Bladder Cancer: Epidemiology and Pathogenesis

Epidemiology

Incidence

• Worldwide
  • 10th most common cancer worldwide§
    • Incidence highest in developed countries
• USA
  • Accounts for 7% of all cancers diagnosed in the USA
  • 2023 estimated incidence: 82,290[1]
• Canada
  • 5th most common cancer overall in Canada
    • 2020 estimated incidence: 12,200 diagnosed with bladder cancer§

Mortality

• USA
  • 2023 estimated mortality: 16,710[2]
• Canada
  • 2020 estimated mortality in Canada: 2,600 deaths from bladder cancer§
• Rate decreased by 5% since 1990, primarily because of smoking cessation, changes in environmental carcinogens, and healthier lifestyles
• Higher mortality rates in Egypt because of highly prevalent squamous cell carcinoma of the bladder
• A study found that 31% of all bladder cancer deaths in the elderly were avoidable, more commonly in non-invasive than invasive disease
• 5 Yr overall survival by stage:
  • Ta: 98%
  • T1: 90%
  • T2: 65%
  • T3 or T4a: 50%
  • T4b or N+ or M1: 15%

Gender

• More common in males than females
  • Ratio M:F 3:1
    • Worse oncological outcomes in females due to (2):
      1. More aggressive disease at diagnosis (e.g., a higher proportion of MIBC)
      2. Higher proportion of certain variant histologies (e.g., squamous cell carcinoma)

Age

• Median age at diagnosis: 70 (for men and women)
  • Incidence of bladder cancer and mortality from the disease increase with age
  • In general, adolescents and young adults (< 40 years) tend to develop well-differentiated noninvasive, rather than invasive, bladder cancer

Race

• Primarily affects Caucasian Americans
  • A white male has a 3.7% chance of developing urothelial cancer in his lifetime, which is roughly 3x the probability in white females or African-American males

Economics of bladder cancer

• Highest lifetime treatment cost per patient among cancers

Pathogenesis

External risk factors (7):

1. Tobacco exposure
   • Most common risk factor
     • Responsible for 30-50% of all bladder cancers in males
   • Relative risk 2-6x;
   • Intensity and duration of smoking are linearly related to risk
     • Smoking cessation reduces the risk of urothelial cancer formation
       • Former smokers still have a higher risk of bladder cancer than those who never smoked
     • Current tobacco use and cumulative lifetime exposure may be associated with recurrence and progression in NMIBC
   • Cigars and pipes are probably associated with bladder cancer formation, but there are few studies evaluating only cigar and pipe smokers because of the high probability that these subjects also smoke cigarettes
   • The risk of second-hand smoke in bladder cancer formation is low and not statistically different from that for non-smokers
2. Occupational exposure
   • Second most common cause (5% of cases)
   • Aromatic β-naphthylamine (most implicated as cause), amines, benzenes, arsenic, polycyclic aromatic hydrocarbons, and chlorinated hydrocarbons
   • Primarily in areas with a heavy concentration of chemical industries:
     • Dye (Aniline dye)
     • Rubber
     • Plastic
     • Dry-cleaning
     • Paint
3. Pelvic radiation
   • Latency period is 15 to 30 years
4. Cyclophosphamide
   • The only chemotherapeutic agent that has been proven to cause bladder cancer
5. Chronic inflammatory changes in the bladder (catheter use, stones, and recurrent infections)
   • Chronic infection with S. haematobium or, to a lesser degree, other bacteria leads to squamous cell carcinoma of the bladder
     • Schistosomiasis-induced bladder cancer is more common in developing countries, such as Egypt; most common histology in these countries is still urothelial
   • Spinal cord–injured patients are also at risk for developing squamous cell carcinoma, most likely because of chronic catheter irritation and infection.
     • Incidence of bladder cancer in spinal-cord injury patients <5%
   • HPV may be associated with increased risk of urothelial carcinoma
6. Chronic phenacetin use/analgesic abuse
   • Consumptions of large quantities of phenacetin (5-15 kg during a 10-year period) or acetaminophen (the active metabolite of phenacetin) have been associated with an increased risk of renal cancer and, perhaps, bladder cancer.
     • However, these studies relied on interviews and questionnaires to ascertain drug exposure rather than actual determination of analgesic use. A nested matched case-control study found no association between acetaminophen or other nonsteroidal anti-inflammatory drug ingestion and bladder cancer
7. Arsenic exposure

• (Diet)
  • In general, a Mediterranean diet leads to the lowest urothelial cancer risk. A diet rich in fruits and vegetables is protective against bladder cancer formation.
  • No evidence of an increased risk of bladder cancer in consumers of artificial sweeteners
  • There are no clear dietary or micronutrient programs to prevent primary bladder cancer

Genetic risk factors

• Family history
  • First-degree relatives: relative risk 2x
• Lynch syndrome (hereditary nonpolyposis colon cancer)
  • Autosomal dominant, germline mutation in mismatch repair genes
  • Associated with extracolonic cancer, including bladder cancer and upper urinary tract urothelial carcinoma
    • ≈5% of patients with LS are diagnosed with bladder cancer
• Null GSTM1 and slow NAT-2 lead to high levels of 3-aminobiphenyl and higher risk of bladder cancer

Questions

1. What are the risk factors for bladder cancer?
2. Which patients are at risk of bladder adenocarcinoma?

Answers

1. What are the risk factors for bladder cancer?
   1. Smoking
   2. Occupational exposure
   3. Cyclophosphamide exposure
   4. Pelvic radiation
   5. Chronic inflammation of the bladder (stones, recurrent UTIs, indwelling catheter, chronic infection with S. haematobium)
   6. Chronic analgesic abuse
   7. Family history
   8. Lynch syndrome

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 92
• Bhindi, Bimal, et al. "Canadian Urological Association guideline on the management of non-muscle invasive bladder cancer." Canadian Urological Association Journal 15.8 (2021).