Bladder cancer incidence is higher in old men, shows geographic variation, and is mostly an environmental disease. Cigarette smoking, occupational exposures, water arsenic, Schistosoma haematobium infestation, and some medications are the best established risk factors. Low-penetrance genetic factors also contribute to its origin, some through interaction with environmental factors. Bladder cancer has high prevalence and a low mortality, being largely a chronic disease. Data on environmental and genetic factors involved in the disease outcome are inconclusive.
Key points
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Bladder cancer incidence increases with age, is higher in men, and is a major burden to the health systems because of the chronic nature of the most common non–muscle-invasive tumors.
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Cigarette smoking, occupational exposures, arsenic, Schistosoma haematobium infection, some medications, and genetic variation are the major risk factors associated with the disease.
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Further evidences are needed to establish the role of disinfection byproducts, fluid intake, urinary tract infections, diabetes, metabolic syndrome, viruses, and medications in bladder cancer.
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GSTM1 -null and NAT2 slow acetylator genotypes are associated with modest increase in risk; other low-penetrance genetic susceptibility loci have been identified but are not yet of clinical utility.
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Further work is needed to establish the role of environmental and genetic factors in patient outcome; the effect of smoking cessation strategies should be tested prospectively.
The burden of the disease
Bladder cancer is mainly a disease of aging; its incidence and prevalence increase around the sixth decade and peak in the seventh to eighth decade of life. It is the ninth most common cancer, with 430,000 new cases diagnosed in 2012 worldwide; on average it is 3 to 4 times more common in men than in women. Incidence rates are highest in Europe, the United States, and Egypt ( Fig. 1 ). Substantial variation exists in the incidence of bladder cancer worldwide, because of differences not only in origin, mainly smoking, but also in registration.
The highest mortality rate in men is 8 per 100,000 person-years in Middle East and Northern Africa (see Fig. 1 ). Mortality rates tended to increase in men in most European countries between 1960 and 1990, with a subsequent decline in many countries; no clear pattern of mortality trends could be observed in women. In the United States, incidence and mortality have essentially not changed in the past 25 years, indicating a lack of progress, and bladder cancer is twice as common in white versus African American men ( Box 1 ).
Number of new cases in 2014: 74,690
Incidence: 20.5
Ranking by incidence: 4th (men); 10th (women)
Percentage of new cases: 4.5%
Number of deaths in 2014: 15,580
Mortality: 4.4
Number of living people with urothelial bladder cancer in 2011: 571,518
Lifetime risk of developing urothelial bladder cancer during lifetime: 2.4%
Male to female ratio: approximately 3
In North Africa a predominance of squamous cell carcinomas is seen, mainly from Schistosoma haematobium infection. However, urothelial cell carcinoma is the most common form of bladder cancer (urothelial bladder cancer [UBC]) in the Western world, accounting for 95% of all cases. Hence, this review will refer exclusively to this tumor subtype. The incidence of UBC is increasing in developing countries probably as a result of a smoking epidemic.
From a clinical standpoint, UBC is classified as non–muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), because invasion of the muscle layer is the major determinant for performing a cystectomy. The 5-year relative survival rate for patients with UBC ranges from 97% (stage I) to 22% (stage IV). The 5-year relative survival for all stages combined is higher among men than among women (84% and 75%, respectively). Most patients have a chronic disease that requires continued surveillance and follow-up, and UBC is the most expensive tumor on a per-patient basis and an important economic burden to the health care system.
So far, the major risk factors associated with UBC have not been shown to differentially affect the development of NMIBC versus MIBC. Increasing evidence shows that under the designation “urothelial bladder cancer” multiple molecular entities are included. Therefore, in the next years a new molecular taxonomy with epidemiologic, clinical, and therapeutic implications will likely be established.
An extensive review of the epidemiology of bladder cancer has been published elsewhere. The present article first summarizes the known and suggested risk factors, both genetic and nongenetic, for UBC, and comments on current needs to disentangle the complex etiologic scenario of UBC.
The burden of the disease
Bladder cancer is mainly a disease of aging; its incidence and prevalence increase around the sixth decade and peak in the seventh to eighth decade of life. It is the ninth most common cancer, with 430,000 new cases diagnosed in 2012 worldwide; on average it is 3 to 4 times more common in men than in women. Incidence rates are highest in Europe, the United States, and Egypt ( Fig. 1 ). Substantial variation exists in the incidence of bladder cancer worldwide, because of differences not only in origin, mainly smoking, but also in registration.
The highest mortality rate in men is 8 per 100,000 person-years in Middle East and Northern Africa (see Fig. 1 ). Mortality rates tended to increase in men in most European countries between 1960 and 1990, with a subsequent decline in many countries; no clear pattern of mortality trends could be observed in women. In the United States, incidence and mortality have essentially not changed in the past 25 years, indicating a lack of progress, and bladder cancer is twice as common in white versus African American men ( Box 1 ).
Number of new cases in 2014: 74,690
Incidence: 20.5
Ranking by incidence: 4th (men); 10th (women)
Percentage of new cases: 4.5%
Number of deaths in 2014: 15,580
Mortality: 4.4
Number of living people with urothelial bladder cancer in 2011: 571,518
Lifetime risk of developing urothelial bladder cancer during lifetime: 2.4%
Male to female ratio: approximately 3
In North Africa a predominance of squamous cell carcinomas is seen, mainly from Schistosoma haematobium infection. However, urothelial cell carcinoma is the most common form of bladder cancer (urothelial bladder cancer [UBC]) in the Western world, accounting for 95% of all cases. Hence, this review will refer exclusively to this tumor subtype. The incidence of UBC is increasing in developing countries probably as a result of a smoking epidemic.
From a clinical standpoint, UBC is classified as non–muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), because invasion of the muscle layer is the major determinant for performing a cystectomy. The 5-year relative survival rate for patients with UBC ranges from 97% (stage I) to 22% (stage IV). The 5-year relative survival for all stages combined is higher among men than among women (84% and 75%, respectively). Most patients have a chronic disease that requires continued surveillance and follow-up, and UBC is the most expensive tumor on a per-patient basis and an important economic burden to the health care system.
So far, the major risk factors associated with UBC have not been shown to differentially affect the development of NMIBC versus MIBC. Increasing evidence shows that under the designation “urothelial bladder cancer” multiple molecular entities are included. Therefore, in the next years a new molecular taxonomy with epidemiologic, clinical, and therapeutic implications will likely be established.
An extensive review of the epidemiology of bladder cancer has been published elsewhere. The present article first summarizes the known and suggested risk factors, both genetic and nongenetic, for UBC, and comments on current needs to disentangle the complex etiologic scenario of UBC.
The causes of the disease: what is known?
Table 1 displays the factors/exposures for which conclusive evidence exists regarding their association with bladder cancer risk.
| Established Evidence | Suggestive Evidence | Inconclusive Evidence |
|---|---|---|
| Age >45 Male sex Cigarette smoking Occupational exposures to aromatic amines and polycyclic aromatic hydrocarbons Water arsenic Medications (phenacetin, cyclophosphamide, chlornaphazine) Radiation Genetic susceptibility variants (see Table 2 ) | Tobacco inhalation Low total fluid intake Low physical activity Low consumption of fresh fruits and vegetables Low plasma levels of vitamin D Disinfection byproducts Diabetes Bacterial urinary tract infections Spinal cord injury and indwelling catheters Medications (nonsteroidal anti-inflammatory drugs, pioglitazone) Family history Sulfotransferases (SULT), DNA repair, and cytochrome P450 enzymes (CYP) variants | Pipe and cigar smoking, chewing and snuffing tobacco Alcohol, coffee, tea consumption Artificial sweeteners Personal use of hair dyes Energy intake Meat, fish, milk, and dairy products Other vitamins and antioxidants Nitrate in drinking water Viral infections Urinary stones Urinary acidic pH Metabolic syndrome Ever-parity Hormone replacement therapy Medications (acetaminophen/paracetamol, aspirin, metformin, isoniazid and phenobarbital) |
Age
UBC is rare in individuals younger than 40 years. Incidence peaks in the population older than 75 years, and the mean age at diagnosis is approximately 67 years.
Gender
The incidence of UBC is higher in men, at least partly because of their higher tobacco smoking rates. However, both human and animal studies support the notion that gender-related liver metabolism differences and the different effect of androgens and estrogens on bladder carcinogenesis may contribute to gender differences. Importantly, women present with more advanced tumors and have worse survival rates than men.
Smoking
Cigarette smoking accounts for 50% to 65% of UBC cases in men and 20% to 35% in women. The most recent and largest cohort study in the United States shows an increased risk of UBC among current (hazard ratio [HR], 4.06; 95% CI, 3.66–4.50) and former smokers (HR, 2.22; 95% CI, 2.03–2.44) compared with never smokers. This study suggests that the population-attributable risk among women is comparable to that of men. The risk is higher for black tobacco and increases with number of cigarettes smoked daily and number of years of smoking, and with the inhalation of tobacco smoke. Evidence suggests that cessation of smoking reduces the risk of UBC only for blond tobacco.
Occupational Exposures
Occupational exposures have been estimated to account for up to 20% to 27% of bladder cancers; changes in legislation over the past 30 years seem to have led to reduced risks in the Western countries. The risks conferred by occupational exposures range from 1.2 to 1.4. Aromatic amines, to which exposure occurs in the chemical and rubber industries, are major occupational carcinogens. Polycyclic aromatic hydrocarbons (PAHs), used in aluminum production, coal gasification, coal tars, roofing, and carbon black manufacture, are also associated with UBC risk. Several high-quality studies and meta-analyses have shown an excess risk of UBC among dyers in textile industries, painters, varnishers, and hairdressers, although the risk varies over time and place. Increased risks have also been reported among truck and bus drivers. The pattern of occupational UBC risk among women is, to some extent, similar to that in men. Despite the banning of some major identified carcinogens, risks have not decreased in certain jobs, such as hairdressers. A substantial concern at the worldwide level is the regulation of exposures among relevant settings in developing countries.
Arsenic
In various geographic areas, studies have consistently shown increased UBC risks associated with exposure to high levels of arsenic in drinking water, and the International Agency for Research on Cancer (IARC) has classified arsenic in drinking water as carcinogenic to humans (bladder, lung, and skin). Recent systematic reviews and meta-analyses have confirmed this relationship; statistically significant increases in risk have been demonstrated for exposures to 50 μg/L or more of arsenic (median odds ratio, 4.2; 95% CI, 2.1–6.3), with less strong evidence for exposures at 10 μg/L.
Medications
The use of phenacetin-containing analgesics has been consistently associated with increased UBC risk in case-control studies. Cyclophosphamide and chlornaphazine also increase the risk of UBC. All 3 drugs are considered bladder cancer carcinogens in humans, based on the evaluation of the IARC.
Radiation
Radiation therapy, used in the past for dysfunctional uterine bleeding, and currently for ovarian, cervical, and prostate cancers, is associated with an increase in UBC risk. No definite evidence shows an increased UBC risk associated with the use of iodine-131 to treat hyperthyroidism.
Genetic Susceptibility
A cohort study of twins from Sweden, Denmark, and Finland estimated that 31% of the risk of UBC may be explained by heritable factors, although the estimation was not statistically significant. A recent study of the heritability of 12 common sporadic cancers found that UBC showed the smallest inherited component (heritability [h 2 g ], 0.01; 95% CI, 0–0.11). Overall, candidate gene studies have yielded inconsistent results regarding the association of genetic variation and UBC risk, an exception being GSTM1 and NAT2 . The most reproducible evidence comes from rigorous genome-wide association studies ( Table 2 ). The risks associated with tobacco and occupational exposures suggested that variation in genes coding for enzymes involved in the metabolism of urothelial carcinogens, such as aromatic amines and PAHs, might contribute to the individual susceptibility to UBC. Glutathione S-transferases (GST) are a large family of enzymes involved in electrophile detoxification by glutathione conjugation to a wide variety of substrates, including PAH epoxides and byproducts of oxidative stress. Gene copy number changes account for GSTM1 variation; approximately 50% of the US Caucasian population is GSTM1 -null (ie, lacks the gene and its product). A meta-analysis of 28 case-control studies estimated an odds ratio (OR) of 1.5 (95% CI, 1.3–1.6) for GSTM1 -null individuals. N -acetyltransferases (NATs) participate in the bioactivation and detoxification of aromatic amines. NAT2 polymorphisms have been extensively studied as a risk factor of UBC; the lack of 2 functional NAT2 alleles leads to a slow acetylation phenotype that has been consistently, but not universally, associated with an increased risk of UBC. A meta-analysis of 46 case-control studies showed a statistically significant increased risk for UBC among NAT2 slow versus intermediate/rapid acetylators (OR, 1.37; 95% CI, 1.24–1.52) with evidence of geographic heterogeneity. An association of smoking and the NAT2 genetic variants is one of the few examples of consistent gene-environment interactions in the literature. NAT2 has wide genetic variation; genotyping 2 single nucleotide polymorphisms (SNPs) is sufficient to capture this variation (rs1041983 and rs1801280). Beyond GSTM1 and NAT2 , a total of 14 independent susceptibility loci have been shown to be significantly associated with UBC risk. Several of these lie in regions where functional relationships have been proposed, including rs798766- FGFR3 somatic mutations, rs2294008- PSCA , and rs7238033- SLC14A1 , involved in urea transport and urine concentration. All of these associations show modest differences in risk for the variant allele, and therefore currently cannot be used in the clinical setting.
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