3. EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY
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 [13,14].
3.2.1. Main risk factors
Tobacco smoking is the most important risk factor for BC, accounting for approximately 50% of cases [14,15,17-19] (LE: 3). 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 .
220.127.116.11. 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 [14,15,21,22]. 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 [14,21,22]. 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) .
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) [14,25-30] that has been confirmed more recently . 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.
3.2.3. 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 non-saturated 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) [33-38]. Western diet (high in saturated fats) and organ meat has been shown to increase the risk of BC in a recent meta-analysis [39,40]. 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 .
3.2.4. 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 [14,43] (LE: 3). 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 .
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  (LE: 3).
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 [14,43,50] (LE: 3).
The information presented in this text is limited to UC, unless otherwise specified.
3.4. Summary of evidence for epidemiology, aetiology, and pathology
Summary of evidence
Worldwide, bladder cancer (BC) is the tenth most commonly diagnosed cancer.
Several risk factors connected with the risk of BC diagnosis have been identified.
Tobacco smoking is the most important risk factor for BC.