Introduction

In the United States, more than 90% of bladder cancers are diagnosed as transitional cell carcinomas. These tumors have been designated urothelial-cell carcinoma (UCC) by a consensus panel of World Health Organization and International Society of Urological Pathology pathologists (1). The remaining 10% of bladder cancers include urothelial carcinomas with variant histology (squamous/glandular differentiation, small-cell carcinoma, sarcomatoid carcinoma, and micro-papillary carcinoma) or non-urothelial carcinomas (squamous-cell carcinoma and adenocarcinoma; 2–4). Squamous-cell carcinoma of the bladder accounts for 3–7% of bladder cancers in the United States, but as many as 75% in Egypt, where it is largely associated with chronic infections caused by Schistosoma haematobium (5). Adenocarcinoma of the bladder accounts for 2% of primary bladder cancers and is further classified by its origin (bladder, urachus, or metastatic; 5). The diverse array of histologic patterns and subtypes are clinically important, as they each carry a different degree of risk for locally advanced disease and metastasis. However, the oncogenic pathways involved in bladder cancer have been largely defined in UCC, and the scope of this chapter is limited to a description of the molecular biology of this subtype.

The majority of patients (70–80%) with UCC present with non-invasive tumors that are confined to the bladder mucosa. Following resection, disease recurrence rates for these tumors are high (≥60%). A small percentage of patients with non-invasive tumors have disease that ultimately progresses to a higher stage, and up to 20% of these patients have disease recurrence that is higher grade and/or invasive. At presentation, approximately 20–30% of patients with UCC are diagnosed with invasive disease. Although many of these patients appear to have no evidence of metastasis at presentation, approximately 50% of those treated with local therapy will ultimately have a relapse with metastatic disease. The prognosis for patients with metastatic disease is dismal, with few surviving more than two years. Understanding the molecular alterations that contribute to the pathogenesis of bladder cancers is essential for the development of novel therapies targeting the pathways implicated in this disease to improve survival rates for these patients.