Bladder cancer (BC) is the seventh most commonly diagnosed cancer in the male population worldwide, and it is the tenth when both genders are considered. The worldwide age-standardised incidence rate (per 100,000 person/years) is 9.5 in men and 2.4 in women. In the European Union, the age-standardised incidence rate is 20 in men and 4.6 in women. Worldwide, the BC age-standardised mortality rate (per 100,000 person/years) is 3.3 for men vs. 0.86 for women. Bladder cancer incidence and mortality rates vary across countries due to differences in risk factors, detection and diagnostic practices, and variations in access to, and delivery of, healthcare. Additionally, epidemiological variations have been attributed to differing methodologies and the quality of data from individual datasets. The incidence and mortality of BC has decreased in some registries, possibly reflecting the decreased impact of causative factors. Approximately 75% of patients with BC present with a disease confined to the mucosa (stage Ta, CIS) or submucosa (stage T1); in younger patients (< 40 years of age), this percentage is even higher. Patients with TaT1 and CIS have a high disease prevalence due to long-term survival in many cases and lower risk of cancer-specific mortality compared to patients with T2-4 disease.
Main risk factors
Tobacco Tobacco smoking is the most important risk factor for BC, accounting for approximately 50% of cases. The aromatic amines and polycyclic aromatic hydrocarbons within the tobacco smoke, which undergo renal excretion, are linked to the development of BC. The risk of BC increases with smoking duration and intensity. Low-tar cigarettes are not associated with a lower risk of developing BC. The risk associated with electronic cigarettes has not been adequately assessed; however, carcinogens have been identified in the urine with electronic cigarettes. ‘Second-hand’ exposure to tobacco smoke is also associated with an increased risk of BC.
Occupational exposure Occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons and chlorinated hydrocarbons is the second most important risk factor for BC, accounting for about 10% of all cases. This type of occupational exposure occurs mainly in industrial plants which process paint, dye, metal, and petroleum products. In developed industrial settings these risks have been reduced by work-safety guidelines; therefore, chemical workers no longer have a higher incidence of BC compared to the general population. Recently, greater occupational exposure to diesel exhaust has been suggested as a significant risk factor (odds ratio [OR]: 1.61; 95% confidence interval [CI]: 1.08–2.40).
Genetic Family history seems to have little impact. To date, no clinically relevant genetic alteration has been linked to BC. Genetic predisposition may lead to a higher susceptibility to other risk factors, and thereby explain the familiar clustering of BC in first- and second-degree relatives (hazard ratio [HR]: 1.69; 95% CI: 1.47−1.95) that has been confirmed more recently [31]. A recent study identified three single nucleotide polymorphisms related to the development of aggressive NMIBC. Currently, there is insufficient evidence to support genetic screening for BC.
Dietary habits Dietary habits seem to have limited impact on the risk of developing BC. A protective impact of flavonoids has been suggested. The Mediterranean diet, characterised by a high consumption of vegetables and nonsaturated fat (olive oil) with moderate consumption of protein, has been linked to some reduction of BC risk (HR: 0.85, 95% CI: 0.77−0.93). Western diet (high in saturated fats) and organ meat has been shown to increase the risk of BC in a recent meta-analysis. The impact of an increased consumption of fruits has been suggested to reduce the risk of BC. This effect has been demonstrated to be significant in women only (HR: 0.92, 95% CI: 0.85–0.99). Higher consumption of tea has been associated with a reduction in risk of BC but only among men with also an interaction with tobacco smoking, thus making the protective effect of this compound questionable .
Environmental exposure Although the impact of drinking habits remains uncertain, the chlorination of drinking water and subsequent levels of trihalomethanes are potentially carcinogenic. Additionally, exposure to arsenic in drinking water has been suggested to increase the risk of BC. Arsenic intake and smoking have a combined effect. However, chronic exposure to nitrate in drinking water does not seem to be associated with increased risk of BC. The association between personal hair dye use and risk of BC remains uncertain; an increased risk has been suggested in users of permanent hair dyes with a slow NAT2 acetylation phenotype but a large prospective cohort study could not identify an association between hair dye and risk of cancer and cancer-related mortality.
Other The impact of metabolic factors (body mass index, blood pressure, plasma glucose, cholesterol, and triglycerides) remains uncertain However, data suggest that high circulating levels of vitamin D are associated with a reduction in the risk of BC . Schistosomiasis, which is an infection caused by a parasitic trematode, can lead to BC. Exposure to pelvic ionizing radiation is associated with an increased risk of BC. In a retrospective analysis of patients with localised prostate cancer, external beam radiotherapy was independently associated with the risk to develop a second primary BC. A weak association was also suggested for cyclophosphamide and pioglitazone.
Bladder cancer is the 7th most commonly diagnosed cancer in males, whilst it drops to 10th position when both genders are considered. The worldwide age-standardised incidence rate (per 100,000 person/years) is 9.5 for men and 2.4 for women. In the European Union, the age-standardised incidence rate is 20 for men and 4.6 for women. In Europe, the highest age-standardised incidence rate has been reported in Belgium (31 in men and 6.2 in women) and the lowest in Finland (18.1 in men and 4.3 in women). Worldwide, the BC age-standardised mortality rate (per 100,000 person/years) was 3.3 for men vs. 0.86 for women in 2012. Bladder cancer incidence and mortality rates vary across countries due to differences in risk factors, detection and diagnostic practices, and availability of treatments. The variations are, however, also partly caused by the different methodologies used in the studies and the quality of data collection. The incidence and mortality of BC has decreased in some registries, possibly reflecting the decreased impact of causative agents. Approximately 75% of patients with BC present with disease confined to the mucosa (stage Ta, carcinoma in situ [CIS]) or submucosa (stage T1). In younger patients (< 40 years) this percentage is even higher. Patients with TaT1 and CIS have a high prevalence due to long-term survival in many cases and lower risk of cancer-specific mortality (CSM) compared to T2-4 tumours.
Tobacco smoking Tobacco smoking is the most well-established risk factor for BC, causing 50–65% of male cases and 20–30% of female cases. A causal relationship has been established between exposure to tobacco and cancer in studies in which chance, bias and confounding can be discounted with reasonable confidence. The incidence of BC is directly related to the duration of smoking and the number of cigarettes smoked per day. A meta-analysis looked at 216 observational studies on cigarette smoking and cancer published between 1961 and 2003, and the pooled risk estimates for BC demonstrated a significant association for both current and former smokers. Recently, an increase in risk estimates for current smokers relative to never smokers has been described suggesting this could be due to changes in cigarette composition. Starting to smoke at a younger age increased the risk of death from BC. An immediate decrease in the risk of BC was observed in those who stopped smoking. The reduction was about 40% within one to four years of quitting smoking and 60% after 25 years of cessation. Encouraging people to stop smoking would result in the incidence of BC decreasing equally in men and women.
Occupational exposure to chemicals Occupational exposure is the second-most important risk factor for BC. Work-related cases accounted for 20–25% of all BC cases in several series and it is likely to occur in occupations in which dyes (with the exception of hair dyes), rubbers, textiles, paints, leathers, and chemicals are used. The risk of BC due to occupational exposure to carcinogenic aromatic amines is significantly greater after ten years or more of exposure; the mean latency period usually exceeds 30 years. Population-based studies established the occupational attribution for BC in men to be 7.1%, while no such attribution was discernible for women.
Radiotherapy Increased rates of secondary bladder malignancies have been reported after external-beam radiotherapy (EBRT) for gynaecological malignancies, with relative risks (RR) of 2–4. In a population-based cohort study, the standardised incidence ratios for BC developing after radical prostatectomy (RP), EBRT, brachytherapy, and EBRT-brachytherapy were 0.99, 1.42, 1.10, and 1.39, respectively, in comparison with the general U.S. population. It has recently been proposed that patients who have received radiotherapy (RT) for prostate cancer with modern modalities such as intensity-modulated RT (IMRT) may have lower rates of in-field bladder- and rectal secondary malignancies. Nevertheless, since longer follow-up data are not yet available, and as BC requires a long period to develop, patients treated with radiation and with a long life expectancy are at a higher risk of developing BC.
Dietary factors Several dietary factors have been related to BC; however, the links remain controversial. The European Prospective Investigation into Cancer and Nutrition (EPIC) study is an on-going multi-centre cohort study designed to examine the association between diet, lifestyle, environmental factors and cancer. They found no links between BC and fluid intake, red meat, vegetable and fruit consumption and only recently an inverse association between dietary intake of flavonoids and lignans and the risk of aggressive BC tumours has been described.
Metabolic disorders In a large prospective study pooling six cohorts from Norway, Sweden, and Austria (The Metabolic syndrome and Cancer project, Me-Can 2.0), metabolic aberrations, especially elevated blood pressure and triglycerides, were associated with increased risks of BC among men, whereas high body mass index (BMI) was associated with decreased BC risk. The associations between BMI, blood pressure and BC risk significantly differed between men and women. The association of diabetes mellitus (DM) with the risk of BC has been evaluated in numerous meta-analyses with inconsistent results. When analysing specific subpopulations, DM was associated with BC or CSM risk especially in men. Thiazolidinediones (pioglitazone and rosiglitazone) are oral hypoglycaemic drugs used for the management of type 2 DM. Their use and the association with BC is still a matter of debate. In a recent meta-analysis of observational studies the summary results indicated that pioglitazone use was significantly associated with an increased risk of BC which appears to be linked to higher dose and longer duration of treatment. The U.S. Food and Drug Administration (FDA) recommend that healthcare professionals should not prescribe pioglitazone in patients with active BC. Several countries in Europe have removed this agent from the market or included warnings for prescription. Moreover, the benefits of glycaemic control vs. unknown risks for cancer recurrence with pioglitazone should be considered in patients with a prior history of BC.
Bladder schistosomiasis and chronic urinary tract infection Bladder schistosomiasis (bilharzia) is the second most common parasitic infection after malaria, with about 600 million people exposed to infection in Africa, Asia, South America, and the Caribbean. There is a well-established relationship between schistosomiasis and urothelial carcinoma (UC) of the bladder, which can progress to squamous cell carcinoma (SCC), however, better control of the disease is decreasing the incidence of SCC of the bladder in endemic zones such as Egypt. Similarly, invasive SCC has been linked to the presence of chronic urinary tract infection (UTI) distinct from schistosomiasis. A direct association between BC and UTIs has been observed in several casecontrol studies, which have reported a two-fold increased risk of BC in patients with recurrent UTIs in some series. However, a recent meta-analysis found no statistical association when pooling data from the most recent and highest quality studies which highlights the need for better quality data to be able to draw conclusions. Similarly, urinary calculi and chronic irritation or inflammation of the urothelium have been described as possible risk factors for BC. A meta-analysis of case-control and cohort studies suggests a positive association between history of urinary calculi and BC.
Gender Although men are more likely to develop BC than women, women present with more advanced disease and have worse survival rates. A meta-analysis including nearly 28,000 patients shows that female gender was associated with a worse survival outcome (hazard ratio [HR]: 1.20, 95% CI: 1.09–1.32) compared to male gender after radical cystectomy (RC). This finding had already been presented in a descriptive nationwide analysis based on 27,773 Austrian patients. After their analysis the authors found that cancer-specific survival (CSS) was identical for pT1-tumours in both sexes, while women had a worse CSS in both age cohorts (< 70 years and > 70 years) with higher tumour stages. However, treatment patterns are unlikely to explain the differences in overall survival (OS). In a population-based study from the Ontario Cancer Registry analysing all patients with BC treated with cystectomy or radical RT between 1994 and 2008, no differences in OS, mortality and outcomes were found between males and females following radical therapy. The genderspecific difference in survival for patients with BC was also analysed in the Norwegian population.
Survival was inferior for female patients but only within the first 2 years after diagnosis. This discrepancy was partly attributed to a more severe T-stage in female patients at initial diagnoses. A population-based study from the MarketScan Databases suggests that a possible reason for worse survival in the female population may be that women experienced longer delays in diagnosis than men, as the differential diagnosis in women includes diseases that are more prevalent than BC. Furthermore, differences in the gender prevalence of BC may be due to other factors besides tobacco and chemical exposure. In a large prospective cohort study, post-menopausal status was associated with an increase in BC risk, even after adjustment for smoking status. This finding suggests that the differences in oestrogen and androgen levels between men and women may be responsible for some of the difference in the gender prevalence of BC. Moreover, a recent population study assessing impact of hormones on BC suggests that younger age at menopause (< 45 years) is associated with an increased risk of BC.
Genetic factors There is growing evidence that genetic susceptibility factors and family association may influence the incidence of BC. A recent population-based study of cancer risk in relatives and spouses of UC patients showed an increased risk for first- and second-degree relatives, and suggests genetic or environmental roots independent of smoking-related behaviour. Shared environmental exposure was recognised as a potentially confounding factor. Recent studies detected genetic susceptibility with independent loci, which are associated with BC risk. Genome-wide association studies (GWAS) of BC identified several susceptibility loci associated with BC risk.
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