Cause–effect? Understanding the risk factors associated with bladder cancer

Keywords::

• associations
• bladder cancer risks
• causal factors

With the highest incidence rates found in North America and Europe, bladder cancer is considered the 11th most common cancer worldwide, and the seventh most prevalent [101]. Understanding the risk factors associated with urothelial carcinoma of the bladder, by far the most common pathologic subtype, is of paramount importance as this disease poses a tremendous burden on health systems worldwide, owing partly to the fact that it is the most expensive cancer to treat on a per patient basis from diagnosis until death [1]. This is not surprising given the high prevalence and recurrence rates of this disease, and the need for frequent monitoring. Associations between risk factors and type of cancer are easily detected. However, establishing a cause–effect relationship between a particular risk factor and any type of cancer remains a challenge as there can be no randomized trials testing for this. However, it is certainly true that a cause–effect relationship can be established via a series of strong associations and other overwhelming evidence in an approach based on the weight of existing evidence. This includes establishing carcinogenicity in animal models, known patterns of human uptake, well-observed mechanisms of molecular action, observations derived from epidemiological studies and other pertinent data. Causal relationships can also be both established and validated via phenotype-specific molecular biomarkers employed in prospective epidemiological studies. These studies can also serve to highlight how individual genetic polymorphisms lead to a difference in susceptibility to various carcinogens, giving further credence to the impact of genetic-environment interactions [2]. All this is indeed true of bladder cancer, allowing us to broadly divide risk factors into causal factors and associations.

Causal factors

Many bladder cancer cases remain sporadic, developing in patients with no identifiable risk factors. In spite of this, solid epidemiological data and multiple studies and observations allow us to identify causative factors responsible for bladder cancer.

Social & environmental factors

Smoking is the most important risk factor associated with the development of bladder cancer, and there is a direct causative link between exposure to tobacco smoke and the development of urothelial carcinoma. Tobacco smoke contains over 60 carcinogenic compounds including polycyclic aromatic hydrocarbons and aromatic amines, substances that are excreted by the kidney, known to be harmful to the urinary tract, and cause bladder cancer [3]. This occurs due to genetic damage secondary to DNA adduct formation. Despite aggressive smoking cessation campaigns, mainly in the developed world, as well as the obvious risks associated with this horrid habit, the laxity towards tobacco advertising and the relative ease by which these products can be obtained does little to mitigate the effects of smoking and simply shifts smoking populations towards less-educated and less-developed regions. It is also rather unfortunate that tobacco companies are allowed to market their harmful products in ways that can obviously be appealing to younger potential customers, including flavoring of products and ‘light’ tobacco. Unlike lung cancer, where an obvious association with smoking is evident because of inhalation, understanding the link between smoking and bladder cancer is more complex and this inevitably leads to less awareness of this deadly disease. It is estimated that smoking increase the risk up to six-times and accounts for 50% of bladder cancer cases, with both duration and intensity of smoking linked to an increased risk of disease [4]. This is why smoking cessation is crucial in reducing the incidence of urothelial carcinoma.

Environmental exposure to various offending and infectious agents is also associated with the development of bladder cancer. Exposure of humans to arsenic concentrations of over 200 µg/l in drinking water in countries such as Bangladesh, Taiwan, China, Argentina and Chile has been confirmed in epidemiological studies to be associated with an increased risk of bladder cancer. Although the exact mechanism of carcinogenesis remains unclear, it is postulated that arsenic inhibits cellular respiration and induces DNA damage through release of free radicals and reactive oxygen species [5,6]. In addition, human exposure to the Schistosoma parasite through infected river and ground water in endemic regions in Africa such as Egypt and Sudan leads to the development of squamous cell carcinoma, the second most common pathologic subtype of bladder cancer, and a disease with an inherently aggressive nature. The dramatically higher incidence rates of this disease in these regions compared to the rest of the world is clearly indicative of the link between squamous cell carcinoma and schistosomiasis [7].

Occupational hazards

Numerous occupations are known to expose workers to various carcinogenic compounds, many of which have been shown to increase the risk of developing urothelial carcinoma. This causal link is supported by over two centuries of epidemiological data and case–control studies, starting with an observation by Rehn in the late 19th century [6]. High-risk occupations include miners, glassmakers and rubber workers [8]. Up to 27% of bladder cancers can be attributed to industrial toxins, including aromatic amines such as benzidine and 2-naphthylamine [9]. These compounds can bind to DNA and are found in everything from byproducts of chemical, rubber and dye industries to plastics, fungicides and vehicle exhausts. However, it is still debatable whether chronic personal use of hair dye leads to the development of bladder cancer [5,10].

Medical conditions & exposure

Although further prospective studies are warranted, there is enough evidence to suggest that chronic irritation to the urothelium increases the risk of developing bladder cancer. Recurrent urinary tract infections and gonorrhea infections lead to an increased risk of bladder cancer. Chronic catheter use and bladder stones are also associated with an increased risk of bladder cancer, although the mechanisms remain unknown. Certain medical conditions such as chronic urinary retention can directly cause bladder cancer by increasing the exposure of the urothelium to carcinogens [10,11,12]. A recent case–control study also revealed an increased risk of bladder cancer among diabetics, more so in those taking oral hypoglycemics and those with diabetes for a longer duration. More recently, the antidiabetic drug pioglitazone has been found to be associated with an increased risk of bladder cancer [13,14]. Although this needs to be further validated, the strength of evidence available allows us to classify this drug as causal.

Patients exposed to pelvic radiation treatment for various cancers including prostate, cervical and colorectal are at increased risk of developing bladder cancer even after a latency period of up to 30 years. Cyclophosphamide, through its mutagenic metabolite phosphoramide mustard, causes bladder cancer in patients exposed to it. The addition of the organosulfur mesna (2-mercaptoethane sulfonate sodium) to chemotherapeutic regimens helps to alleviate the carcinogenic effects of cyclophosphamide on the bladder [15,16].

Factors associated with bladder cancer

Understanding the link between genetic, racial and other factors and the development of bladder cancer still requires further research, particularly due to the complexity of environment-genetic interactions. However, it is clear that an association between those factors and bladder cancer does exist.

Genetic & racial factors

The risk of developing urothelial carcinoma in first-degree relatives of patients affected with the disease is twofold higher. In addition, several genetic polymorphisms have been linked to bladder cancer, some of which may explain the racial disparity in the incidence of this disease. Both the slow N-acetyltransferase (NAT-2) and null glutathione S-transferase Mu 1 (GSTM1) mutations lead to higher levels of carcinogens such as 3-aminobiphenyl, thereby conveying an increased susceptibility of the genitourinary tract to environmental toxins. NAT-2 is an enzyme responsible for the detoxification of aromatic amines found in tobacco smoke. Consequently, smokers with the slow NAT-2 phenotype have a higher risk of bladder cancer. This further points to the complex genetic–environment interaction, with genetic disposition altering individual susceptibility to carcinogens, in this case tobacco smoke [6,10]. More recently, bladder cancer has been linked to mutations in the ubiquitous FGFR3 oncogene and the SLC14A gene [10].

Bladder cancer is also up to four-times more common in men than in women, with the incidence higher in Caucasians than in African–Americans. The reasons for this gender disparity partially include the historically lower prevalence of smoking among women, as well as the higher exposure to industrial carcinogens in men. However, with less men smoking and with more women taking up smoking, the difference in prevalence of smoking between both sexes has become smaller. This, along with the increasing incidence of bladder cancer among women is further indicative of the detrimental effects of smoking and points to a long latency period of over 30 years for the development of bladder cancer [10,17]. However, smoking does not solely explain the difference in bladder cancer risk between sexes, pointing more to gender-specific susceptibility to bladder cancer. Furthermore, despite the higher male preponderance, recent data suggest that female gender is to be a prognostic factor for worse cancer-specific survival following diagnosis with bladder cancer. One possible hypothesis may be differing hormone levels between males and females [18]. It is difficult to understand this racial and gender disparity in survival, although it does seem to stem from a complex interaction between individual genetics and exposure to various environmental factors. Despite lower incidence rates, being of a black race has also been shown to be associated with worse survival. More recently, marital status and socioeconomic status have been shown to be associated with survival in bladder cancer patients [19,20].

Dietary considerations

It is postulated that an increased fluid intake lowers the exposure of the urinary tract to renally excreted carcinogens via dilution and more frequent voiding; however, there are no concrete studies neither to support nor refute this hypothesis. There is also inconclusive data on whether the consumption of fruits and vegetables or certain supplemental vitamins and minerals decreases the risk of bladder cancer, though it is a healthy diet. The consumption of alcohol has been linked to the formation of certain cancers, but not bladder cancer. In addition, most studies that show a link between coffee drinking and bladder cancer are confounded by smoking [10,21,22]. There is also no evidence to confirm that the chronic use of the analgesics phenacetin and acetaminophen or the consumption of large quantities of artificial sweeteners leads to the formation of bladder cancer [23].

Summary

Bladder cancer is common in both males and females. It is associated with and known to be caused by several important risk factors, most notably smoking, occupational and environmental exposure to carcinogens, as well as conditions leading to chronic bladder irritation. Genetic and hereditary factors continue to be elucidated. A strong understanding of those risk factors is important in disease prevention. Without a doubt, stricter measures need to be enforced to curb tobacco use.

Financial & competing interests disclosure

W Kassouf is a recipient of a Research Scholar Award from the Fonds de la Recherche en Santé du Québec. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.