The urinary tract conveys urine from the confluence of urinary tubules in the renal papillae to the outside world. This entire path is lined by a specialized epithelial surface known as the urothelium, which is composed primarily of transitional cells, and extends from the renal pelvis through the ureters, bladder, and urethra. In males, it also lines the terminal prostatic ducts and prostatic urethra. While tumors arising from the urothelium can involve any organ along this path, about 90% of these cancers arise in the urinary bladder.
Urothelial cancer is the fifth most common cancer diagnosis in the United States and is strikingly related to cigarette smoking. In 2009, about 74,500 new cases were expected, with about 71,000 arising in the bladder. Altogether, these cases account for just over 15,000 deaths (1). These incidence figures are somewhat misleading, however, since it is an historical anomaly that only in the bladder are histologically bland hyperplastic lesions counted as cancers. In other sites, such lesions would be counted as benign or at most premalignant, and thus the incidence figures include many patients with lesions that do not meet the conventional definition of malignancy. (Imagine what the incidence figures for colon cancer would be if every patient with a polyp was counted as a case of colon cancer!) Many such lesions recur but few progress to true malignancy, and thus it is critically important to separate risk models that are designed to predict recurrence from those that predict progression, which is far more biologically significant. Because of this anomaly of classification, the literature on "risk of bladder cancer," both for incidence and recurrence must be interpreted very carefully.
In contrast to most other carcinomas, the majority of patients with urothelial cancer (even after excluding the low-grade papillary "cancers") have early-stage, potentially curable disease at presentation. Only about 20% of patients present with disease that invades into the muscle wall. Fewer than 5% of patients present with locally advanced (ie, clinically extravesical) disease, and another 5% or so present with clinically apparent metastatic disease. Once clinically metastatic, urothelial cancer is remarkably aggressive, exhibiting a natural history reminiscent of small cell carcinoma of the lungs: untreated, the survival is measured in weeks; it is markedly chemosensitive; responses are typically short- lived; the brain is a typical "sanctuary" site of relapse after response to initial therapy; and cure of patients with distant metastases, while well documented, remains anecdotal.
The ready accessibility of urine, and the fact that the urothelium itself can be accessed via minimally invasive cystoscopy, makes urothelial cancer an important context for understanding the processes of carcinogenesis and clonal evolution, and an important platform for the development of human gene therapy.
The current state of the art is rather sobering:
- Careful patient selection has made it possible for some patients to have organ preservation, but this strategy clearly results in some patients dying unnecessarily....