A population-based cohort study examining the association of documented bladder diverticulum and bladder cancer risk in urology patients
Authors:
Chu-Wen Fang aff001; Vivian Chia-Rong Hsieh aff002; Steven Kuan-Hua Huang aff001; I-Ju Tsai aff003; Chih-Hsin Muo aff003; Shih-Chi Wu aff004
Authors place of work:
Division of Urology, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan
aff001; Department of Health Services Administration, China Medical University, Taichung, Taiwan
aff002; Management Office for Health Data, China Medical University and Hospital, Taichung, Taiwan
aff003; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
aff004; Trauma and Emergency Center, China Medical University Hospital, Taichung, Taiwan
aff005
Published in the journal:
PLoS ONE 14(10)
Category:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0222875
Summary
Objectives
Studies have shown a high risk of tumor development within a bladder diverticulum (BD). We were interested in the relationship between BD and the development of bladder cancer. Herein, we attempted to investigate whether there exists an association between documented BD and subsequent risk of bladder cancer.
Methods
We identified 10,662 hospitalized urology patients, including 2,134 documented BD patients (study cohort) and 8,528 non-BD subjects (comparison cohort) from Taiwan’s National Health Insurance database. Only urology patients were enrolled in the study to minimize selection bias. The two cohorts were frequency-matched 1:4 by age, sex and index-year. Patients with less than one year of follow-up were excluded to avoid inverting cause and effect. Risks of developing bladder cancer were estimated using the Cox proportional hazard regression model.
Results
There was an increased bladder cancer risk in the documented BD patients. The incidence of bladder cancer in documented BD patients was 2.60-fold higher than that in the comparison group, and the overall risk-factor-adjusted hazard ratio was 2.63 (95% CI, 1.74–3.97). Moreover, stratified analysis by sex also showed that documented BD patients were at higher risk of subsequent bladder cancer than the comparison cohort. The effect of BD on the risk of bladder cancer was higher in males than in females and was more profound in patients without comorbidities than in those with comorbidities.
Conclusion
In this population-based longitudinal study, urology patients with documented BD might have an elevated risk of subsequent bladder cancer. Based on the limitations of the retrospective study design, further studies are required.
Keywords:
Urology – Cancer detection and diagnosis – chronic kidney disease – Urine – Carcinomas – Taiwan – Bladder cancer – bladder
Introduction
Bladder cancer is the ninth most common malignancy worldwide and is the most common malignancy involving the urinary system [1], while urothelial carcinoma is the predominant histologic type around the world [2–3].
Risk factors for bladder cancer may include age, sex, smoking, diabetes, race, exposure to chemicals, chronic inflammation, and genetic factors [4]. In addition, the risk of tumor development within a bladder diverticulum (BD) has been suggested to be higher than that in the main bladder, which might be attributed to prolonged exposure to carcinogens within the intradiverticular mucosal lining [5].
BD is an outpouching of the bladder urothelium through the muscular wall of the bladder, creating a defect. This condition leads to ineffective emptying of urine due to a lack of muscle fibers, causing retention of urine and potential exposure to carcinogens [5–6]. However, there is a lack of direct symptoms and signs in BD patients. The diagnosis is often made incidentally and is often established by contrast images, echography, and cystoscopy [5].
Recent studies have observed various types of carcinoma arising from within BD [7–12]. However, there is still limited evidence regarding the link between BD and the development of bladder cancer. Therefore, we aimed to investigate whether there exists an association between documented BD and subsequent risk of bladder cancer in urology patients.
Methods
Data source
We used inpatient claims data from the Taiwan National Health Insurance Research Database (NHIRD) from 1996 to 2013. This database contains detailed medical histories of the hospitalized enrollees in Taiwan. The National Health Insurance (NHI) program is a universal health care system that was launched in 1995 with a current coverage of over 99%. The disease diagnoses were identified using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). Under the current system, a disease diagnosis without valid supporting clinical evidence may be considered medical fraud by the NHI program, potentially with a penalty of 100 times the payment claimed by the treating physician or hospital.
Study subjects
We identified patients with new diagnoses of BD (ICD-9-CM 596.3) between 2000 and 2012 from the urology hospitalization records. To minimize selection bias, only urology patients were enrolled in the study. The index date for BD patients was defined as the date of BD admission. Patients less than 18 years of age or with malignancy (ICD-9-CM 140–208) before the index date were excluded from this study. Patients with less than one year of follow-up were also excluded to avoid inverting cause and effect. The comparison group was randomly selected from patients hospitalized in urology without a diagnosis or any documentation of BD. They were then frequency-matched to BD patients by age (exact year), sex and index year at a 1:4 case-to-control ratio. The exclusion criteria for the comparison group were the same as those for the BD group.
To comply with the Personal Information Protection Act for research use, all the identifying information of the insured people was removed and replaced with surrogate numbers. This study was approved by the Research Ethics Committee of China Medical University and Hospital in Taiwan [CMUH106-REC3-085].
Outcomes and risk factors
The main outcome of interest in this study was the development of bladder cancer (ICD-9-CM 188) subsequent to the diagnosis of BD. All study subjects were followed from the index date to the occurrence of bladder cancer, withdrawal from the insurance program, or December 31, 2013, whichever came first. The comorbidities examined included diabetes (ICD-9-CM 250) [13–14], hydronephrosis (ICD-9-CM 591) [15–16], smoking-associated diseases (ICD-9-CM 305.1, 430–438, 410–414, 493, 496) [17–18], and chronic kidney disease (CKD) (ICD-9-CM 585) [19–20], which were extracted within two years before the index date and considered confounding factors. In addition, geographical regions of residence were also considered; we classified residential areas into four categories: northern, central, southern, and eastern Taiwan.
Diagnosis of bladder cancer
In addition to the use of ICD-9 codes. In Taiwan, various cancer patients were precisely diagnosed by specialists based on pathology and clinical reports and were registered as “catastrophic illness patients”. Thus, we could define bladder cancer patients from this registry.
Statistical analysis
Differences in demographics and comorbidities between the BD and comparison cohorts were examined using Chi-square tests for categorical variables and Student’s t-tests for continuous variables. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazard regression models. Proportional hazard assumption was measured by adding an interaction term between the study groups (BD/comparison group) and the logarithm of follow-up time in the Cox regression model. The hazard functions were proportional over time, and the assumptions for the Cox proportional model were not violated. Multivariate Cox regression models were adjusted for multiple variables that appeared to be statistically significant in the crude model. Kaplan-Meier estimates were used to plot the cumulative incidence. A log-rank test was used to detect the difference in incidence between the two groups. All statistical analyses were performed using SAS version 9.4 software (SAS Institute, Cary, NC, USA). The significance threshold was set at 0.05 for a two-tailed p-value.
Results
We identified 10,662 hospitalized urology patients, including 2,134 documented BD patients (study cohort) and 8,528 non-BD subjects (comparison cohort) from Taiwan’s National Health Insurance database (Fig 1).
Distributions of age and sex were similar between the cohorts after matching. A total of 36.3% of BD patients lived in northern Taiwan, and 42.0% lived in southern Taiwan, while 42.5% of non-BD patients led in northern Taiwan, and 27.8% lived in southern Taiwan. Diabetes and hydronephrosis were more prevalent in non-BD patients than in BD patients (17.9% and 21.3%, respectively) (Table 1).
Overall, the incidence of bladder cancer in the BD cohort was 2.60-fold higher than that in the comparison cohort (3.17/1000 person-years for BD and 1.22/1000 person-years for the comparison cohort). The overall risk-factor-adjusted HR (aHR) was 2.63 (95% CI 1.74–3.97) after controlling for age and CKD (Table 2).
After stratification by age, sex, comorbidity and follow-up duration, the risk of bladder cancer in BD patients was significantly higher in all stratifications compared to control patients, except in the female group (Table 3). For sex-stratified analysis, the effect of BD on bladder cancer was higher in males than in females (interaction p<0.05). In the comorbidity-stratified analysis, the effect of BD on the risk of bladder cancer was also more profound among patients without comorbidity (aHR: 4.86, 95% CI 2.50–9.44) than among those with comorbidity (aHR: 1.78, 95% CI 1.04–3.04) (interaction p<0.05) (Table 3).
Because the association between bladder cancer and BD was different according to sex as previously seen in Table 3, we performed CKD-, benign prostatic hyperplasia (BPH), and transurethral resection of the prostate (TURP)-stratified analyses in males, as shown in Table 4. Consistent with our previous analyses, we found that BD patients still had an overall increased bladder cancer risk compared with non-BD patients in different CKD, BPH, and TURP stratifications (Table 4). The observed adjusted HRs appeared to be more statistically significant when we compared men among the non-comorbidity groups versus the comorbidity groups.
Fig 2 shows that the cumulative incidence of bladder cancer in the BD cohort was 2.14% higher than that in the comparison cohort after a follow-up of 14 years (3.50% vs. 1.36%, respectively, log-rank test p<0.0001).
Discussion
The development of a neoplasm within BD is an important issue because of its difficult diagnosis and early invasion secondary to a lack of musculature. The risk of developing a tumor within a bladder diverticulum is considered to be higher than that in the main bladder and may account for approximately 1% of all urinary bladder tumors.5
It has been reported that carcinogens in the urine accelerate the process of bladder carcinogenesis [21–22]. In addition, urinary hesitancy and residual urine retention may play some roles in the development of bladder cancer in males [21, 23].
Urinary stasis in BD might be associated with chronic infection and inflammation that lead to stone formation, dysplasia development, squamous cell metaplasia and leukoplakia, which increase the possibility of intradiverticular neoplasm development [24]. In addition, types of carcinoma that arise from BD include squamous cell carcinoma [7–8], adenocarcinoma [9], urothelial carcinoma [10], small cell carcinoma [11], and primary osteosarcoma [12]. Among these malignancies, urothelial carcinoma is the most common (78%), followed by squamous cell carcinoma (17%), a combination of transitional and squamous cell types (2%), and adenocarcinoma (2%) [25].
In our study, the overall adjusted hazard ratio for bladder cancer was high in BD patients compared to non-BD subjects (HR = 2.63). Given that there were a lack of intradiverticular residual urine volume data in BD patients, BDs might be effectively drained in some patients after micturition. It is plausible that this result might, at least in part, support the idea that urinary stasis in BD is associated with chronic inflammation and could potentially lead to the development of malignancy. In addition, the hazard ratio for bladder cancer was higher in patients aged more than 65 years (HR = 2.34 Table 2), which is consistent with the notion that there is a close relationship between aging and cancer [26–27].
In the current study, the prevalence of CKD was approximately 2% (Table 1), which is not consistent with other Taiwanese studies (6.9~11.9%) [28–31]. However, there were different sources and methods of selecting CKD patients among these studies. For instance, patients aged ≥20 years were selected from a community-based multiple screening program in one study [28], while another study selected patients from a standard medical program run by a private firm [29], and another study used the diagnostic code for CKD from inpatient or outpatient services to select patients [30]. In the current study, we selected urology patients from an inpatient rather than an outpatient data file, which may have accounted for the lower prevalence of CKD than that found in other Taiwanese studies.
There is a close relationship between CKD and bladder cancer [20, 32], and BPH has been reported to be a risk factor for bladder cancer in males [33]. However, in the current study, there was an increased incidence of bladder cancer in CKD patients (HR = 4.46. Table 2). After CKD- and BPH-stratified analyses in male patients, the BD cohort still had a higher bladder cancer risk than the comparison cohort with different CKD and BPH stratifications (Table 4). This result indicates that BD might be a risk factor for the development of bladder cancer in urology patients.
Early diagnosis of BD is challenging, and the prognosis of bladder diverticulum cancer can be poor [34–36]. The reported incidence of BD ranges from 1.7% to 13% [34, 37–39]. A recent cadaver study showed a higher rate of up to 23.4% [40]. This suggests that there are asymptomatic cases of BD. However, the prevalence of BD is low (0.31%, 2,993/960,511) in the current study. This could be attributed to lack of necessary examination or procedures to confirm a diagnosis of BD in the study population. Moreover, BD seems not to be a very important coding system in clinical urological practice in Taiwan. Thus, the coding of BD might not always be added by urologists since there are usually other major problems present, such as urinary tract infection, BPH, or other obstructive uropathy. Together, result in a probability of undocumented BD and a low prevalence of BD in our results. Therefore, our results cannot be generalized to all BD patients; however, they may be relevant to urology patients with documented BD.
Because there was lack of information on the location, severity, and specific identification of intradiverticular or intravesical bladder tumors in BD patients in the current data, it is difficult to confirm that whether the bladder cancer is developed from a BD. Therefore, our results are only representative of an overall elevated incidence of bladder cancer in urology patients with documented BD. The findings are also difficult to relate to the association between BD and the development of intradiverticular tumors. Owing to few data regarding the pathogenesis in this issue, we assume that urinary stasis and residual urine retention in BD may play some roles in the development of bladder cancer [21–23]. Therefore, further studies are required to elucidate this concern. However, our findings may suggest the need for a regular monitoring protocol in urology patients with documented BD.
To the best of our knowledge, no study has ever longitudinally examined the association between documented BD and the development of bladder cancer. In conclusion, the present large cohort study may reveal an association between documented BD and subsequent risk of bladder cancer in urology patients. This finding might partially be attributed to prolonged contact of urinary carcinogens due to urinary stasis. Future studies are warranted to investigate this proposed relationship and the underlying mechanisms.
Limitations of the study
Our study has strengths of including a large study population, longitudinal design, reliable diagnosis and high follow-up rate, as well as subgroup analyses of the bladder cancer risks in urology patients with documented BD. However, certain limitations exist. First, the documented BD cases were based on admission diagnoses and codes. The information for location and severity, residual urine amount, size of BD, and accurate diagnosis of intradiverticular or intravesical bladder tumors was lacking. In addition, there were no pathology reports or stage/grade information for bladder cancer. Second, several factors, such as lifestyle (e.g., smoking, drinking), socioeconomic status, nutrition, and genetic factors, were not available for adjusting the risk of bladder cancer development. Third, relevant clinical variables (e.g., imaging results, histological findings, and laboratory data) were also unavailable because the data used were anonymous. Fourth, since urology patients with documented BD may have a higher likelihood of being diagnosed with bladder cancer during their follow-ups, detection biases do exist. However, this bias was minimized with the use of a washout period for analysis during the study period. Finally, despite our meticulous study design and control of confounding factors, there were still biases that resulted from the retrospective study design.
Conclusion
In this long-term population cohort study, urology patients with documented BD might have an elevated risk of subsequent bladder cancer, which might suggest the need for a regular monitoring protocol in these patients. However, further studies are required to investigate the underlying mechanisms.
Zdroje
1. Ploeg M, Aben KK, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol 2009; 27:289. doi: 10.1007/s00345-009-0383-3 19219610
2. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017; 67:7–30. doi: 10.3322/caac.21387 28055103
3. Marcos-Gragera R, Mallone S, Kiemeney LA, et al. Urinary tract cancer survival in Europe 1999–2007: Results of the population-based study EUROCARE-5. Eur J Cancer. 2015 Oct; 51(15]:2217–2230. doi: 10.1016/j.ejca.2015.07.028 26421824
4. Burger M, Catto JW, Dalbagni G, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013; 63(2]:234–41. doi: 10.1016/j.eururo.2012.07.033 22877502
5. Walker NF, Gan C, Olsburgh J, et al. Diagnosis and management of intradiverticular bladder tumours. Nat Rev Urol. 2014 Jul; 11(7]:383–90. doi: 10.1038/nrurol.2014.131 24934450
6. Kelalis PP, McLean P. The treatment of diverticulum of the bladder. J Urol 1967; 98:349–52. doi: 10.1016/s0022-5347(17)62888-x 4963798
7. Uemura K, Namura K, Umemoto S, et al. A Case of Squamous Cell Carcinoma in Bladder Diverticulum Producing Granulocyte Colony Stimulating Factor. Hinyokika Kiyo. 2017 May; 63(5]:211–215. doi: 10.14989/ActaUrolJap_63_5_211 28625029
8. El Abiad Y, Bakloul F. Squamous cell carcinoma in a giant bladder diverticulum. Pan Afr Med J. 2015 Apr 16; 20:378. doi: 10.11604/pamj.2015.20.378.6765 26185568
9. Fu LY, Adeniran AJ. Adenocarcinoma Arising from a Bladder Diverticulum. J Urol. 2015 Aug; 194(2]:527–8. doi: 10.1016/j.juro.2015.05.033 25986516
10. Raheem OA, Besharatian B, Hickey DP. Surgical management of bladder transitional cell carcinoma in a vesicular diverticulum: case report. Can Urol Assoc J. 2011 Aug; 5(4]:E60–4 21806896
11. Dong WX, Ping YX, Liang WC, et al. Small cell carcinoma of the urinary bladder diverticulum: a case report and review of the literature. J Cancer Res Ther. 2013 Jan-Mar; 9(1]:151–3. doi: 10.4103/0973-1482.110372 23575101
12. Abou Ghaida RR, Saoud RM, Bulbul M. Primary osteosarcoma in a bladder diverticulum. Can J Urol. 2014 Aug; 21(4]:7393–5. 25171286
13. Tseng CH. Diabetes and risk of bladder cancer: a study using the National Health Insurance database in Taiwan. Diabetologia. 2011 Aug; 54(8):2009–15. doi: 10.1007/s00125-011-2171-z 21544514
14. Lo SF, Chang SN, Muo CH, Chen SY, Liao FY, Dee SW, Chen PC, Sung FC. Modest increase in risk of specific types of cancer types in type 2 diabetes mellitus patients. Int J Cancer. 2013 Jan 1; 132(1):182–8. doi: 10.1002/ijc.27597 22510866
15. Bartsch GC, Kuefer R, Gschwend JE, et al. Hydronephrosis as a prognostic marker in bladder cancer in a cystectomy-only series. Eur Urol. 2007 Mar; 51(3):690–7; discussion 697–8. doi: 10.1016/j.eururo.2006.07.009 16904815
16. Lin HY, Wang SZ, Chen JX, et al. The prognostic value of hydronephrosis in bladder cancer treated by radical cystectomy. Urologia. 2011 Jan-Mar; 78(1):17–21. 21452155
17. Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between smoking and risk of bladder cancer among men and women. JAMA. 2011 Aug 17; 306(7):737–45.2 21846855
18. Rink M, Crivelli JJ, Shariat SF, et al. Smoking and Bladder Cancer: A Systematic Review of Risk and Outcomes. Eur Urol Focus. 2015 Aug; 1(1):17–27. doi: 10.1016/j.euf.2014.11.001 28723350
19. Kobatake K, Hayashi T, Black PC, et al. Chronic kidney disease as a risk factor for recurrence and progression in patients with primary non-muscle-invasive bladder cancer. Int J Urol. 2017 Aug; 24(8):594–600. doi: 10.1111/iju.13389 28734027
20. Li CE, Chien CS, Chuang YC, et al. Chronic kidney disease as an important risk factor for tumor recurrences, progression and overall survival in primary non-muscle-invasive bladder cancer. Int Urol Nephrol. 2016 Jun; 48(6):993–9. doi: 10.1007/s11255-016-1264-5 26995008
21. Matsumoto S, Shimizu N, Hanai T, et al. Bladder outlet obstruction accelerates bladder carcinogenesis. BJU Int 2009, 103:1436–1439. doi: 10.1111/j.1464-410X.2008.08261.x 19076130
22. Sarma AV, Wei JT. Clinical practice. Benign prostatic hyperplasia and lower urinary tract symptoms. N Engl J Med. 2012; 367(3]:248–57 doi: 10.1056/NEJMcp1106637 22808960
23. Zhou J, Kelsey KT, Smith S, et al. Lower Urinary Tract Symptoms and Risk of Bladder Cancer in Men: Results from the Health Professionals Follow-Up Study. Urology. 2015; 85(6]:1312–1318. doi: 10.1016/j.urology.2015.02.024 25863833
24. Lowe FC, Goldman SM, Oesterling JE. Computerized tomography in evaluation of transitional cell carcinoma in bladder diverticula. Urology 1989;34:390–395 doi: 10.1016/0090-4295(89)90451-2 2595887
25. Shinai T, Anai M, Sakata T, et al. Primary carcinomas of urinary bladder diverticula. Acta Pathol Jpn 1984; 34:417–424. doi: 10.1111/j.1440-1827.1984.tb07570.x 6430029
26. Serrano M, Blasco MA. Cancer and ageing: convergent and divergent mechanisms. Nat Rev Mol Cell Biol. 2007; 8:715–722. doi: 10.1038/nrm2242 17717516
27. Toren Finkel T, Serrano M & Blasco MA. The common biology of cancer and ageing. Nature 448, 767–774. doi: 10.1038/nature05985 17700693
28. Tsai MH, Hsu CY, Lin MY, et al. Incidence, Prevalence, and Duration of Chronic Kidney Disease in Taiwan: Results from a Community-Based Screening Program of 106,094 Individuals. Nephron. 2018; 140(3):175–184. doi: 10.1159/000491708 30138926
29. Wen CP, Cheng TY, Tsai MK et al. All‐cause mortality attributable to chronic kidney disease: A prospective cohort study based on 462 293 adults in Taiwan. Lancet. 2008; 371: 2173–82. doi: 10.1016/S0140-6736(08)60952-6 18586172
30. Kuo HW, Tsai SS, Tiao MM, Yang CY. Epidemiological features of CKD in Taiwan. Am. J. Kidney Dis. 2007; 49: 46–55. doi: 10.1053/j.ajkd.2006.10.007 17185145
31. Hsu CC, Hwang SJ, Wen CP et al. High prevalence and low awareness of CKD in Taiwan: A study on the relationship between serum creatinine and awareness from a nationally representative survey. Am. J. Kidney Dis. 2006; 48: 727–38. doi: 10.1053/j.ajkd.2006.07.018 17059992
32. Chien CC, Han MM, Chiu YH, et al. Epidemiology of cancer in end-stage renal disease dialysis patients: a national cohort study in Taiwan. J Cancer. 2017 Jan 1; 8(1):9–18. doi: 10.7150/jca.16550 28123593
33. Fang CW, Liao CH, Wu SC, et al. Association of benign prostatic hyperplasia and subsequent risk of bladder cancer: an Asian population cohort study. World J Urol. 2018 Jun; 36(6):931–938. doi: 10.1007/s00345-018-2216-8 29427001
34. Melekos MD, Asbach HW, Barbalias GA: Vesical diverticula: etiology, diagnosis tumorgenesis and treatment. Analysis of 74 cases. Urology 1987; 30: 453–457. doi: 10.1016/0090-4295(87)90378-5 3118548
35. Faysal MH, Freiha FS. Primary neoplasm in vesical diverticula: A report of 12 cases. Br J Urol 1981; 53:141–3. doi: 10.1111/j.1464-410x.1981.tb03153.x 6786409
36. Golijanin D, Yossepowitch O, Beck SD, et al. Carcinoma in a bladder diverticulum: presentation and treatment outcome. J Urol. 2003 Nov; 170(5]:1761–4. doi: 10.1097/01.ju.0000091800.15071.52 14532771
37. Fox M, Power RF, Bruce AW. Diverticulum of the bladder: Presentation and evaluation of treatment of 115 cases. Br J Urol 1962; 34:286–98. doi: 10.1111/j.1464-410x.1962.tb09459.x 13959030
38. Haecker A, Riedasch G, Langbein S, et al. Diverticular carcinoma of the urinary bladder: diagnosis and treatment Problems. A case report. Med Princ Pract 2005; 14:121–4. doi: 10.1159/000083925 15785107
39. Lawrence WW (Ed]: Current Surgical Diagnosis and treatment, 10th e Englewood Cliffs, New Jersey, Prentice-Hall, 1994; 952–954.
40. Prakash Rajini T, Bhardwaj AK, Jayanthi V, Rao PK, Singh G. Urinary bladder diverticulum and its association with malignancy: an anatomical study on cadavers. Rom J Morphol Embryol 2010; 51:543–5. 20809034
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