Dr. med. Dirk Manski

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Bladder Cancer: Definition, Epidemiology, and Etiology


Bladder cancer is a malignant tumor that originates from the epithelial cells of the urinary bladder. Review Literature: EAU guidelines superficial bladder cancer. EAU guidelines of muscle-invasive and metastatic bladder cancer. German S3 guidelines bladder carcinoma Harnblasenkarzinom.

Bladder cancer as seen in cystoscopy.
Bladder cancer as seen in cystoscopy

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 more often experience tumor recurrence after superficial bladder treatment than 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 in the tumor risk (IARC, 2004).

Occupational Exposure:

Occupations with exposure to risk factors for bladder cancer are in the chemical industry processing paint, metal or petroleum products, steel industry, auto mechanics, leather industry, and dental technicians. Identified risk factors are azo dyes, benzidine, naphthylamine, toluidine, aminobiphenyl, aromatic amines, diesel exhaust, and carbon black. Urothelial carcinoma is a recognized occupational disease with 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 higher mortality after cystectomy (HR 1,2) \parencite{Liu2015}. The higher tumor stage in women 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 diet rich in fruits and vegetables (e.g., Mediterranean diet) lowers the risk of bladder cancer. The metabolic syndrome is an established risk factor for bladder carcinoma (Teleka et al., 2018). Sweeteners were suspected to be a risk factor for bladder cancer, but modern studies did not find any evidence (Brinkmann et al., 2008).

Aristololchic acid:

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

Drugs and Bladder Cancer Risk:

The following substances are recognized risk factors for bladder carcinoma: cyclophosphamide, Chinese herbs containing aristolochic acid, and 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 infections over a long time are a risk factor for bladder cancer (e.g., patients with schistosomiasis, bladder stones, or long-term catheters). The risk is more pronounced for squamous cell carcinoma than for urothelial carcinoma (Abol-Enein et al., 2008).

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 essential 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 the 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 are additional findings.

Further molecular changes of bladder cancer:

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

Molecular subclassification:

Modern laboratory methods (including next-generation sequencing) can simultaneously record numerous changes at protein, RNA, and DNA levels and allow a molecular subclassification of bladder carcinomas into luminal, basal-squamous, and neuronal subtypes (Robertson et al., 2017). The changes at the molecular level can enable a better selection of targeted therapies.

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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  Deutsche Version: Harnblasenkarzinom