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Epidemiology and Risk Factors of Urothelial Bladder Cancer
European Urology, 2, 63, pages 234 - 241
Urothelial bladder cancer (UBC) is a disease of significant morbidity and mortality. It is important to understand the risk factors of this disease.
To describe the incidence, prevalence, and mortality of UBC and to review and interpret the current evidence on and impact of the related risk factors.
A literature search in English was performed using PubMed. Relevant papers on the epidemiology of UBC were selected.
UBC is the 7th most common cancer worldwide in men and the 17th most common cancer worldwide in women. Approximately 75% of newly diagnosed UBCs are noninvasive. Each year, approximately 110 500 men and 70 000 women are diagnosed with new cases and 38 200 patients in the European Union and 17 000 US patients die from UBC. Smoking is the most common risk factor and accounts for approximately half of all UBCs. Occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons are other important risk factors. The impact of diet and environmental pollution is less evident. Increasing evidence suggests a significant influence of genetic predisposition on incidence.
UBC is a frequently occurring malignancy with a significant impact on public health and will remain so because of the high prevalence of smoking. The importance of primary prevention must be stressed, and smoking cessation programs need to be encouraged and supported.
Keywords: Urothelial bladder cancer, Epidemiology, Risk factors, Genetics, Smoking, Occupation.
Urothelial bladder cancer (UBC) is the 7th most common cancer in men and the 17th most common in women worldwide. UBC is more common in developed countries and is the fourth and ninth most common cancer in men and women, respectively in the Western world  . This frequency, coupled with the relapsing nature of UBC, means that UBC poses an enormous burden on health care systems  . Approximately 75% of newly diagnosed UBCs are noninvasive and have a high rate of recurrence and progression despite local therapy. The remaining 25% of newly diagnosed UBCs present with muscle invasion and need either radical surgery or radiotherapy but often still have poor outcomes despite systemic therapy  and . Several reviews have focused on the clinical challenges in managing bladder cancer (BCa) , , and . In this work we will elucidate epidemiologic aspects of UBC and focus on factors that increase the incidence of urothelial carcinoma of the bladder, since this represents the most common histology  and .
2. Evidence acquisition
In preparation for this review, a literature search in English was performed using PubMed between February and May 2012 for the keywords bladder cancer, incidence, prevalence, risk, risk factor, and hazard, and one keyword for each risk factor described in the literature retrieved. More than 5000 publications were retrieved. Relevant papers were preselected by two authors (M.B. and Y.L.), and the list of papers to be included was edited by all of the authors.
3. Evidence synthesis
3.1. Epidemiology of urothelial bladder cancer: incidence, prevalence, and mortality
Although exact numbers for cancer incidence and outcome are difficult to obtain and inherently delayed, the International Agency for Research on Cancer provides statistics and estimates. Details are depicted in Fig 1 and Fig 2. The incidence of UBC ranks it as the sixth most common cancer and as the fourth most common if UBC stage Ta is included  . The variations noted can partly be attributed to different methodology, mainly the inclusion of UBC stage Ta or carcinoma in situ in different national registries; thus, even among countries with comparable intensity of care and similar UBC risks, epidemiologic data vary  . Generally, the quality and transferability of databases and population-based studies available vary, and some details cannot be assessed by published reports. Respective biases warrant careful interpretation of results.
The incidence of UBC has decreased in some registries, which has been interpreted to reflect the decreased exposure to causative agents (mainly decreased smoking and better occupational hygiene)  . There is no uniform trend, however, as the age-standardized incidence rates declined in the United Kingdom while the rates remained stable in white Americans in the same time period. Future UBC incidence can be projected from current epidemiologic data. Mistry et al. estimated age-standardized cancer incidence rates by gender and age group based on trends from the UK Association of Cancer Registries and projected a decline  . Despite methodological inaccuracies in such predictions, especially if changes in smoking prevalence are not accounted for, the trend projectable into the future suggests that UBC will remain a major health burden and stresses the need for primary prevention measures  . Globally, the health burden by UBC is likely to increase in the future, since rising UBC incidence rates are expected in developing countries, especially China, mainly related to the pronounced and ongoing prevalence of smoking  .
UBC prevalence and mortality are mainly determined by the initial tumor stage, success of treatment, and other cause (competing) mortality. Non–muscle-invasive tumors have a high prevalence because their low progression rates allow many patients to survive a long time, while patients with muscle-invasive disease are at significantly higher risk of dying from their disease. The prevalence of UBC is among the highest for all urologic malignancies  . In the United States, 500 000 patients with a history of UBC are currently alive  and . Mortality is mainly determined by progression rates of high-risk non–muscle-invasive UBC and by cure rates of muscle-invasive UBC. Current details of mortality are depicted in Fig 1 and Fig 2. In 2008, UBC was the eighth most common cause of cancer-specific mortality in Europe  .
3.2. Risk factors for urothelial bladder cancer
Risk factors are best differentiated into inherited genetic predispositions and external exposures (to carcinogens such as smoke). Each risk factor may have a different impact on the incidence and pathophysiology of UBC. This phenomenon is called etiologic fraction or attributable risk. As most bladder tumors are associated with an acquired carcinogen exposure, avoidance of carcinogens could decrease the incidence of the disease significantly. Perhaps the difference in incidence between men and women reflects in part the impact of such carcinogens. While secondary prevention (ie, screening) has been debated for high-risk populations  , it is primary prevention (ie, avoidance of causative agents) that seems most effective at reducing disease-specific mortality.
3.2.1. Genetic susceptibility
Our understanding of genetic risks is growing steadily. The risk of UBC is two-fold higher in first-degree relatives of UBC patients. Inherited genetic factors, such as the genetic slow acetylator N-acetyltransferase 2 (NAT2) variants and glutathione S-transferase mu 1 (GSTM1)–null genotypes, have been established as risk factors for UBC. Factors such as slow acetylation may not intrinsically lead to UBCs but may confer additional risk to exposure of carcinogens such as tobacco products.
While NAT2 slow acetylation and GSTM1-null genotypes exhibited similar associations among noninvasive and invasive UBC, Kiemeney et al. recently reported data from a large genome-wide association study demonstrating a sequence variant on 4p16.3 not only associated with UBC but also located close to the well-established oncogene fibroblast growth factor receptor 3 (FGFR3), which is often mutated in low-grade, noninvasive UBC. In addition, the frequency of this sequence variant is higher in UBCs carrying an activating FGFR3 mutation, demonstrating a link between germline variants, somatic mutations of FGFR3, and risk of UBC  and . Three large genome-wide association studies demonstrated eight common sequence variants associated with UBC located at 8q24.21, 3q28, 8q24.3, 4p16.3, 22q13.1, 19q12, 2q37.1, and 5p15.33 (eg, missense variant rs2294008 in the prostate stem cell antigen gene (PSCA)—hazard ratio [HR]: 1.15; 95% confidence interval [CI], 1.10–1.20; and T allele of rs798766 on 4p16.3—HR: 1.24; 95% CI, 1.17–1.32) , , and , which were all replicated extensively  . Data from these studies were recently reported, suggesting genetic predisposition in relation to the solute carrier family 14 (urea transporter) gene (SLC14A) that is associated with renal urine concentration, and thus with variations in contact of carcinogens with urothelial surfaces (HR: 1.17; 95% CI, 1.11–1.22)  . Genetic disposition has been suggested to affect the individual susceptibility to extrinsic carcinogens, mainly tobacco smoke. N-acetyl transferase enzymes (NAT1, NAT2) are involved in bioactivation and detoxification of such carcinogens; a slow NAT2 acetylator genotype was found to be a significant risk factor for UBC pronouncedly in smokers (HR: 1.31; 95% CI, 1.01–1.70)  . Increasing evidence suggests a significant influence of genetic predisposition on incidence, especially via the impact on susceptibility of other risk factors. Future research could help tailor individual prevention and screening strategies.
3.2.2. Tobacco smoking
Smoking is recognized as the most important risk factor for UBC and is estimated to account for 50% of tumors (former tobacco smoking—HR: 2.22; 95% CI, 2.03–2.44; current tobacco smoking—HR: 4.1; 95% CI, 3.7–4.5)  . There is a direct pathophysiologic link between tobacco and UBC. Tobacco smoke contains aromatic amines, such as β-naphthylamine, and polycyclic aromatic hydrocarbons known to cause UBC. These are renally excreted and exert a carcinogenic effect on the entire urinary system. Tobacco consumption is common, and thus its epidemiologic impact is massive. An estimated 20% of adults in the United States and Europe are current cigarette smokers. The differences in incidence rates between genders are frequently attributed to different historical smoking patterns, although it is not known whether hormonal differences play a role as well. In most Western communities, the prevalence of smoking among men in the 1950s was much higher than among women. This prevalence among men dropped sharply in the second half of the previous century, while women started to smoke more in the 1970s and 1980s. Currently, the prevalence of smoking is more or less similar in both genders, while the BCa incidence is dropping in men and rising in women. This pattern reflects the long latency period for BCa of ≥30 yr.
In light of the reduced prevalence of smoking, this phenomenon has been viewed as reflective of several trends. First, smoking populations are changing, as cessation of smoking is more common in higher-educated and more health-oriented persons. Thus, persons continuing to smoke are more likely to harbor other health risks. Second, compositions of tobacco products (eg, flavored ingredients) have changed over the years, with unclear effect on UBC risk. Decreases in mortality from cardiac disease have resulted in older patients developing cancer who might otherwise have died of other causes.
Smoking and tobacco type seem to influence UBC risk as well; inhaling into the chest increases risk compared with inhaling into the mouth only  and . The risk in smokers of black tobacco has been reported to exceed the risk in smokers of blond tobacco, as the former has higher concentrations of N-nitrosamine and 2-napthylamine. Samniac et al. found significantly decreased risk with increasing time since quitting smoking blond tobacco, while no such trend was observed since quitting smoking black tobacco  .
Environmental exposure to tobacco smoke has also been suspected as a risk factor of UBC. One large analysis found environmental exposure to be significantly related to UBC incidence in women exposed to cigarette smoke during childhood and adulthood (HR: 3.08; 95% CI, 1.16–8.22)  . The effect of environmental exposure to tobacco smoke was generally stronger in women and strongest in women who had never smoked. The exact intrinsic and environmental factors for this gender difference remain unclear.
Cessation of smoking has been suggested to benefit UBC outcomes by some studies. Recently, Lammers et al. demonstrated previous recurrences, multiplicity of tumors, and smoking status to predict recurrence-free survival of patients with non–muscle-invasive UBC in multivariate analyses  . A similar effect has been suggested for invasive UBC. Boström et al. found smokers to have worse disease-free survival after radical cystectomy, but this was not an independent prognostic factor  . Similarly, Yafi et al. found smoking to be independently associated with prolonged disease-specific and overall survival  .
3.2.3. Occupational risk
Following smoking, occupational exposure to carcinogens—namely, aromatic amines (benzidine, 4-aminobiphenyl, 2-naphthylamine, 4-chloro-o-toluidine), polycyclic aromatic hydrocarbons, and chlorinated hydrocarbons—is viewed as the second most important risk factor for UBC. Roughly 20% of all UBCs have been suggested to be related to such exposure, mainly in industrial areas processing paint, dye, metal, and petroleum products. In more recent years, the extent and pattern of occupational exposure have changed dramatically because of awareness prompting safety measures. Yet a recent population-based survey by Rushton et al. describes the occupational attribution for men to UBC to be 7.1%, while no such attribution was discernible for women  . A case–control study by Samniac et al. found statistically significantly increased risk in men employed as machine operators in the printing industry, while reduced risk was found in male farmers, and no significant associations between occupation and risk were found among women after adjustment for smoking duration (HR: 5.4; 96% CI, 1.6–17.7)  . No exact data on occupational exposure exist; personal use of hair dye has been related to UBC risk to a lesser extent. In a population-based case–control study, Koutros et al. found no relation between hair dye use and UBC risk in women but did find evidence of gene–environment interaction, as risk among exclusive users of permanent hair dyes who had the NAT2 slow acetylation phenotype was increased compared with never users who had the NAT2 rapid/intermediate acetylation phenotype (HR: 7.3; 95% CI, 1.6–32.6)  . A recent population-based case–control study by Ros et al. found no relation between personal hair dye use and UBC incidence (HR: 0.87; 95% CI, 0.65–1.18)  .
3.2.4. Dietary factors
As for other cancers, nutritional aspects have been attributed to UBC risk. Fluid intake is commonly evaluated because of its impact on voiding, but the association with BCa is controversial. On the one hand, the amount of fluid ingested may reduce exposure of urothelial tissue to carcinogens by diluting urine and increasing the frequency of micturition. On the other hand, the type of fluid is related to UBC risk if it contains relevant carcinogens such as arsenic and disinfection by-products. Michaud et al. performed a case–control study finding water intake to be inversely associated with UBC risk, as they observed UBC risk halved in subjects consuming greater compared with smaller amounts of fluids per day (≥1.4 1/d compared with 0.4 1/d; HR: 0.47; 95% CI, 0.33–0.66)  . Chlorination of drinking water and subsequent levels of trihalomethanes have been viewed as one source of relevant carcinogens. The chemistry of disinfection by-products is complex and hard to assess, as various reactions occur during heating. In contrast to Michaud et al, Villanueva et al. reported UBC risk to increase with exposure to trihalomethanes and to be related to consumption of tap water independently from chlorination in an analysis of pooled case–control studies  . Recent prospective data reveal no obvious link, however. Ros et al. report data from the European Prospective Investigation into Cancer and Nutrition (EPIC) showing no influence of total fluid intake on UBC risk in approximately 250 000 individuals after a mean follow-up of 9 yr (HR: 1.12; 95% CI, 0.86–1.45)  .
While coffee, a complex mixture of chemicals, has been suggested as a possible UBC-relevant carcinogen, such an effect remains controversial. Villanueva et al. recently evaluated the relation of coffee consumption to UBC incidence in a case–control study and found only a modest increase in risk among coffee drinkers, which was confounded by smoking  . In a recent meta-analysis of 16 case–control and 3 cohort studies, Pelucchi et al. found no association between amount of alcohol consumption and UBC risk  . Similar to the findings of uncertain influence of type and amount of fluid intake on UBC incidence, Donat et al. found no impact of habitual fluid intake on recurrence rate in a prospective series of UBC patients  .
Besides fluid intake, dietary habits have been considered relevant in UBC tumorigenesis, as many carcinogens ingested via food are excreted into the urine, resulting in direct exposure of the urothelium. In other cancers, consumption of meat has been suggested to increase risk while consumption of vegetables and fruits has been suggested to be beneficial. In UBC, however, neither effect is evident. A recent prospective series assessing the nutritional data of approximately 500 000 persons (EPIC) found intake of red meat not to be associated with UBC after a mean follow-up of 9 yr. The EPIC series also found no obvious link between vegetable and fruit consumption and UBC risk. Only when comparing the highest tertile of combined fruit and vegetable consumption compared with the lowest tertile was risk of BCa marginally significant (HR: 1.30; 95% CI, 1.00–1.69)  .
Hotaling et al. analyzed the impact of long-term use of supplemental vitamins and minerals on UBC risk in a prospective series of approximately 80 000 persons (VITamins); after a mean follow-up of 6 yr, no supplement was found to be significantly related in multivariate models  . There was also no association of intake of selenium and vitamin E and UBC incidence in a secondary analysis of the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a prospective placebo-controlled study randomizing patients with placebo, vitamin E, selenium, or combined vitamin E and selenium  . A recent smaller case–control study reported by Brinkman et al. suggested a trend toward an impact of type of fat ingested: a reduced odds ratio for UBC incidence that was apparent for the highest compared with the lowest quartile of α-linolenic acid and vegetable fat intake (HR: 0.26; 95% CI, 0.10–0.65)  . Similar to the uncertain influence of diet on UBC incidence, no impact of body mass index as a surrogate parameter of diet on outcome in UBC patients has been reported to date  .
3.2.5. Environmental pollution
Exposure to arsenic in drinking water has been recognized as a cause of UBC; following pollution of drinking water in Bangladesh, lifetime mortality risk from UBC was at least doubled. In a more recent analysis, a long-term impact of arsenic pollution was observed in Chile; >20 yr after cessation of such pollution, UBC mortality was significantly higher in affected regions (HR: 3.6; 95% CI, 3.0–4.7)  .
3.2.6. Gender, race, and socioeconomic status
With regard to gender, women have a lower UBC incidence (up to four-fold, as reported by Fajkovic et al.  ) and a higher mortality rate than men. While the lower UBC incidence is likely to represent historically lower smoking prevalences and less occupational exposures to carcinogens in women, the reasons for the higher mortality rate are unclear. Palou et al. found female gender to be an adverse prognosticator of time to recurrence, progression, and cancer-specific survival in patients with pT1 UBC undergoing UBCG therapy (death due to UBC HR: 3.53; p = 0.004)  . May et al. report reduced cancer-specific survival in women following cystectomy for muscle-invasive UBC compared with men, with a trend to equal results in later time periods of treatment (HR: 1.35; p = 0.048)  . While there is no uniform theory to explain these phenomena, unequal access to health care, delays in diagnosis and treatment, environmental exposure to carcinogens, and anatomic and hormonal factors have been suggested.
Few data on the impact of race on UBC incidence exist. However, African Americans show a lower age-standardized incidence rate per 100 000 of 13, compared with 22 in white individuals in the United States, and black race has been reported to be associated with adverse stage at initial presentation and reduced survival in a recent Surveillance Epidemiology and End Results (SEER) analysis (5-yr disease-specific survival: whites, 82.8%; blacks, 70.2%; Hispanics, 80.7%; Asian/Pacific Islanders, 81.9%)  .
In a further SEER analysis, marital status has been reported to affect UBC survival, as married men had better survival than unmarried men independent of other factors such as race, socioeconomic status, comorbidities, or aggressive treatment  . Low socioeconomic status has been related to unfavorable UBC-specific survival in an analysis of patients receiving social welfare medical aid in a recent analysis, while previous reports did not find such an effect  . While no stringent explanations have been established for these phenomena, reduced access to health care and increased exposure to the main UBC-related carcinogen—that is, smoking—have been postulated.
3.2.7. Medical conditions
Medical conditions may predispose individuals to bladder tumorigenesis through direct causation or as a side effect of treatment. Examples of direct causative roles include (1) chronic urinary retention and upper tract dilation increasing urothelial exposure to carcinogens and (2) carcinogenesis associated with chronic inflammation or schistosomiasis (a chronic cystitis that is based on recurrent infection with a parasitic trematode and is endemic in some parts of northern Africa, mainly squamous cell, as opposed to urothelial cell, carcinomas).
With regard to treatment, UBC may arise as a consequence of exposure to ionizing radiation and pharmaceutical agents. Recently, Abern et al. found an increased age-standardized incidence rate of UBC following external-beam radiotherapy for prostate cancer (HR: 1.70; 95% CI, 1.57–1.86)  . Two pharmacologic agents have also been related to UBC; cyclophosphamide is an alkylating agent mainly applied in lymphoma and leukemia, and a long-term increase in UBC incidence has been suggested in older literature. The use of 2-mercaptoethane sulfonate Na (mesna) can reduce this risk. Pioglitazone, an antidiabetic drug of the thiazolidinedione class, has been found to have a weak relation to UBC incidence with longer-term use (HR: 1.4; 95% CI, 1.03–2.0)  . For diabetes mellitus, an increased UBC incidence has been reported, which was greater with longer duration and use of oral hypoglycemic medication (HR: 2.2; 95% CI, 1.3–3.8)  .
UBC is a common malignancy. Most data available are based on retrospective analyses, and each risk factor for UBC has to be seen in light of genetic–environmental interactions to better evaluate its impact. It is evident, however, that UBC will remain frequent because of the ongoing high prevalence of smoking, which represents its main risk factor. The importance of primary prevention needs to be stressed, and smoking cessation programs should be encouraged and supported.
Author contributions: Maximilian Burger had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Burger, Lotan.
Acquisition of data: Burger, Catto, Grossman, Kiemeney, Shariat, Lotan.
Analysis and interpretation of data: Burger, Catto, Dalbagni, Grossman, Herr, Karakiewicz, Kassouf, Kiemeney, La Vecchia, Shariat, Lotan.
Drafting of the manuscript: Burger, Lotan.
Critical revision of the manuscript for important intellectual content: Burger, Catto, Dalbagni, Grossman, Herr, Karakiewicz, Kassouf, Kiemeney, La Vecchia, Shariat, Lotan.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: None.
Other (specify): None.
Financial disclosures: Maximilian Burger certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
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a Department of Urology and Pediatric Urology, Julius-Maximilians-University Medical Center, Würzburg, Germany
b Academic Urology Unit, Royal Hallamshire Hospital, Sheffield, UK
c Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
d Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
e Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Centre, Montreal, QC, Canada
f Department of Urology, McGill University, Montreal, QC, Canada
g Department of Epidemiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
h Department of Epidemiology, Mario Negri Institute for Pharmacological Research, University of Milan, Milan, Italy
i Department of Urology, Division of Medical Oncology, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY, USA
j Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA
Corresponding author. Department of Urology and Pediatric Urology, Julius-Maximilians-University Medical Center, Oberdürrbacherstr. 6, 97080 Würzburg, Germany. Tel. +49 931 201 320 12; Fax: +49 931 201 320 13.
© 2012 European Association of Urology, Published by Elsevier B.V.