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World Journal of Nephrology & Urology

Original Article

Volume 4, Number 3, September 2015, pages 227-231

Adenocarcinoma of the Urinary Bladder in Egypt: Potential Risk Factors

Urinary bladder cancer ranks seventh overall among men but 17th among women. In Egypt, it is the second leading cause of cancer death, with a mortality rate three times the rate in Europe and the United States [1], due to endemic schistosomiasis and male tobacco smoking [2].

Urinary bladder cancer subtypes include urothelial carcinoma (UC), squamous cell carcinoma (SCC), adenocarcinoma, anaplastic, and other rare forms. The most prevalent subtype is UC, accounting for about 90% of incident cases in developed countries. SCC, representing about 5% of all bladder cancer cases worldwide, is much more common in areas where schistosoma hematobium (SH) infection is endemic, such as in Egypt where currently it accounts for over 30% of the cases [2]. It is well established that cigarette smoking and occupational exposure to chemicals are major contributing factors to the development of UC, while SH infection accounts for most of SCC [3]. The risk factors for adenocarcinoma, which is characterized by its invasiveness and aggressive clinical presentation [4], are largely unknown, because of its rare occurrence in most populations, e.g. only 2% of cases.

Between 2006 and 2014, we conducted a large multi-center case-control study in Egypt, to address the risk factors associated with urinary bladder cancer and how they differ between men and women. We found that history of tobacco use, exposure to environmental tobacco smoke (ETS), and SH infection were associated with both UC and SCC among Egyptian men and women [2, 5, 6]. To address the gaps in epidemiologic information regarding adenocarcinoma of the urinary bladder, we examined the associations between the latter and potential risk factors in Egypt.

Detailed methods about the study have been previously reported [2]; key aspects of the study population and variables are summarized below.

The study was approved by the Institutional Review Boards of the three recruitment sites described below, Egypt’s Ministry of Health, the University of Maryland Baltimore, and Georgetown University. Bladder cancer cases were recruited from three cancer centers in Egypt: the National Cancer Institute in Cairo, the Minia Oncology Center in Minia, and the South Egypt Cancer Institute in Assiut. Cases were considered eligible if: they were diagnosed with primary bladder cancer within the last year, were between the ages of 19 and 80 years, and able to participate in an interview. Patients were excluded if they had a history of other cancers. For the cases, referred slides, or specimens collected from either biopsy or following surgical resection were reviewed by the pathologists and classified as: UC, SCC, adenocarcinoma, or other cancer types. This report includes only those cases that were confirmed as adenocarcinoma.

Controls were randomly selected from the population to frequency-match the cases on gender, age, and region of current residence. Controls were eligible if: they had no history of any cancer, were between the ages of 19 and 80 years, and were able to participate in an interview. The controls also underwent an ultrasound exam to check for any abdominal masses, including the bladder. There were two recruitment methods for the controls: random sampling of households and random sampling of family health records. The number of required controls and the necessary age and gender distributions were determined by the number of cases recruited per governorate, and controls were recruited as previously described [2].

The study was explained to the eligible subjects, and those who agreed to participate signed a consent form. Trained interviewers administered a questionnaire to obtain information on socio-demographic characteristics, occupational and environmental exposure histories, tobacco smoking (cigarettes, water pipes, or both, and ETS), and medical history including history of SH infection and other urinary tract infections (UTI).

The tobacco use variables were only analyzed in men because women seldom reported using any tobacco products. Tobacco use was divided into four categories: “never users”, “water pipe only”, “cigarette only”, and users of “both water pipe and cigarette”. “Never users” were defined as those participants who had never smoked a water pipe and had smoked less than 100 cigarettes in their lifetime. Cigarette smoking was analyzed using the following variables: cigarette smoking status, categorized as “never,” “former” (quit for at least 1 year prior to interview), and “current” smokers. We also calculate pack-years of cigarettes smoked as the product of the number of daily packs by the number of smoking years. ETS exposure was categorized as: “no exposure”, or “exposure at either home or outside the home”.

We used multivariable logistic regression models to estimate adjusted odds ratio (AOR) and 95% confidence interval (CI): all models were stratified by gender and adjusted for age. All analyses were conducted using SAS software, version 9.3 (SAS Institute Inc., Cary, NC).

Of the 2,347 total bladder cancer cases in our study confirmed by pathology review as primary bladder cancer malignancies, 101 (4.3%) were adenocarcinoma.

Table 1 displays the demographic characteristics of the study population, separately for males and females. The cases included 70 males and 31 females (approximately 2.2:1 ratio). The mean ages of cases were significantly (P = 0.01) younger (55.3) than the controls (58.5) among men, but not among women (54.2) (P = 0.8). The proportions of men who reported history of schistosomiasis (64% and 47%) were higher than those of women (38% and 11%) among cases and controls, respectively (Table 1). Smoking was highly prevalent among men (> 70% ever smoked and approximately half of them were current cigarette smokers), but rare among women (Table 1). On an average, the cases who used only cigarettes smoked 27.8 ± 16.5 (mean ± SD) pack-years of cigarettes, while the controls smoked 32.8 ± 18.5, not statistically significantly different (P = 0.1).

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Table 1. Sociodemographic Characteristics of Adenocarcinoma Cases and Controls in Egypt Stratified by Gender

The majority of tumors (83% and 80% among men and women, respectively) were characterized as grade 2 or 3. Examination of the pathology specimen revealed evidence of SH infection in 38% of the cases regardless of their gender.

History of schistosomiasis was significantly associated with adenocarcinoma of the bladder in both women and men, although the magnitude of the association was greater among the former as compared to the latter (AOR (95% CI): 4.58 (2.13 - 9.86) and 1.97 (1.08 - 3.58), respectively). Similarly, UTI other than schistosomiasis was also associated with adenocarcinoma of the bladder (adjusted OR (95% CI): 2.48 (1.13 - 5.43) and 1.66 (0.95 - 2.91), for women and men, respectively) (Table 2).

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Table 2. Associations Between Adenocarcinoma of the Urinary Bladder and History of Schistosomiasis and Other Urinary Tract Infection Among Egyptian Men and Women

Eighty-five percent (60/70) of male cases reported a history of any type of tobacco smoking compared to 76% of controls. Smoking water pipe tobacco was associated with increased risk of having adenocarcinoma even after adjustment for history of SH infection, UTI and age (AOR (95% CI): 1.97 (0.79 - 4.91)). The highest risk was observed among those who smoked both cigarettes and water pipes (3.34 (1.38 - 8.09)) (Table 3). The number of pack-years of smoking cigarettes was inversely associated with the risk of adenocarcinoma; the AOR for men who smoked less than 20 pack-years was higher than the AOR of those who smoked more than 20 (Table 3). The number of those who smoked only water pipes was too small to allow meaningful analysis, and so was the number of women who reported smoking (two among cases and 14 among controls).

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Table 3. Associations Between Adenocarcinoma of the Urinary Bladder and Smoking Among Men in Egypt

This study is one of the few epidemiologic case-control studies focusing on adenocarcinoma of the bladder. We found that smoking, schistosomiasis, and UTI among men, and schistosomiasis and UTI among women, increased the risk for adenocarcinoma, a rare form of urinary bladder cancer. These factors have been previously reported as contributing to the risk of UC and SCC in Egypt (7 - 9), and elsewhere (10 - 12), with the exception of schistosomiasis which is not endemic in most countries where epidemiological studies were performed. Egyptian men who smoked both cigarettes and water pipes had three times greater risk (OR: 3.34) of developing adenocarcinoma than men who did not smoke either type of tobacco. This result is similar to what we observed for UC and to a lesser extent SCC in Egypt [2]. Thus it appears that tobacco smoking is a commonly associated exposure across all the major subtypes of bladder cancer.

Adenocarcinoma, like SCC, appears to occur at a younger age than UC. Indeed the mean ages for men and women were respectively 54.3 and 54.2, significantly younger than the mean ages we reported for UC, 61.3 and 60.2, respectively [2]. Similarly, Lughezzani et al [13] reported a younger age at diagnosis in an SEER-based series of 306 adenocarcinoma cases compared to nearly 12,000 UC, but did not report gender-specific age differences. Compared to SCC and UC, we found a smaller male/female ratio, i.e. 2:1 in adenocarcinoma versus 3:1 for SCC and 6:1 for UC in Egypt [2], and this smaller ratio was nearly identical to that reported by Lughezzani et al [13].

We found a significant association between history of schistosomiasis infection and increased risk of adenocarcinoma in both men (OR: 1.7) and women (4.5), an increased risk that was comparable to that for SCC risk, among men (1.4), but greater among women (1.9) [2].

In one of the largest reported case series of adenocarcinoma, El Mekresh et al [14] described 185 consecutive cases presenting in Mansoura, Egypt, a high incidence area for bladder cancer: 82% of the surgical specimens were positive for schistosomal eggs, confirming a possible etiological role for this potential risk factor, but male-female differences were not reported. In our study, we found evidence for SH infection only in 38% or the pathological specimens, regardless of gender.

The odds of having adenocarcinoma were higher among women than among men who reported a history of UTI other than schistosomiasis. In the US SEER-based study reported by Kantor et al [10], cigarette smoking and UTIs were associated with increased risk of SCC but not with adenocarcinoma; the study’s sample size was too small to draw conclusions about gender differences.

This study has some notable strength, including the confirmation of cases by a pathologist’s standardized review of surgical and biopsy specimens, and the population-based recruitment of controls. Nonetheless, the relatively small number of cases, especially when stratified by gender, limited our ability to discern statistically significant associations with other potential risk factors. There were some inconsistencies in the associations with self-reported tobacco smoking history: despite the overall higher prevalence of current and former smoking by cases than controls, the mean pack-years was somewhat higher for controls, which may possibly reflect recent quitting among the cases due to the effects of the cancer.

Acknowledgement

The authors thank Drs. Iman Gouda and ImanLoay of the NCI-Cairo who evaluated the pathology of all the cases. We thank Dr. Nabiel N. Mikhail for data management and for supervising case and control recruitment in Assiut, and Drs. Doa’a Saleh and Sameera Ezzat for supervising and coordinating the field staff in Cairo and Minia.

Grant Support

This research was supported by the US National Cancer Institute (grant numbers R01CA115618 and R01CA132996).

Conflict of Interest

None of the authors declare any conflicts of interest.

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World Journal of Nephrology and Urology is published by Elmer Press Inc.