i ncluding altered patterns of expression of downstream effector protein s such as mdm2 and p21/WAF1, A well-characterized cohort of 125 patien ts affected with bilharzial-related bladder tumors was studied, Tumors were classified as squamous carcinomas (n = 68), transitional cell ca rcinomas (n = 55), or adenocarcinomas (n = 2), The products encoded by TP53, mdm2, and p21/WAF1 genes were analyzed by immunohistochemistry. Furthermore, the patterns of expression of these molecules were corre lated with the Ki67 proliferative index. In addition, the microanatomi cal distribution of programmed cell death was assessed in a subset of tumors, using the so-called terminal deoxynucleotidyl transferase-medi ated nick end labeling method, p53 nuclear overexpression was identifi ed in 25 (20%) of 125 cases, Nuclear overexpression of mdm2 was detect ed in 74 (59.2%) of 125 cases, There was a statistically significant a ssociation 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 o bserved in 99 (86%) of 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 = 0.0 26) as well as lymph node metastases (P = 0.039), Apoptosis was observ ed in terminally differentiated tumor cells identified in the superfic ial layers of well-differentiated squamous carcinoma or exfoliating ce lls in transitional lesions, However, only rare apoptotic tumor cells were found in basal or suprabasal layers as well as in the invasive el ements of the neoplasms studied, These results suggest that the freque ncy of p53 nuclear overexpression in BBC is lower than that reported f or 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 th is may be an early incident in BBC and should be regarded as a potenti al oncogenic phenomenon, This is supported by the significant correlat ion 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 th at develops in tumor progression.