INTRODUCTION — Bladder cancer is the most common malignancy involving the urinary system and the ninth most common malignancy worldwide [1]. Urothelial (previously known as transitional cell [TCC]) carcinoma is the predominant histologic type in the United States and Western Europe, where it accounts for approximately 90 percent of bladder cancers. In other areas of the world, such as the Middle East, both urothelial and non-urothelial histologies are seen, with the latter due at least in part to the prevalence of schistosomiasis [2]. (See "Non-urothelial bladder cancer", section on 'Schistosomal bladder cancer'.)
Studies of urothelial bladder cancer have identified multiple risk factors, the most important of which are cigarette smoking and various occupational exposures. Numerous other factors have also been identified that may play an etiologic role in some cases of urothelial cancer, although interpretation of the evidence is frequently confounded by exposure to tobacco use.
The epidemiology and risk factors associated with urothelial cancer of the bladder will be reviewed here. Non-urothelial bladder cancer is discussed separately. (See "Non-urothelial bladder cancer".)
EPIDEMIOLOGY
Incidence and prevalence — Bladder cancer is the ninth most common cancer in the world, with 437,000 new cases and 186,000 deaths diagnosed in 2016 [3]. In the United States, approximately 80,000 new cases and 17,000 deaths occur each year due to bladder cancer [4]. In Europe, there were an estimated 118,000 cases and 52,000 deaths in 2012 [5]. In developed regions such as North America and Europe, bladder cancer is predominantly urothelial.
Since the 1970s, the five-year survival rate for those diagnosed with bladder cancer in the United States has improved to approximately 80 percent [4]. Mortality rates in several western European countries have shown similar downward trends over the last two decades but are still increasing in some eastern European countries [6].
Many bladder cancer patients do not die of their disease but do experience multiple recurrences. As a consequence, there are a relatively large number of people alive with a history of bladder cancer. In middle-aged and older adult males, bladder cancer is the second most prevalent malignancy after prostate cancer [7,8].
Geographic distribution — Geographically, there is a wide variation in the incidence of urothelial cancer of the bladder, with Western Europe and North America having the highest incidence and Eastern Europe and Asian countries having the lowest rates [6,9]. Even within the United States, there are substantial regional differences in the incidence of bladder cancer between states [4]. These differences are only slightly attenuated after controlling for smoking [10].
Age, sex, and race — Bladder cancer is typically diagnosed in older individuals. A majority (approximately 73 percent) of patients with bladder cancer are older than 65 years of age [11]. The median age at diagnosis is 69 years in males and 71 years in females [12,13]. The incidence increases with age from 142 to 296 per 100,000 in males aged 65 to 69 years and 85 and over, respectively, and from 33 to 74 per 100,000 in females in the same age groups. The age of onset is younger in current smokers than in never smokers [14]. The relative risk for current versus never cigarette smokers is the same in males and females (4.0 and 4.7, respectively), reflecting converging smoking patterns [15]. (See 'Cigarette smoke' below.)
Although extremely rare, bladder cancer can be seen in children and young adults, where it usually presents with low-grade, noninvasive disease [16].
There are racial and ethnic variations in bladder cancer incidence. In the United States, White males have the highest risk with roughly twice the incidence seen in African American and Hispanic males [17]. Postulated explanations for these racial and ethnic differences include variations in acetylator phenotypes among different racial/ethnic groups and occupational differences among underrepresented groups that influence exposure to industrial carcinogens [18]. (See 'Occupational carcinogen exposure' below and 'Detoxification of carcinogens' below.)
In addition to differences in incidence, sex and race also affect the stage at presentation and prognosis. Although the overall incidence of bladder cancer is lower in females and African Americans, these groups have more advanced-stage tumors at presentation compared with White males [13].
RISK FACTORS — Environmental exposures account for most cases of bladder cancer. The surface epithelium (urothelium) that lines the mucosal surfaces of the entire urinary tract is exposed to potential carcinogens that are either excreted in the urine or activated from precursors in the urine by hydrolyzing enzymes. This "field cancerization" effect is one hypothesis to explain the multifocal occurrence that is a characteristic feature of urothelial carcinomas of both the urinary bladder and the upper urinary tract [19-22].
However, in the majority of cases, multifocal urothelial carcinomas are monoclonal [21,23-25]. This supports their presumed origin from a single genetically altered cell, which then spreads through the urothelium via intraluminal seeding or intraepithelial migration. This is referred to as the monoclonality hypothesis.
Although the monoclonality hypothesis appears to conflict with field cancerization, both mechanisms are probably operative in urothelial carcinogenesis, as has been shown with squamous carcinogenesis in the oral cavity. (See "Epidemiology and risk factors for head and neck cancer".)
ENVIRONMENTAL FACTORS
Chemical carcinogenesis — Chemical carcinogenesis is believed to be responsible for much of the burden of bladder cancer, including the increased risk associated with cigarette smoke as well as various industrial exposures. The relationship of bladder cancer to chemical carcinogens was initially suggested by the high incidence of bladder cancer in workers with particular chemical exposures. (See 'Occupational carcinogen exposure' below.)
Subsequent epidemiologic and laboratory studies have identified a large number of chemical compounds thought to be carcinogenic. Most are aromatic amines, such as 2-naphthylamine, benzidine, and their precursors or derivatives. Other well-characterized carcinogenic chemicals include 4-aminobiphenyl, 4-nitrobiphenyl, and 2-amino-1-naphthol [26-28]. The long latent period between exposure and the development of urothelial carcinoma, combined with exposures to multiple compounds, has complicated studies attempting to identify specific carcinogens.
Cigarette smoke — Cigarette smoking is the most important factor contributing to the overall incidence of urothelial cancer in western countries [29,30]. The carcinogenic compounds present in cigarettes that are responsible for bladder cancer have not been definitively identified. There are over 60 known carcinogens and reactive oxygen species present, including 4-aminobiphenyl (4-ABP), polycyclic aromatic hydrocarbons, N-nitroso compounds, and unsaturated aldehydes [31,32].
The relationship between cigarette smoking and the risk of bladder cancer is illustrated by a prospective analysis in the National Institutes of Health-AARP Diet and Health Study Cohort [29]. This database included over 465,000 individuals followed from 1995 to 2006 in the United States. For current smokers, there was a significant increase in the risk of bladder cancer for both males and females (multivariate adjusted hazard ratios [HRs] 3.89 and 4.65, respectively). Although there was an attenuation of risk in former smokers, the risk remained significantly elevated (HRs 2.14 and 2.52 for males and females, respectively). There was a small but statistically significant increase in the incidence of bladder cancer among males who smoked a pipe or cigars but not cigarettes (HR 1.29).
In this analysis, the population attributable risk was 50 and 52 percent for males and females, respectively [29]. Compared with prospective cohort studies from earlier time periods [33,34], the percentage of cases attributable to cigarette smoking has remained constant in males despite a decrease in the overall incidence of smoking, while the percentage has increased in females, presumably reflecting the increase in cigarette smoking among females [29]. Increases in the content of specific carcinogens such as beta naphthylamine in cigarettes were postulated as contributing to these changes.
The extent of cigarette smoking appears to be related to the aggressiveness of bladder cancer. In a study of 740 patients diagnosed over a 22 year period, heavy smokers (≥30 pack years) were more likely to have a high-grade tumor and to have muscle-invasive disease at their original presentation compared with nonsmokers [35]. Additionally, patients who continue to smoke at the time of treatment for bladder cancer also can experience worsened clinical outcomes, such as increased risk of recurrent disease, decreased response to chemotherapy, and higher mortality rates [36].
Smoking cessation — Smoking cessation decreases but does not eliminate the increased risk of bladder cancer [29,30].
A meta-analysis that included data from 88 studies found that the relative risks of bladder cancer for all smokers, current smokers, and former smokers compared with nonsmokers were 2.62 (95% CI 2.43-2.83), 3.49 (3.13-3.88), and 2.07 (1.84-2.33), respectively [30]. Smoking cessation also appears to decrease the recurrence rate for patients with non-muscle-invasive bladder cancer even after the diagnosis [37].
Approaches to smoking cessation are discussed separately. (See "Overview of smoking cessation management in adults".)
Secondhand smoke — Exposure to secondhand cigarette smoke in females appears to be a risk factor for the development of bladder cancer [38,39].
The role of secondhand smoke was illustrated by a study from Los Angeles County that included 148 individuals with bladder cancer and 292 controls, all of whom were never smokers [39]. Females who lived with two or more smokers during childhood had a threefold increased risk of bladder cancer compared with those without a childhood exposure to secondhand smoke, while females with a domestic partner who smoked for 10 or more years had a twofold increased risk compared with those without such exposure. These associations were not observed in male never smokers.
Levels of environmental carcinogens were compared in those with exposure to secondhand smoke by directly quantifying 4-aminobiphenyl (4-ABP) hemoglobin adducts, which are established biomarkers of 4-ABP exposure [39]. Mean levels of 4-ABP adducts were highest in females with current exposure to environmental smoke and lowest in those with no history of exposure.
Is cannabis smoke a risk factor? — Cannabis smoke, however, has not been found to be a risk factor for bladder cancer [23,40]. Further details on the association between cannabis smoke and cancer are discussed separately. (See "Cannabis use: Epidemiology, pharmacology, comorbidities, and adverse effects", section on 'Medical and systemic effects'.)
Opium — The use of opium has been associated with an increased risk of bladder cancer, and it is considered carcinogenic to humans by the International Agency on Research for Cancer (IARC) [41,42]. Opium is an illicit substance derived from the poppy plant, specifically from the juice of the unripe seedpod. Opium contains multiple alkaloids and is considered carcinogenic to humans when smoked or ingested in various forms (eg, raw, dross, or sap opium).
Observational data consistently support an association between opium use and bladder cancer [42,43]. As an example, in one meta-analysis that included data from five case-control studies, the odds ratio for developing bladder cancer with opium but not tobacco use was 3.4 (95% CI 1.6-7.2) [43]. Of note, these data do not include other opiates such as heroin, morphine, codeine, or fentanyl.
Occupational carcinogen exposure — The relationship between workplace exposure to various chemical carcinogens and an increased risk of urothelial cancer was first noted over a century ago. Such exposures are thought to account for approximately 10 to 20 percent of bladder cancers [44,45]. For workers with substantial industrial exposure, the risk may be elevated as much as 200-fold compared with matched controls without such chemical carcinogen exposure [46]. The risk of death from bladder cancer appears to be elevated for more than 30 years after cessation of exposure to occupational carcinogens [47].
Occupations that have been linked to an increased risk of bladder cancer include metal workers, painters, rubber industry workers, leather workers, textile and electrical workers, miners, cement workers, transport operators, excavating-machine operators, and jobs that involve manufacture of carpets, paints, plastics, and industrial chemicals [26,48,49].
Bladder cancer also has been associated with exposure to paint components, polycyclic aromatic hydrocarbons (PAHs), and diesel exhausts [49,50]. In a cohort study that included more than 58,000 males in the Netherlands, investigators found only "marginal" evidence for increased risk of bladder cancer due to diesel exhaust, although this risk was more pronounced in current smokers [50]. In a meta-analysis of 35 studies reviewing occupational exposure to diesel exhaust, the summary relative risk (RR) of developing bladder cancer was 1.13 (95% CI 1-1.27) with a positive dose response relation (RR 1.44 for high diesel exposure) [51].
Firefighters are exposed to a variety of potential chemical carcinogens at the scene of a fire and its aftermath as well as at the firehouse. Potential carcinogenic compounds include benzene, polyaromatic hydrocarbons, and diesel exhausts, among others. Although some individual studies found a modest increase in the risk of developing bladder cancer among firefighters [50,52,53], two meta-analyses could not identify clear evidence that employment as a firefighter was associated with an increased risk of bladder cancer [54,55].
Carcinogenic compounds have also been identified in hair dyes [56]. Numerous epidemiologic studies have investigated the relationship between occupational exposure to hair dye use and the risk of bladder cancer [57-61]. As an example, a fivefold increase in risk of bladder cancer was observed in subjects who worked for 10 or more years as hairdressers or barbers in a population-based case-control study of 1514 incident cases of bladder cancer in Los Angeles [61]. Changes in hair dye formulations and the widespread implementation of safety measures appear to have decreased this risk [59].
This increase in risk does not appear to extend to personal users of such hair dyes. (See 'Other factors' below.)
Drinking water
Chlorination — Chlorination is the most common process by which drinking water is decontaminated for use by the general population. Trihalomethanes (THMs) are formed as a by-product when chlorine or bromine is used to disinfect water for drinking and may have adverse health effects at high concentrations. Many governments now set limits on the maximum level permissible in drinking water.
Several epidemiologic studies have investigated a possible relationship between chlorination of drinking water and the risk of bladder cancer [62-64]. As an example, one meta-analysis that included six case-control and two cohort studies with more than 6000 bladder cancer cases and 10,000 controls in total showed that long-term consumption of chlorinated drinking water was associated with an increased risk of bladder cancer in males (odds ratio [OR] 1.4, 95% CI 1.1-1.9) and a nonsignificant increase in females (OR 1.2, 95% CI 0.7-1.8) [62].
Further evidence supporting this hypothesis comes from a study suggesting that ozonation decreases the concentration of THMs and reduces the risk of bladder cancer associated with the chlorination of drinking water [65].
Arsenic — Multiple epidemiologic studies have established a link between high concentrations of arsenic in drinking water and the subsequent development of bladder cancer [66-68]. This relationship has been most clearly defined in areas of Chile and Taiwan, where subsequent removal of arsenic from drinking water sources led to a decline in the incidence of bladder cancer [67,68]. Although the precise mechanism by which arsenic induces bladder cancer is unknown, it probably acts by causing chromosomal alterations [69].
The association between arsenic and bladder cancer is influenced by the level of arsenic in drinking water. Data from Taiwan indicate that bladder cancer cases in high arsenic areas are associated with more aggressive disease and a poorer prognosis [70]. However, multivariate analysis suggested that the prognosis was similar when corrected for stage and grade. Other studies have also shown that low-level arsenic exposure alone did not appear to be a significant independent risk factor for bladder cancer, although the data remain uncertain [71].
The relationship of arsenic in drinking water to bladder cancer and other malignancies is discussed separately. (See "Arsenic exposure and poisoning", section on 'Cancer'.)
Fluid intake — An increase in total fluid intake may dilute excreted urinary carcinogens and reduce contact time with the urothelium. In the Health Professional Follow-up Study involving almost 48,000 participants over a period of 10 years, multivariate analysis found that total daily fluid intake was inversely associated with the risk of bladder cancer (RR 0.51, 95% CI 0.32-0.80 for daily fluid intake >2.5 L per day compared with <1.3 L per day) [72].
Additional evidence supporting a relationship between the extent of urothelial exposure to potential carcinogens and the risk of bladder cancer comes from a case-control study of 884 individuals with bladder cancer and 996 controls [73]. An increased frequency of urination, particularly nocturia, was associated with a significantly decreased risk of bladder cancer. Other epidemiologic studies, however, have not confirmed this association [6].
Aristolochic acid — Consumption of Chinese herbs that contain aristolochic acid or prescription of aristolochic acid has been associated with an increased incidence of urinary tract infections and urothelial malignancies of the bladder, ureter, and renal pelvis [74]. (See "Nephropathy induced by aristolochic acid (AA) containing herbs", section on 'Pathogenesis'.)
Chemoprevention — The recognition that environmental factors are responsible for most cases of lung cancer provides an opportunity to minimize the incidence of bladder cancer by blocking these changes. A variety of approaches are being studied, but none has been shown to effectively decrease the incidence of bladder cancer. Further data on chemoprevention of bladder and lung cancer incidence are discussed separately. (See "Chemoprevention of urothelial carcinoma of the bladder" and "Chemoprevention of lung cancer".)
MISCELLANEOUS FACTORS
Chronic cystitis — Individuals with recurrent or chronic bladder infections and those who have an ongoing source of bladder inflammation (eg, prolonged indwelling catheters in the setting of spinal cord injury, bladder calculi, gonorrhea, neurogenic bladder, spina bifida) have a higher risk of bladder cancer compared with the general population [75-78]. In this setting, there is a substantially higher incidence of non-urothelial cancers, especially squamous cell carcinoma. (See "Non-urothelial bladder cancer".)
Chronic urinary tract infections are thought to contribute to bladder carcinogenesis by several mechanisms:
●Repeated chronic irritation can lead to metaplastic changes, then dysplasia, and finally carcinoma.
●Chronic infection predisposes to obstructive uropathy, bacterial superinfection, and the production of nitrosamines in the acidic urine environment. Nitrosamines are capable of inducing bladder cancer in animal models [79,80]. In addition, the bacteria themselves are capable of activating N-nitroso compounds to nitric oxide radicals, which can produce oxidative damage to tissues and DNA.
●Inflammatory cells, including neutrophils, eosinophils, and macrophages, are also rich sources of reactive oxygen species that are produced by endogenous enzymatic reactions. Local infiltration of these cells into the bladder mucosa provides angiogenic and lymphangiogenic growth factors, cytokines, and proteases, all of which may enhance tumor progression [81]. In addition, the proinflammatory signals that target the elimination of infection in the acute phase subsequently switch their function from the killing of the intruder to tissue healing, thereby providing further growth opportunities for incipient tumors [82,83].
●Genetic variations in the genes involved in the inflammatory response (eg, single-nucleotide polymorphisms in the interleukin-6 gene [84]) may alter their expression and function, potentially affecting the risk of developing bladder cancer in the setting of chronic inflammation.
Human papillomavirus infection — Multiple studies have suggested that there is a relationship between human papillomavirus (HPV) infection and urothelial bladder cancer [85]. A meta-analysis that included data from 52 studies and 2855 cases of bladder cancer found that the prevalence of HPV was 17 percent [86]. Most of these were associated with high-risk serotypes of HPV, especially HPV 16.
Upper urinary tract cancer — Urothelial cancers of the renal pelvis and ureter are thought to be due to the same etiologic factors as urothelial cancer of the bladder. Thus, it is not surprising that patients with urothelial cancer of the upper urinary tract are at high risk for the subsequent development of urothelial cancer of the urinary bladder as well as contralateral upper urinary tract malignancy [87,88].
The magnitude of this effect was illustrated by a series of 82 patients who had complete resection of a urothelial cancer of the renal pelvis or ureter. In this series, urothelial carcinoma of the bladder was subsequently diagnosed in 36 (44 percent) at a median interval of 14 months [87]. The bladder tumors were frequently multifocal (mean 2.1 per patient). (See "Malignancies of the renal pelvis and ureter".)
The role of various risk factors for bladder recurrence or contralateral upper tract recurrence was illustrated in a series of 223 patients with documented primary upper urinary tract urothelial carcinoma, who had been managed definitively by either complete surgical extirpation or endoscopic resection [20]. Recurrent bladder tumors and contralateral upper urinary tract tumors were identified in 31 and 6 percent, respectively. Multiplicity of the initial upper urinary tract tumor was a risk factor for recurrence in the bladder.
The high frequency of bladder cancer in patients with urothelial cancer of the upper urinary tract requires that patients who have received definitive therapy for upper urinary tract urothelial cancer undergo close surveillance for primary tumors arising in the bladder as well as the contralateral upper urinary tract.
Tumor implantation into the bladder after radical nephroureterectomy is also a known risk factor for the development of bladder cancer due to drop metastases. Patients who undergo radical nephroureterectomy can be treated with a single postoperative dose of intravesical chemotherapy, which reduces the risk of secondary bladder tumors. (See "Malignancies of the renal pelvis and ureter", section on 'Drop metastases' and "Malignancies of the renal pelvis and ureter", section on 'Postoperative intravesical chemotherapy'.)
Bladder augmentation — Augmentation cystoplasty is occasionally used to treat neurogenic bladder and may also be undertaken if the bladder does not develop to a sufficient size to allow for continence.
Patients who undergo a bladder augmentation procedure (including both ileocystoplasty and gastrocystoplasty) appear to be at increased risk for the subsequent development of urothelial cancer [89-91]. The cumulative risk is estimated to be approximately 1 percent, with a latent period of less than 20 years [91].
These cancers may arise in the residual bladder urothelium or in the intestinal mucosa of the augmented bladder. Tumors have included urothelial carcinomas, adenocarcinomas [92], and at least one case of signet cell carcinoma [93].
Because of this increased risk, patients who undergo bladder augmentation procedures require close long-term follow-up, including annual cystoscopy beginning 10 years after the bladder augmentation [89].
Iatrogenic
Radiation therapy — Several studies have shown an increased risk of bladder cancer following pelvic radiation for rectal, cervical, prostate, and testicular cancers [94,95]. However, this relationship has not been observed in all studies, and the magnitude of the risk appears to be small [96,97]. (See "External beam radiation therapy for localized prostate cancer", section on 'Secondary malignancies' and "Approach to the long-term survivor of colorectal cancer", section on 'Second malignancies'.)
Patients with a history of prior pelvic radiation who do develop urothelial cancer appear to have more advanced tumors with poorer survival than age- and stage-matched controls [98-102].
Cyclophosphamide — Patients treated with cyclophosphamide have up to a ninefold increase in risk of developing bladder cancer, with a latency period that is generally less than 10 years [103-105]. The risk of bladder cancer in patients receiving cyclophosphamide as an antitumor or immunosuppressive agent is illustrated by the following examples:
●In a study of 145 patients receiving chronic cyclophosphamide therapy for granulomatosis with polyangiitis (GPA) between 1967 and 1993, urothelial cancer of the bladder developed in seven (5 percent) at a median follow-up of 8.5 years [104]. Six of these patients had received cumulative doses exceeding 100 grams with a cumulative duration of cyclophosphamide therapy of 2.7 years; all had episodes of gross hematuria during cyclophosphamide treatment. The duration and extent of cyclophosphamide exposure is far greater than current regimens used in GPA. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Cyclophosphamide-based regimen'.)
●A series of more than 6000 two-year survivors of non-Hodgkin lymphoma found a 4.5-fold increased risk of bladder cancer following therapy with cyclophosphamide [103]. The absolute risk depended upon the cumulative dose and was greatest in those receiving ≥50 grams of cyclophosphamide [103].
Acrolein, a urinary metabolite of cyclophosphamide, is thought to be responsible for both hemorrhagic cystitis as well as bladder cancer [106]. The uroprotectant mesna inactivates urinary acrolein and can lower the subsequent risk of hemorrhagic cystitis as well as bladder cancer when used in conjunction with cyclophosphamide [107]. (See "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients".)
Analgesics — Phenacetin, an analgesic that was widely used until the third quarter of the 20th century, has been linked to an increased risk of urothelial carcinoma, particularly of the renal pelvis [108,109]. In the late 1980s, it was recognized as a carcinogen and removed from analgesic compounds in the United States and Europe and largely replaced by acetaminophen, which does not increase the bladder cancer risk.
A number of studies have documented a decrease in the risk of bladder cancer with regular use of any nonsteroidal antiinflammatory drug (NSAID) [110], with a meta-analysis suggesting that NSAIDs, excluding aspirin, are associated with a reduction in risk of bladder cancer, particularly for nonsmokers, suggesting a protective effect by inhibition of the inflammatory and proliferative response, although others have found no association [111].
The relationship between analgesics and urinary tract malignancy is discussed in more detail separately. (See "Urinary tract malignancy and atherosclerotic disease in patients with chronic analgesic abuse", section on 'Urinary tract malignancy' and "Epidemiology and pathogenesis of analgesic-related chronic kidney disease".)
Thiazolidinediones — Thiazolidinediones are oral hypoglycemic agents indicated in the treatment of diabetes mellitus. There is concern about increased risk of bladder cancer with pioglitazone. However, the association is controversial, and whether this represents a class effect is unclear. Different reports have given conflicting results, and these data are discussed in detail separately. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Bladder cancer'.)
Other factors — A number of other factors have been postulated as risk factors for bladder cancer. The available evidence for these suggests that these factors either are not associated with causing urothelial cancer or the increased risk is relatively small.
●Air pollution – Air pollution has been postulated to increase the risk of bladder cancer, but studies have given conflicting results. A case-control study from Spain found a 30 percent increased risk of bladder cancer in individuals who lived for more than 40 years in a city with a population >100,000, presumably secondary to emissions of polycyclic aromatic hydrocarbons and diesel from industries near the residence [112]. Other studies have not documented an excess in cancers related to air pollution compared with the general population [113].
●Artificial sweeteners – Large doses of artificial sweeteners, including saccharin and cyclamates, induce bladder tumors in rats [114]. The extremely high levels of the compounds, the timing of exposure during the perinatal period, and the lack of reproducibility in primate studies make the relevance of these findings unclear. Multiple case-control studies failed to show a definitive association between saccharin use and bladder cancer risk [115,116].
●Coffee and tea – A possible association of coffee and tea consumption with bladder cancer has been studied in numerous epidemiologic investigations. Although caffeine is a potentially mutagenic substance in vitro, observational studies have been inconsistent and have failed to demonstrate a significant relationship between regular use of coffee and bladder cancer. As examples, a meta-analysis that included 34 case-control and three follow-up studies found that coffee consumption increased the risk of urinary tract cancer by approximately 20 percent, while tea consumption was not associated with an increased risk [117]. By contrast, other studies suggested that normal coffee consumption is unlikely to be associated with an increased risk of bladder cancer when adjusted for smoking, consumption of large amounts (7 to 10 cups a day) may cause a slightly increased risk [118,119]. Similarly, a pooled analysis of 12 cohort studies suggested that the association between coffee consumption and bladder cancer in male smokers is not causal but rather confounded by smoking status, as this association was absent in nonsmokers and females [120].
●Hair dyes – Although exposure to chemical carcinogens in hair stylists has been linked to an increased risk of bladder cancer, one meta-analysis based upon 10 studies did not identify an increased risk of bladder cancer in personal users of permanent hair dyes [121]. Other observational studies have consistently supported these results [122]. (See 'Occupational carcinogen exposure' above.)
GENETIC EFFECTS — Carcinogenesis within the urothelium is the result of complex interactions involving oncogenes, tumor suppressor genes, and amplification or overexpression of normal genes that encode for growth factors or their receptors. These genetic abnormalities may directly modify the risk of developing bladder cancer or alter its natural history, and such factors may act alone or in concert with extrinsic factors.
Alternatively, genetic factors may indirectly affect the risk of bladder cancer by activating carcinogen precursors or by detoxifying carcinogens.
Heredity — Multiple epidemiologic studies have looked at the role of genetic factors as risk factors for the development of bladder cancer.
In most studies, there has been a small increase in risk in relatives of those with bladder cancer, and the risk appears to be greatest in those whose affected relatives were diagnosed before age 60 years [123-125]. Although the risk is increased in never smokers, there appears to be an interaction with smoking and a larger increase in risk has been observed in smokers [124].
The possible relationship of heredity to the development of bladder cancer is illustrated by the following examples:
●A case-control study from the MD Anderson Cancer Center analyzed 713 bladder cancer patients and 658 controls [124]. Probands who had smoked and who had a positive family history for bladder cancer had a fivefold increased risk of developing bladder cancer. In an associated analysis of families of this cohort, the risk of bladder cancer was increased nearly sevenfold in relatives of patients who had been diagnosed with bladder cancer between ages 40 and 65 years who had a history of smoking, compared with never smokers with a negative family history.
●In the Swedish Family History Cancer Database from 1958 to 1996, bladder cancer was identified in a parent-offspring pair in 65 families [123]. The risk of bladder cancer was elevated in offspring of parents with bladder cancer (standardized incidence ratios [SIRs] 1.35 and 2.29 in sons and daughters, respectively). The highest risk was observed in brothers of patients diagnosed before age 45 (SIR 7.3), suggesting an X-linked inheritance.
●The Spanish Bladder Cancer Study analyzed 1158 patients with newly diagnosed bladder cancer and 1244 controls [126]. There was a nonsignificant increase in the risk of bladder cancer in patients with a positive family history (odds ratio [OR] 2.34, 95% CI 0.95-5.77). An interaction with extrinsic factors was suggested by the observation that the risk was significantly increased in slow N-acetyltransferase-2 (NAT2) acetylators (OR 4.76, 95% CI 1.25-18.09) but not rapid or intermediate NAT-2 acetylators (OR 1.17, 95% CI 0.17-7.86) [126].
●Another observational analysis of 586 patients with urothelial carcinoma showed that traditional family history-based criteria may not identify all patients with hereditary urothelial cancer susceptibility [127].
Lynch syndrome — Patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer) are at risk for developing urothelial malignancies, especially those with mutations in mutS homolog 2 (MSH2) [127]. Upper tract urothelial carcinoma occurs in 5 percent of patients with Lynch syndrome, making it the third most common malignancy in this patient population. Patients with Lynch syndrome also have a lifetime risk of developing upper tract urothelial carcinoma of up to 20 percent [128].
The approach to screening patients with Lynch syndrome for urinary tract cancers is discussed separately. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management", section on 'Urinary tract cancer'.)
Oncogene and tumor suppressor genes — A number of oncogenes and tumor suppressor genes may play a role in the pathogenesis of bladder cancer.
●The p53 tumor suppressor gene expresses a transcription factor that regulates the cell cycle. Over one-half of bladder tumors contain a mutation in the TP53 gene [22,129,130]. However, there is significant discordance between mutations in the p53 gene and protein alterations detectable by immunohistochemistry. A meta-analysis of 168 studies assessing the prognostic value of p53 overexpression showed a significant, although weak, association with the overall risk of recurrence and mortality [131].
●The retinoblastoma gene (RB) encodes a nuclear phosphoprotein that indirectly controls the cell division process. Alterations of the RB gene have been associated with bladder cancer progression [129,132-136].
●Other genes that may be involved in the initiation of bladder cancer or its subsequent progression include p16 [137-139], matrix metalloproteinases [140], and genes involved in folate metabolism (methylene-tetrahydrofolate reductase and methionine synthase) [141,142].
Activation of carcinogens — Most arylamines require in vivo activation to acquire carcinogenic potential, and several metabolic pathways have been identified. Genetic factors that regulate these metabolic steps may serve to modify the risk of developing bladder cancer after occupational or environmental exposure [143].
As an example, a series of P450 cytochrome enzymes (CYP1A2, CYP2D6, and CYP3A4) are involved in N-oxidation to N-hydroxylated metabolites, the initial step of arylamine activation. These enzymes are polymorphic in the general population, meaning that there are variants with slightly different molecular structures and biologic activities. High levels of enzymatic activity may facilitate the formation of activated arylamine metabolites and predispose to bladder carcinogenesis [144-147].
Case-control studies suggest that cigarette smokers with a genotype consistent with extensive metabolic activators have a significantly higher incidence of bladder cancer compared with controls [148].
Detoxification of carcinogens — Differences in the endogenous mechanisms responsible for metabolizing chemical carcinogens may contribute to an altered risk of bladder cancer in response to such agents.
Acetylation can detoxify aromatic amines, which are known bladder cancer carcinogens. There are two known N-acetyltransferase genes (NAT1 and NAT2), which are important acetylating enzymes. The NAT2 enzyme is polymorphic and variations in the activity of NAT2 have been implicated as risk factors in the pathogenesis of bladder cancer [149]. Two normal NAT2 alleles allow for rapid acetylation and "fast" deactivation of carcinogens. By contrast, "slow" acetylators, who have two altered NAT2 alleles, appear to be at increased risk for bladder cancer when exposed to cigarette smoke or occupational aromatic amines [150]. (See 'Cigarette smoke' above and 'Occupational carcinogen exposure' above.)
A meta-analysis of 22 case-control studies found an increased risk of bladder cancer among NAT2 slow acetylators compared with rapid acetylators (relative risk 1.4, 95% CI 1.2-1.6). Using the predominantly male European study population and assuming a 2.5-fold increased risk of bladder cancer from smoking, the authors estimated that the population attributable risk was 35 percent for slow acetylators who had ever smoked and 13 percent for rapid acetylators who had ever smoked.
Another enzyme that may detoxify carcinogens in urine is glutathione S transferase M1 (GSTM1) [151]. Approximately half of White individuals in the United States have a deletion of both GSTM1 alleles with no enzymatic activity [152]. Epidemiologic data suggest that a deficiency of GSTM1 is also associated with an increased bladder cancer risk [151,153].
Further evidence in support of a role of both NAT2 and GSTM1 come from studies of genetic studies that have identified an increased risk of bladder cancer with polymorphisms in both of these genes [154].
SUMMARY
●Epidemiology of urothelial carcinoma – Urothelial carcinoma of the bladder is the most frequent urinary tract malignancy, accounting for approximately 90 percent of bladder cancers in the United States and Western Europe. Urothelial cancer is approximately three times more common in males than females, and is primarily seen in older adults. (See 'Epidemiology' above.)
●Chemical carcinogenesis – Epidemiologic studies have identified various chemical carcinogens that are believed to be responsible for most cases of urothelial carcinoma. (See 'Chemical carcinogenesis' above.)
•Cigarette smoke – Cigarette smoke is responsible for approximately one-half of cases of urothelial cancer in both males and females. (See 'Cigarette smoke' above.)
•Opium – The use of opium has been associated with an increased risk of bladder cancer. (See 'Opium' above.)
•Occupational carcinogen exposure – Occupational exposure to various chemical carcinogens is estimated to contribute approximately 20 percent of the bladder cancer burden. (See 'Occupational carcinogen exposure' above.)
●Genetic effects – Genetic effects may play a direct role in the initiation and progression of urothelial carcinoma. (See 'Genetic effects' above.)
Genetic factors may also modify the risk associated with exogenous agents, either through the activation or detoxification of potential carcinogens. (See 'Activation of carcinogens' above and 'Detoxification of carcinogens' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas M Becker, MD, PhD, who contributed to earlier versions of this topic review.
