Book chapter:تاليف د شريف سالم Bladder Cancer in Asia. Elsayed Salim

8/7/2019 Book chapter: Bladder Cancer in Asia. Elsayed Salim

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Depression) and the Caspian and Black Seas.It is bordered to the east by the Pacific Ocean,to the south by the Indian Ocean and to thenorth by the Arctic Ocean. Geographically,Asia is divided into 6 regions which are, North,Central, Southeast, Southwest, South andEast Asia. All the communities in Asia and thePacific are burdened by bladder cancer. Themore developed countries worldwidecomprise the areas shown in (Figure 1) whichare areas: 9, 10b, and 14 to 18, whereas thedeveloping countries comprise the remainder.

The terms "Westernized" and "industrialized"are sometimes used as synonyms of"developed", therefore in the Asian-Pacificregion, the developed regions could beprojected as Japan (part of Eastern Asia),Australia and New Zealand, while thedeveloping countries comprise the remainderof Asia and the Pacific islands (Figure 1).

In Asia and the Pacific region, bladder cancer

incidence data is available from cancerregistries. From 20 large "areas" of the worldregions containing most cancer registriesestimated by the International Agency forResearch on Cancer (IARC) (see the map inFigure 1), Asia is divided into 4 large areas:(Eastern Asia (area no. 10), South-EasternAsia (area no. 11), South-Central Asia (area no.12) and Western Asia (area no. 13). Moreover,the cancer registries in the Pacific region(Oceania) are divided into 3 main regions;Australia/New Zealand (area no. 18),

Melanesia (area no. 19) which includes Fiji,Papua New Guinea, Solomon Islands andVanuatu, and Micronesia Polynesia (area no.20) which includes Guam and Samua. Thedocumented cancer registries within Asia andthe Pacific region are shown in (Table 1). Theoldest population-based registries are fromJapan, Singapore, Hawai and New Zealandwhich have been reporting to the CancerIncidence in Five Continents since Volume 1;all the countries represented in the table wereincluded in the last issue in 2007, exceptKyrgyzstan (Table 1).

Worldwide, the median age-standardizedbladder cancer incidence rates/100,000population (3) for males is highest in SouthernEurope (27.1), and is in the middle forAustralia/New Zealand, Western Asia andJapan, respectively (15.5, 12.8, 7.9).

Cancer Registration in Asia and the PacificRegion

Global Comparison of Bladder CancerIncidence

Worldwide, about 77% of bladder canceroccurs in men, and the age standardizedincidence rate (ASR) is highest in industrialcountries compared to developing countries.ASR rates higher than 40 per 100,000 in themale populations were reported in SouthEurope, while the rates were between 20-30 inthe USA and Canada. In general, the lowestmedian bladder cancer ASR for males in theworld is in Asia, at approximately 70% lowerthan those in Western industrial countries.Bladder cancer incidence and mortality rates

are markedly higher in New Zealand, Australiaand Japan which are industrialized countries,and relatively high in Western Asia which isless developed. Therefore, the markedsubcontinental variations in the incidence,mortality rates and prevalence of the diseaseshould be highlighted and explained.

In this review, we discuss the bladder cancersituation in general and in different areas ofAsia and the Pacific region. As well, this reportdescribes many established risk factors forbladder cancer in Asia and the Pacific region,

for which pertinent biological mechanisms arebeing ever more clarified. For the most part,understanding the causes of bladder cancerprovides an opportunity for cancer control andpossibly early detection in the region. Thusincidence, mortality, and other data are used inthis article to offer insight into the prognosisand efficacy of handling bladder cancer. Thedata is estimated from the statistics of"Incidence of Cancer in Five Continents IX (1),Globocan 2002: Ferlay et al., 2004 (2), Parkinet al. (2005) (3), mecc (4, 5), and from

available publications in the PubMed.

The variation in the impact of bladder cancerbetween different regions of the world hasbeen studied for more than 50 years. AsianPacific countries vary a great deal in terms ofculture and differ dramatically with regards totheir level of economic development andlifestyle. While parts of Asia and the Pacificregion have highly developed countries suchas Japan, Australia and New Zealand, the

remaining countries are less developed. Thereare also great ethnic-racial variations andgenetic differences between populations evenwithin the same country. Economical vari-ations and genetic susceptibilities have majordirect impacts on bladder cancer and othercancer types causation. Asia is located east ofEurope, east of the Suez Canal in Egypt, eastof the Ural Mountains and south of theCaucasus Mountains (or the Kuma-Manych

Introduction

Background

Urinary bladder cancer (or bladder cancer) isthe world's ninth most common cancer inmales and females with the last estimatesshowing 357,000 new bladder cancer casesworldwide and about 145,000 deaths in 2002.Asia and the Pacific (Oceania) are the world'slargest and most populous continentscovering more than 33% of the earth's landarea and with approximately 4.2 billion people;both regions are hosts to about 61% of theworld's current human population (1 July 2008est.). This allows for regional differences anddiversity in the bladder cancer burden which isknown to be highest in affluent regions, andlower in the under-developing areas.

Asia has the lowest incidence rates ofbladder cancer for men and women in theworld in spite of the presence of many regionalrisk factors such as arsenic in certain areas ofSouth-Eastern and South-Central Asia, whichis carcinogenic to the liver, lung, skin andurinary bladder, as well as the presence of the

infectious disease Schistomiasis in manyparts of Western Asia that could possiblyincrease the bladder cancer rate in theseareas. The Asia Pacific region includesdifferent societies and comprises nations andcommunities divided by the "more developed"and "less developed" categories, with variousethnic-racial and genetic variations. Thus, therisk of bladder cancer (and other cancers) isevocative between one region and the other.

5.1.12 Bladder CancerElsayed I. Salim, PhD, DMedSci; Shoji Fukushima, MD, PhD

Bladder Cancer


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called urothelial carcinoma, squamous cellcarcinoma (SCC) and adenocarcinoma(Figure 5). The most prevalent type in all theAsian-Pacific countries is the UCC, while theother two types comprise less than 1-3% ofbladder cancer incidence in all regions for bothmales and females (Figure 6). UCCs may

show evidence of squamous or ade-nocarcinomatous differentiation. There arealso other rare types of bladder cancer inc-luding small cell carcinoma, carcinosarcoma,primary lymphoma, and sarcoma. UCCs arealso most prevalent in Western andindustrialized countries, and the SCCs aremore frequently seen in some Middle Easternand African countries, where urinaryschistosomiasis is an endemic disease. Indeveloped and Western countries, UCCscomprise 90%-95% of bladder tumors while

about 3%-7% are SCCs, and 1%-2% areadenocarcinomas (6). However, the ratio ofSCCs is now decreasing in developingcountries due to the control of Schistosomiasisand other factors known to cause squamousmetaplasia. For example, in Egypt, wheremore than 90% of bladder tumors were of thesquamous cell type as estimated in 1983,recently the incidence of SCC has beendecreasing due to the successful control ofSchistosomiasis in exposed societies, withcomplete eradication in some providences;

the ratio of UCC is increasing gradually

International comparisons show that Asiancountries generally (except Japan andWestern Asia) have lower rankings of bladdercancer incidence for males and femalesamong the world nations (Figures 2 and 3).The Pacific islands of Micronesia/Polynesia

and Melanesia show the lowest bladdercancer ASR in the Asian/Pacific region wherethe lowest incidence rates were recorded inMelanesia (ASR=1.8 for males and 0.5 forfemales (Figure 3).

Figure 4 shows the differences in bladdercancer ASR of incidence and mortalities

between developed and non-developedcountries in the Asian-Pacific region asextrapolated from cancer registry data fromthe Cancer Incidence In Five continents Vol.IX", IARC (1). The estimated bladder cancermedian ASR in the Asian/Pacific developedcountries (Japan, Australia and New Zealand)collectively showed higher incidence in malesand females (12.4 and 3.03 respectively) thanthe median rates of all the remaining non-developed countries collectively (8.9 for malesand 1.98 for females). The median agestandardized (AS)-bladder cancer mortalityrates in males does not vary significantlybetween developed and non-developedcountries in the region (3.55 and 3respectively), however, it was almost twice ashigh in females from developed countries thanthose from non-developed countries (Figure 4).These figures are in line with the world's trendof bladder cancer incidence data which showsbladder cancer incidence rates to be higher in

A comparison between bladder cancerASR of incidence and mortalities in thedeveloped and non-developed countries ofthe Asian-Pacific region

developed than in non-developed countries(3).

In Asian-Pacific countries, bladder cancer ishistologically divided into three main types:

Urothelial cell carcinoma (UCC) or recently

Histological Types of Bladder Cancer

Bladder Cancer

Figure 1.The 20 large areas of the world regions containing most cancer registries estimated by IARC. (3)

Table 1. The number of Asian/Pacific Countries and Registries in the Series of Nine Volumes of the CancerIncidence in Five Continents (CIV)

Vol.

I

Vol.

II

Vol.

III

Vol.

IV

Vol.

V

Vol.

VI

Vol.

VII

Vol.

VIII

Vol.

IXAsia:

Japan 1 1 1 1 1 1 1 1 1

Singapore 1 1 1 1 1 1 1 1

India 1 1 1 1 1 1 1 1

Israel 1 1 1 1 1 1 1 1

China 1 1 1 1 1 1

Kuwait 1 1 1 1 1Philippines 1 1 1 1 1

Thailand 1 1 1 1

Kyrgyzstan 1

Korea 1 1 1

Viet Nam 1 1

Oman 1 1

Pakistan 1 1

Bahrain 1

Cyprus 1

Malaysia 1

Turkey 1Egypt* 1

Pacific (Oceania):

Hawai 1 1 1 1 1 1 1 1 1

New Zealand 1 1 1 1 1 1 1 1 1

Australia 1 1 1 1 1 1

French Polynesia 1 1

* Part of Egypt (Sinai Peninsula) is geographically in Western Asia


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probably due to other etiological factors suchas tobacco smoking (7).

The age-standardized incidence rates byhistological types show that UCCs, SCCs andadenocarcinomas in males are higher in WestAsia compared to other parts of Asia and the

Pacific region. The next highest rates are inOceania, while Eastern Asia had higher ratesof UCCs in males and females compared toother regions of Asia. East, South-Eastern andSouth-Central Asia have almost similarincidences of SCCs and Adenocarcinomas in

males and females (Figure 6). The lowest

incidence rates of SCCs are found in EasternAsia in both males and females, while the ratesof adenocarcinomas were not comparablebetween these three regions.

The risk factor for cancer is anything thatincreases the chance of getting cancer.Different cancers have different risk factors.For example, exposing skin to strong sunlightis a risk factor for skin cancer. Smoking is a riskfactor for many cancers, including lung andbladder cancer. But risk factors themselvesare not whole indicators for cancer initiation.Having a risk factor, or even several, does notmean the person will get cancer. Many peoplewith one or more risk factors never develop

bladder cancer, while others with this diseasehave no known risk factors. Urinary bladder isthe final exit from the body for many chemicalsthat are introduced to the body throughoccupational pollution, cigarette smoking,food and environmental pollutants. Thefollowing are the major risk factors for bladdercancer:

The strongest risk factor for bladder cancer iscigarette smoking. Smokers are more than

twice as likely to get bladder cancer asnonsmokers. Smoking causes about half ofthe bladder cancer deaths among men (48%)and almost a third of bladder cancer deaths inwomen (28%). It is estimated that in somepopulations, 50% of bladder cancer in malesand 25% of bladder cancer in females could beprevented with the elimination of cigarettesmoking (8). Some of the carcinogens (can-cer-causing chemicals) in tobacco smoke are

The Risk Factors of Bladder Cancer in the

Asian-Pacific Region

Smoking

Bladder Cancer

Figure 2.Worldwide incidence of bladder cancer in males and females

Bladder, MalesAge-Standardized incidence rate per 100,000

Bladder, FemalesAge-Standardized incidence rate per 100,000

< 3.7 < 5.4 < 9.9 < 15.6 < 37.3

GLOBOCAN 2002, IARC

< 1.1 < 1.7 < 2.9 < 3.7 < 13.8

GLOBOCAN 2002, IARC

Figure 3. Worldwide bladder cancer incidence rates (3).


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hydroxylated in the liver by CYP1A2,transported to the bladder, and then taken upby the bladder epithelium. There they mayundergo O-acetylation by NAT1, which ishighly expressed in the bladder, to form ahighly reactive species and DNA adducts.Alleles that lead to decreased NAT2 activity

and those that lead to increased NAT1 activitywould be expected to increase the cancer riskfrom arylamine exposure (11). The lack of thetwo functional NAT2 alleles in a populationconfers the slow acetylation phenotype, whichis thought to compromise the detoxificationability. For that reason, Lower et al., (1979)(12) hypothesized that slow acetylators wouldbe at an elevated bladder cancer risk. Apossible explanation for this phenomenon isthe difference in the acetylator phenotypes(NAT2) between the racial-ethnic groups. The

prevalence of the slow acetylator phenotypeamong these groups was predicted by theirbladder cancer incidences (54% of whiteswere slow acetylators versus 34% of blacksversus 14% of Asians) (10). Slow acetylatorsexhibited higher mean levels of 4-ami-nobiphenyl (ABP)-hemoglobin adducts thanrapid acetylators, regardless of race andcigarette smoking status. The formation ofthese DNA adducts is affected by liver en-zymes such as cytochrome p450 1A2(CYP1A2), N-acetyltransferase 2 (NAT2), and

glutathione S-transferase M1 (GSTM1). Someof these enzymes are also present in theurothelial cells. CYP1A2 is an inducibleenzyme that demethylates aromatic aminesand thereby increases DNA adduct formation(13). NAT2 is a major acetylating enzyme thatdetoxifies amines and thus decreases DNAadduct formation (14). These enzymes arepolymorphic in the general population; that is,there are variants of these enzymes in apopulation with slightly different molecularstructures and biologic activities. Studies have

been carried out to determine whether or notindividual variations in amine-associated DNAadduct formation are due to a particularphenotype and correlates with an increasedrisk. These studies indicate that cigarettesmokers with slow NAT2/rapid CYP1A2phenotypes were at a higher risk fordeveloping bladder cancer than those withrapid NAT2/slow CYP1A2 phenotypes (15).Similarly, smokers whose detoxifying enzyme,GSTM1, is homozygously deleted are at a 1.8-fold greater risk for developing bladder cancerthan smokers with one or two copies (16).

The demographics of tobacco smoking inthe Asian-Pacific region

According to the WHO statistics shown inTable 2, the frequency of male smokers have ahigher percentage ranging from 66.9% inChina, 60% in South Korea and Kyrgyzstan,60-65% in Turkey, and lowest in Oman at15.5%. Except for Israel, Turkey, New Zealand

absorbed from the lungs and get into the blood.From the blood, they are filtered by the kidneys

and concentrated in urine. These chemicals inthe urine damage the transitional epithelialcells lining the bladder lumen, which increasesthe chance of cancer developing. Cigarettescontain 599 possible ingredients. Whenburned, cigarette smoke contains over 4,000chemicals, with over 40 of them knowncarcinogens. There is a strong correlationbetween the number of pack-years of smokingand the risk of developing bladder cancer.Quitting smoking decreases the risk, but therisk never returns to that of a non-smoker. The

average latency between carcinogenexposure and bladder cancer development isestimated at about 20 years (8). Definitecarcinogen(s) and molecular pathway(s) have

focused on aromatic amines such as 4-aminobiphenyl (ABP) because they are found

not only in cigarette smoke but also in severalindustrial chemicals. One potential mecha-nism by which amines cause carcinogenesis isby forming DNA adducts that result intransitional mutations.

Aromatic amines are suspected to be theprimary causative agent for bladder cancer intobacco smoke (9). Monoarylamines (e.g., 4-

aminobiphenyl) may be N-acetylated by N-acetyltransferase 2 (NAT2) enzyme, which ishighly expressed in the liver, rendering themnonreactive (10). Alternatively, they may be N-

Molecular acetylation of aromatic aminesfrom tobacco smoke and genetic poly-morphism in Asian-Pacific populations

Bladder Cancer

Figure 4. Comparison of average bladder cancer incidence and mortality age-standardized rates in moreand less developed Asian-Pacific countries combined

Figure 5. Main histological types of bladder cancer.Left, TCC:transitional cell carcinoma; Middle,SCC:Squamous cell carcinoma withSchistosomahaematobium egg(arrow);Right,adenocarcinoma.

Males Femaales

Developed Non-developed Non-developedDeveloped


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Alexandria. They showed that the odds ratioswere 15.8 for male ever-smokers with a historyof urinary schistosomiasis, compared withnever-smokers without such a history, and 3.2for men ever-infected with urinary Schis-tosoma haematobium and ever-employed inhigh-risk occupations, compared with those

never-infected and with no high-riskoccupational history (18).

in Asian-Pacific populations. However, themetabolic polymorphism in the NAT2acetylation phenotype in combination withtobacco smoking could possibly explain thisphenomenon. The relationship betweencigarette smoking and bladder cancer risk is ofconsiderable interest as the relationship is

stronger among slow acetylators than amongrapid acetylators (17). Bedwani et al. (7)assumed that the levels of exposure ofpopulations to smoking may interfere in 75% ofbladder cancer causation among males from

and Australia, the frequency of femalesmokers in the Asian-Pacific countries isgenerally low, coinciding well with low bladdercancer incidence rates between females in theregion. In developed countries of the Asian-Pacific region which had higher rates ofbladder cancer in males, the smoking rate was

higher in Japan at 52.8% but was average inNew Zealand at 25% and Australia at 21.1%.In fact, these variations alone seem not to bethe only end-point indications for the directimpact of tobacco smoking for bladder cancer

Bladder Cancer

Figure 6. Asian-Pacific age-standardized bladder cancer incidence rates by histological type


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Chronic bladder inflammation

Schistosomiasis

Urinary infections, kidney and bladder stones,and other causes of chronic bladder irritationhave been linked with bladder cancer(especially squamous cell carcinomas (SCCs)

of the bladder), but they do not necessarilycause bladder cancer. Schistosomiasis, alsoknown as bilharzia, is a parasitic disease ofwhich some species may lead to chronicinflammation in the bladder. Schistosomiasisis a major health risk in the rural areas ofCentral China and Egypt and also in 75 othercountries worldwide, affecting more than 200million people, and putting more than 1 billionpeople at great risk (19). Among the differentspecies of Schistosoma inhibiting variouscountries and causing several diseases in the

liver and colorectum (20, 21), the relationshipbetween Schistosoma hematobium andurinary bladder cancer is the most important;this organism has been classified by theWHO/IARC as a "Class 1" carcinogen tohuman (22). Compared with their non-Schistosomal counterparts, Schistosoma-associated bladder carcinomas have twomajor clinicopathological features: the

rd thincidence reaches a peak in the 3 -5 decades

thof life vs. the 7 in non-endemic areas, andthere is significant increases in the ratios of

SCCs to typical UCCs. Fukushima et al.compared bladder cancer histological typesbetween the Japanese and Egyptian casesand found that the SCCs were morepredominant in Egyptian cases due to S.haematobium infections over the predominant

UCCs in Japanese cases (Table 3) (23).

The SCCs associated with Schistosoma(Figure 5) are extremely complex and hetero-geneous, exhibiting a high level of resistanceto radiotherapy and chemotherapy. However,they do not show distant metastasis in spite oftheir invasive characteristics and advanced

clinical grades. N-Nitroso com-pounds aresuspected etiologic agents in the process ofbladder carcinoma induction due to Schis-tosomiasis (24). Elevated levels of DNAalkylation damage have been detected inSchistosoma-infected carcinomas with highfrequencies of G to A transition mutations inthe H-ras gene and in the CpG sequences ofthe p53 tumor suppressor gene (25). Werecently pointed to a significant relationshipbetween oxidative stress induced by chronicinflammation after a S. haematobium infection

and nitric oxide (NO)-mediated DNAgenotoxicity in Egyptian patients (26). Wesuggested an interaction between the geneticexpression levels of NO synthase (iNOS), 8-hydroxy-deoxyguanosine (8-OHdG), andincreased DNA damage and subsequentlyrepair levels as an explanation for themolecular mechanisms predisposing toinitiation, promotion and progression ofSchistosomal bladder carcinomas (Figure 7).

Schistosomiasis and haematouria have beenrecognized since the time of the EgyptianPharaohs. This parasite is an extremely rarecause of bladder cancer in the United States

The occurrence ofSchistosoma haemato-bium

in the Asian-Pacific region

and Western countries except for someimported cases. In East Asia and the Pacificregion, S. haematobium does not exist, while itappears sporadic in the South-Eastern Asiancountries. However, it is endemic in Egypt andWestern Asia particularly in the Middle East,especially in Iraq (27), Iran (28), certain parts

of Saudi Arabia, (29) and Yemen (30). Somecases were also reported in Israel and inPalestine (31) however they were probablyimported cases. S. haematobium is alsoendemic but to a lesser extent, in the South-Central Asian countries particularly in WestIndia and Bangladesh (32, 33). Although onlyone case of imported urinary schistosomiasishas been reported from Malaysia (34)probably because the geographical location isnearer to the Middle East.

The prevalence and severity of urinary

schistosomiasis has decreased in the easternpart of South Asia. In many parts of Asia thatare endemic with schistosomiasis, theprevalence of infection has decreased in thelast two decades. In Yemen, the prevalence ofS. haematobium infection fell from 58.9% to5.8% and the frequency of heavy infectionsfrom 40.0% to 18.9% after health educationand intervention (30). Health educationsessions resulted in significant decreases inthe frequency of contact with water sourcesand greater adherence to preventive

measures. Many other studies show that aglobal inclination is under way to controlschistosomiasis. As opposed to theaforementioned studies, some reports statethat urinary schistosomiasis is still a public

Bladder Cancer

CountryPopulation

(in thousands)Adult Smoking Prevalence

Total Male FemaleJapan 127,096 33.1% 52.8% 13.4%

Singapore 4.018 15.0% 26.9% 3.1%India 1,008,937 16.0% 29.4% 2.5%Sri Lanka 18,924 13.7% 25.7% 1,7%Israel 6.040 28.5% 33.0% 24.0%Jordan 4.913 29.0% 48.0% 10.0%China 1,282,437 35.6% 66.9% 4.2%Kuwait 1.914 15.6% 29.6% 1.5%Philippines 756553 32.4% 53.8% 11.0%Thailand 62,806 23.4% 44.1% 2.6%Iran 70,330 15.3% 27.2% 3.4%Kyrgyzstan 4,921 37.8% 60.0% 15.6%Saudi Arabia 20,346 11.5% 22.0% 1.0%S. Korea 46,740 35% 65.1% 4.8%Viet Nam 78,137 27.1% 50.7% 3.5%

Oman 2,638 8.5% 15.5% 1.5%Pakistan 141,256 22.5% 36.0% 9.0%Bahrain 640 14.6% 23.5% 5.7%Cyprus 784 29.0% 38.5% 7.6%Malaysia 22,218 26.4% 49.2% 3.5%Turkey 66,668 44.0% 60-65% 20-24%Egypt* 67,884 18.3% 35% 18%New Zealand 3,778 25.0% 25.0% 25.0%Australia 19.138 19.5% 21.1% 18.0%

Youth Smoking Prevalence Cigarettes Smoked Annually(per person)

Quit RatesTotal Male Female

- - - 3,023 -

9.1% 10.5% 7.5% 1,230 -variable variable variable 129 -

9.9% 13.7% 5.8% 374 -

- - - 2,162 10.0%

20.6% 27.0% 13.4% 1.832 -

10.8% 14.0% 7.0% 1,691 10%

- - - 3,062 9%

23.3% 31.2% 17.2% 1,849 -

- - - 1,067 1%

- - - 765 20%

- - - 1,886 -

- - - 810 9%

- - - 200 -

- - - 1,025 -

- - - - -- - - 564 -

- - - 2,179 -

- - - - 11.0%

- - - 910 -

- - - 2,394 10%

- - - 1.275 50.0%

- - - 1,213 -

- - - 1,907 -

Table 2. Adult and youth smoking prevalence, cigarettes smoked, and quit rates in some Asian/Pacific countries(Source: Mackay J and Eriksen M. The tobacco atlas. Geneva (Switzerland): World Health Organization; 2002).

*Part of Egypt (S inal Peninsula) is geograophically in Western Asia


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region of Nepal, Myanmar, Taiwan, and partsof China (Figure 8). The arsenic problem inBangladesh is known as the best documentedoccurrence and has, in essence, become thereference for arsenic contamination in otherparts of the world (37).

Among the overall population of Bangladesh

for the year 2000, lifetime mortality risks (per100,000 population) of cancer of the bladder,lung, and liver were 5.4, 159.1, and 9.2 formales and 0.3, 23.1, and 9.5 for females,respectively. The overall mortality risk for the 3cancers combined was 103.5 per 100,000.Lifetime excess risks (per 100,000 population)of mortality from liver, bladder, and lungcancers attributable to arsenic in drinkingwater were 0.9, 21.5, and 175.9 for males and3.4, 2.1, and 48.3 for females, respectively.Overall lifetime excess mortality risks (per

100,000) from the 3 cancers combined were198.3 for males and 53.8 for females, with anaverage across gender lifetime risk of 126.1(38). In India, increased risks of lung andbladder cancer and of arsenic-associated skinlesions have been observed in drinking-waterarsenic concentrations of less than 0.05 mg/L(39).

In Taiwan, Chen et al. found a positivecorrelation between bladder cancer rates andblack foot disease (BFD) incidence rates (40).

They calculated higher standardized mortalityratio (SMRs) for the populations using deep

health problem which must be tacked by globalauthorities. In the last 2 decades, Egypt hassucceeded in lowering the prevalence ofSchistosomiasis from 35% in 1983 to 1.7% in2003, with a complete eradication in certaindistricts (5, 35). However, Egypt is still payingthe price for the previously high prevalence of

the disease. A comparison of the frequency ofactive urinary schistosomiasis previously re-ported during the era of the high prevalence ofthe disease and the age-specific incidencerate indicates a strong cohort effect (36). Itcould be anticipated that in the near future,there will be a marked decrease in schi-stosomal bladder cancer incidence in Egypt asa consequence of schistosomiasis control.The potential risk is the rise in incidence ofbladder cancer related to other risk factors,especially smoking (7).

Arsenic in drinking water has been associatedwith an increased risk of bladder cancer inmany Asian countries. Arsenic contaminationof groundwater has led to a massive epidemicof arsenic poisoning in Bangladesh andneighboring countries. Arsenic in drinkingwater is also a major problem in other parts ofthe world like the USA and South America. It isestimated that approximately 57 million peopleare drinking groundwater with arsenic

concentrations above the World HealthOrganization's standard of 10 parts per billion.The arsenic in groundwater is of a naturalorigin, and is released from sediments into thegroundwater due to the anoxic conditions ofthe subsurface.

Toxicity and carcinogenicity of arsenic

Elemental arsenic and arsenic compounds areclassified as "toxic" and "dangerous for theenvironment" in the European Union underdirective 67/548/EEC. The IARC recognizesarsenic and arsenic compounds as group 1carcinogens, and the EU lists arsenic trioxide,arsenic pentoxide and arsenate salts ascategory 1 carcinogens. Arsenic is known tocause arsenicosis due to its manifestation indrinking water, the most common species

2-being arsenate [HAsO ; As (V)] and arsenite4[H AsO ; As(III)]. The ability of arsenic to3 3undergo redox conversion between As(III) andAs(V) makes its availability in the environmentpossible. Arsenic can enter groundwaterthrough human activities, such as runoff from

mining wastes (37), or natural sources, suchas ferrous and nonferrous ores, in volcanic ash,and in areas of geothermal activity. In manyparts of the world, arsenic occurs ingroundwater through natural geologicalprocesses. The areas in Asia where arsenichas been found through natural processes areBangladesh/West Bengal, Mekong RiverDelta in Cambodia and southern Vietnam, RedRiver Delta near Hanoi in Vietnam, the Terai

Arsenic

artesian wells. Chen and Wang also found asignificant dose-response relation betweenbladder cancer mortality and the averagearsenic concentrations of precinct or townwells (41). They found an increase of 3.90.5bladder cancer deaths/100,000 person years

for each 100 ppb increase in the averagearsenic concentration using a population-time-weighted regression analysis. Guo et al. foundthat only the proportion of wells with arsenicconcentrations >640 ppb had a positiveassociation with the incidence of UCC of theurinary bladder (42). For every 1% increase inthis proportion, there was an increase of 0.57bladder cancers per 100,000 person years inmales in Taiwan.

Mechanisms of arsenic carcinogenicity in

the bladderRecent studies indicate that the methylated

Bladder Cancer

Histology Japan Egypt

UCC 93% 16%

SCC 5% 75%

AC 0% 5%

UC 2% 4%UCC, Urothelial cell carcinoma; SCC, Squamouscell carcinoma; AC, Adenocarcinoma; UC,Undifferentiated carcinoma.

Table 3. Histological classification of bladdercarcinomas in Japan and Egypt in 1989 (23)

Figure 7. Proposed mechanism (Salim et al., 2008) suggesting the involvement of oxidative stress andincreased levels of subsequent DNA damage during Schistosomal bladder cancer initiation and progression.


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(53) contributes to their carcinogenicity in therat liver and bladder, and is likely to play animportant role in the early stages of arseniccarcinogenesis.

Worldwide, Asians have the lowest incidence

rates of bladder cancer. However, there arevariant ethnic-racial groups in the Asian-Pacific region. Whites, Caucasians, Arabs andJews in the region are about twice as likely todevelop bladder cancer as compared to otherAsian racial-ethnic descents. In the UnitedStates, whites have a 37% greater risk thanblacks of developing bladder cancer.Conversely, localized disease is found in 72%of whites compared to only 50% of blacks.Americans of Asian descent have ratesroughly 40% lower than rates seen in Whites.

In a study of Los Angeles men, blacks had ahigher smoking prevalence than Whites orAsian Americans who had similar smokingrates. Nevertheless, white men have a bladdercancer rate twice that of Blacks and nearly 2.5times that of Asian-Americans (55). The

Race, Age and Gender

forms of arsenic are both toxic and directlycarcinogenic. Both dimethylarsinic acid [DMA(III)] and monomethylarsonic acid [MMA (III)]can cause enzyme inhibition, cell toxicity andgenotoxicity. In a review of Kitchin, hedescribed nine different possible modes ofarsenic carcinogenesis (43). These include

induced chromosomal abnormalit ies,oxidative stress, altered DNA repair, alteredDNA methylation patterns, altered growthfactors, enhanced cell prol i feration,promotion/progression, gene amplification,and suppression of p53. Bladder cancer mayresult from arsenic exposure because thisorgan contains relatively high concentrationsof DMA and MMA in the lumen. Kitchin (43)demonstrated that DMA acts as either apromoter or complete carcinogen for bladdercancer. Methylated forms of arsenic can

produce oxidative stress by creating reactiveoxygen species (ROS) that attack DNA of thebladder epithelium. Carcinogenicity of arsenicto the urinary bladder and other organs wasconfirmed in experimental animals withunderlying mechanisms likely to be affectingthe oxidative stress status besides many othergenes controlling cell cycle progression andproliferation (44). For a long time, our researchgroup has validated the carcinogenic effects ofrelated metabolites to arsenic using variousexperimental protocols in rats and mice such

as: 1. A multi-organ promotion bioassays inrats (45); 2. A 2-year carcinogenicity test ofDMA in rats (46); 3. Promotion of skincarcinogenesis by DMA in keratin (K6)/ornithine decarboxylase (ODC) trans-genicmice (47); 4. Studies on the effects of DMA onlung carcinogenesis in rats (48); 5. Promotingeffects of DMA and related organic arsenicalsin rat liver (49); 6. Carcinogenicity of DMA inp53(+/-) knockout (50) and Mmh/8-OXOG-DNA glycolase (OGG1) mutant mice (51); 7.Two-year carcinogenicity tests of mono-methylarsonic acid (MMA) and trimethylarsineoxide (TMAO) in rats (52); 8. A two-stagepromotion bioassay by DMA of rat urinarybladder and liver carcinogenesis (53) andothers. The results revealed that the adverseeffects of arsenic occurred either by promotingor initiating carcinogenesis. This data, ascovered in the present review, suggests thatseveral mechanisms may be involved inarsenic carcinogenesis, and demonstratesthat arsenic metabolites are a carcinogen forthe rat urinary bladder and other organs suchas the liver, and suggested that exposure maybe relevant to the carcinogenic risk ofinorganic arsenic in humans. Diverse geneticalterations observed in arsenic-inducedurinary bladder tumors imply that multiplegenes are involved in stages of arsenic-relatedtumor development (54). Furthermore,generation of ROS by elevation of 8-hydroxydeoxyguanosine and cell proliferationvia of oxidative stress by organic arsenicals

reason for this difference is not wellunderstood, however, the genetic poly-morphism for NAT2, GST2 and CYP1A1 givesa possible explanation for this phenomenon.

As in all parts of the world, the risk of bladdercancer in the Asian-Pacific countriesincreases with age. Over 70% of people with

bladder cancer are older than 65 with anincreasing incidence in both gender and allraces with aging (56). This gender difference inrisk exists even after accounting fordifferences in cigarette smoking andoccupational exposure to environmentalcarcinogens. Men in Asia have a 3-4 timeshigher incidence rate of bladder cancer thanwomen (Figure 9). Men have traditionally hadincreased exposures to putative bladdercancer carcinogens found in the workplaceand in cigarette smoke. However, a variety of

social trends over the past quarter century inWestern countries and in Japan would predicta relative rise of bladder cancer incidence inwomen, which has not been seen (57). Onehypothesis for the gender difference in bladdercancer risk is the difference in CYP1A2 activity.

Bladder Cancer

Figure 8. Areas in Asia and the Pacific regions affected with arsenic in ground water.(Modified from KarinKemper, Khawaja Minnatullah. Arsenic Contamination of GroundWaterin South and East Asian Countries.Study Launch - ESSD Week - April 1,2005)


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incidence rates for purposes of assessment.

Certain industrial chemicals have been linkedwith bladder cancer. Aromatic amines, such asbenzidine and beta-naphthylamine, which aresometimes used in the dye industry, can cause

bladder cancer. The industries with the highestrisks include the makers of rubber, leather,textiles, and paint products as well as printingcompanies. Other workers with an increasedrisk of developing bladder cancer includepainters, hairdressers, machinists, printers,and truck drivers because of exposure todiesel fumes. Chemotherapy and radiationtherapy could also cause bladder cancer. Highdoses of the chemotherapy drugs cyclo-phosphamide (Cytoxan) and ifosfamide (Ifex)increase the risk of bladder cancer. A drug

called mesna can be used with these drugs toprotect the bladder from irritation anddecrease the risk of bladder cancer. On theother hand, some birth defects or personalhistory of urinary tract cancer could causebladder cancer. Low fluid consumption can bealso considered as a risk factor for bladdercancer (59). People who are treated withradiation to the pelvis are more likely todevelop bladder cancer (60). Studiesconducted on women who were treated withradiation therapy for cervical cancer haveshown an increased risk for developingbladder cancer. This appeared among104,760 one-year survivors of cervical cancerwho were reported to 13 population-basedcancer registries in Denmark, Finland, Norway,Sweden, and the United States (61). Theyconcluded that the standardized incidenceratios (SIRs) for second cancers overall andcancers at particular sites were increased to astatistically significant extent (n=12,496;SIR=1.30; 95% confidence interval [CI]=1.28to 1.33). In the same study, compared with thegeneral population, in both radiotherapy

Other Risk Factors

Horn et al. observed elevated CYP1A2 activityas determined by the caffeine breath test inmen compared with women, although thisincrease was not statistically significant (58).Interestingly, they found a statisticallysignificant difference between parous andnulliparous women (P=0.03). Men and parous

women had similar caffeine breath test values.Nulliparous women, however, had lowervalues, suggesting hormones such asprogesterone may influence CYP1A2 activity.

Figure 10 presents the populations of thecountries in the 5 Asian regions registered inthe "Cancer Incidence in Five Continents Vol.IX (1)" subdivided by sex and 5-year agegroups (cohorts), averaged over the reportingperiod between 1998-2002. The age

distributions in these populations differedwidely between the different regions of theAsian-Pacific region. The percentage ofindividuals under the age of 20 is relativelyhigher in South-Central Asia (38.8% for males,39.9% for females), West Asia (38.2% formales, 37.7% for females) and South-EasternAsia (35.6% for males, 34% for females) thanEast Asia (27.4%, 25%) and the Pacific region(28.9%, 27.1), respectively. The overallpercentage of populations in all the registeredAsian-Pacific countries collectively showedthe percentage of individuals under the age of20 is 31.9% for males and 30.3% for females.Conversely, the percentage over 50 is lower inSouth-Central Asia (12.52%, 13.18%), South-Eastern Asia (15.9%, 17.1%) and West Asia(16.9%, 19.4%) for males and femalesrespectively compared to East Asia (21.9%,25.6%) and the Pacific region (26.7%, 29.1%).These reflective differences in age distributionformulate a difficult comparison of cancerincidence across the Asian-Pacific regionsusing crude incidence rates; thus, this reviewuses age standardized and age specific

Age distribution by region

(N=52,613) and no-radiotherapy groups(N=27,382), risks of smoking-related cancers(of the urinary bladder, pharynx, tra-chea/bronchus/lung and pancreas,) wereelevated to a statistically significant extent.

Despite the ongoing research in the molecularand genetic etiologies of bladder cancer, nosingle defect or marker has been identified.The genetic background is well established toplay a pivotal role in the susceptibility tobladder cancer. People who have familymembers with bladder cancer have anincreased risk of getting it themselves. Variousgenes, proteins and enzymes have beenstudied intensively since it has beendiscovered that they do play an essential role

in both the transformation of normal cells totumor cells, and the progression of non-invasive tumors to invasive and metastaticones. About 70% of the UCC patients withsuperficial tumors of stages pTa, pT1, or pTis.UCCs are of two types; superficial andinvasive UCC. A great deal of studies wereundertaken to find the molecular basis for thisdivergent disease pathogenesis of UCC. Thefollowing will briefly describe some of the morewell-studied concepts in molecular andgenetic oncology as it relates to bladdercancer and its phenotypes, grades and stages.It is important to note that most of theseconcepts have not been applied to generalmedical practice. Papillary and invasivecancers of the urinary bladder appear toevolve and progress through distinctmolecular pathways. Invasion in bladdercancer forebodes a graver prognosis, andthese tumors are generally characterized byalterations in the p53 and retinoblastoma (RB)pathways that normally regulate the cell cycleby interacting with the Rasmitogen activatedprotein kinase signal transduction pathway.

Oncogene is a gene whose protein producthas a normal function in causing cells to divide,but when out of control, can result intumorigenesis. Several oncogenes have beenidentified in bladder cancer cells. The c-myconcogene has been identified in superficialbladder tumors that have a greater tendency torecur and progress to invasive disease. Finally,the c-jun gene codes transcription factorproteins (62). These proteins are literally the

"on-off" switches for the replication genedescribed above. A mutation in the c-jun genemight lead to the inability of this so-calledswitch to be in the "on" position, resulting inuncontrolled cell replication. Mutations in theH-ras gene have been implicated in thedevelopment and progression of humanbladder cancer. Alterations involving codons12 and 61 of the ras oncogene which codes for

Molecular Biology and Genetics of BladderCancer

1) Oncogenes:

Bladder Cancer

Figure 9. Annual incidence of bladder cancer in All Asian-Pacific Regions per 100,000 by age group(date extrapolated from CIV[Curadoet al., 2007])


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Bladder Cancer

Figure 10. Age distribution in the Asian-Pacific regions(1998-2002) at all ages


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Mutations in p53 result in the production of adysfunctional protein product with a longerhalf-life than the wild-type protein. Because ofthis difference in protein longevity, p53-mutated gene products accumulate in the cellnucleus and can be easily detected byimmunohistochemical (IHC) methods. Struc-

tural alterations of the p53 gene, such asintragenetic mutations, homozygous deletions,and structural rearrangements, are frequentevents in bladder cancer (72). Structuralalterations of the p53 gene were investigatedusing single strand conformation poly-morphism (SSCP) in 25 bladder tumors, andmutations in 50% of invasive carcinomas werefound, while only 1 of 13 superficial bladdertumors had such mutations (73). Moreover,mutations were not identified in any of the 10grade 1 and 2 lesions, while 8 of 15 grade 3

bladder carcinomas were found to haveintragenic mutations. In another study (74),immunohistochemical (IHC) detectable p53protein was studied in 42 bladder carcinomas.One out of 11 (9%), 12/22 grade 2 (55%) and8/9 (89%) tumors showed positivity for p53.There were significantly more p53 positivecases in grade 2-3 tumors than in grade 1tumors. There were significantly more p53positive cases in stage T2-T4 tumors than instage T1 tumors. Another study usinginterphase cytogenetics with fluorescence insitu hybridization technique (FISH) found thatp53 deletion was significantly correlated withgrade, stage, S-phase fraction, and DNAploidy, while p53 protein overexpressioncorrelated only with grade (75). Moch et al.(76) studied the overexpression of p53 by IHCin 179 patients and found that p53immunostaining strongly correlates with tumorstage. In addition, this was driven by a markeddifference in p53 expression between pTa(37% positive) and pT1 (71%) tumors, whilethere was no difference between pT1 and pT2-4 tumors. Similarly, there was a strong overalldifference between grade 1 (28%) and grade 2tumors (71%), and there was no significantdifference between grade 2 and grade 3tumors.

All tumor cells have damaged DNA, and it islikely that p53 or a protein like it is eitherabnormally absent or malfunctioning, suchthat the cell continues to divide out of control.Both the p53 and pRb proteins are thought bysome to play important roles in determiningprognosis and survival in bladder cancer (77).

Conversely, conflicting results have beenobtained when RB status has been examinedin patients with invasive tumors (ref.),indicating perhaps that this gene may have itsprimary role in progression from superficial tomuscle invasive disease rather than furtherdown-stream in the metastatic cascade.Reduced expression of p21WAF/CYP1,p27Kip1 and cyclins D and E correlates with anincreased grade, stage, recurrence and

p21 protein have been found in up to 39% ofbladder cancers (63). A potential prognosticrole for the cHras oncogene was suggested byFontana et al. (64), where the overexpressionof the cHras oncogene was correlated withearly recurrence in patients with superficialbladder cancer. Complete loss of p53 is a

prerequisite for collaborating with cHras topromote bladder cancer (65). The HER2/neuoncogene encodes a transmembraneglycoprotein similar to epidermal growth factor(EGF) receptor, having tyrosine kinase activity(66) and the ability to stimulate cellular growth.Several studies noted an association betweenHER2/ neu expression and higher stagetumors (67), tumor progression, greaterincidence of metastatic disease and reducedoverall survival.

These genes encode proteins which work tocontrol or regulate cell growth and replication.A mutation in a tumor suppressor gene willtake the "off" switch out of the process of celldivision, leading to uncontrolled replication.Two important and well-studied tumorsuppressor genes are known as the"retinoblastoma tumor suppressor gene" (Rb)and the "p53 tumor suppressor gene".Regarding the former, despite its name, thisgene and its encoded protein, pRb, is found inmany types of tumors, not the least of whichare bladder tumors (60). Deletions of the longarm of chromosome 13, including the RB locuson 13q14, were found in 28 of 94 cases, with26 of these 28 lesions being present in muscle-invasive tumors (68). Rb alterations in bladdercancer as a function of stage was studied in 48primary bladder tumors where a spectrum ofaltered patterns of expression, fromundetectable Rb levels to heterogeneousexpression of Rb, was observed in 14 patients(69). Of the 38 patients diagnosed with muscleinvasive tumors, 13 were categorized as Rbaltered, while only 1 of the 10 superficialcarcinomas had the altered Rb phenotype.Patient survival was decreased in Rb alteredpatients compared with those with normal Rbexpression. Functional reduction of Rb isassociated with progression of bladder cancerto a more malignant and aggressive behavior(69). Further evidence for this was reportedfrom studies by Cordon-Cardo et al., (70), inwhich the loss of Rb immunoexpression wasassociated with significantly shorter survival inpatients with muscle-invasive bladder tumors.

The P53 gene, at 17p13, encodes the proteinof the same name (p53 protein). To restate,these proteins work by stopping a cell fromdividing. For example, when a mutation occurswithin a cell's DNA, levels of p53 within that cellwill rise to effectively halt that cell from furtherreplication causing cell cycle arrest (71). Thisnecessarily allows for DNA repair andprevents the propagation of DNA defects.

2) Tumor suppressor genes:

mortality in bladder cancer (78). Severalgroups have reported data suggesting that lowp27 expression with or without low cyclin Eexpression is adversely prognostic in bladdercancer (79). Decreased p27Kip1 expression isprognostic in several cancers, including breast,prostate and nonsmall cell lung cancer, and is

usually associated with increased cyclin Eexpression. The loss of p21WAF/Cip1expression was found to be associated withhigher recurrence rates and lower overallsurvival than p21WAF/Cip1-positive tumors(80).

Cells use these chemicals to communicatewith one another throughout the body. If atissue is damaged, the surrounding cells mayreact by releasing growth factors into the blood

stream or even locally within their own tissue.These complex molecules will attach to thereceptor of a nearby cell and cause a series ofreactions within it, which in this case mightlead to cell division to replace the ones thatwere damaged. Scientists have noticed thatcertain growth factors are in higherconcentration either within tumors or in theurine of patients with bladder tumors.Examples of these factors are epidermalgrowth factor (EGF), fibroblast growth factor(FGF), and transforming growth factor (TGF).Despite the ability of these growth factors tocause bladder cancer cells to grow in thelaboratory, their detection in humans have notdemonstrated any profound effect onprognosis or survival (81). Previously, it wasfound that the fibroblast growth factorreceptor3 (FGFR3) mutations were found inlow-stage/-grade tumors and were associatedwith a favorable disease course (82). FGFR3mutations were observed in 59% of theprimary UCCs, while FGFR3 and p53alterations were mutually exclusive becausethey coincided in only 5.7% of tumors. Thusthis confirms that FGFR3 and p53characterize different pathogenesis pathwaysfor UCC (83).

While urinary bladder cancer age-stan-dardized (AS) incidence rates are highest inAustralia/New Zealand and Western Asian

countries for both sexes (being 15.6, 12.8 per100,000 population in males and 4.6, 2.8 per100,000 population in females respectively),the age-standardized mortality rates arehigher in Western Asia than in Australia/NewZealand (6.8 vs 4.3 per 100,000 population formales) while they were almost similar infemales (1.3 and 1.5 per 100,000 populationrespectively) (Figure 11). The high mortalityrates in West Asia are probably due to a higher

3) Growth factors:

All Asian-Pacific median incidence andmortality rates

Incidence and Mortalities of BladderCancer in Asian-Pacific Regions

Bladder Cancer


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(Figure 13). The highest AS rates of bladdercancer incidence and mortality in South-EastAsia are in Singapore 7.3, 7/100,000population for incidence and 2.4, 2.3/100,000population for mortality in males (Table 4). Infemales, the figures of the AS incidence ratesare still higher in Singapore than in other

countries; however, the mortality rates arealmost similar to those of other countries inSouth-Eastern Asia (Table 5). The lowest ASincidence and mortality rates in males arefound in Cambodia, while in females, thelowest figures are in Bruni and in Lao.

For South-Central Asia, bladder cancer ASth

incidence and mortality rates in males rank 10th

and in females, it is ranked 13 among all othertypes of cancer in the region (Figure 13). In thisregion, the highest AS incidence and mortality

rates for males and females are seen inKazakhstan (Tables 4 and 5), while the lowestrates are in Bangladesh. Although Bangladesh

incidence of more aggressive SCCs or to amore advanced detection and medicaltreatment in Australia and New Zealand ascompared to the Western Asian countries (84).The lowest AS incidence and mortalities ofbladder cancer are found in the Pacific islands,namely Melanesia, Micronesia and Polynesia

combined together, while AS incidence andmortality rates were almost the same in East,South-East and South-Central Asia (Figure 11).In a combination of the average AS rates andmortalities in all the Asian-Pacific countries,the rates remained average, being; 7.4, 1.85for males and 3.4, 0.82 per 100,000 populationfor females respectively (Figure 12). Thisindicates that the mix of ethnic groups and theuneven distribution of risk factors in the Asian-Pacific regions rendered these rates to beaverage.

In Eastern Asia, the bladder cancer incidenceth

and mortality rates are ranked 9 among allth

cancers in males and 11 in females (Figure13). Eastern Asia which includes Japan, China,North and South Korea, and Mongoliacomprise nations of highly developed andless-developed categories. Accordingly, thedistribution of bladder cancer is evocative ofhigher incidences in Japan (7.9/100,000

population and mortality rates are 2.8/100,000population in males) (Table 4). In femaleshowever, the incidence and mortality rates inJapan are close to those of the other countriesin the region. The lowest incidence andmortality rates are seen in Mongolia (Table 5).

In South-Eastern Asia, bladder cancerth

incidence and mortality rank 11 among allth

cancer types in males and 13 in females

Median incidence and mortality rates byregion (2)

is considered to be the major problematiccoun t ry fo r d r ink ing wate r -a rsen iccontamination in the world, it is unlikely thatbladder cancer incidence in Bangladesh iscorrelated to arsenic exposure. Explanationsbased on differential susceptibility have beenproposed previously, including, for example,

genetic polymorphisms in ethnic groups ofmetabolic enzymes such as N-Acetyl-transferase and Glutathione S-transferase 1(85, 86). In Iran during a 30 year period (1973-2003), the total number of bladder cancerpatients was 603. The male/female ratio was5.8 and the mean age at diagnosis was 61.9years (63 for males and 61.4 for females, non-significant) (87). On the other hand, whenbladder cancer incidence and mortality rateswere compared among South Asians in fourgeographic regions: India, Singapore, UK andUS, (88) the total bladder cancer incidencerates were 3.2 and 0.7 per 100,000 populationamong males and females in India,respectively, (age-standardized to the 1960world population), 5.4/100,000 population formales among Singapore Indian (no data wasavailable for Singapore Indian females), and6.8 or 7.9/100,000 population for males or 2.4or 2.8/100,000 population for males(according to US Census which provided twovalues for the US Asian Indian/Pakistanipopulation at 2000) for Indians/Pakistaniesliving in the USA. Variations in environmentalexposures such as tobacco use, diet andinfection, as well as better health care accessand knowledge may explain some of theobserved incidence differences.

In Western Asia, AS incidence and mortalityth

rates for bladder cancer are ranked 4between other types of cancer in the region inmales while these values are much lower forfemales (Figure 13). The highest bladdercancer AS incidence rates for males are inIsrael (25.8/100,000 population), however the

mortality rates in Israel are within averagelevels (6/100,000 population). The highestmortality rates in males were in Armenia

Bladder Cancer

Figure 12. Comparison between median male and female bladder cancerincidence and mortalities in the all Asian-Pacific countries combined

Figure 11. Bladder cancer age-standardized rates (ASR) for incidence and mortalities in the Asian-Pacificregions per 100,000 population (data extrapolated from Globocan 2002)


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Bladder Cancer

Figure 13. Age-standardized incidence and mortality rates per 100,000 in five different subcontinental areas of Asia and the Pacific region(all ages).


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Table 4. Crude and age-standardized rates, mortalities per 100,000 population and prevalence due tobladder cancer in the Asian/Pacific regions (Males) (2).

Table 4. Crude and Age-Standardized rates, Mortalities per 100,000 Population and Prevalence Dueto Bladder Cancer in the Asian/Pacific Regions (Males) (2).

*U.A.E: United Arab Emirates.

Bladder Cancer

(15.8/100,000 populations) which also hadhigh incidence rates of 19.9/100,000populations. The lowest AS incidence andmortality rates for males in Western Asia are inOman and Kuwait (Table 4). Among females,Iraq has the highest incidence and mortalityra tes (6 .9 , 3 .6 /100 ,000 popu la t ion

respectively) while Yemen has the lowestincidence and mortality in Western Asia (1.4,0.6/100,000 population respectively). All thisdata points to considerable variations in riskfactors across Western Asia (Tables 4 and 5).

In Australia/New Zealand, the bladderth

cancer AS incidence and mortality rates are 6among all lesions in males (Figure 13). Thefigures of incidence and mortality were non-comparable between the two countries inmales or in females. The incidence andmortality of the Pacific islands of Melanesia

are as low as 1.8 and 1.3/100,000 populationsfor males and 0.5 and 0.4/100,000 populationsfor females. In Micronesia (Guam) the figuresare a little higher than Melanesia (3.1, 2.3) formales and (0.4, 0.3) for females. In Polynesia(Samoa) the incidence is 5.1 and the mortalityis 3.8/100,000 population in males and therewas no data available for females (Tables 4and 5). In general, Miller et al., (89) concludedthat overall cancer incidence rates for theAsian and Pacific Islander population groupstended to be lower than overall rates for non-

Hispanic whites. Incidence and mortality rateswere highest for Samoan and Hawaiian menand women due to high rates for cancers of theprostate, lung, liver, and stomach but not theurinary bladder among Samoan men, andcancers of the breast and lung among SamoanWomen. Asian Indian and Guamanian menand women also had the lowest cancer deathrates.

As estimated by Parkin et al. (3), there were860,000 crude prevalent bladder cancer casesworldwide (Five-year Survival) in 2002,

thranking it as the 5 most prevalent cancer inthe world for males, after colorectal, prostate,stomach and lung cancers; there were about250,000 5-year survival cases for females,

thwhich ranks it the 6 most common prevalentcancer in the world for females after breast,colorectum, stomach, cervix uteri, and lungcancers (Figure 14). The prevalence rates formales in the main five regions of Asia (2, 3, 90)

show that the 5-year survival rates are highestin Eastern Asia (112,658 cases for males and36,607 for females), then in South-CentralAsia (58,865 cases for males and 16,142 forfemales) followed by Western Asia (23,452cases for males and 5,150 for females), South-Eastern Asia (20,220 cases for males and5,767 for females). The 5-year survival rates ofOceania (when the rates of Australia/NewZealand, Melanesia, Micronesia and

Prevalence of Bladder Cancer in the Asian-Pacific Region

Asia, Males

Eastern Asia 37,035 4.8 4.7 16,272 2.1 2.1 28,015 112,658

China 24,125 3.6 3.8 11,692 1.8 1.9 17,053 66,522Japan 9793 15.7 7.9 3,586 5.8 2.8 8,787 38,325

North Korea 884 7.8 8.8 269 2.4 2.9 670 2,407

South Korea 1,973 8.3 8.8 608 2.6 2.9 1,497 5,377

Mongolia 10 0.8 1.4 4 0.3 0.6 8 27

South-Eastern Asia 7,273 2.7 4 3,958 1.5 2.2 5,553 20,220

Brunei 3 1.7 3.9 2 1.1 2.1 3 11

Cambodia 73 1.1 2.4 32 0.5 1.2 58 227

Indonesia 3,117 2.9 4 1,631 1.5 2.1 2,388 8,724

Lao 47 1.7 3.3 24 0.9 1.8 36 140

Malaysia 382 3.3 5.1 205 1.8 2.8 290 1041

Myanmar 607 2.5 3.6 311 1.3 1.9 468 1742

Philippines 967 2.5 4.6 674 1.7 3.3 739 2689Singapore 153 7.3 7 49 2.4 2.3 113 393

Thailand 1,195 3.8 4.8 628 2 2.6 910 3,283

Viet Nam 719 1.8 2.6 393 1 1.4 548 1,970

South-Central Asia 21,370 2.7 4 12,968 1.7 2.5 16,254 5 8,865

Afghanistan 474 3.9 8 239 2 4.3 364 1,344

Bangladesh 508 0.7 1.3 250 0.3 0.7 394 1,505

Bhutan 26 2.3 4 14 1.3 2.1 20 72

India 12,444 2.3 3.2 8,005 1.5 2.1 9,423 33,769

Iran 1,677 4.6 8 855 2.3 4.3 1,290 4,807

Kazakhstan 897 11.6 14.7 682 8.8 11.2 671 2,374

Kyrgyzstan 137 5.6 8.4 126 5.1 7.7 104 373Nepal 284 2.3 4 149 1.2 2.1 217 784

Pakistan 3,889 5.1 8.8 2,003 2.6 4.7 2,990 10,978

Sri Lanka 216 2.2 2.4 115 1.2 1.3 165 595

Tajikistan 125 4.1 7.3 83 2.7 4.8 96 348

Turkmenistan 128 5.3 9.8 85 3.5 6.6 99 363

Uzbekistan 551 4.3 7.4 354 2.8 4.8 421 1,553

Western Asia 8,452 8.4 12.8 4,395 4.4 6.8 6,430 23,452

Armenia 366 20.1 19.9 295 16.2 15.8 274 975

Azerbaijan 494 12.4 15.6 385 9.7 12.1 377 1372

Bahrain 30 8 16 17 4.5 9.4 22 78

Cyprus 131 33 24.4 73 18.4 13.3 99 347

Georgia 394 15.9 11.9 177 7.2 5.1 295 1,033

Country/RegionIncidence Mortality Prevalence

Cases CrudeRate

ASR(W) DeathsCrudeRate

ASR(W) 1-year 5-yearCountry/Region

Incidence Mortality Prevalence

CasesCrudeRate


ASR(W) 1-year 5-year

Iraq 1,013 8.2 17.7 533 4.3 9.7 775 2,818

Israel 874 28.2 25.8 213 6.9 6 767 2,991

Jordan 195 7.2 15 97 3.6 7.8 149 556

Kuwait 42 3.6 5.5 22 1.9 3.1 32 120

Lebanon 228 12.9 17.5 120 6.8 9.1 172 628

Oman 39 2.7 4.8 19 1.3 2.5 30 108

Qatar 41 11.1 12 17 4.6 5.8 30 110

Saudi Arabia 539 4.7 7.9 274 2.4 4.3 410 1,512

Syria 620 7.2 15.2 309 3.6 7.9 477 1,790

Turkey 2,952 8.6 11 1586 4.6 6 2237 8,001

U.A.E* 174 9.9 11.8 88 5 6.5 130 469Yemen 202 2 6.7 110 1.1 3.8 154 544

Australia/New Zealand 2,607 22.5 15.6 756 6.5 4.3 1,856 7,983

Australia 2,184 22.5 15.4 635 6.5 4.3 1,552 6,676

New Zealand 423 22.4 16.2 120 6.4 4.4 304 1,307

Melanesia 32 0.9 1.8 20 0.6 1.3 18 59

Fiji 0 0 0 0 0 0 0 0

Papua N. Guinea 20 0.8 1.6 13 0.5 1.1 16 50


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Polynesia were combined together) were thelowest among the Asian-Pacific region in 2002.In general, these rates depend proportionallyon the population density curve in every region,however, the survival rates of males inWestern Asia seem to be higher proportionallythan in South-Eastern Asia although the

population density in the latter is much higher.

Although most of the registries in the Asian-Pacific region have not been in use longenough to give information on time-trends,data has been available for a long time in somecountries such as Japan, Singapore, India andIsrael (Table 1). Actually, the cancer registry inthe Asian-Pacific region is not fully inclusiveespecially for countries with large populationsand for some countries in the region which arenot included. Thus, the overview of bladdercancer in the Asian-Pacific region presentedhere represents a somehow shallow exa-mination of the sufficient data that is availableconcerning the distribution of bladder cancer.Despite the limitations of the present review,certain principles are clearly evident. Theburden of bladder cancer in the Asian-Pacificregion varies according to community. Theextent of variation when subcontinentalregions are compared is apparent at a nationallevel and may be clear even at a local districtlevel occupied by racial-ethnic groups, or by acommunity exposed to a certain risk factor.Thus, this report describes variations in cancerincidence in terms of, and indicative of, theinfluence of particular risk factors and geneticsusceptibilities. Many established risk factorsoperate as causes of the disease, for which thebiological mechanisms are being progressi-vely clarified. For example, Schistosomiasis incertain parts of Asia increased the rate ofbladder cancer particularly of the squamouscell type. When the incidence of Schistosoma

infection was decreased or eliminated bycertain governmental measures in somecountries, the urothelial transitional type ofbladder cancer overcame the squamous celltype; however the incidence of bladder cancerremained almost the same in general.Occupational and environmental pollutionfactors and smoking are thus probably the keyrole for bladder cancer initiation. Highlydeveloped countries such as Japan, NewZealand and Australia had significantly higherratios of bladder cancer incidence and

mortalities in both males and females,irrespective of the ethic-racial differencesbetween the Japanese and the Whites inAustralia and New Zealand indicating againthat the environmental risk factors are mostcomprehensive for bladder cancer initiation.The populations in West Asia have higherincidence and mortality rates of bladdercancer as compared to the East, South-

Future Perspectives for Bladder CancerPrevention and Treatment

Bladder Cancer

Solomon Islands 2 0.8 2.9 2 0.8 2 2 8

Vanuatu 1 0.9 1.2 0 0 0.9 0 1

Micronesia 6 2.1 3.1 3 1.1 2.3 3 11Guam 2 2.4 3.1 1 1.2 2.3 1 4

Polynesia 9 2.8 5.1 7 2.2 3.8 11 30

Samoa 2 2.4 5.1 2 2.4 3.8 2 6

Table 4. Crude and age-standardized rates, mortalities per 100,000 population and prevalence due tobladder cancer in the Asian/Pacific regions (Males) (2). (Continued)



CasesCrudeRate



Table 5. Crude and age-standardized rates, mortalities and prevalence per 100,000 population due tobladder cancer in the Asian/Pacific regions (Females) (2).

Asia, Females

Eastern Asia 12,830 1.8 1.5 5,799 0.8 0.7 9,111 36,607

China 9,105 1.5 1.4 3,900 0.6 0.6 6,457 25,733

Japan 2,945 4.5 1.8 1,607 2.5 0.9 2,126 8,987

North Korea 201 1.8 1.7 72 0.6 0.6 153 551

South Korea 494 2.1 1.7 182 0.8 0.6 374 1,331

Mongolia 2 0.2 0.3 2 0.2 0.3 1 5

South-Eastern Asia 2,194 0.8 1.1 1,229 0.5 0.6 1,614 5,767

Brunei 0 0 1.1 0 0 0.6 0 3

Cambodia 50 0.7 1.3 30 0.4 0.8 0 0

Indonesia 887 0.8 1 490 0.5 0.6 654 2,249

Lao 7 0.3 0.5 4 0.1 0.3 5 20

Malaysia 117 1 1.4 61 0.5 0.7 89 328

Myanmar 241 1 1.3 128 0.5 0.7 186 681

Philippines 303 0.8 1.2 215 0.6 0.9 233 841

Singapore 52 2.5 2.1 19 0.9 0.8 39 142

Thailand 366 1.1 1.3 194 0.6 0.7 278 1,000

Viet Nam 166 0.4 0.5 85 0.2 0.3 130 503

South-Central Asia 5,745 0.8 1 3,421 0.5 0.6 4,400 16,142

Afghanistan 123 1.1 2.1 62 0.6 1.1 95 355

Bangladesh 56 0.1 0.1 20 0 0 42 183

Bhutan 8 0.7 1 3 0.3 0.5 7 21

India 3,031 0.6 0.7 1,907 0.4 0.5 2,319 8,452

Iran 406 1.2 1.9 204 0.6 1 312 1,163

Kazakhstan 352 4.3 3.7 292 3.5 3.1 266 945

Kyrgyzstan 33 1.3 1.4 21 0.8 0.9 25 90

Nepal 73 0.6 1 38 0.3 0.5 57 213


CasesCrude

RateASR(W) Deaths

Crude

RateASR(W) 1-year 5-year

Pakistan 1,469 2 3.4 764 1.1 1.8 1131 4,186

Sri Lanka 43 0.5 0.5 21 0.2 0.3 33 124

Tajikistan 22 0.7 1 11 0.4 0.5 17 60

Turkmenistan 21 0.9 1.2 12 0.5 0.7 17 59


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Eastern and South-Western populationsalthough most communities in the region arenot as highly developed as Australia and NewZealand. But smoking prevalence, occu-pational exposure to chemicals as well as thegenetic variations together rendered theincidence of bladder cancer to be higher in thisregion in both males and females. As arsenic isa major bladder and other cancer-causingpollutant in many Asian regions and in theworld, particularly in Bangladesh, India,Taiwan and some parts of China, the incidenceof bladder cancer in these countries isrelatively low. In general, the lowest bladdercancer rates in the world are in the Pacificislands of Melanesia, Micronesia andPolynesia and in Eastern and South-EasternAsian regions. The genetic polymorphism inAsian people for rapid acetylation of N-acetyltransferase 2, and glutathione S-transferase M1 and lower incidence ofcigarette smoking could possibly be the mainfactor for the lower incidence of bladder cancerin these regions. For the most part,understanding the causes of bladder cancerprovides a prospect for cancer prevention orpremature detection. The changeover from thedocumentation of the disease to a startingpoint of action against bladder cancer mayalso be pursued in relation to treatment. Thusincidence, mortality and other data of geneticphenotypes and risk factors offer insight into

the prognosis and efficacious treatment ofbladder cancer.

Bladder Cancer

Uzbekistan 102 0.8 1.1 59 0.5 0.6 79 291

Western Asia 1,886 2 2.6 955 1 1.3 1,409 5,150

Armenia 74 3.8 2.9 51 2.6 1.9 55 194

Azerbaijan 96 2.3 2.1 66 1.6 1.4 74 259

Bahrain 6 2.1 3.7 3 1.1 2.1 3 18

Cyprus 22 5.5 3.3 12 3 1.9 16 56

Georg ia 95 3.5 1.9 39 1.4 0.8 70 240

Iraq 438 3.7 6.9 221 1.9 3.6 335 1,246

Israel 218 6.8 4.9 61 1.9 1.3 167 644


Table 5. Crude and Age-Standardized rates, Mortalities and Prevalence per 100,000 Population Due toBladder Cancer in the Asian/Pacific Regions (Females) (2). (Continued)

Jordan 29 1.2 2.4 15 0.6 1.3 22 83

Kuwait 10 1.2 2.9 5 0.6 1.7 7 23

Lebanon 42 2.3 2.5 26 1.4 1.6 31 111

Oman 14 1.1 2.2 6 0.5 1.1 10 41

Qatar 0 0 0 0 0 0 0 0

Saudi Arabia 121 1.2 2.3 63 0.6 1.3 91 332

Syria 102 1.2 2.5 62 0.7 1.5 74 255

Turkey 518 1.5 1.7 274 0.8 0.9 397 1,452

U.A.E.* 18 2 3.6 8 0.9 1.8 14 51

Yemen 58 0.6 1.4 26 0.3 0.6 43 145

Australia/New Zealand 915 7.8 4.6 324 2.8 1.5 635 2,715

Australia 763 7.8 4.6 269 2.8 1.5 535 2,291

New Zealand 152 7.8 4.8 56 2.9 1.7 100 424

Melanesia 12 0.4 0.5 7 0.2 0.4 6 29

Fiji 1 0.3 0.4 1 0.3 0.3 0 2

Papua N. Guinea 8 0.3 0.5 5 0.2 0.3 6 24

Solomon Islands 0 0 0.8 0 0 0.5 0 3

Vanuatu 0 0 0 0 0 0 0 0

Micronesia 1 0.4 0.4 1 0.4 0.3 0 3

Guam 0 0 0.4 0 0 0.3 0 1

Polynesia 0 0 0 0 0 0 0 0

Samoa 0 0 0 0 0 0 0 0


CasesCrudeRate




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