Transitional epithelium lining the bladder may undergo various forms of metaplasia. Nests of urothelium (Brunn nests) sometimes grow downward into the lamina propria. Here, their central epithelial cells may variously differentiate into a cuboidal or columnar epithelium lining (cystitis glandularis); cystic spaces filled with clear fluid lined by flattened urothelium (cystitis cystica); or goblet cells resembling intestinal mucosa (intestinal metaplasia). As a response to injury, the urothelium often undergoes squamous metaplasia, which must be differentiated from normal glycogenated squamous epithelium, commonly found at the trigone in women.
Bladder cancer accounts for approximately 5% of cancers and 3% of cancer deaths in the United States. The vast majority of bladder cancers (95%–97% in the United States; 60%–90% in Africa) are urothelial carcinomas. Squamous cell carcinomas represent about 3% to 7% of bladder cancers in the United States but are much more common in countries such as Egypt, where urinary schistosomiasis is endemic. Adenocarcinomas of the bladder are rare. Carcinoma of the bladder is more common in men than in women, in industrialized than in developing nations, in urban than in rural dwellers, and in whites than in African-Americans. About 80% of patients are between 50 and 80 years of age.
Environmental factors are important in the pathogenesis of urothelial carcinoma and include cigarette smoking, various occupational carcinogens, and prior cyclophosphamide or radiation therapy. A family history of bladder cancer is a known risk factor. Squamous cell carcinoma is related to Schistosoma haematobium infections in areas where it is endemic. Cancers occurring in the setting of schistosoma infections arise in a background of chronic inflammation, which you will recall provides the “soil” for the development of a number of different cancers (Chapter 6).
Acquired genetic aberrations have been identified in urothelial carcinoma. Based on these observations, a model for bladder carcinogenesis has been proposed in which the tumor is initiated by deletions of tumor-suppressor genes on 9p and 9q, leading to the formation of superficial papillary tumors, which may then acquire TP53 mutations and progress to invasive disease. A second pathway, possibly initiated by TP53 mutations, leads first to carcinoma in situ and then, with loss of genes from chromosome 9, progresses to invasion. Additional genetic alterations in superficial tumors include mutations in telomerase, as well as mutations in fibroblast growth factor receptor 3 (FGFR3) and components of the RAS and PI3K/AKT pathways. Muscle invasive tumors often have mutations involving both TP53 and RB (Chapter 6).
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