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Platinum Priority Review Bladder Cancer

Epidemiology and Risk Factors of Urothelial Bladder Cancer


Maximilian Burger a,*, James W.F. Catto b, Guido Dalbagni c, H. Barton Grossman d, Harry Herr c,
Pierre Karakiewicz e, Wassim Kassouf f, Lambertus A. Kiemeney g, Carlo La Vecchia h,
Shahrokh Shariat i, Yair Lotan j
a

Department of Urology and Pediatric Urology, Julius-Maximilians-University Medical Center, Wurzburg, Germany;

Hallamshire Hospital, Sheffield, UK;

Academic Urology Unit, Royal

Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA;

Department of Urology,

University of Texas MD Anderson Cancer Center, Houston, TX, USA; Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Centre,
Montreal, QC, Canada; f Department of Urology, McGill University, Montreal, QC, Canada;

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

Article info

Abstract

Article history:
Accepted July 12, 2012
Published online ahead of
print on July 24, 2012

Context: Urothelial bladder cancer (UBC) is a disease of significant morbidity and


mortality. It is important to understand the risk factors of this disease.
Objective: 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.
Evidence acquisition: A literature search in English was performed using PubMed.
Relevant papers on the epidemiology of UBC were selected.
Evidence synthesis: 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 signicant
inuence of genetic predisposition on incidence.
Conclusions: UBC is a frequently occurring malignancy with a signicant 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.
# 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Keywords:
Urothelial bladder cancer
Epidemiology
Risk factors
Genetics
Smoking
Occupation

* Corresponding author. Department of Urology and Pediatric Urology, Julius-Maximilians-University


Medical Center, Oberdurrbacherstr. 6, 97080 Wurzburg, Germany. Tel. +49 931 201 320 12;
Fax: +49 931 201 320 13.
E-mail address: Burger_M2@klinik.uni-wuerzburg.de (M. Burger).

1.

Introduction

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 [1]. This
frequency, coupled with the relapsing nature of UBC,
means that UBC poses an enormous burden on health care
systems [2]. Approximately 75% of newly diagnosed UBCs

0302-2838/$ see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.eururo.2012.07.033

Please cite this article in press as: Burger M, et al. Epidemiology and Risk Factors of Urothelial Bladder Cancer. Eur Urol (2012),
http://dx.doi.org/10.1016/j.eururo.2012.07.033

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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 [3,4].
Several reviews have focused on the clinical challenges
in managing bladder cancer (BCa) [57]. 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 [3,4].

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 Figures 1
and 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 [1]. 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 [8]. 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

Fig. 1 Estimated age-standardized (European) incidence and mortality rates from urothelial bladder cancer per 100 000 in (A) men and (B) women
(GLOBOCAN). From Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC
CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr.

Please cite this article in press as: Burger M, et al. Epidemiology and Risk Factors of Urothelial Bladder Cancer. Eur Urol (2012),
http://dx.doi.org/10.1016/j.eururo.2012.07.033

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Fig. 2 Estimated age-standardized (world) incidence and mortality rates from urothelial bladder cancer per 100 000 in (A) men and (B) women
(GLOBOCAN). From Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC
CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr.

and better occupational hygiene) [9]. 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 [10]. 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 [10].
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 [8].
UBC prevalence and mortality are mainly determined by
the initial tumor stage, success of treatment, and other
cause (competing) mortality. Nonmuscle-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 [1]. In the
United States, 500 000 patients with a history of UBC are
currently alive [11,12]. Mortality is mainly determined by
progression rates of high-risk nonmuscle-invasive UBC

and by cure rates of muscle-invasive UBC. Current details of


mortality are depicted in Figures 1 and 2. In 2008, UBC was
the eighth most common cause of cancer-specific mortality
in Europe [1].
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 [13], 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,

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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 [14,15]. 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], 1.101.20; and T allele of rs798766 on
4p16.3HR: 1.24; 95% CI, 1.171.32) [1517], which were
all replicated extensively [18]. 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, 1.111.22) [19].
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, 1.011.70) [20]. 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 smokingHR: 2.22; 95% CI, 2.032.44; current
tobacco smokingHR: 4.1; 95% CI, 3.74.5) [21]. There is
a direct pathophysiologic link between tobacco and
UBC. Tobacco smoke contains aromatic amines, such as
b-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 [21,22]. 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 [22].
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, 1.168.22) [23].
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 nonmuscle-invasive UBC in multivariate
analyses [24]. A similar effect has been suggested for
invasive UBC. Bostrom et al. found smokers to have worse
disease-free survival after radical cystectomy, but this was
not an independent prognostic factor [25]. Similarly, Yafi
et al. found smoking to be independently associated with
prolonged disease-specific and overall survival [26].
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 hydrocarbonsis 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

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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 [27]. A casecontrol 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, 1.617.7) [28]. No exact data on
occupational exposure exist; personal use of hair dye has
been related to UBC risk to a lesser extent. In a populationbased casecontrol study, Koutros et al. found no relation
between hair dye use and UBC risk in women but did find
evidence of geneenvironment 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, 1.632.6) [29]. A recent
population-based casecontrol study by Ros et al. found no
relation between personal hair dye use and UBC incidence
(HR: 0.87; 95% CI, 0.651.18) [30].
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 casecontrol 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, 0.330.66) [31]. 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 casecontrol studies
[32]. 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, 0.861.45) [33].
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 casecontrol study and found only a modest
increase in risk among coffee drinkers, which was
confounded by smoking [34]. In a recent meta-analysis of

16 casecontrol and 3 cohort studies, Pelucchi et al. found


no association between amount of alcohol consumption and
UBC risk [35]. 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 [36].
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, 1.001.69) [37].
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
[38]. 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 [39]. A recent smaller casecontrol 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 a-linolenic acid and vegetable fat
intake (HR: 0.26; 95% CI, 0.100.65) [40]. 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 [41].
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, 3.04.7) [42].
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. [43]) 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

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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)
[44]. 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) [45]. 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 diseasespecific survival: whites, 82.8%; blacks, 70.2%; Hispanics,
80.7%; Asian/Pacific Islanders, 81.9%) [46].
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 [47]. 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 [48]. While no stringent explanations have been
established for these phenomena, reduced access to health
care and increased exposure to the main UBC-related
carcinogenthat is, smokinghave been postulated.

greater with longer duration and use of oral hypoglycemic


medication (HR: 2.2; 95% CI, 1.33.8) [51].
4.

Conclusions

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 geneticenvironmental 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.
Supervision: Lotan.
Other (specify): None.
Financial disclosures: Maximilian Burger certies that all conicts of

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, 1.571.86) [49]. 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, 1.032.0) [50]. For diabetes mellitus, an
increased UBC incidence has been reported, which was

interest, including specic nancial interests and relationships and


afliations relevant to the subject matter or materials discussed in the
manuscript (eg, employment/afliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties,
or patents led, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.

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