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There are several epidemiologic factors associated with the risk of developing bladder cancers, the most important of which is cigarette smoking, a risk that persists for many years after cessation. Other risk factors include chemical exposure (especially napthylamine and benzidine), certain occupations (chimney sweeps, aluminum workers), and cyclophosphamide exposure. Patients with chronic irritation of the bladder mucosa (long-term indwelling catheters, Schistosoma infection) are at risk for developing squamous cell carcinomas.
Since the vast majority of bladder cancers are of transitional cell subtype, this discussion will be restricted to that histologic entity. Seventy five percent (75%) of transitional cell cancers are superficial lesions, presenting as a low-grade papillary tumor. These tumors rarely invade the muscularis propria, but have a high frequency of recurrence. In contrast, the muscle-invasive cancers, many of which are high-grade, are not preceded by papillary cancers but by flat carcinoma-in-situ. These tumors frequently metastasize and have a poor long-term outcome. Thus there is a histologic dichotomy in bladder cancers and separation of these two types is important not only in patient management, but also in the understanding of molecular mechanisms underlying carcinogenesis.
Molecular studies have established that there are two distinct pathways by which bladder cancers can arise, reflecting their disparate clinical and histologic presentations. The low-grade papillary tumors are associated with chromosome 9 alterations (involving both 9p and 9q), while the high-grade tumors are associated with p53 mutations and chromosome 17p deletions. Loss of chromosome material at chromosome 9q32-34 is the most frequent genetic aberration in low-grade papillary tumors, and several candidate genes have been proposed in this region. Up to 50% of papillary tumors demonstrate loss of 9p21 material and consequently inactivation of p16INK4a, a cell cycle inhibitor. Similarly, inactivation of the p21WAF1 cyclin dependent kinase inhibitor is frequent in the papillary tumors and is a means of escaping G1-S checkpoint control. In contrast, up to 75% of high-grade urothelial carcinomas demonstrate p53 inactivation or loss of chromosome 17p, and this change can be demonstrated at the stage of flat urothelial dysplasia. These high-grade tumors have other genetic aberrations including deletions of the retinoblastoma gene on 13q14, FHIT gene on 3p14.2 and overexpression of Her-2/neu and epidermal growth factor receptor. Several of these genetic aberrations have a bearing on prognosis. p53 abnormalities are associated with increased frequency of progression to an advanced stage and poor survival. Similarly, Rb negative tumors have a worse outcome than those that retain Rb function. DNA ploidy analysis is an extremely valuable tool in independently predicting tumor recurrence and survival in papillary lesions. Ploidy analysis can be performed on bladder washings making it an effective biomarker. Amplification of Her-2/neu oncogene, present in 20-30% of bladder cancers, correlates with both stage and grade and is an independent predictor of prognosis in several studies.
Veripath OncoDiagnostics offers VysisŪ UroVysion Bladder Cancer Fluorescence in-situ Hybridization for the detection of recurrent cancer. The UroVysion Kit is designed to detect aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus via fluorescence in-situ hybridization (FISH) in urine specimens from subjects with transitional cell carcinoma of the bladder. Results from the UroVysion test are intended for use as a noninvasive method for monitoring for tumor recurrence in conjunction with cystoscopy in patients previously diagnosed with bladder cancer.
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