Filling the Void: Urinary Markers for Bladder Cancer Risk and Diagnosis

Because most advanced invasive or metastatic cancers have low cure rates, risk assessment and early detection of the clinically occult premalignant phases of neoplasia are of particular importance. The National Cancer Institute (Bethesda, MD) has recently implemented an innovative new program, the Early Detection Research Network (its website is http://cancer.gov.edrn), where clinicians and scientists collaborate closely to develop and validate new markers and technologies for achieving these goals. For studies of risk assessment and early detection, carcinomas arising in the urinary bladder are as close to ideal as any of the cancers arising in the internal organs. Urinary bladders are highly accessible and can be monitored by a variety of noninvasive or minimally invasive techniques. The entire mucosal surface at risk, the bladder urothelium, can be examined and biopsy specimens can be taken via a simple endoscopic procedure; moreover, exfoliated cells or secreted products can be examined repeatedly in voided urine or bladder washes with minimal or no risk to the patient. By contrast with voided urine, bladder washes are collected by cystoscopy. However, bladder washes provide the advantage of collecting larger numbers of well-preserved, recently shed cells in an isotonic fluid. Consequently, bladder washes may be useful for studies of some of the less stable cellular constituents, such as messenger RNA. In this issue of the Journal, Hemstreet et al. (1) describe the usefulness of measuring three biomarkers in voided urine for risk assessment and cancer detection in a large cohort at increased risk of bladder cancer. Urinary bladder cancer is the fifth most common cancer in the Western world and is responsible for about 3% of all cancer-related deaths. Approximately 53 000 cases of bladder cancer were diagnosed in the United States in the year 2000, and approximately 23% of these patients will eventually die of their disease (2). Approximately 90% of bladder tumors are carcinomas derived from the bladder epithelial surface (the urothelium). In most regions of the world, transitional cell carcinoma is the most common histologic type of bladder cancer. Current concepts postulate that the common transitional cell cancers, papillary and nonpapillary, arise via two distinct but overlapping pathogenetic pathways (3,4). Approximately 80% of urothelial bladder cancers are superficial, growing as exophytic papillary lesions, which may recur but usually do not invade and metastasize. These cancers originate from hyperplastic urothelium. The remaining 20% of urothelial bladder cancers are highly aggressive, solid, nonpapillary carcinomas, which have a strong propensity to invade and metastasize. The vast majority of invasive bladder cancers occur in patients without a history of papillary tumors and originate from clinically occult, mild to moderate dysplasia (low-grade intraurothelial neoplasia), progressing to severe dysplasia and carcinoma in situ (high-grade intraurothelial neoplasia) and then to invasive cancer. However, in some patients who present with low-grade superficial papillary lesions, intraurothelial neoplasia may eventually develop and progress to invasive cancer. In such instances, urothelial dysplasia and/or carcinoma in situ may develop in the adjacent urinary bladder epithelium or within the superficially growing papillary lesions. Habitual exposures to chemical carcinogens, either environmental or industrial, are well-established major risk factors for the development of bladder cancer (5). Cigarette smoking is the most important risk factor, contributing to approximately 50% of all bladder cancers in men. Occupational exposures to aromatic amines, including benzidine, contribute to approximately 25% of bladder cancers in some Western countries and possibly to a higher percentage in some developing countries (6). Inherited polymorphisms of enzymes involved in the metabolism of aromatic amines may modulate the risk of bladder cancer in exposed individuals (7). The mean time from the initial carcinogen exposure to the development of urothelial bladder cancers is 18 years (5). This time period provides ample opportunities for finding the genotypic and phenotypic fingerprints of clinically occult premalignant conditions that are the antecedents to clinically aggressive invasive disease. Cystoscopy (a minimally invasive procedure) and histopathologic examination are the gold standards for bladder cancer diagnosis but are unsuitable for mass screening. However, examination of urine, which is voided as a natural physiologic function, is suitable for mass screening studies. Although routine screening by urine cytology is not helpful for risk assessment or identification of early preinvasive phases of bladder neoplasia, the technique is effective in diagnosing high-grade invasive cancer and carcinoma in situ (8). Because many genotypic and phenotypic changes precede progression to invasive cancer and may begin in cytologically normal cells, urine testing for changes antecedent to the development of invasive disease may detect occult intraurothelial neoplasia. Thus, the identification of genotypic and phenotypic changes that predict the tendency of in situ preneoplastic conditions to progress to invasive carcinoma is of particu-