865 Review www.expert-reviews.com ISSN 1473-7140 © 2010 Expert Reviews Ltd 10.1586/ERA.10.73 “It would appear that epidermoid carci- noma … originates in a process of ‘ield cancer- ization’, in which an area of epithelium has been preconditioned by an as-yet-unknown carcinogenic agent. ” [1] Carcinoma of the urinary bladder is the fourth most common malignancy in men, accounting for an estimated 70,980 new cases and 14,330 cancer deaths in the USA in 2009 [2] . Worldwide, blad- der cancer is the seventh most common cancer, accounting for approximately 336,000 new cases each year [3–7] . In most countries of the Western world, bladder cancer is predominantly of tran- sitional type and the great majority of cases are thought to be induced by inhaled carcinogens in cigarette smoke, whereas in countries in which bilharziosis is endemic, most bladder cancers are squamous cell carcinomas. There are signiicant variations in incidence, morbidity and mortal- ity rates of bladder cancer in different coun- tries and ethnicity groups. African–American men have a much lower incidence of bladder cancer, but their mortality rates are similar to white Caucasians [5,6,8,9] . Bladder cancer in the USA occurs two–ive times more frequently in men than women. This has been attributed to different smoking habits and more prevalent occupational exposure in men compared with women [5–10] . The typical cost per bladder can- cer patient from diagnosis to death is estimated to be the highest among all cancers. Such high costs are due, in part, to the high propensity for recurrence and progression of bladder tumors. Early detection and identiication of precursor lesions may reduce costs and may eventually lead to decreased morbidity and mortality. Bladder cancer is morphologically hetero- geneous; more than 90% of bladder cancer cases are urothelial (transitional cell) carcinoma, whereas primary squamous cell carcinoma, adenocarcinoma, small cell carcinoma and other tumors are less common [11–13] . Urothelial carci- noma in situ (CIS) is a well established precursor of invasive bladder cancer; however, other forms of early lesions may also exist [14–22] , including Liang Cheng †1,2 , Darrell D Davidson 1 , Gregory T MacLennan 3 , Sean R Williamson 1 , Shaobo Zhang 1 , Michael O Koch 2 , Rodolfo Montironi 4 and Antonio Lopez-Beltran 5 1 Departments of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA 2 Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA 3 Department of Pathology, Case Western Reserve University, Cleveland, OH, USA 4 Institute of Pathological Anatomy & Histopathology, Polytechnic University of the Marche Region (Ancona), United Hospitals, Ancona, Italy 5 Department of Pathology, Cordoba University, Cordoba, Spain † Author for correspondence: Tel.: +1 317 491 6442 Fax: +1 317 491 6419 liang_cheng@yahoo.com It is now widely believed that there are two major pathways for urothelial carcinogenesis. One pathway usually involves mutation of FGF receptor 3 and gives rise to low-grade papillary tumors that frequently recur but seldom invade. By contrast, high-grade urothelial malignancies, including high-grade papillary urothelial carcinoma and urothelial carcinoma in situ (CIS) usually exhibit deletions or mutations of TP53. Urothelial CIS is the most likely precursor of high-grade invasive bladder cancer. It is a ‘lat lesion’ that may be relatively inconspicuous at cystoscopy, or even endoscopically undetectable. The clinical hazards associated with this elusive and biologically dangerous neoplasm have been increasingly well documented since the original studies by Melicow in 1952. Primary or secondary urothelial dysplasia is even more challenging to detect and diagnose than CIS. It is theorized that dysplasia may antedate the onset of CIS, but support for the putative progression of dysplasia to CIS is found in fewer than 20% of cases. Since many benign urothelial changes may resemble CIS at cystoscopy, in biopsies and even with molecular proiling, care must be exercised when making a diagnosis of CIS. For patients whose screening tests are worrisome for the presence of premalignant urothelial disease, newer bladder imaging modalities, including Raman spectral imaging and optical coherence tomography, may enable improved biopsy site selection. In this article, we discuss the above-noted topics, as well as other related issues, such as the possible role of papillary urothelial hyperplasia as a preneoplastic lesion and the roles of cancer stem cells and ield cancerization in urothelial carcinogenesis. KEYWORDS: carcinogenesis • carcinoma in situ • dysplasia • early detection • FGFR3 • ield cancerization • ield effect • molecular genetics • precursor lesion • TP53 mutation • transitional cell (urothelial) carcinoma • tumorigenesis • urinary bladder • urothelial carcinoma in situ The origins of urothelial carcinoma Expert Rev. Anticancer Ther. 10(6), 865–880 (2010) For reprint orders, please contact reprints@expert-reviews.com