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Bladder Cancer Pathophysiology

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General Information About Bladder Cancer

Incidence and Mortality

Bladder cancer is the sixth most common cancer in the United States after lung cancer, prostate cancer, breast cancer, colon cancer, and lymphoma. It is the third most common cancer in men but only the eleventh most common cancer in women. Of the roughly 70,000 new cases annually, about 53,000 are in men and about 18,000 are in women. Of the roughly 15,000 annual deaths, over 10,000 are in men and fewer than 5,000 are in women. The reasons for this disparity between the sexes are not well understood.

Estimated new cases and deaths from bladder cancer in the United States in 2017:[1]

  • New cases: 79,030.
  • Deaths: 16,870.

Anatomy

The urinary tract consists of the kidneys, the ureters, the bladder, and the urethra. The urinary tract is lined with transitional cell urothelium from the renal pelvis to the proximal urethra. Transitional cell carcinoma (also referred to as urothelial carcinoma) can develop anywhere along this pathway.

Histopathology

Under normal conditions, the bladder, the lower part of the kidneys (the renal pelvises), the ureters, and the proximal urethra are lined with a specialized mucous membrane referred to as transitional epithelium (also called urothelium). Most cancers that form in the bladder, the renal pelvises, the ureters, and the proximal urethra are transitional cell carcinomas (also called urothelial carcinomas) that derive from transitional epithelium. (Refer to the PDQ summaries on Renal Cell Cancer Treatment and Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment for more information.)

Transitional cell carcinoma of the bladder can be low-grade or high-grade:

  • Low-grade bladder cancer often recurs in the bladder after treatment but rarely invades the muscular wall of the bladder or spreads to other parts of the body. Patients rarely die from low-grade bladder cancer.
  • High-grade bladder cancer commonly recurs in the bladder and also has a strong tendency to invade the muscular wall of the bladder and spread to other parts of the body. High-grade bladder cancer is treated more aggressively than low-grade bladder cancer and is much more likely to result in death. Almost all deaths from bladder cancer are due to high-grade disease.

Bladder cancer is also divided into muscle-invasive and nonmuscle-invasive disease, based on invasion of the muscularis propria (also referred to as the detrusor muscle), which is the thick muscle deep in the bladder wall.

  • Muscle-invasive disease is much more likely to spread to other parts of the body and is generally treated by either removing the bladder or treating the bladder with radiation and chemotherapy. As noted above, high-grade cancers are much more likely to be muscle-invasive than low-grade cancers. Thus, muscle-invasive cancers are generally treated more aggressively than nonmuscle-invasive cancers.
  • Nonmuscle-invasive disease can often be treated by removing the tumor(s) via a transurethral approach, and sometimes chemotherapy or other treatments are introduced into the bladder with a catheter to help fight the cancer.

Under conditions of chronic inflammation, such as infection of the bladder with the Schistosoma haematobiumparasite, squamous metaplasia may occur in the bladder; the incidence of squamous cell carcinomas of the bladder is higher under conditions of chronic inflammation than is otherwise seen. In addition to transitional cell carcinomas and squamous cell carcinomas, adenocarcinomas, small cell carcinomas, and sarcomas can form in the bladder. In the United States, transitional cell carcinomas represent the vast majority (over 90%) of bladder cancers. However, a significant number of transitional cell carcinomas have areas of squamous or other differentiation.

Carcinogenesis and Risk Factors

Increasing age is the most important risk factor for most cancers. Other risk factors for bladder cancer include:

  • Use of tobacco, especially cigarettes.[2]
  • Family history of bladder cancer.[3]
  • Genetic mutations.[4-6]
    • HRAS mutation (Costello Syndrome, Facio-Cutaneous-Skeletal Syndrome).
    • Rb1 mutation.
    • PTEN/MMAC1 mutation (Cowden Syndrome).
    • NAT2 slow acetylator phenotype.
    • GSTM1 null phenotype.
  • Occupational exposure to chemicals in processed paint, dye, metal, and petroleum products that include:
    • Aluminum production (polycyclic aromatic hydrocarbons, fluorides).[2]
    • Aminobiphenyl and its metabolites.[2]
    • Aromatic amines, benzidine and its derivatives.[2]
    • Certain aldehydes.[7]
    • 2-Napthylamine, beta-napthylamine.[2]
    • o-Toluidine.[8]
  • Treatment with cyclophosphamide, ifosfamide, or pelvic radiation for other malignancies.[9-11]
  • Chinese herbs: aristolochic (AA) extracted from species of Aristolochia fangchi.[12]
  • Exposure to arsenic.
    • Arsenic in well water.[13,14,2]
    • Inorganic arsenic compounds (gallium arsenide).
  • Chlorinated aliphatic hydrocarbons and chlorination by-products in treated water.[15]
  • Schistosoma haematobium bladder infections (Bilharzial bladder cancer).[16]
  • Neurogenic bladder and associated indwelling catheters.[17]

There is strong evidence linking exposure to carcinogens to bladder cancer. The most common risk factor for bladder cancer in the United States is cigarette smoking. It is estimated that up to half of all bladder cancers are caused by cigarette smoking and that smoking increases a person’s risk of bladder cancer two to four times above baseline risk.[18,19] Smokers with less functional polymorphisms of N-acetyltransferase-2 (known as slow acetylators) have a higher risk of bladder cancer than other smokers, presumably because of their reduced ability to detoxify carcinogens.

Certain occupational exposures have also been linked to bladder cancer, and higher rates of bladder cancer have been reported in textile dye and rubber tire industries; among painters; leather workers; shoemakers; and aluminum-, iron-, and steelworkers. Specific chemicals linked to bladder carcinogenesis include beta-naphthylamine, 4-aminobiphenyl, and benzidine. Although these chemicals are now generally banned in Western countries, many other chemicals still in use are also suspected of causing bladder cancer.[19]

Exposure to the chemotherapy drug cyclophosphamide has also been associated with an increased risk of bladder cancer.

Chronic urinary tract infections and infection with the parasite S. haematobium have also been associated with an increased risk of bladder cancer, often squamous cell carcinomas. Chronic inflammation is thought to play a key role in carcinogenesis in these settings.

Clinical Features

Bladder cancer typically presents with gross or microscopic hematuria. Less commonly, patients may complain of urinary frequency, nocturia, and dysuria, symptoms that are more common in patients with carcinoma in situ. Patients with upper urinary tract urothelial carcinomas may present with pain due to obstruction by the tumor.

It is important to note that urothelial carcinomas are often multifocal—the entire urothelium needs to be evaluated if a tumor is found. In patients with bladder cancer, upper urinary tract imaging is essential for staging and surveillance. This can be accomplished with ureteroscopy, retrograde pyelograms during cystoscopy, intravenous pyelograms, or computed tomography (CT) urograms. Similarly, patients with an upper urinary tract transitional cell carcinoma have a high risk of developing bladder cancer; these patients need periodic cystoscopy and surveillance of the contralateral upper urinary tract.

Diagnostics

When bladder cancer is suspected, the most useful diagnostic test is cystoscopy. Radiological studies such as CT scans or ultrasound do not have sufficient sensitivity to be useful for detecting bladder cancers. Cystoscopy can be performed in a urology clinic.

If cancer is seen on cystoscopy, the patient is typically scheduled for bimanual examination under anesthesia and a repeat cystoscopy in an operating room so that transurethral resection of the tumor(s) and/or biopsies can be performed. If a high-grade cancer (including carcinoma in situ) or invasive cancer is seen, the patient is staged with a CT scan of the abdomen and pelvis (or CT urogram) and either a chest x-ray or chest CT scan. Patients with a nonhepatic elevation of alkaline phosphatase or symptoms suggestive of bone metastases undergo a bone scan.

Prognostic Factors

The major prognostic factors in carcinoma of the bladder are the following:

  • Depth of invasion into the bladder wall.
  • Pathologic grade of the tumor.
  • Presence versus absence of carcinoma in situ.

Among nonmuscle-invasive cancers, the following factors are also prognostic:[20]

  • Number of tumors.
  • Tumor size (e.g., >3 cm or <3 cm).
  • Invasion of the lamina propria (Ta vs. T1).
  • Whether the tumor is the primary tumor or a recurrence.

Most superficial tumors are well differentiated. Patients in whom superficial tumors are less differentiated, large, multiple, or associated with carcinoma in situ (Tis) in other areas of the bladder mucosa are at greatest risk of recurrence and the development of invasive cancer. These patients may be considered to have the entire urothelial surface at risk of cancer development.

Survival

Patients who die from bladder cancer almost always have disease that has metastasized from the bladder to other organs. Low-grade bladder cancers rarely grow into the muscular wall of the bladder and rarely metastasize, so patients with low-grade (grade I) bladder cancers very rarely die from their cancer. Nonetheless, they may experience multiple relapses that need to be resected.

Almost all deaths from bladder cancer are among patients with high-grade disease, which has a much greater potential to invade deeply into the bladder’s muscular wall and spread to other organs.

Approximately 70% to 80% of patients with newly diagnosed bladder cancer will present with superficial bladder tumors (i.e., stage Ta, Tis, or T1). The prognosis of these patients depends largely on the grade of the tumor. Patients with high-grade tumors have a significant risk of dying of their cancer even if it is not muscle-invasive.[21] Among patients with high-grade tumors, those who present with superficial, nonmuscle-invasive bladder cancer can usually be cured, and those with muscle-invasive disease can sometimes be cured.[22-24] Studies have demonstrated that some patients with distant metastases have achieved long-term complete response after being treated with combination chemotherapy regimens, although most such patients have metastases limited to their lymph nodes and have a near-normal performance status.[25,26]

There are clinical trials suitable for patients with all stages of bladder cancer; whenever possible, clinical trials designed to improve upon standard therapy should be considered.

General information about clinical trials is also available from the NCI website.

Follow-up

Bladder cancer tends to recur, even when it is noninvasive at the time of diagnosis; therefore standard practice is to perform surveillance of the urinary tract after a diagnosis of bladder cancer. However, no trials have been conducted to assess whether surveillance affects rates of progression, survival, or quality of life; nor have clinical trials defined an optimal surveillance schedule. Urothelial carcinomas are thought to reflect a so-called field defect whereby the cancer emerges due to genetic mutations that are widely present in the patient’s bladder or entire urothelium. Thus, people who have had a bladder tumor resected often subsequently have recurrent tumors in the bladder, often in different locations from the site of the initial tumor. Similarly, but less commonly, they may have tumors appear in the upper urinary tract (i.e., in the renal pelvises or ureters).

An alternative explanation for these patterns of recurrence is that cancer cells that are disrupted when a tumor is resected may reimplant elsewhere in the urothelium. Support for this second theory is that tumors are more likely to recur downstream than upstream from the initial cancer. Upper urinary tract cancers are more likely to recur in the bladder than bladder cancers are to recur in the upper urinary tract.[27-30]

 

References

  1. American Cancer Society: Cancer Facts and Figures 2017. Atlanta, Ga: American Cancer Society, 2017. Available onlineExit Disclaimer. Last accessed October 13, 2017.
  2. Burger M, Catto JW, Dalbagni G, et al.: Epidemiology and risk factors of urothelial bladder cancer. Eur Urol 63 (2): 234-41, 2013. [PUBMED Abstract]
  3. Fraumeni JF Jr, Thomas LB: Malignant bladder tumors in a man and his three sons. JAMA 201 (7): 97-9, 1967.
  4. Marees T, Moll AC, Imhof SM, et al.: Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up. J Natl Cancer Inst 100 (24): 1771-9, 2008. [PUBMED Abstract]
  5. Gallagher DJ, Feifer A, Coleman JA: Genitourinary cancer predisposition syndromes. Hematol Oncol Clin North Am 24 (5): 861-83, 2010. [PUBMED Abstract]
  6. Lindor NM, McMaster ML, Lindor CJ, et al.: Concise handbook of familial cancer susceptibility syndromes – second edition. J Natl Cancer Inst Monogr (38): 1-93, 2008. [PUBMED Abstract]
  7. Stadler WM: Molecular events in the initiation and progression of bladder cancer (review). Int J Oncol 3: 549-557, 1993.
  8. Brown T, Slack R, Rushton L, et al.: Occupational cancer in Britain. Urinary tract cancers: bladder and kidney. Br J Cancer 107 (Suppl 1): S76-84, 2012. [PUBMED Abstract]
  9. Nieder AM, Porter MP, Soloway MS: Radiation therapy for prostate cancer increases subsequent risk of bladder and rectal cancer: a population based cohort study. J Urol 180 (5): 2005-9; discussion 2009-10, 2008. [PUBMED Abstract]
  10. Abern MR, Dude AM, Tsivian M, et al.: The characteristics of bladder cancer after radiotherapy for prostate cancer. Urol Oncol 31 (8): 1628-34, 2013. [PUBMED Abstract]
  11. Monach PA, Arnold LM, Merkel PA: Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases: a data-driven review. Arthritis Rheum 62 (1): 9-21, 2010. [PUBMED Abstract]
  12. Cosyns JP: Aristolochic acid and ‘Chinese herbs nephropathy’: a review of the evidence to date. Drug Saf 26 (1): 33-48, 2003. [PUBMED Abstract]
  13. Letašiová S, Medve’ová A, Šovčíková A, et al.: Bladder cancer, a review of the environmental risk factors. Environ Health 11 (Suppl 1): S11, 2012. [PUBMED Abstract]
  14. Fernández MI, López JF, Vivaldi B, et al.: Long-term impact of arsenic in drinking water on bladder cancer health care and mortality rates 20 years after end of exposure. J Urol 187 (3): 856-61, 2012. [PUBMED Abstract]
  15. Villanueva CM, Cantor KP, Grimalt JO, et al.: Bladder cancer and exposure to water disinfection by-products through ingestion, bathing, showering, and swimming in pools. Am J Epidemiol 165 (2): 148-56, 2007. [PUBMED Abstract]
  16. Kantor AF, Hartge P, Hoover RN, et al.: Urinary tract infection and risk of bladder cancer. Am J Epidemiol 119 (4): 510-5, 1984. [PUBMED Abstract]
  17. Locke JR, Hill DE, Walzer Y: Incidence of squamous cell carcinoma in patients with long-term catheter drainage. J Urol 133 (6): 1034-5, 1985. [PUBMED Abstract]
  18. Brennan P, Bogillot O, Greiser E, et al.: The contribution of cigarette smoking to bladder cancer in women (pooled European data). Cancer Causes Control 12 (5): 411-7, 2001. [PUBMED Abstract]
  19. Kirkali Z, Chan T, Manoharan M, et al.: Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology 66 (6 Suppl 1): 4-34, 2005. [PUBMED Abstract]
  20. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al.: Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49 (3): 466-5; discussion 475-7, 2006. [PUBMED Abstract]
  21. Herr HW: Tumor progression and survival of patients with high grade, noninvasive papillary (TaG3) bladder tumors: 15-year outcome. J Urol 163 (1): 60-1; discussion 61-2, 2000. [PUBMED Abstract]
  22. Stein JP, Lieskovsky G, Cote R, et al.: Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 19 (3): 666-75, 2001. [PUBMED Abstract]
  23. Madersbacher S, Hochreiter W, Burkhard F, et al.: Radical cystectomy for bladder cancer today–a homogeneous series without neoadjuvant therapy. J Clin Oncol 21 (4): 690-6, 2003. [PUBMED Abstract]
  24. Manoharan M, Ayyathurai R, Soloway MS: Radical cystectomy for urothelial carcinoma of the bladder: an analysis of perioperative and survival outcome. BJU Int 104 (9): 1227-32, 2009. [PUBMED Abstract]
  25. Loehrer PJ Sr, Einhorn LH, Elson PJ, et al.: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 10 (7): 1066-73, 1992. [PUBMED Abstract]
  26. von der Maase H, Sengelov L, Roberts JT, et al.: Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 23 (21): 4602-8, 2005. [PUBMED Abstract]
  27. Millán-Rodríguez F, Chéchile-Toniolo G, Salvador-Bayarri J, et al.: Primary superficial bladder cancer risk groups according to progression, mortality and recurrence. J Urol 164 (3 Pt 1): 680-4, 2000. [PUBMED Abstract]
  28. Nieder AM, Brausi M, Lamm D, et al.: Management of stage T1 tumors of the bladder: International Consensus Panel. Urology 66 (6 Suppl 1): 108-25, 2005. [PUBMED Abstract]
  29. Babjuk M, Oosterlinck W, Sylvester R, et al.: EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol 54 (2): 303-14, 2008. [PUBMED Abstract]
  30. Babjuk M, Oosterlinck W, Sylvester R, et al.: EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol 59 (6): 997-1008, 2011. [PUBMED Abstract]

 

Source:

https://www.cancer.gov/types/bladder/hp/bladder-treatment-pdq

Hyperlink:
https://www.cancer.gov/types/bladder/hp/bladder-treatment-pdq