Carcinoma of the Bladder

Etiology

Tobacco use is the most significant risk factor for bladder cancer and for many of the accompanying comorbid illnesses, including cardiovascular disease, peripheral vascular disease, and pulmonary disease, that make the management of patients with bladder cancer challenging. In an evaluation of the association between tobacco smoking and bladder cancer including men and women in the National Institutes of Health–AARP (NIH-AARP) Diet and Health Study cohort, former smokers (119.8 per 100,000 person-years; hazard ratio [HR], 2.22; 95% confidence interval [CI], 2.03–2.44) and current smokers (177.3 per 100,000 person-years; HR, 4.06; 95% CI, 3.66–4.50) had higher risks of bladder cancer than never-smokers (39.8 per 100,000 person-years). These results were higher than a pooled estimate of US data from cohorts initiated between 1963 and 1987 (HR, 2.94 [95% CI, 2.45–3.5]). The population attributable risk for ever smoking in the NIH-AARP study was 0.50 (95% CI, 0.45–0.54) in men and 0.52 (95% CI, 0.45–0.59) in women. Additional data from the New England Bladder Cancer Study, a population-based case-control study, supports a strengthening association between smoking and bladder cancer in spite of the decreased prevalence of bladder cancer in the US population. Changes in cigarette composition including higher concentrations of certain carcinogens such as β-naphthylamine, and specific nitrosamines may be responsible for this increased association of smoking with bladder cancer risk. For equivalent total pack-years of cigarettes smoked, smoking fewer cigarettes over a longer time appears more harmful than smoking more cigarettes over a shorter time. Inherited polymorphisms in the carcinogen detoxification gene NAT2 are associated with smoking and bladder cancer risk. Specifically, aromatic amines, the major carcinogen in tobacco smoke, are detoxified by NAT2; NAT2 slow acetylators as compared with rapid acetylators have an increased relative risk (RR) from smoking for the development of bladder cancer. The NAT2 slow acetylator phenotype interacts with smoking as a function of exposure intensity (i.e., at least 40 cigarettes per day). Continued tobacco use is associated with bladder cancer recurrence as compared with never-smokers and is also associated with worse disease-associated outcomes as compared with those who quit smoking.

Occupational exposures to polycyclic aromatic hydrocarbons and aromatic amines represent the next most important risk factor for bladder cancer after smoking. Occupational risk has generally been associated with exposure to paint, dyes, metals, and petroleum products. Specific occupations include dyestuffs workers, painters, leather workers, truck drivers, aluminum workers, and workers in the dry cleaning industry. In a population-based survey examining exposure to aromatic amines, diesel engine exhaust, products used by hairdressers and barbers, mineral oils, polycyclic aromatic hydrocarbons, and paint, the occupational attribution for men to bladder cancer was 7.1%, and no clear attribution was seen for women. Environmental exposure to arsenic in drinking water has been associated with an increased risk of bladder cancer. In a well-studied arsenic-exposed area in Northern Chile, a long-term impact of arsenic exposure was observed 20 years after the end of exposure with an increase in bladder cancer mortality as compared with the rest of the country (HR, 3.6 [95% CI, 3.0–4.7]).

Several medications have been associated with an increased risk of bladder cancer, including phenacetin, cyclophosphamide, and pioglitazone. In a population-based case-control study evaluating phenacetin and other analgesic and nonsteroidal antiinflammatory drugs (NSAIDs), an elevated odds ratio (OR) was seen with phenacetin-containing medications used for a longer duration (>8 years; OR, 3.00 [95% CI, 1.4–6.5]). Medical use of the alkylating agent cyclophosphamide for indications including cancer and rheumatologic disease has been associated with an increase in risk for bladder cancer. In a Danish study of patients with Wegener granulomatosis treated with cyclophosphamide, the standardized incidence ratio (SIR) for bladder cancer was significantly increased (SIR, 3.6 [95% CI, 1.2–8.3]). The association was seen with high cumulative cyclophosphamide doses, and malignancies occurred 6.9 to 18.5 years after initiation of cyclophosphamide. In a retrospective cohort study of people with type 2 diabetes who were newly treated with oral hypoglycemic agents, ever use of pioglitazone was associated with an increased rate of bladder cancer (rate ratio, 1.83 [95% CI, 1.10–3.05]), with the rate increasing with duration of use and with a higher cumulative dose. Ionizing radiation has also been associated with the development of bladder cancer. An increased risk has been seen after radiation for survivors of germ cell testicular cancer.

Chronic irritation of the bladder is associated with bladder cancer. Infection with Schistosoma haematobium, a trematode that is prevalent in certain parts of Africa and the Middle East, is associated with an increased risk of both squamous and urothelial carcinomas of the bladder. Spinal cord injury patients are at an increased risk for the development of squamous and urothelial carcinomas of the bladder. Squamous cell carcinoma is more common in patients with chronic indwelling catheters; the neurogenic bladder itself may also pose an increased risk.

Genome-wide association studies have identified multiple susceptibility loci associated with bladder cancer risk. One such susceptibility locus within SLC14A1, a urea transporter gene on chromosome 18q12.3, is involved in regulation of cellular osmotic pressure. Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant inherited disorder caused by germline mutations in DNA mismatch repair genes including MLH1, MSH2, and MSH6. In addition to colon and endometrial cancer, less common cancers seen in mutation carriers include urothelial cancers of the bladder and upper urinary tract.

Molecular Biology

Divergent molecular pathways in urothelial tumorigenesis lead to the distinct clinical phenotypes of low-grade noninvasive disease and high-grade invasive disease. Low-grade noninvasive tumors account for 80% of urothelial carcinomas, and although these tumors are often multifocal and recurrent, progression to muscle-invasive disease is uncommon. In contrast, invasive tumors often develop in the absence of a preexisting lesion or in the setting of high-grade carcinoma in situ (CIS) and are associated with a lethal phenotype, with more than 50% of patients developing metastases and dying from urothelial cancer despite aggressive therapy.

Deletion of chromosome 9 is one of the earliest events in urothelial tumorigenesis. Low-grade noninvasive papillary tumors are characterized by mutations in the HRAS gene and fibroblast growth factor receptor 3 gene (FGFR3), indicating that receptor tyrosine kinase–Ras activation has an early and major role in bladder cancer tumorigenesis. HRAS was the first human oncogene identified in urothelial carcinomas, with mutations most commonly seen in codons 12, 13, and 61 leading to constitutive activation of the HRAS protein with transformation of the NIH-3T3 cell line. Activation of Ras signaling also occurs as a result of overexpression of HRAS in the urothelium, which occurs in more than 50% of urothelial cancers. In addition to HRAS mutations and protein overexpression, constitutive activation of several receptor tyrosine kinases occurring upstream of RAS leads to activation of Ras signaling. Most notable in bladder cancer are mutations in the FGFR3 gene. In the case of bladder cancer, mutations in FGFR3 are found predominantly in low-stage or low-grade disease, with a frequency of 50% to 67%; however, these mutations also occur in approximately 14% of invasive tumors. There are conflicting data with regard to the prognostic value of FGFR3 mutation status. Mutations in phosphatidylinositol 3-kinase, catalytic, alpha polypeptide (PIK3CA), also represent a common event in early bladder carcinogenesis and have been associated with mutations in FGFR3 in noninvasive papillary bladder tumors.

High-grade invasive tumors are characterized by defects in the p53 and retinoblastoma protein (RB) tumor suppressor genes; p53 nuclear overexpression independently predicts for progression and decreased survival. In a series of 80 patients with bladder cancer who underwent radical cystectomy and pelvic lymph node dissection, immunohistochemical expression for p53, p21, pRB, and p16 demonstrated that altered expression of each of these cell cycle regulators was associated with bladder cancer outcome, with p53 as the strongest predictor, followed by p21—suggesting a pivotal role of the p53/p21 pathway in bladder cancer progression. A phase III study of molecularly targeted therapy in locally advanced urothelial cancer of the bladder based on p53 status failed to confirm the prognostic or the predictive value for chemotherapy in p53-positive tumors. Frequent mutations in a variety of chromatin remodeling genes occur in urothelial cancer. The comprehensive molecular characterization of urothelial bladder carcinoma by The Cancer Genome Atlas (TCGA) research network demonstrated significant recurrent mutations in 32 genes involved in processes such as cell cycle regulation, chromatin regulation, and kinase signaling pathways. The analysis identified alterations with potential therapeutic relevance in 69% of the tumors studied involving pathways such as the phosphatidylinositol-3-OH kinase/AKT/mammalian target of rapamycin (mTOR) pathway and the RTK/MAPK pathway. These advances in genomic profiling of bladder cancer have led to several examples of effective targeting of genetic alterations in patients. One example involves the use of whole-genome sequencing to investigate a long-term durable response in a patient with metastatic bladder cancer treated with the mTOR pathway inhibitor everolimus, demonstrating a loss of function mutation in TSC1 (tuberous sclerosis complex 1), a regulator of mTOR pathway activation. Recent studies have demonstrated the promise of novel FGFR3 inhibitors in patients harboring FGFR3 alterations including the activating novel gene fusion, FGFR3-TACC3. In addition to DNA-based analyses, whole-genome mRNA expression profiling has led to the identification of intrinsic subtypes of muscle-invasive bladder cancer (MIBC) that have been associated with prognosis and may also predict response to therapy. These intrinsic subtypes include luminal and basal subtypes that reflect the hallmarks of breast cancer biology.

Bladder cancer has one of the highest mutational loads of any malignancy, and both mutational load and neoantigen load have been associated with response to novel checkpoint inhibitor immunotherapies. Studies have demonstrated promising results with novel immune checkpoint inhibitors targeting both programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) in patients with locally advanced and metastatic bladder cancer.