In most populations, bladder cancer is 3–4 times more common in men than in women (Parkin et al., 1999). This reflects the more frequent exposure of men to tobacco smoking and to occupations that imply contact with certain chemicals, such as aromatic amines, which are the two major recognized risk factors for bladder cancer (Matanoski and Elliott, 1981;Ross et al., 1996;Silverman et al., 1996;La Vecchia and Airoldi, 1999).
Transitional cell carcinoma (TCC) is by far the most frequent histotype, although the distribution of histotypes varies in different populations. In American White populations, 93% of all bladder cancers were TCC, while they comprised 85% in American Black populations and even less in Egypt (La Vecchia and Airoldi, 1999). Tobacco and occupation, however, are risk factors also for non-TCC of the bladder (Kantor et al., 1988;Fortuny et al., 1999).
Most bladder carcinogens exert their action by direct contact with the bladder epithelium. Inhaled or ingested compounds that are either directly carcinogenic or can be transformed by the body in carcinogenic by-products are excreted via the urine, and in this way they reach the urinary bladder (Cohen, 1995). There is also evidence that chronic inflammation, caused either by infections or by stones, has a role in the promotion of bladder cancer (Burin et al., 1995).
The interpretation of incidence rates of bladder cancer is difficult, since it is not easy to distinguish between papillomas and malignant tumour, and thus the rates recorded in various cancer registries may partly reflect different diagnostic criteria (Hankey et al., 1991;Lynch et al., 1991). This caution notwithstanding, the highest incidence rates are recorded in Europe and North America, although North Africa and Western Asia are also high-risk areas (Parkin et al., 1999).
In Europe, the highest incidence rates for men were recorded in northern Italy, Spain and Geneva, Switzerland, with rates of over 30 per 100 000 men, while rates were intermediate in the UK, Germany and France and low in several eastern and northern European countries as well as in most other Swiss registration areas (Levi et al., 1998). The highest mortality rates in men were around 9/100 000 men in Denmark, Italy, Malta and Spain, while low rates (around 4/100 000 men) were recorded in Sweden, Finland and Iceland. In women, the highest mortality rates were between 2 and 3/100 000 women and were recorded in Denmark and the UK (Levi et al., 1998).
With regard to time trends, incidence rates tended to increase in both sexes in the United States in the period 1969–1990, whereas mortality tended to decline, particularly in men (Silverman et al., 1996). In Europe, mortality rates increased in southern and Eastern Europe between the mid-1950s and the late 1980s, while a decline was observed in several northern European countries over the last two decades (La Vecchia et al., 1992;Levi et al., 1999). This pattern was similar to that of lung cancer, and underlines the importance of tobacco smoking as an aetiologic factor, as well as the size of the tobacco-related cancer epidemic in Eastern Europe (Levi et al., 1999).
Cigarette smoking and occupational exposure to aromatic amines are known risk factors for bladder cancer. Several other factors (Table 1
) may influence bladder carcinogenesis (Matanoski and Elliott, 1981;Ross et al., 1996;Silverman et al., 1996; La Vecchia et al., 1999). In the following sections, each factor is briefly discussed.
The association between cigarette smoking and bladder cancer has been known for several decades, and has been consistently observed in a number of case–control and cohort studies. The risk of bladder cancer in smokers is 2–4 times that of non-smokers, and increases with number of cigarettes and duration of smoking (US Office on Smoking and Health, 1982;Hartge et al., 1987;Augustine et al., 1988;Dolin, 1991). In heavy smokers, the risk increases up to fivefold as compared with never smokers. The risk is higher for smokers of unfiltered, high tar or black tobacco cigarettes than for filtered, low-tar or blond-tobacco ones (Matanoski and Elliott, 1981;Hartge et al., 1987;Wynder et al., 1988;D’Avanzo et al., 1990).
Former smokers have a 30–60% lower risk of bladder cancer than current ones, but published studies have not been totally consistent with respect to the relation of risk with time since quitting (IARC, 1985;Silverman et al., 1996). It is not clear whether exposure to tobacco, other than cigarette smoking, increases the risk of bladder cancer. Several studies reported an increased risk for pipe smokers, while the relation with cigars, snuff and chewing is still unsettled (Silverman et al., 1996).
It is not clear which of the several carcinogens contained in cigarette smoke are responsible for this association. Besides aromatic amines (Patrianakos and Hoffman, 1979), tar and selected tobacco hydrocarbons can also be carcinogenic for the bladder (Ross et al., 1996).
Several occupations have been associated with an increased risk of bladder cancer. Excesses of bladder cancer have been reported among workers employed in aromatic amine manufacture, dyestuff manufacture and use, rubber manufacture, painting, aluminium industry, leather industry and truck drivers and other drivers (Matanoski and Elliott, 1981;Moolgavkar and Stevens, 1981; IARC, 1982;IARC, 1989;Silverman et al., 1996;La Vecchia and Airoldi, 1999). A number of other occupations have also been associated with increased risk of bladder cancer, although the evidence is less convincing (Silverman et al., 1996).
Exposure to some aromatic amines, and particularly 2-naphthylamine and benzidine (IARC, 1987) is the major determinant of the excesses of bladder cancer observed in workers in several types of industries, such as dyestuff or rubber manufactures. In a study of 664 dyestuff factory workers in northern Italy exposed to 2-naphthylamine, benzidine and other aromatic amines, 41 deaths from bladder carcinoma were registered (i.e. 46 times the expected number). The large number of cases in the cohort allowed the evaluation of the role of several time factors, according to different models of carcinogenesis (Decarli et al., 1985;Piolatto et al., 1991). According to these models, workers directly involved in the manufacture of aromatic amines had a higher risk than those with an intermittent exposure. Moreover, the risk was higher for workers exposed at younger ages, also after controlling for duration. This suggests that aromatic amines may act on one of the early stages of the carcinogenic process (Armitage and Doll, 1961;Day and Brown, 1980). Thus, workers exposed to aromatic amines should be monitored several years after cessation of exposure. However, the relative risk, but not the absolute risk, tended to decrease after exposure ceased, suggesting that aromatic amines may also have a late stage effect in the process of carcinogenesis (Piolatto et al., 1991).
The presence of aromatic amines in hair dyes may explain the increased risk found in hairdressers in some studies. This has raised concern for the personal use of hair dyes, but the studies that investigated this issue have not found an increase in risk of bladder cancer associated with personal use of hair dyes (Hartge et al., 1982;IARC, 1993;La Vecchia and Tavani, 1995).
Fluid intake and water source
A higher amount of fluid intake may dilute metabolites in the urine and increase the frequency of voiding, thus reducing contact of carcinogens with the bladder epithelium. Consistent with this hypothesis, data from the Health Professionals Follow-up Study found that men in the highest fluid intake category had half the risk of bladder cancer as compared with those in the lowest one, and the protection was observed for water as well as for other fluid intake (Michaud et al., 1999a). Epidemiological results, however, are not totally consistent (Slattery et al., 1988;Brockmöller et al., 1994;Wilkens et al., 1996), perhaps because of the difficulties in measuring total fluid intake, and the issue remains therefore unsettled (Jones and Ross, 1999).
The source of the drinking water may also be important. Some studies found that drinking tap water disinfected with chlorine and containing chlorination by-products may increase the risk of bladder cancer (Kiemeney and Schoenberg, 1996;Cantor et al., 1998). Arsenic in drinking water has also been associated with increased risk of bladder cancer in Taiwan (Chen et al., 1986) and Argentina (Hopenhayn-Rich et al., 1996).
Caffeine and its metabolites, as well as several other compounds contained in coffee, are excreted in the urine, and thus, a role of coffee in bladder carcinogenesis is plausible. There is no clear evidence of a carcinogenic effect of coffee or caffeine in experimental animals (IARC, 1991). In humans, a case–control study of bladder cancer published in 1971 (Cole, 1971) reported an association with coffee consumption.
Thereafter, over 30 studies have investigated the association between coffee and bladder cancer. They generally reported a higher risk in coffee drinkers as compared with non-drinkers, but no trend with dose or duration (IARC, 1991;La Vecchia, 1993).
The largest study published to date is a case–control study conducted in 10 geographic areas of the United States on 2982 incident cases of bladder cancer and 5782 population controls (Hartge et al., 1983). It reported relative risks (RR) of 1.6 and 1.2 respectively in male and female ever-coffee drinkers with respect to non-drinkers, and the combined estimate was 1.4. Among drinkers, men in the highest consumption category had the highest odds ratio, but no evidence of any dose–response relation was noted for women.
Thus, the results from epidemiological studies exclude a strong association between coffee and bladder cancer risk, although a modest one cannot be ruled out. The question of whether this association is causal, or due to residual confounding by smoking or to an association between coffee drinking and an as yet unidentified risk factor is still unresolved. The epidemiological evidence on decaffeinated coffee is scanty and inadequate for evaluation (La Vecchia, 1993).
In 1977, a case–control study on 408 cases reported a 60% increase in risk of bladder cancer in men (but not women) who used artificial sweeteners (Howe et al., 1977). Thereafter, several other studies have investigated the issue, and in general, failed to confirm the association. The largest and more informative study was a case–control study conducted in 10 areas of the USA on over 3000 cases and over 5700 population controls (Hoover and Strasser, 1980). In that study, the RR for ever use of artificial sweeteners was 1.02 (95% CI 0.92–1.11). No association was found in men (OR = 0.99) or women (RR = 1.07), or according to type or form of artificial sweeteners, and there was no dose–response relation.
In general, the overall epidemiological evidence does not support an association between saccharin and other artificial sweeteners and bladder cancer, and the International Agency for Research on Cancer has recently changed the evaluation of saccharin from group 2B (possibly carcinogenic to humans) to group 3 (not classifiable as to its carcinogenicity to humans) (IARC, 1999).
Many compounds contained in food and their metabolites are execreted through the urinary tract, and thus a role of dietary factors in bladder carcinogenesis is plausible. Although there are some studies that have investigated the relation between diet and bladder cancer risk (Mettlin and Graham, 1979;Claude et al., 1986;Risch et al., 1988;Slattery et al., 1988Steineck et al., 1988, 1990La Vecchia et al., 1989;Mills et al., 1991;Nomura et al., 1991;Riboli et al., 1991;Vena et al., 1992;Chyou et al., 1993;Momas et al., 1994;Bruemmer et al., 1996;Wilkens et al., 1996;Michaud et al., 1999b), epidemiological data from analytical studies are relatively scanty, and most studies had a limited dietary questionnaire, that did not allow assessment of total energy, macro- and micronutrient intake (La Vecchia and Negri, 1996).
Most studies that investigated fruit and vegetable intake reported a lower risk of bladder cancer in subjects with high consumption (La Vecchia and Negri, 1996), including the Health Professional Follow-up Study, based on 252 cases of bladder cancer, which found an inverse association between bladder cancer risk and intake of cruciferous vegetables (Michaud et al., 1999b). Some (Steineck et al., 1990;Riboli et al., 1991;Vena et al., 1992) but not all (Nomura et al., 1991;Chyou et al., 1993) studies suggested a possible direct association with fat intake, and some studies found an inverse one with vitamin A and carotenoids intake (Mettlin and Graham, 1979;La Vecchia et al., 1989;Nomura et al., 1991;Vena et al., 1992). In the prospective study of atomic bomb survivors (Nagano et al., 2000) the RR was 0.6 for the highest versus the lowest level of vegetable intake, and 0.5 for fruit; both estimates were significant.
A meta-analysis of 38 articles on six dietary variables (Steinmaus et al., 2000) estimated an RR of 0.7 (95% CI 0.5–0.9) for high vegetable, of 0.8 (95% CI 0.7–1.0) for high fruit, and of 1.4 (95% CI 1.2–1.8) for high fat. No significant association was found for meat (RR = 1.0), retinol (RR = 1.0) or beta-carotene (RR = 0.9).
Epidemiological data remain inadequate to allow definite insight on the role of diet and specific dietary factors in bladder carcinogenesis (La Vecchia and Negri, 1996).
Urinary tract diseases
Several studies have found a higher prevalence of bladder cancer in areas with a high prevalence of infection with Schistosoma haematobium than in those where infection is less frequent (IARC, 1994), and the percentage of squamous cell carcinoma is higher in endemic areas (Morrison and Cole, 1982;Kantor et al., 1984;Bedwani et al., 1993). Also the few analytical studies conducted in endemic areas consistently reported an association between bladder cancer and schistosomiasis (IARC, 1994;Bedwani et al., 1998). The relation has been explained through chronic irritation of the urothelium, or altered metabolism with consequent high urinary levels of carcinogenic metabolites (Matanoski and Elliott, 1981;IARC, 1994).
Also other urinary tract infections and urinary tract stones may cause chronic irritation of the bladder epithelium, and may thus increase bladder cancer risk (Wynder et al., 1963;Dunham et al., 1968;Kantor et al., 1984;Gonzáles et al., 1991;La Vecchia et al., 1991;King and Marrett, 1996). Although the association with cystitis and other urinary tract infections has been observed in several case–control studies, it is difficult to rule out recall bias as a possible explanation. In general, most studies are consistent with an approximately doubled risk in patients with (recurrent) urinary tract infections, and with a possible role of these on one of the later stages of the process of carcinogenesis (La Vecchia and Airoldi, 1999).
In a cohort of 61 114 Swedish patients hospitalized for kidney or urethra stones followed for up to 18 years by means of record-linkage, there were 46 cases of renal pelvis or urethra cancer, and 319 cases of bladder cancer. The corresponding standardized incidence ratios were 2.5 and 1.4 respectively (Chow et al., 1997). Thus, there is some evidence that kidney and urinary stones may moderately increase the risk of bladder cancer in humans, as they do in rodents (La Vecchia and Airoldi, 1999). Microsatellite alterations, moreover, have been reported in urinary sediments from patients with cystitis and bladder cancer (Christensen et al., 2000).
Heavy consumption of phenacetin-containing analgesics has been linked to increased risk of bladder cancer, while results for acetaminophen are reassuring (Derby and Jick, 1996;Silverman et al., 1996). In a case–control study of 1514 cases from Los Angeles, the RR was 0.81 (95% CI 0.7–1.0) for regular use of non-steroidal anti-inflammatory drugs, 1.52 (95% CI 0.9–2.7) for phenacetin, and 0.85 (95% CI 0.6–1.2) for acetaminophen (Castelao et al., 2000). Some studies found that patients treated with cyclophosphamide for non-Hodgkin's lymphoma had an increased risk of developing bladder cancer (Silverman et al., 1996). In a few studies, treatment with phenobarbital was inversely associated with bladder cancer risk, particularly among smokers (Habel et al., 1998).
Family history of bladder cancer
First-degree relatives of bladder cancer patients have an approximately double risk of bladder cancer as compared with subjects with no family history of the disease (Kjaer et al., 1989). The increase in risk appears larger when the index case is young (Kantor et al. 1985;Goldgar et al., 1994).
Biomarkers of cancer susceptibility
To exert their carcinogenic effect, aromatic amines, like most chemical carcinogens, require metabolic activation to reactive species that bind to DNA. The activation of aromatic amines is performed by certain enzymes, whose polymorphic distribution in the population may give rise to a genetically determined different individual susceptibility. In particular, N -acetyltransferase (NAT) is an enzyme whose activity may result in the detoxification of aromatic amines. In humans it is coded by two genes, named NAT1 and NAT2 (Grant et al., 1989). The NAT2 enzyme is polymorphic, and in about 50% of Caucasians, the so-called ‘slow acetylators’, the activity of this enzyme is reduced. In a case–control study of bladder cancer, a large proportion of slow acetylators was observed among cases of bladder cancer occupationally exposed to aromatic amines, but not in smoking-related bladder cancer patients (Cartwright et al., 1982). Other studies, however, reported an excess of slow acetylators in bladder cancer patients with a history of smoking (Marcus et al., 2000) or occupational exposure to aromatic amines (Risch et al., 1995;Okkels et al., 1997).
Glutathione S -transferase M1 (GSTM1) is an enzyme involved in the detoxification of a number of carcinogens. The genetically determined deletion of two copies of the gene coding for GSTM1 has been reported in about 50% of Caucasians. Individuals with no functional allele of the GSTM1 gene have been shown to be at higher risk of bladder cancer in several studies (Bell et al., 1993;Daly et al., 1993;Bruemmer et al., 1997;La Vecchia and Airoldi, 1999).
Implications for prevention
There are several factors that are known to influence bladder cancer carcinogenesis. The proportion of bladder cancer attributable to each factor (population attributable risk), however depends not only on the relative risk associated to a factor, but also on the frequency of exposure, and thus varies according to geographical area and calendar period.
Cigarette smoking is the major identified cause of bladder cancer. The proportion of cases attributable to tobacco was about 80% in men and 30% in women in a study in Great Britain (Monson and Christiani, 1997), about 50% in men and 30% in women in a study from the United States (Hartge et al., 1987), around 70% in men and 30% in women in a study from Italy (D’Avanzo et al., 1995) and over 70% in men (but very low in women) in Alexandria, Egypt (Bedwani et al., 1997). Clearly, reducing cigarette smoking is an imperative for prevention of bladder cancer.
Occupational exposure to aromatic amines and other chemicals has been estimated to cause 5–10% of bladder cancers in Great Britain and North America (Monson and Christiani, 1997). In several developed countries, the control of occupational exposure to bladder carcinogens has probably led to a substantial decrease of the proportion of cases of bladder cancer due to occupational factors, and this reduction may become even more evident in the next decades, when the effects of exposure that occurred decades ago will affect incidence rates to a smaller degree. Less information is available for some other heavily industrialized areas of the world, where measures to reduce occupational hazard may still not be adequate (La Vecchia and Airoldi, 1999).
Reduction of infection by Schistosoma haematobium is an important preventive measure in endemic areas, such as, for instance, Egypt and Tanzania. It is difficult to quantify the potential for prevention of reducing urinary tract infections in other populations.
Selected aspects of diet may influence bladder carcinogenesis but – apart from a possibly favourable effect of vegetable and fruit consumption – available data are still inadequate to provide indications for prevention.
IARC (International Agency for Research on Cancer) 1982
This work was conducted with the contributions of the Italian Association for Cancer Research and Mrs Angela Marchegiano Borgomainerio. The authors wish to thank Ms. M. Paola Bonifacino for editorial assistance.
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