Bladder cancer and diabetes

Bladder cancer affects the epithelial lining (urothelium) and is in the USA the fourth most common cancer in men and the tenth in women; men are affected ~3 times as often as women. There are ~380,000 new cases around the world each year. The tumors are heterogeneous, and the prognosis depends upon the degree of tumor differentiation and invasion of the muscle wall of the bladder. Recurrence is common. The risk of bladder cancer is increased by around 40% in type 2 diabetes, more so in men than in women. Bladder tumors over-express the insulin and IGF-1 receptors, which may partly explain this association. Other risk factors include cigarette smoking and occupational exposures, and treatment with pioglitazone has also been implicated.

Background

Bladder cancer is heterogeneous. Some 90% are due to transitional cell carcinoma. Tumors are classified by the degree of tissue differentiation (tumor grade ) and by the extent of invasion into surrounding tissues (tumor stage). Tumors with a higher stage and grade have a worse prognosis. The overall 5-year survival for bladder cancer ranges from 97% for non-muscle invasive tumors, to 65% to 56% for muscle invasive tumors, although once the bladder tumor metastasizes and invades the lymph nodes or other tissues, survival drops to 22%[1].

Bladder cancer also has a high rate of recurrence, affecting 60-70% of patients with non-muscle invasive tumors[2]. Estimates of the time taken for bladder cancer to develop range from less than 10 years to over 30 years, although the true latency period of bladder cancer is unknown[3][4].

Incidence and Prevalence of Bladder Cancer

An estimated 382,660 new cases bladder cancers occur globally each year, making bladder cancer the 6th most common cancer.

By sex, bladder cancer is the fourth most common cancer in men and the 10th most common in women in the USA.

Bladder cancer incidence rates (age-standardized) are highest in Europe and North America, followed by North and West Africa. Age standardized incidence rates of bladder cancer in the European Union (27 countries) are 27.4 per 100,000 males and 5.6 per 100,000 females. The highest rates are in Spain, followed by Denmark, the Czech Republic and Germany, and the lowest rates are in Slovenia, Finland and the United Kingdom [5].

Data from the National Cancer Institute in the United States show the incidence of bladder cancer is higher among white individuals (approximately 23 per 100,000) than African American, Hispanic, and Asian/Pacific Islander individuals (between 10 and 15 per 100,000). Bladder cancer mortality among white and African American individuals is approximately 4 per 100,000; mortality among Hispanic and Asian/Pacific Islander individuals is approximately 2 per 100,000. Bladder Cancer in Individuals with Type 2 Diabetes

Epidemiologic Evidence

The risk of bladder cancer is approximately 40% higher in individuals with diabetes than in individuals without diabetes[6]. Evidence suggests this increased risk may be especially in diabetic men[7]. Type 2 diabetes is also associated with a higher number of bladder tumors and a higher tumor grade[8]. Individuals with type 2 diabetes and bladder cancer also have significantly reduced survival compared to non-diabetic individuals[9].

Biologic Evidence

The insulin-like growth factor 1 receptor (IGF1R) and the insulin receptor (IR) play an important role in tumor growth, differentiation, motility and protection from apoptosis[10]. IGF1R is also overexpressed in malignant bladder cells and is indirectly stimulated by insulin, as insulin increases circulating levels of the IGF1R ligand, IGF-1[11]. Through this mechanism, hyperinsulinemia in individuals with type 2 diabetes may more strongly promote bladder cancer than in non-diabetic individuals[12].

Factors Influencing the Association

There are several known modifiable and non-modifiable risk factors for bladder cancer. Non-modifiable risk factors include older age and male sex. Smoking is the most widespread modifiable risk factor, and is present in about 50% of affected men and 30% of affected women. A number of occupations predispose to bladder cancer via exposure to carcinogens including benzidine. At risk occupations include bus drivers, motor mechanics, rubber and leather workers and possibly hairdressers.

Such well-documented factors are known to increase the risk of bladder tumor development and progression, and may confound the relationship between type 2 diabetes and bladder cancer.

Non-modifiable risk factors:

  • Age - More than 85% of individuals are over the age of 60 at the time of bladder cancer diagnosis, with a two to three fold increased risk in individuals over the age of 70, relative to individuals aged 55-69[13].
  • Sex – Men have three to four times the risk of bladder cancer, compared to women[14].
  • Ethnicity - Bladder cancer risk differs by ethnicity and white individuals have a higher risk of bladder cancer than non-white individuals[15].

Modifiable risk factors:

Smoking - Cigarette smoking is the primary modifiable risk factor for bladder cancer and accounts for up to half of cases[16]. Cigarette smokers have two to four times the risk of bladder cancer as that of non-smokers, and risk increases with the duration and amount of smoking[17].

Other potential bladder cancer risk factors, particularly occupational exposures, have been noted in the literature; however evidence is unclear or conflicting. Comprehensive reviews of risk factors are available [18][19].

Bladder Cancer Detection and Diagnosis

Emerging epidemiologic evidence from Canada and Denmark suggests the risk of cancer in individuals with type 2 diabetes changes over time following diagnosis[20]. Compared to individuals who do not have diabetes, the risk of being diagnosed with bladder cancer in the first year after a new diagnosis of type 2 diabetes is increased by 30%[21]. Similar trends have been observed for other cancers, including breast, colorectal, prostate, endometrial and thyroid cancers, where the risk of cancer diagnosis is increased in the first months or years following a new diagnosis of type 2 diabetes. After this initial period, the increased risk of diagnosis with bladder or other cancers declines, although to varying degrees.

Researchers hypothesize that at the time of diabetes diagnosis, the physician conducts a thorough inventory of health problems, including routine history and physical examination, screening, bloodwork and urinalysis. During this diagnostic work-up, clinically detectable but previously undiagnosed health problems, such as bladder cancer, may be detected[22]. A visit with the physician provides an opportunity for the doctor to discover symptoms of undiagnosed health problems, such as cancer. Thus, the chance of a doctor finding symptoms of cancer during, or shortly after, the visit where they diagnose diabetes, depends on how often the patient saw a physician before that visit. In other words, if the patient had undiagnosed cancer, the more prior opportunity the patient gave doctors to detect symptoms of the disease (i.e., through doctor’s visits), the more likely that cancer would have already been discovered before the visit where the patient was diagnosed with type 2 diabetes. Research suggests an inverse relationship between the number of physician visits in the two years before type 2 diabetes diagnosis and the subsequent short-term (12 months or less) risk of several different types of cancer, including bladder cancer. In fact, those who saw the physician the least often before diabetes diagnosis had more than two times the risk of bladder cancer in the first year.

This short term increased risk (sometimes referred to as “detection bias”) may blur our understanding of the true long-term risk of bladder cancer and other cancers associated with type 2 diabetes. Additional studies will be required to determine if the long-term risk of bladder cancer is elevated, and by how much.

References

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  2. ^ Soloway MS. Overview of treatment of superficial bladder cancer. Urology. 1985Oct.;26(4 Suppl):18–26.

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  11. ^ Rochester MA et al. The type 1 insulin-like growth factor receptor is over-expressed in bladder cancer. BJU Int. 2007Dec.;100(6):1396–401.

  12. ^ Giovannucci E et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010. p. 1674–85.

  13. ^ Society CC. Canadian Cancer Statistics 2012. Statistics CCSSCOC, editor. Toronto, ON: Canadian Cancer Society; 2012. p. 1–69.

  14. ^ Bladder cancer - UK incidence statistics [Internet]. info.cancerresearchuk.org. Cancer Research UK; [cited 2012 Aug.2]. Available from: http://info.cancerresearchuk.org/cancerstats/types/bladder/incidence/uk-bladder-cancer-incidence-statistics

  15. ^ Miller B, Kolonel L, Bernstein L, Young J Jr, Swanson G, West D, editors. Racial/ethnic patterns of cancer in the United States 1988–1992. Bethesda, MD: National Cancer Institute; 1996.

  16. ^ Strope SA et al. The causal role of cigarette smoking in bladder cancer initiation and progression, and the role of urologists in smoking cessation. J Urol. 2008Jul.;180(1):31–7.

  17. ^ Zeegers MP et al. The impact of characteristics of cigarette smoking on urinary tract cancer risk: a meta-analysis of epidemiologic studies. Cancer. 2000Aug.1;89(3):630–9.

  18. ^ Murta-Nascimento C et al. Epidemiology of urinary bladder cancer: from tumor development to patient's death. World Journal of Urology. 2007Jun.;25(3):285–95.

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  20. ^ Johnson JA et al. Time-varying incidence of cancer after the onset of type 2 diabetes: evidence of potential detection bias. Diabetologia. 2011Sep.;54(9):2263–71.

  21. ^ Colmers IN et al. Evidence of detection bias and overestimated risk of bladder cancer in type 2 diabetes. BMJ (Submitted).

  22. ^ Johnson JA et al. Diabetes and cancer (1): evaluating the temporal relationship between type 2 diabetes and cancer incidence. Diabetologia. 2012;55(6):1607–18.

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