Bladder cancer

(This image show superficial papillary tumors of the bladder. The top left image shows a tumor in diverticulum within the bladder wall.)



Bladder cancer refers to any of several types of malignant growths of the urinary bladder. It is a disease in which abnormal cells multiply without control in the bladder. The bladder is a hollow, muscular organ that stores urine; it is located in the pelvis. The most common type of bladder cancer begins in cells lining the inside of the bladder and is called urothelial cell or transitional cell carcinoma (UCC or TCC).

Signs and symptoms

Bladder cancer characteristically causes blood in the urine; this may be visible to the naked eye (frank hematuria) or detectable only by microscope (microscopic hematuria). Other possible symptoms include pain during urination, frequent urination (Pollakiuria) or feeling the need to urinate without results. These signs and symptoms are not specific to bladder cancer, and are also caused by non-cancerous conditions, including prostate infections and cystitis.

Causes

Risk factors

Exposure to environmental carcinogens of various types is responsible for the development of most bladder cancers. In a 10-year study involving almost 48,000 men, researchers found that men who drank 1.5L of water a day had a significantly reduced incidence of bladder cancer when compared with men who drank less than 240mL (around 1 cup) per day. The authors proposed that bladder cancer might partly be caused by the bladder directly contacting carcinogens that are excreted in urine. It is postulated, therefore, that by drinking higher quantities of water, urine is more dilute, thereby reducing the chance of disease. Tobacco use has been linked to bladder cancer. Thirty percent of bladder tumors probably result from occupational exposure in the workplace to carcinogens such as benzidine. Occupations at risk are metal industry workers, rubber industry workers, workers in the textile industry and people who work in printing. Some studies also suggest that auto mechanics have an elevated risk of bladder cancer due to their frequent exposure to hydrocarbons and petroleum-based chemicals. Hairdressers are thought to be at risk as well because of their frequent exposure to permanent hair dyes. It has been proposed that hair dyes are a risk factor, and some have shown an odds ratio of 2.1 to 3.3 for risk of developing bladder cancer among women who use permanent hair dyes, while others have shown no correlation between the use of hair dyes and bladder cancer. Certain drugs such as cyclophosphamide and phenacetin are known to predispose to bladder TCC. Chronic bladder irritation (infection, bladder stones, catheters, bilharzia) predisposes to squamous cell carcinoma of the bladder. Approximately 20% of bladder cancers occur in patients without predisposing risk factors.

Genetics

Like virtually all cancers, bladder cancer development involves the acquisition of mutations in various oncogenes and tumor supressor genes. Genes which may be altered in bladder cancer include H19, FGFR3, HRAS, RB1 and TP53. Several genes have been identified which play a role in regulating the cycle of cell division, preventing cells from dividing too rapidly or in an uncontrolled way. Alterations in these genes may help explain why some bladder cancers grow and spread more rapidly than others.

A family history of bladder cancer is also a risk factor for the disease. Many cancer experts assert that some people appear to inherit reduced ability to break down certain chemicals, which makes them more sensitive to the cancer-causing effects of tobacco smoke and certain industrial chemicals.

Diagnosis

The gold standard of diagnosing bladder cancer is urine cytology and transurethral (through the urethra) cystoscopy. Urine cytology can be obtained in voided urine or at the time of the cystoscopy ("bladder washing"). Cytology is very specific (a positive result is highly indicative of bladder cancer) but suffers from low sensitivity (a negative result does not exclude the diagnosis of cancer). There are newer urine bound markers for the diagnosis of bladder cancer. These markers are more sensitive but not as specific as urine cytology. They are much more expensive as well. Many patients with a history, signs, and symptoms suspicious for bladder cancer are referred to a urologist or other physician trained in cystoscopy, a procedure in which a flexible tube bearing a camera and various instruments is introduced into the bladder through the urethra. Suspicious lesions may be biopsied and sent for pathologic analysis.

Pathological Classification

90% of bladder cancer are Transitional cell carcinomas (TCC) that arise from the inner lining of the bladder called the urothelium. The other 10% of tumours are squamous cell carcinoma, adenocarcinoma, sarcoma, small cell carcinoma and secondary deposits from cancers elsewhere in the body.

TCCs are often multifocal, with 30-40% of patients having more than one tumour at diagnosis. The pattern of growth of TCCs can be papillary, sessile (flat) or carcinoma-in-situ (CIS).

The 1973 WHO grading system for TCCs (papilloma, G1, G2 or G3) is most commonly used despite being superseded by the 2004 WHO grading (papillary neoplasm of low malignant potential (PNLMP), low grade and high grade papillary carcinoma.

CIS invariably consists of cytologically high grade tumour cells.

Bladder TCC is staged according to the 1997 TNM system:

• Ta Non-invasive papillary tumour
• T1 Invasive but not as far as the muscular bladder layer
• T2 Invasive into the muscular layer
• T3 Invasive beyond the muscle into the fat outside the bladder
• T4 Invasive into surrounding structures like the prostate, uterus or pelvic wall

Staging

The following stages are used to classify the location, size, and spread of the cancer, according to the TNM (tumor, lymph node, and metastasis) staging system:

• Stage 0: Cancer cells are found only on the inner lining of the bladder.

• Stage I: Cancer cells have proliferated to the layer beyond the inner lining of the urinary bladder but not to the muscles of the urinary bladder.

• Stage II: Cancer cells have proliferated to the muscles in the bladder wall but not to the fatty tissue that surrounds the urinary bladder.

• Stage III: Cancer cells have proliferated to the fatty tissue surrounding the urinary bladder and to the prostate gland, vagina, or uterus, but not to the lymph nodes or other organs.

• Stage IV: Cancer cells have proliferated to the lymph nodes, pelvic or abdominal wall, and/or other organs.

• Recurrent: Cancer has recurred in the urinary bladder or in another nearby organ after having been treated.

Treatment

The treatment of bladder cancer depends on how deep the tumor invades into the bladder wall. Superficial tumors (those not entering the muscle layer) can be "shaved off" using an electrocautery device attached to a cystoscope. Immunotherapy in the form of BCG instillation is also used to treat and prevent the recurrence of superficial tumors. BCG immunotherapy is effective in up to 2/3 of the cases at this stage. Instillations of chemotherapy, such as valrubicin (Valstar) into the bladder can also be used to treat BCG-refractory CIS disease when cystectomy is not an option.

Untreated, superficial tumors may gradually begin to infiltrate the muscular wall of the bladder. Tumors that infiltrate the bladder require more radical surgery where part or all of the bladder is removed (a cystectomy) and the urinary stream is diverted. In some cases, skilled surgeons can create a substitute bladder (a neobladder) from a segment of intestinal tissue, but this largely depends upon patient preference, age of patient, renal function, and the site of the disease.

A combination of radiation and chemotherapy can also be used to treat invasive disease. It has not yet been determined how the effectiveness of this form of treatment compares to that of radical ablative surgery.

There is weak observational evidence from one very small study (84) to suggest that the concurrent use of statins is associated with failure of BCG immunotherapy.

The hemocyanin found in Concholepas concholepas blood has immunotherapeutic effects against bladder and prostate cancer. In a research made in 2006 mice were primed with C. concholepas before implantation of bladder tumor (MBT-2) cells. Mice treated with C. concholepas showed a significant antitumor effect as well. The effects included prolonged survival, decreased tumor growth and incidence and lack of toxic effects.

Epidemiology

In the United States, bladder cancer is the fourth most common type of cancer in men and the ninth most common cancer in women. More than 47,000 men and 16,000 women are diagnosed with bladder cancer each year. One reason for its higher incidence in men is that the androgen receptor, which is much more active in men than in women, plays a major part in the development of the cancer.