++
Transitional cell epithelium lines the urinary tract from the renal pelvis to the ureter, urinary bladder, and the proximal two-thirds of the urethra. Cancers can occur at any point: 90% of malignancies develop in the bladder, 8% in the renal pelvis, and 2% in the ureter or urethra. Bladder cancer is the fourth most common cancer in men and the thirteenth in women, with an estimated 72,570 new cases and 15,210 deaths in the United States predicted for the year 2013. The almost 5:1 ratio of incidence to mortality reflects the higher frequency of the less lethal superficial variants compared to the more lethal invasive and metastatic variants. The incidence is roughly four times higher in men than in women and twofold higher in white men than in black men, with a median age of 65 years.
++
Once diagnosed, urothelial tumors exhibit polychronotropism, which is the tendency to recur over time in new locations in the urothelial tract. As long as urothelium is present, continuous monitoring is required.
++
Cigarette smoking is believed to contribute to up to 50% of urothelial cancers in men and nearly 40% in women. The risk of developing a urothelial cancer in male smokers is increased two- to fourfold relative to nonsmokers and continues for 10 years or longer after cessation. Other implicated agents include aniline dyes, the drugs phenacetin and chlornaphazine, and external beam radiation. Chronic cyclophosphamide exposure also increases risk, whereas vitamin A supplements appear to be protective. Exposure to Schistosoma haematobium, a parasite found in many developing countries, is associated with an increase in both squamous and transitional cell carcinomas of the bladder.
++
Clinical subtypes are grouped into three categories: 75% are superficial, 20% invade muscle, and 5% are metastatic at presentation. Staging of the tumor within the bladder is based on the pattern of growth and depth of invasion. The revised tumor, node, metastasis (TNM) staging system is illustrated in Fig. 43-1. About half of invasive tumors presented originally as superficial lesions that later progressed. Tumors are also rated by grade. Low-grade (highly differentiated) tumors rarely progress to a higher stage, whereas high-grade tumors do.
++
++
More than 95% of urothelial tumors in the United States are transitional cell in origin. Pure squamous cancers with keratinization constitute 3%, adenocarcinomas 2%, and small cell tumors (often with paraneoplastic syndromes) <1%. Adenocarcinomas develop primarily in the urachal remnant in the dome of the bladder or in the periurethral tissues. Paragangliomas, lymphomas, and melanomas are rare. Of the transitional cell tumors, low-grade papillary lesions that grow on a central stalk are most common. These tumors are very friable, have a tendency to bleed, and have a high risk for recurrence, yet they rarely progress to the more lethal invasive variety. In contrast, carcinoma in situ (CIS) is a high-grade tumor that is considered a precursor of the more lethal muscle-invasive disease.
++
The multicentric nature of the disease and high recurrence suggests a field effect in the urothelium that results in a predisposition to develop cancer. Molecular genetic analyses suggest that the superficial and invasive lesions develop along distinct molecular pathways. Low-grade noninvasive papillary tumors harbor constitutive activation of the receptor tyrosine kinase-Ras ...