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INTRODUCTION

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Expectant optimism is now pervading the field of urothelial cancer as we anticipate that we will soon be soaring above the plateaus established with cisplatin-based chemotherapy in the 1980s and finally have new agents approved for the treatment of urothelial carcinoma. Immune checkpoint inhibitors, which are transforming the field of oncology, are showing evidence of clinical activity in early clinical trials in this disease (1). In addition, there are several ongoing trials of targeted agents including fibroblast growth factor (FGF) receptor inhibitors and vascular endothelial growth factor (VEGF) inhibitors currently in clinical trials with the goal of obtaining US Food and Drug Administration (FDA) approval. Our fundamental understanding of the biology of urothelial cancer is changing as well, with molecular characterization suggesting that urothelial cancer is no longer only one disease (2). These nascent technologies suggest we will soon be able to personalize therapy for urothelial cancer and reliably predict which patients will benefit from specific chemotherapy and/or other targeted agents, transforming our current treatment of urothelial cancer.

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OVERVIEW

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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. Although tumors arising from the urothelium can involve any organ along this path, about 90% of these cancers arise in the urinary bladder.

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EPIDEMIOLOGY

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Urothelial cancer is the fifth most common cancer diagnosis in the United States and is strikingly related to cigarette smoking. In 2015, about 80,000 new cases were expected, with about 74,000 arising in the bladder. Altogether, these cases account for just over 18,000 deaths (3). These incidence figures are somewhat misleading, however, because it is a 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; however, few progress to true malignancy. 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.

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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 ...

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