Dr. med. Dirk Manski

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Bladder cancer (1/7): Definition, Epidemiology, and Etiology

Review Literature: EAU guidelines: superficial bladder cancer (Babjuk et al, in 2008 and 2013). Advanced bladder cancer (Stenzl et al, 2009 and Witjes et al, 2013).


Bladder cancer is a malignant tumor that originates from the epithelial cells of the urinary bladder.

Epidemiology of bladder Cancer

Etiology and Pathogenesis of Bladder Cancer

Review literature: (Kalble, 2001) (Leppert et al, 2006) (Plná and Hemminki, 2001).

Smoking and Bladder Cancer:

Smoking increases the risk for bladder cancer three to fourfold. In Europe, about half of urothelial carcinomas in men and one-third in women are attributable to smoking. Smokers and ex-smokers do more often experience tumor recurrence after treatment of superficial bladder compared with non-smokers (Lammers et al, 2011). A dose-effect relationship is well established. The relative risk increases by 1 to 6 times, depending on the length of smoking and the number of cigarettes smoked. Quitting smoking avoids a further increase of the tumor risk (IARC, 2004).

Occupational Exposure:

Occupations with exposure of risk factors for bladder cancer are: chemical industry processing paint, metal or petrolium products, steel industry, auto mechanics, leather industry and dental technicians. Identified risk factors are azo dyes, benzidine, naphthylamine, toluidine, aminodiphenyl, aromatic amines, diesel exhaust and carbon black. Urothelial carcinoma is a recognized occupational disease, if there has been sufficient exposure and a reasonable latency period. In Europe, up to 10% of bladder cancers are caused by occupational exposure. In developing countries figures of bladder carcinoma are rising due to increased occupational exposure without safety guidelines.

Influence of gender:

Although the risk of developing the disease is significantly higher for men, bladder carcinoma is in a higher tumor stage in women at the time of initial diagnosis; this corresponds to a higher mortality after cystectomy (HR 1,2) \parencite{Liu2015}. This is partly explained by a different diagnostic approach in the case of hematuria, in women the differential diagnosis urinary tract infection is more often accepted as the cause and cystoscopy is not done (Cohn et al, 2014).

Fluid Intake and Bladder Cancer:

It is controversial whether an increased fluid intake leads to a reduction in the risk of bladder cancer. Individual studies have shown this connection. Coffee or alcohol are not risk factors for bladder cancer (Brinkman et al, 2008).

Nutrition and Bladder Cancer:

A healthy nutrition rich of fruits and vegetables (e.g. Mediterranean diet) lowers the risk for bladder cancer. Sweeteners were suspected to be a risk factor for bladder cancer, but modern studies did not find any evidence for an relationship.

Aristololchic acid:

Aristololchic acid causes Balkan nephropathy (chronic interstitial nephritis, chronic renal insufficiency and urothelial carcinoma). Aristololchic acid is found in the plant Aristolochia clematitis and consumed through contaminated flour, additional sources are Chinese herbs medicine (Grollman et al, 2007).

Drugs and Bladder Cancer Risk:

The following substances are recognized risk factors for bladder carcinoma: cyclophosphamide, Chinese herbs which contain aristocholchic acid and the antidiabetic pioglitazone. The causal relationship between phenacetin and other NSAIDs in causing bladder cancer remains contradictory.

Chronic Urinary Tract Infection and Bladder Cancer:

Chronic urinary tract infection (over years) is a risk factor to cause a squamous cell carcinoma of the bladder (e.g. patients with schistosomiasis, chronic catheter use).

Molecular Biology of Bladder Cancer:

The following genetic changes increase the risk of bladder cancer or correlate with tumor stage:

Activity of N-acetyltransferases (NAT1 and NAT2):

N-acetyltransferases are important for the inactivation and elimination of nitrosamines. Slow enzyme activity of N-acetyltransferases carries a higher risk of developing bladder cancer, since environmental factors causing bladder cancer are slower inactivated. The epidemiological relationship is particular prominent in patients with a smoking history.

Lynch syndrome:

Lynch syndrome or hereditary non-polyposis-associated colorectal cancer (HNPCC) is an inherited form of colon cancer without occurrence of many polyps in the colon. Mutations in DNA mismatch repair proteins also increase the risk of urothelial carcinoma.

Oncogenes and tumor suppressor genes:

increased expression of oncogenes like RAS or p21. Deletion or loss of action mutations of tumor suppressor genes like p53 or retinoblastoma gene RB1. The expression of PD-L1 correlates with the treatment response with immune checkpoint inhibitors.

Chromosomal changes:

The loss of the long arm of chromosome 9 is detectable in all stages of bladder cancer. In advanced tumors, the loss of the short arm of chromosome 11 and 17 can be detected.

Further molecular changes of bladder cancer:

FGF receptor mutations, increased expression of laminin receptors, increased secretion of type IV collagenase and autocrine motility factor, increased expression of EGF receptors.

Index: 1–9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z


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