Disease: Bladder Cancer
(Cancer of the Urinary Bladder)

    Bladder cancer facts

    • The bladder is a hollow organ that collects urine for storage and eventual removal from the body through the urethra. Bladder cancer is the abnormal growth of bladder cells and is one of the common cancers; men have a higher risk of getting bladder cancer than women.
    • The most common symptom of bladder cancer is bleeding in the urine (hematuria).
    • Cigarette smoking is the most significant risk factor, with smokers three to four times more likely to get the disease than nonsmokers.
    • Bladder cancer can be subdivided into noninvasive and invasive, with the former having much better treatment outcomes than the latter.
    • The initial treatment for bladder cancer is transurethral resection (TURBT), which removes the tumor from the bladder through the urethra and provides information regarding stage and grade of the tumor.
    • Bladder cancer is staged (classified by the classified by extent of spread of the cancer) and graded (how abnormal and/or aggressive the cells appear under the microscope) to both determine treatments and possible prognosis for individual patients.
    • Low-grade superficial tumors (Ta) are treated with TURBT followed by an optional instillation of a chemotherapy medication in the bladder to reduce recurrence rates. These tumors have high recurrence rates but a very low chance of progression to higher stages.
    • High-grade T1 tumors have high chances of recurrence and progression and may need additional treatment in the form of BCG or chemotherapy instillation in the bladder. Patients unresponsive to these may be best treated by radical cystectomy.
    • Radical cystectomy provides the best chances of cure in patients with muscle invasive disease.
    • Chemotherapy is used in patients with metastatic disease at presentation or those in which bladder cancer cells are present outside the bladder wall or in lymph nodes during radical cystectomy.
    • The prognosis of bladder cancer ranges from good to poor and depends on the stage and grade of the cancer.
    • People may reduce the risk of bladder cancer by not smoking and by avoiding environmental carcinogens.
    • Informational and support groups are available for anyone concerned about bladder cancer.

    What is the bladder?

    The urinary bladder, or the bladder, is a hollow organ in the pelvis. Most of it lies behind the pubic bone of the pelvis, but when full of urine, it can extend up into the lower part of the abdomen. Its primary function is to store urine that drains into it from the kidney through tube-like structures called the ureters. The ureters from both the kidneys open into the urinary bladder. The bladder forms a low-pressure reservoir that gradually stretches out as urine fills into it. In males, the prostate gland is located adjacent to the base of the bladder where urethra joins the bladder. From time to time, the muscular wall of the bladder contracts to expel urine through the urinary passage (urethra) into the outside world. The normal volume of the full bladder is about 400 ml-600 ml, or about 2 cups.

    What are the layers of the bladder?

    The bladder consists of three layers of tissue. The innermost layer of the bladder, which comes into contact with the urine stored inside the bladder, is called the "mucosa" and consists of several layers of specialized cells called "transitional cells," which are almost exclusively found in the urinary system of the body. These same cells also form the inner lining of the ureters, kidneys, and a part of the urethra. These cells form a waterproof lining within these organs to prevent the urine from going into the deeper tissue layers.

    The middle layer is a thin lining known as the "lamina propria" and forms the boundary between the inner "mucosa" and the outer muscular layer. This layer has a network of blood vessels and nerves and is an important landmark in terms of the staging of bladder cancer (described in detail below in the bladder cancer staging section).

    The outer layer of the bladder comprises of the "detrusor" muscle and is called the "muscularis." This is the thickest layer of the bladder wall. Its main function is to relax slowly as the bladder fills up to provide low-pressure urine storage and then to contract to compress the bladder and expel the urine out during the act of passing urine. Outside these three layers is a variable amount of fat that lines and protects the bladder like a soft cushion and separates it from the surrounding organs such as the rectum and the muscles and bones of the pelvis.

    Picture of the urinary system: kidneys, ureters, and bladder

    What is bladder cancer?

    Bladder cancer is an uncontrolled abnormal growth and multiplication of cells in the urinary bladder, which have broken free from the normal mechanisms that keep uncontrolled cell growth in check. Bladder cancer (like cancers of other organs) has the ability to spread (metastasize) to other body parts, including the lungs, bones, and liver.

    Bladder cancer invariably starts from the innermost layer of the bladder (for example, the mucosa) and may invade into the deeper layers as it grows. Alternately, it may remain confined to the mucosa for a prolonged period of time. Visually, it may appear in various forms. Most common is a shrub-like appearance (papillary), but it may also appear as a nodule, an irregular solid growth or a flat, barely perceptible thickening of the inner bladder wall (see details in subsequent sections).

    What is the burden of bladder cancer in the U.S.?

    Bladder cancer has the dubious distinction of inclusion on the top 10 list of cancers, with an estimated 74,690 new cases occurring in 2013-2014 within the U.S. Bladder cancer is three to four times more likely to be diagnosed in men than in women and about two times higher in white men than in African-American men. Bladder cancer killed an estimated 15,210 people in 2013. In the U.S., the lifetime bladder cancer risk for men is about one in 26 and for women about one in 90.

    What are the types of bladder cancer?

    Bladder cancer is classified on the basis of the appearance of its cells under the microscope (histological type). The type of bladder cancer has implications in selecting the appropriate treatment for the disease. For example, certain types may not respond to radiation and chemotherapy as well as others. The extent of surgery required for maximizing the chances of cure may also be impacted by the histological type of the cancer. In addition, bladder cancers are often described based on their position in the wall of the bladder. Noninvasive bladder cancers are located in the inner layer of cells (transitional cell epithelium) but have not penetrated into deeper layers. Invasive cancers penetrate into the deeper layers such as the muscle layer. Invasive cancers are more difficult to treat.

    The more common types of bladder cancer and their relative incidence are given below:

    • Urothelial carcinoma (previously known as "transitional cell carcinoma") is the most common type and comprises 90%-95% of all bladder cancers. This type of cancer has two subtypes, papillary carcinoma (growing finger-like projections into the bladder lumen) and flat carcinomas that do not produce fingerlike projections. Urothelial carcinoma (transitional cell carcinoma) is strongly associated with cigarette smoking.
    • Adenocarcinoma of the bladder comprises about 1%-2% of all bladder cancers and is associated with prolonged inflammation and irritation. Most adenocarcinomas of the bladder are invasive.
    • Squamous cell carcinoma comprises 1%-2% of bladder cancers and is also associated with prolonged infection, inflammation, and irritation such as that associated with longstanding stones in the bladder. In certain parts of the Middle East and Africa (for example, Egypt), this is the predominant form of bladder cancer and is associated with chronic infection caused by Schistosoma worm (a blood fluke, that causes schistosomiasis, also termed bilharzia or snail fever).
    • Other rare forms of bladder cancer include small cell cancer (in bladder nerves), pheochromocytoma (rare), and sarcoma (in muscle tissue).

    What are bladder cancer causes and risk factors?

    About 50% of all bladder cancers may be caused by cigarette smoking. The longer and heavier the exposure, greater are the chances of developing bladder cancer. The toxic chemicals in cigarette smoke, many of which are known cancer-causing substances (carcinogens), travel in the bloodstream after being absorbed from the lungs and get filtered into the urine by the kidneys. They then come in contact with the cells in the inner lining of the urinary system, including the bladder, and cause changes within these cells that make them more prone to developing into cancer cells. Quitting smoking decreases the risk of developing bladder cancer but takes many years to reach the level of people who have never smoked. However, as time passes after the quit date, the risk progressively decreases. In view of the above, it is extremely important for patients with bladder cancer to stop smoking completely since the chances of the cancer coming back after treatment are higher in those people who continue to smoke.

    People who smoke also have a higher risk of many other types of cancer, including leukemia and cancers of the lung, lip, mouth, larynx, esophagus, stomach, and pancreas. Smokers also have a higher risk of diseases like heart attacks, peripheral vascular disease, diabetes, stroke, bone loss (osteoporosis), emphysema, and bronchitis.

    Age and family history are other risk factors as is male sex. About 90% of people with bladder cancer are over age 55, though in exceptional cases the disease may surface in the third or fourth decade of life. Men are more prone to developing bladder cancer probably due to a higher incidence of smoking and exposure to toxic chemicals. A close relative with a history of bladder cancer may increase the predisposition for the development of this disease.

    Exposure to toxic chemicals such as arsenic, phenols, aniline dyes, and arylamines increase the risk of bladder cancer. Dye workers, rubber workers, aluminum workers, leather workers, truck drivers, and pesticide applicators are at the highest risk. Recently, the drug pioglitazone (Actos), used to treat type 2 diabetes, has been suspected to increase a person’s risk to develop bladder cancer.

    Radiation therapy (such as that for prostate or cervical cancer) and chemotherapy with cyclophosphamide (Cytoxan) has been shown to increase the risk for development of bladder cancer. Moreover, it may also delay the diagnosis of bladder cancer in patients presenting with symptoms of bleeding in urine since this bleeding may be incorrectly attributed by the patient and/or the physician to the bladder irritation caused by the chemotherapy or radiation (radiation cystitis).

    Learn more about: Cytoxan

    Long-term chronic infections of the bladder, irritation due to stones or foreign bodies, and infections with the blood fluke prevalent in certain regions of the world (as mentioned earlier) are some other factors which predispose to bladder cancer.

    What are bladder cancer symptoms and signs?

    The most common symptom of bladder cancer is bleeding in the urine (hematuria). Most often the bleeding is "gross" (visible to the naked eye), episodic (occurs in episodes), and is not associated with pain (painless hematuria). However, sometimes the bleeding may only be visible under a microscope (microscopic hematuria) or may be associated with pain due to the blockage of urine by formation of blood clots. There may be no symptoms or bleeding for prolonged periods of time between episodes, lulling the patient into a false sense of security ("I don't know what the problem was, but it is fine now!"). Some types of bladder cancer may cause irritative symptoms of the bladder with little or no bleeding. The patients may have the desire to urinate small amounts in short intervals (increased urinary frequency), an inability to hold the urine for any length of time after the initial desire to void (urgency), or a burning sensation while passing urine (dysuria). These symptoms occur more commonly in patients with high-grade, flat urothelial cancers called "carcinoma in situ" or "CIS" (described subsequently in the section on staging of bladder cancer). Other problems may cause blood to appear in the urine; for example, infections, kidney stones, and kidney disease, so it is important to have a physician check for the exact cause of blood in the urine.

    Rarely, patients may have signs and symptoms of more advanced disease such as a distended bladder (due to obstruction by a tumor at the bladder neck), an inability to pass any urine, pain in the flanks (due to obstruction of urine flow from kidney to the bladder by the growing tumor mass in the bladder), bone pains, foot and/or ankle swelling, or cough/blood in the phlegm (due to spread to cancer cells to bones or lungs).

    How is bladder cancer diagnosed?

    Bladder cancer is most frequently diagnosed by investigating the cause of bleeding in the urine that a patient has noticed. The following are investigations or tests that come in handy in such circumstances:

    • Urinalysis: A simple urine test that can confirm that there is bleeding in the urine and can also provide an idea about whether an infection is present or not. It is usually one of the first tests that is asked for by a physician. It does not confirm that a person has bladder cancer but can help the physician in short-listing the potential causes of bleeding.
    • Urine cytology: This test is performed on a urine sample that is centrifuged and the sediment is examined under the microscope by a pathologist. The idea is to detect malformed cancerous cells that may be shed into the urine by a cancer. A positive test is quite specific for cancer (for example, it provides a high degree of certainty that cancer is present in the urinary system). However, many early bladder cancers may be missed by this test so a negative or inconclusive test doesn't effectively rule out the presence of bladder cancer.
    • Ultrasound: An ultrasound examination of the bladder can detect bladder tumors. It can also detect the presence of swelling in the kidneys in case the bladder tumor is located at a spot where it can potentially block the flow of urine from the kidneys to the bladder. It can also detect other causes of bleeding, such as stones in the urinary system or prostate enlargement, which may be the cause of the symptoms or may coexist with a bladder tumor.
    • CT scan/MRI: A CT scan or MRI provides greater visual detail than can be afforded by an ultrasound exam and may detect smaller tumors in the kidneys or bladder than can be detected by an ultrasound. It can also detect other causes of bleeding more effectively than ultrasound, especially when intravenous contrast is used.
    • Cystoscopy and biopsy: This is probably the single most important investigation for bladder cancer. Since there is always a chance to miss bladder tumors on imaging investigations (ultrasound/CT/MRI) and urine cytology, it is recommended that all patients with bleeding in the urine, without an obvious cause, should have a cystoscopy performed by a urologist as a part of the initial evaluation. This entails the use of a thin tube-like optical instrument connected to a camera and a light source (cystoscope). It is passed through the urinary passage into the bladder and the inner surface of the bladder is visualized on a video monitor. Small or flat tumors that may not be visible on other investigations can be seen by this method, and a piece of this tissue can be taken as a biopsy for examination under the microscope. The presence and type of bladder cancer can be diagnosed most effectively by this method. In addition, fluorescence cystoscopy may be done at the same time; fluorescent dyes are placed in the bladder and are taken up by cancer cells. These cancer cells are visible (fluoresce) when a blue light is shined on them through the cystoscope and thus become visible, thereby making identification of cancer cells easier with this technique.
    • Newer biomarkers like NMP 22 and fluorescent in-situ hybridization (FISH) are currently in use to detect bladder cancer cells by a simple urine test. Some newer diagnostic tests are known as UroVysion, BTA, and the ImmunoCyt test. However, they have not yet achieved the level of accuracy to replace cystoscopy and cytology in the diagnosis and follow-up of bladder cancer.

    How is bladder cancer staging determined?

    Bladder cancer is staged using the tumor node metastases (TNM) system developed by the International Union Against Cancer (UICC) in 1997 and updated and used by the American Joint Committee on Cancer (AJCC). In addition, the American Urologic Association (AUA) has a similar staging system that varies slightly from that used by the AJCC. Both are combined and are listed below. This staging gives your physician a fairly complete picture of the extent of the person's bladder cancer.

    The tumor or the T stage is accorded by a pathological examination of the tumor specimen removed surgically. This refers to the depth of penetration of the tumor from the innermost lining to the deeper layers of the bladder. The T stages are as follows:

    • Tx - Primary tumor cannot be evaluated
    • T0 - No primary tumor
    • Ta - Noninvasive papillary carcinoma (tumor limited to the innermost lining or the epithelium)
    • Tis - Carcinoma in situ (flat tumor)
    • T1 - Tumor invades connective tissue under the epithelium (surface layer)
    • T2 - Tumor invades muscle of the bladder
      • T2a - Superficial muscle affected (inner half)
      • T2b - Deep muscle affected (outer half)
    • T3 - Tumor invades perivesical (around the bladder) fatty tissue
      • T3a - Microscopically (visible only on examination under the microscope)
      • T3b - Macroscopically (for example, visible tumor mass on the outer bladder tissue)
    • T4 - Tumor spreads beyond fatty tissue and invades any of the following: prostate, uterus, vagina, pelvic wall, or abdominal wall

    The node or the N stage is determined by the presence and extent of involvement of the lymph nodes in the pelvic region of the body near the urinary bladder. The N stages are as follows:

    • Nx - Regional lymph nodes cannot be evaluated
    • N0 - No regional lymph node metastasis
    • N1 - Metastasis in a single lymph node < 2 cm in size
    • N2 - Metastasis in a single lymph node > 2 cm, but < 5 cm in size, or two or more lymph nodes < 5 cm in size
    • N3 - Metastasis in a lymph node > 5 cm in size and/or to lymph nodes along the common iliac artery

    The metastases or the M stage signifies the presence or absence of the spread of bladder cancer to other organs of the body.

    • Mx - Distant metastasis cannot be evaluated (This stage is not used by some clinicians.)
    • M0 - No distant metastasis
    • M1 - Distant metastasis

    The proper staging of bladder cancer is an essential step which has significant bearings on the management of this condition. The implications of bladder stage are as follows:

    • It helps select proper treatment for the patient. Superficial disease (Ta/T1/Tis) can generally be managed with less aggressive treatment as compared to invasive disease (T2/T3/T4).
    • Invasive tumors have a higher likelihood of spread to lymph nodes and distant organs as compared to superficial tumors.
    • The chances of cure and long-term survival progressively decrease as the bladder cancer stage increases.
    • Staging allows proper classification of patients into groups for research studies and study of newer treatments.

    What is bladder cancer grading?

    Grading of bladder cancer is done by the pathologist by examination of the tumor specimen under a microscope. It is a measure of the extent by which the tumor cells differ in their appearance from normal bladder cells. The greater the distortion of appearance, the higher the grade assigned. High-grade cancers are more aggressive than low-grade ones and have a greater propensity to invade into the bladder wall and spread to other parts of the body. An example of grading is listed as follows:

    • Grade 1 cancers have cells that look very much like normal cells. They are called low grade or well differentiated and tend to grow slowly and are not likely to spread.
    • Grade 2 cancers have cells that look more abnormal. They are called medium grade or moderately differentiated and may grow or spread more quickly than low grade.
    • Grade 3 cancers have cells that look very abnormal. They are called high grade or poorly differentiated and are more quickly growing and more likely to spread.

    Depending upon which cancer organization your clinician follows, the grades above may differ slightly. In general, they all follow the same pattern. Bladder cancers with a higher number (zero through four) are considered more aggressive and more difficult to treat.

    In 2004, the World Health Organization developed a new grading system for bladder cancer. This system divides bladder cancers into the following groups.

    • Urothelial papilloma - Noncancerous (benign) tumor
    • Papillary urothelial neoplasm of low malignant potential (PUNLMP) - Slow growing and unlikely to spread (some clinicians lump urothelial papillomas and PUNLMP neoplasms together)
    • Low-grade papillary urothelial carcinoma - Slow growing and unlikely to spread
    • High-grade papillary urothelial carcinoma - More quickly growing and more likely to spread

    However, the World Health Organization (WHO) has recommended changing bladder grading to only two categories; the first category being well differentiated or low grade and the second category being poorly differentiated or high grade. These categories are being adopted by the American Joint Committee on Cancer (AJCC). The older categories listed above may still be used by some clinicians and may be listed in individual patient's medical records, so they were included here.

    Stage and grade of bladder cancer play a very important role not just in deciding the treatment that an individual patient should receive but also in quantifying the chances of success with that treatment. Of note, carcinoma in situ (CIS or Tis, as mentioned in the section on staging) is always high grade.

    What is transurethral surgery (TURBT) for bladder cancer?

    The initial surgical procedure that a patient undergoes after the diagnosis of bladder cancer is established is usually a transurethral resection of bladder tumor or "TURBT." It is done with the help of special instruments attached to a cystoscope (mentioned earlier in the section on investigations) and involves cutting out the tumor and removing it from the bladder with the help of an electrical cautery device. This surgery is done through the normal urinary passage and does not involve an external cut on the body. It is the initial treatment of bladder cancer as well as a staging procedure since the specimen retrieved from the surgery is sent to a pathologist who gives his/her inference on the depth of invasion of the tumor in the bladder wall (T stage) as well as the grade (high/low). Further treatment depends to a large extent on the findings of this initial surgery as well as the other staging investigations and is covered in the sections to follow. TURBT is the most common treatment for bladder cancer.

    What is the treatment for superficial bladder cancer?

    Superficial bladder cancer is a cancer which has not invaded the muscle wall of the bladder and is confined to the inner lining of the bladder. The T stage is Ta, T1, or Tis (also known as carcinoma in situ or "CIS"). After the initial TURBT or biopsy in case of CIS, the subsequent treatment in these cases may involve observation with regular follow-up with cystoscopy examinations of the bladder, instillation of medications in the bladder, or in certain cases, surgical removal of the bladder (radical cystectomy).

    Small low-grade, superficial bladder cancers may not require aggressive management after the initial TURBT and may be simply followed up by doing repeated cystoscopy examinations at regular intervals (usually every three months for the initial two years and then at increasing intervals). Recurrent tumors may be surgically removed or fulgurated (burnt out) with special instruments passed through the cystoscope. It is very important to note that 30%-40% of these tumors tend to recur and these recurrences may not be associated with any symptoms. Hence, it is imperative to stick to a regular follow-up protocol to ensure that the disease does not go out of control. It has also been shown that a single dose of a chemotherapy medication (for example, mitomycin C [Mutamycin]) put inside the bladder immediately after a TURBT can decrease the chances of recurrence within the first two years after surgery.

    Learn more about: Mutamycin

    High-grade, larger, multiple, or recurrent superficial bladder cancers may require additional treatment after the initial TURBT. One of the most effective and widely used medications is called the Bacille Calmette Guerin, commonly referred to as BCG. It is a modified form of a bacterium that causes tuberculosis in cattle (Mycobacterium bovis). It is instilled into the bladder in the form of a solution using a catheter placed in the urinary passage. It acts by stimulating the immune system of the body to act against the cancerous bladder cells and prevent their growth and development. It has been shown to decrease the chances of recurrence of bladder cancer as well as its invasion into the muscle layer of the bladder. However, it is only partially effective in achieving these objectives, and its use does not obviate the need for a regular follow-up. It is usually administered in six initial doses at weekly intervals followed by a "maintenance" schedule that is usually recommended for at least once per year but may be needed for as long as three years.

    Patients who do not respond to BCG treatment, have recurrent bladder cancer in spite of treatment, or those who have medical issues which preclude the use of BCG may require other forms of treatment. These include bladder instillation of immunotherapy agents such as interferon or chemotherapy medicines like valrubicin (Valstar), mitomycin C, epirubicin (Ellence), or doxorubicin (Adriamycin). In general, these medications are not as effective as BCG and help only a small minority of patients who have not responded to BCG.

    Learn more about: Valstar | Ellence

    In patients who have an aggressive form of high-grade superficial bladder cancer and those who have not responded or who have recurrent bladder cancer in spite of treatments mentioned above, a more aggressive form of treatment may be warranted. This is usually in the form of a major surgical procedure called radical cystectomy. It entails removal of the bladder and the prostate and diverting the urinary stream using parts of the intestine. This surgery will be described in the subsequent section on treatment of invasive bladder cancer.

    What are the layers of the bladder?

    The bladder consists of three layers of tissue. The innermost layer of the bladder, which comes into contact with the urine stored inside the bladder, is called the "mucosa" and consists of several layers of specialized cells called "transitional cells," which are almost exclusively found in the urinary system of the body. These same cells also form the inner lining of the ureters, kidneys, and a part of the urethra. These cells form a waterproof lining within these organs to prevent the urine from going into the deeper tissue layers.

    The middle layer is a thin lining known as the "lamina propria" and forms the boundary between the inner "mucosa" and the outer muscular layer. This layer has a network of blood vessels and nerves and is an important landmark in terms of the staging of bladder cancer (described in detail below in the bladder cancer staging section).

    The outer layer of the bladder comprises of the "detrusor" muscle and is called the "muscularis." This is the thickest layer of the bladder wall. Its main function is to relax slowly as the bladder fills up to provide low-pressure urine storage and then to contract to compress the bladder and expel the urine out during the act of passing urine. Outside these three layers is a variable amount of fat that lines and protects the bladder like a soft cushion and separates it from the surrounding organs such as the rectum and the muscles and bones of the pelvis.

    Picture of the urinary system: kidneys, ureters, and bladder

    What is bladder cancer?

    Bladder cancer is an uncontrolled abnormal growth and multiplication of cells in the urinary bladder, which have broken free from the normal mechanisms that keep uncontrolled cell growth in check. Bladder cancer (like cancers of other organs) has the ability to spread (metastasize) to other body parts, including the lungs, bones, and liver.

    Bladder cancer invariably starts from the innermost layer of the bladder (for example, the mucosa) and may invade into the deeper layers as it grows. Alternately, it may remain confined to the mucosa for a prolonged period of time. Visually, it may appear in various forms. Most common is a shrub-like appearance (papillary), but it may also appear as a nodule, an irregular solid growth or a flat, barely perceptible thickening of the inner bladder wall (see details in subsequent sections).

    What is the burden of bladder cancer in the U.S.?

    Bladder cancer has the dubious distinction of inclusion on the top 10 list of cancers, with an estimated 74,690 new cases occurring in 2013-2014 within the U.S. Bladder cancer is three to four times more likely to be diagnosed in men than in women and about two times higher in white men than in African-American men. Bladder cancer killed an estimated 15,210 people in 2013. In the U.S., the lifetime bladder cancer risk for men is about one in 26 and for women about one in 90.

    What are the types of bladder cancer?

    Bladder cancer is classified on the basis of the appearance of its cells under the microscope (histological type). The type of bladder cancer has implications in selecting the appropriate treatment for the disease. For example, certain types may not respond to radiation and chemotherapy as well as others. The extent of surgery required for maximizing the chances of cure may also be impacted by the histological type of the cancer. In addition, bladder cancers are often described based on their position in the wall of the bladder. Noninvasive bladder cancers are located in the inner layer of cells (transitional cell epithelium) but have not penetrated into deeper layers. Invasive cancers penetrate into the deeper layers such as the muscle layer. Invasive cancers are more difficult to treat.

    The more common types of bladder cancer and their relative incidence are given below:

    • Urothelial carcinoma (previously known as "transitional cell carcinoma") is the most common type and comprises 90%-95% of all bladder cancers. This type of cancer has two subtypes, papillary carcinoma (growing finger-like projections into the bladder lumen) and flat carcinomas that do not produce fingerlike projections. Urothelial carcinoma (transitional cell carcinoma) is strongly associated with cigarette smoking.
    • Adenocarcinoma of the bladder comprises about 1%-2% of all bladder cancers and is associated with prolonged inflammation and irritation. Most adenocarcinomas of the bladder are invasive.
    • Squamous cell carcinoma comprises 1%-2% of bladder cancers and is also associated with prolonged infection, inflammation, and irritation such as that associated with longstanding stones in the bladder. In certain parts of the Middle East and Africa (for example, Egypt), this is the predominant form of bladder cancer and is associated with chronic infection caused by Schistosoma worm (a blood fluke, that causes schistosomiasis, also termed bilharzia or snail fever).
    • Other rare forms of bladder cancer include small cell cancer (in bladder nerves), pheochromocytoma (rare), and sarcoma (in muscle tissue).

    What are bladder cancer causes and risk factors?

    About 50% of all bladder cancers may be caused by cigarette smoking. The longer and heavier the exposure, greater are the chances of developing bladder cancer. The toxic chemicals in cigarette smoke, many of which are known cancer-causing substances (carcinogens), travel in the bloodstream after being absorbed from the lungs and get filtered into the urine by the kidneys. They then come in contact with the cells in the inner lining of the urinary system, including the bladder, and cause changes within these cells that make them more prone to developing into cancer cells. Quitting smoking decreases the risk of developing bladder cancer but takes many years to reach the level of people who have never smoked. However, as time passes after the quit date, the risk progressively decreases. In view of the above, it is extremely important for patients with bladder cancer to stop smoking completely since the chances of the cancer coming back after treatment are higher in those people who continue to smoke.

    People who smoke also have a higher risk of many other types of cancer, including leukemia and cancers of the lung, lip, mouth, larynx, esophagus, stomach, and pancreas. Smokers also have a higher risk of diseases like heart attacks, peripheral vascular disease, diabetes, stroke, bone loss (osteoporosis), emphysema, and bronchitis.

    Age and family history are other risk factors as is male sex. About 90% of people with bladder cancer are over age 55, though in exceptional cases the disease may surface in the third or fourth decade of life. Men are more prone to developing bladder cancer probably due to a higher incidence of smoking and exposure to toxic chemicals. A close relative with a history of bladder cancer may increase the predisposition for the development of this disease.

    Exposure to toxic chemicals such as arsenic, phenols, aniline dyes, and arylamines increase the risk of bladder cancer. Dye workers, rubber workers, aluminum workers, leather workers, truck drivers, and pesticide applicators are at the highest risk. Recently, the drug pioglitazone (Actos), used to treat type 2 diabetes, has been suspected to increase a person’s risk to develop bladder cancer.

    Radiation therapy (such as that for prostate or cervical cancer) and chemotherapy with cyclophosphamide (Cytoxan) has been shown to increase the risk for development of bladder cancer. Moreover, it may also delay the diagnosis of bladder cancer in patients presenting with symptoms of bleeding in urine since this bleeding may be incorrectly attributed by the patient and/or the physician to the bladder irritation caused by the chemotherapy or radiation (radiation cystitis).

    Learn more about: Cytoxan

    Long-term chronic infections of the bladder, irritation due to stones or foreign bodies, and infections with the blood fluke prevalent in certain regions of the world (as mentioned earlier) are some other factors which predispose to bladder cancer.

    What are bladder cancer symptoms and signs?

    The most common symptom of bladder cancer is bleeding in the urine (hematuria). Most often the bleeding is "gross" (visible to the naked eye), episodic (occurs in episodes), and is not associated with pain (painless hematuria). However, sometimes the bleeding may only be visible under a microscope (microscopic hematuria) or may be associated with pain due to the blockage of urine by formation of blood clots. There may be no symptoms or bleeding for prolonged periods of time between episodes, lulling the patient into a false sense of security ("I don't know what the problem was, but it is fine now!"). Some types of bladder cancer may cause irritative symptoms of the bladder with little or no bleeding. The patients may have the desire to urinate small amounts in short intervals (increased urinary frequency), an inability to hold the urine for any length of time after the initial desire to void (urgency), or a burning sensation while passing urine (dysuria). These symptoms occur more commonly in patients with high-grade, flat urothelial cancers called "carcinoma in situ" or "CIS" (described subsequently in the section on staging of bladder cancer). Other problems may cause blood to appear in the urine; for example, infections, kidney stones, and kidney disease, so it is important to have a physician check for the exact cause of blood in the urine.

    Rarely, patients may have signs and symptoms of more advanced disease such as a distended bladder (due to obstruction by a tumor at the bladder neck), an inability to pass any urine, pain in the flanks (due to obstruction of urine flow from kidney to the bladder by the growing tumor mass in the bladder), bone pains, foot and/or ankle swelling, or cough/blood in the phlegm (due to spread to cancer cells to bones or lungs).

    How is bladder cancer diagnosed?

    Bladder cancer is most frequently diagnosed by investigating the cause of bleeding in the urine that a patient has noticed. The following are investigations or tests that come in handy in such circumstances:

    • Urinalysis: A simple urine test that can confirm that there is bleeding in the urine and can also provide an idea about whether an infection is present or not. It is usually one of the first tests that is asked for by a physician. It does not confirm that a person has bladder cancer but can help the physician in short-listing the potential causes of bleeding.
    • Urine cytology: This test is performed on a urine sample that is centrifuged and the sediment is examined under the microscope by a pathologist. The idea is to detect malformed cancerous cells that may be shed into the urine by a cancer. A positive test is quite specific for cancer (for example, it provides a high degree of certainty that cancer is present in the urinary system). However, many early bladder cancers may be missed by this test so a negative or inconclusive test doesn't effectively rule out the presence of bladder cancer.
    • Ultrasound: An ultrasound examination of the bladder can detect bladder tumors. It can also detect the presence of swelling in the kidneys in case the bladder tumor is located at a spot where it can potentially block the flow of urine from the kidneys to the bladder. It can also detect other causes of bleeding, such as stones in the urinary system or prostate enlargement, which may be the cause of the symptoms or may coexist with a bladder tumor.
    • CT scan/MRI: A CT scan or MRI provides greater visual detail than can be afforded by an ultrasound exam and may detect smaller tumors in the kidneys or bladder than can be detected by an ultrasound. It can also detect other causes of bleeding more effectively than ultrasound, especially when intravenous contrast is used.
    • Cystoscopy and biopsy: This is probably the single most important investigation for bladder cancer. Since there is always a chance to miss bladder tumors on imaging investigations (ultrasound/CT/MRI) and urine cytology, it is recommended that all patients with bleeding in the urine, without an obvious cause, should have a cystoscopy performed by a urologist as a part of the initial evaluation. This entails the use of a thin tube-like optical instrument connected to a camera and a light source (cystoscope). It is passed through the urinary passage into the bladder and the inner surface of the bladder is visualized on a video monitor. Small or flat tumors that may not be visible on other investigations can be seen by this method, and a piece of this tissue can be taken as a biopsy for examination under the microscope. The presence and type of bladder cancer can be diagnosed most effectively by this method. In addition, fluorescence cystoscopy may be done at the same time; fluorescent dyes are placed in the bladder and are taken up by cancer cells. These cancer cells are visible (fluoresce) when a blue light is shined on them through the cystoscope and thus become visible, thereby making identification of cancer cells easier with this technique.
    • Newer biomarkers like NMP 22 and fluorescent in-situ hybridization (FISH) are currently in use to detect bladder cancer cells by a simple urine test. Some newer diagnostic tests are known as UroVysion, BTA, and the ImmunoCyt test. However, they have not yet achieved the level of accuracy to replace cystoscopy and cytology in the diagnosis and follow-up of bladder cancer.

    How is bladder cancer staging determined?

    Bladder cancer is staged using the tumor node metastases (TNM) system developed by the International Union Against Cancer (UICC) in 1997 and updated and used by the American Joint Committee on Cancer (AJCC). In addition, the American Urologic Association (AUA) has a similar staging system that varies slightly from that used by the AJCC. Both are combined and are listed below. This staging gives your physician a fairly complete picture of the extent of the person's bladder cancer.

    The tumor or the T stage is accorded by a pathological examination of the tumor specimen removed surgically. This refers to the depth of penetration of the tumor from the innermost lining to the deeper layers of the bladder. The T stages are as follows:

    • Tx - Primary tumor cannot be evaluated
    • T0 - No primary tumor
    • Ta - Noninvasive papillary carcinoma (tumor limited to the innermost lining or the epithelium)
    • Tis - Carcinoma in situ (flat tumor)
    • T1 - Tumor invades connective tissue under the epithelium (surface layer)
    • T2 - Tumor invades muscle of the bladder
      • T2a - Superficial muscle affected (inner half)
      • T2b - Deep muscle affected (outer half)
    • T3 - Tumor invades perivesical (around the bladder) fatty tissue
      • T3a - Microscopically (visible only on examination under the microscope)
      • T3b - Macroscopically (for example, visible tumor mass on the outer bladder tissue)
    • T4 - Tumor spreads beyond fatty tissue and invades any of the following: prostate, uterus, vagina, pelvic wall, or abdominal wall

    The node or the N stage is determined by the presence and extent of involvement of the lymph nodes in the pelvic region of the body near the urinary bladder. The N stages are as follows:

    • Nx - Regional lymph nodes cannot be evaluated
    • N0 - No regional lymph node metastasis
    • N1 - Metastasis in a single lymph node < 2 cm in size
    • N2 - Metastasis in a single lymph node > 2 cm, but < 5 cm in size, or two or more lymph nodes < 5 cm in size
    • N3 - Metastasis in a lymph node > 5 cm in size and/or to lymph nodes along the common iliac artery

    The metastases or the M stage signifies the presence or absence of the spread of bladder cancer to other organs of the body.

    • Mx - Distant metastasis cannot be evaluated (This stage is not used by some clinicians.)
    • M0 - No distant metastasis
    • M1 - Distant metastasis

    The proper staging of bladder cancer is an essential step which has significant bearings on the management of this condition. The implications of bladder stage are as follows:

    • It helps select proper treatment for the patient. Superficial disease (Ta/T1/Tis) can generally be managed with less aggressive treatment as compared to invasive disease (T2/T3/T4).
    • Invasive tumors have a higher likelihood of spread to lymph nodes and distant organs as compared to superficial tumors.
    • The chances of cure and long-term survival progressively decrease as the bladder cancer stage increases.
    • Staging allows proper classification of patients into groups for research studies and study of newer treatments.

    What is bladder cancer grading?

    Grading of bladder cancer is done by the pathologist by examination of the tumor specimen under a microscope. It is a measure of the extent by which the tumor cells differ in their appearance from normal bladder cells. The greater the distortion of appearance, the higher the grade assigned. High-grade cancers are more aggressive than low-grade ones and have a greater propensity to invade into the bladder wall and spread to other parts of the body. An example of grading is listed as follows:

    • Grade 1 cancers have cells that look very much like normal cells. They are called low grade or well differentiated and tend to grow slowly and are not likely to spread.
    • Grade 2 cancers have cells that look more abnormal. They are called medium grade or moderately differentiated and may grow or spread more quickly than low grade.
    • Grade 3 cancers have cells that look very abnormal. They are called high grade or poorly differentiated and are more quickly growing and more likely to spread.

    Depending upon which cancer organization your clinician follows, the grades above may differ slightly. In general, they all follow the same pattern. Bladder cancers with a higher number (zero through four) are considered more aggressive and more difficult to treat.

    In 2004, the World Health Organization developed a new grading system for bladder cancer. This system divides bladder cancers into the following groups.

    • Urothelial papilloma - Noncancerous (benign) tumor
    • Papillary urothelial neoplasm of low malignant potential (PUNLMP) - Slow growing and unlikely to spread (some clinicians lump urothelial papillomas and PUNLMP neoplasms together)
    • Low-grade papillary urothelial carcinoma - Slow growing and unlikely to spread
    • High-grade papillary urothelial carcinoma - More quickly growing and more likely to spread

    However, the World Health Organization (WHO) has recommended changing bladder grading to only two categories; the first category being well differentiated or low grade and the second category being poorly differentiated or high grade. These categories are being adopted by the American Joint Committee on Cancer (AJCC). The older categories listed above may still be used by some clinicians and may be listed in individual patient's medical records, so they were included here.

    Stage and grade of bladder cancer play a very important role not just in deciding the treatment that an individual patient should receive but also in quantifying the chances of success with that treatment. Of note, carcinoma in situ (CIS or Tis, as mentioned in the section on staging) is always high grade.

    What is transurethral surgery (TURBT) for bladder cancer?

    The initial surgical procedure that a patient undergoes after the diagnosis of bladder cancer is established is usually a transurethral resection of bladder tumor or "TURBT." It is done with the help of special instruments attached to a cystoscope (mentioned earlier in the section on investigations) and involves cutting out the tumor and removing it from the bladder with the help of an electrical cautery device. This surgery is done through the normal urinary passage and does not involve an external cut on the body. It is the initial treatment of bladder cancer as well as a staging procedure since the specimen retrieved from the surgery is sent to a pathologist who gives his/her inference on the depth of invasion of the tumor in the bladder wall (T stage) as well as the grade (high/low). Further treatment depends to a large extent on the findings of this initial surgery as well as the other staging investigations and is covered in the sections to follow. TURBT is the most common treatment for bladder cancer.

    What is the treatment for superficial bladder cancer?

    Superficial bladder cancer is a cancer which has not invaded the muscle wall of the bladder and is confined to the inner lining of the bladder. The T stage is Ta, T1, or Tis (also known as carcinoma in situ or "CIS"). After the initial TURBT or biopsy in case of CIS, the subsequent treatment in these cases may involve observation with regular follow-up with cystoscopy examinations of the bladder, instillation of medications in the bladder, or in certain cases, surgical removal of the bladder (radical cystectomy).

    Small low-grade, superficial bladder cancers may not require aggressive management after the initial TURBT and may be simply followed up by doing repeated cystoscopy examinations at regular intervals (usually every three months for the initial two years and then at increasing intervals). Recurrent tumors may be surgically removed or fulgurated (burnt out) with special instruments passed through the cystoscope. It is very important to note that 30%-40% of these tumors tend to recur and these recurrences may not be associated with any symptoms. Hence, it is imperative to stick to a regular follow-up protocol to ensure that the disease does not go out of control. It has also been shown that a single dose of a chemotherapy medication (for example, mitomycin C [Mutamycin]) put inside the bladder immediately after a TURBT can decrease the chances of recurrence within the first two years after surgery.

    Learn more about: Mutamycin

    High-grade, larger, multiple, or recurrent superficial bladder cancers may require additional treatment after the initial TURBT. One of the most effective and widely used medications is called the Bacille Calmette Guerin, commonly referred to as BCG. It is a modified form of a bacterium that causes tuberculosis in cattle (Mycobacterium bovis). It is instilled into the bladder in the form of a solution using a catheter placed in the urinary passage. It acts by stimulating the immune system of the body to act against the cancerous bladder cells and prevent their growth and development. It has been shown to decrease the chances of recurrence of bladder cancer as well as its invasion into the muscle layer of the bladder. However, it is only partially effective in achieving these objectives, and its use does not obviate the need for a regular follow-up. It is usually administered in six initial doses at weekly intervals followed by a "maintenance" schedule that is usually recommended for at least once per year but may be needed for as long as three years.

    Patients who do not respond to BCG treatment, have recurrent bladder cancer in spite of treatment, or those who have medical issues which preclude the use of BCG may require other forms of treatment. These include bladder instillation of immunotherapy agents such as interferon or chemotherapy medicines like valrubicin (Valstar), mitomycin C, epirubicin (Ellence), or doxorubicin (Adriamycin). In general, these medications are not as effective as BCG and help only a small minority of patients who have not responded to BCG.

    Learn more about: Valstar | Ellence

    In patients who have an aggressive form of high-grade superficial bladder cancer and those who have not responded or who have recurrent bladder cancer in spite of treatments mentioned above, a more aggressive form of treatment may be warranted. This is usually in the form of a major surgical procedure called radical cystectomy. It entails removal of the bladder and the prostate and diverting the urinary stream using parts of the intestine. This surgery will be described in the subsequent section on treatment of invasive bladder cancer.

    Source: http://www.rxlist.com

    About 50% of all bladder cancers may be caused by cigarette smoking. The longer and heavier the exposure, greater are the chances of developing bladder cancer. The toxic chemicals in cigarette smoke, many of which are known cancer-causing substances (carcinogens), travel in the bloodstream after being absorbed from the lungs and get filtered into the urine by the kidneys. They then come in contact with the cells in the inner lining of the urinary system, including the bladder, and cause changes within these cells that make them more prone to developing into cancer cells. Quitting smoking decreases the risk of developing bladder cancer but takes many years to reach the level of people who have never smoked. However, as time passes after the quit date, the risk progressively decreases. In view of the above, it is extremely important for patients with bladder cancer to stop smoking completely since the chances of the cancer coming back after treatment are higher in those people who continue to smoke.

    People who smoke also have a higher risk of many other types of cancer, including leukemia and cancers of the lung, lip, mouth, larynx, esophagus, stomach, and pancreas. Smokers also have a higher risk of diseases like heart attacks, peripheral vascular disease, diabetes, stroke, bone loss (osteoporosis), emphysema, and bronchitis.

    Age and family history are other risk factors as is male sex. About 90% of people with bladder cancer are over age 55, though in exceptional cases the disease may surface in the third or fourth decade of life. Men are more prone to developing bladder cancer probably due to a higher incidence of smoking and exposure to toxic chemicals. A close relative with a history of bladder cancer may increase the predisposition for the development of this disease.

    Exposure to toxic chemicals such as arsenic, phenols, aniline dyes, and arylamines increase the risk of bladder cancer. Dye workers, rubber workers, aluminum workers, leather workers, truck drivers, and pesticide applicators are at the highest risk. Recently, the drug pioglitazone (Actos), used to treat type 2 diabetes, has been suspected to increase a person’s risk to develop bladder cancer.

    Radiation therapy (such as that for prostate or cervical cancer) and chemotherapy with cyclophosphamide (Cytoxan) has been shown to increase the risk for development of bladder cancer. Moreover, it may also delay the diagnosis of bladder cancer in patients presenting with symptoms of bleeding in urine since this bleeding may be incorrectly attributed by the patient and/or the physician to the bladder irritation caused by the chemotherapy or radiation (radiation cystitis).

    Learn more about: Cytoxan

    Long-term chronic infections of the bladder, irritation due to stones or foreign bodies, and infections with the blood fluke prevalent in certain regions of the world (as mentioned earlier) are some other factors which predispose to bladder cancer.

    Source: http://www.rxlist.com

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