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Overview of bladder cancer

Cancer is a disease that results from abnormal growth and division of cells that make up the body's tissues and organs. Under normal circumstances, cells reproduce in an orderly fashion to maintain tissue health and to repair injuries. However, when growth control is lost and cells divide too much and too fast, a cellular mass —or "tumor" —is formed. If the tumor is confined to a few (for example, surface) cell layers and it does not invade surrounding tissues or organs, it is considered benign. By contrast, if the tumor spreads to surrounding tissues or organs, it is considered malignant, or cancerous. If cancerous cells break away from the original tumor, travel, and grow within other body parts, the process is known as metastasis.

The bladder is a hollow, balloon-shaped organ that is located within the pelvis. The bladder stores urine -- the liquid waste made by the kidneys when they clean the blood. Muscular tissue within the bladder wall allows it to enlarge or shrink as urine is held or voided. When cancer occurs in the bladder, it usually begins growing within the bladder's inner lining, which is composed of specialized expanding and deflating cells known as transitional cells. From here, the cancer may spread deeper into the lining, extend into the bladder's muscular wall, and eventually invade nearby reproductive organs, abdominal tissues, the pelvis (hip bones), and lymph nodes. Although most bladder cancers are slow-growing, once they have spread to the bladder's muscular tissue, they often metastasize to sites such as the lungs, liver, bone, or lymph nodes.

Bladder cancer rarely occurs in people who are younger than 40 years of age. Within the United States, bladder cancer rates are higher among people who reside in northern versus southern states. Recent studies suggest that certain genes (for example, the p53 and RB genes) and inherited metabolic abilities may play a role in bladder cancer. For example, rapid acetylators —people with the ability to metabolize certain chemicals —may be less susceptible to bladder cancer than slow acetylators, if exposed to aromatic amines (see also Causes of Bladder Cancer).

* American Cancer Society. Cancer Facts and Figures (Atlanta: ACS, 1998), pp. 1‚18.

What are the signs and symptoms?

Bladder cancer that is in an early stage of growth may not produce any noticeable signs or symptoms. And the most common sign of bladder cancer -- hematuria (bloody urine; urine that appears bright red or rusty) -- usually is painless and may appear only from time to time over a period of months. Over 80% of all bladder cancer patients eventually do experience either gross (visible to the naked eye) or microscopic (visible by microscope) hematuria.

When bladder cancer causes noticeable symptoms, such symptoms usually are related to the irritation brought about by tumor growth. "Irritative" voiding symptoms include urination that is frequent, urgent, or painful or difficult (known as dysuria). Irritative symptoms are more common among patients with the "carcinoma in situ" (CIS or TIS; cancer that has not spread and is still "in place") type of bladder cancer versus patients with low-grade wart-like (papillary) tumors. In fact, irritative voiding may be the only noticeable symptom of CIS. Since irritative voiding symptoms also are caused by bacterial infections and kidney stones, it is essential to see a physician to rule out these conditions. Any symptoms that last longer than 2 weeks should be evaluated by a health care practitioner.

If a bladder tumor blocks a ureter (one of two tubes that pass urine out of the kidneys and into the bladder), a patient may experience pain in the flank -- the side of the body between the ribs and the top of the hip. In some cases, tumor growth may constrict the urethra (the tube that passes urine from the bladder out of the body) and slow the flow of the urine stream. Bladder cancers that become necrotic (have dead areas) may shed pieces of dead tissue into the urine. Fragments of papillary tissue and calcareous (chalky) deposits are other forms of tumor-related matter that may be passed out with the urine.

If the tumor has spread outside of the bladder to surrounding tissues, the patient may experience pelvic pain. In addition, metastases from a bladder cancer may cause secondary symptoms, such as bone pain at the site of the new cancer or leg edema (swelling) due to involvement of the lymph nodes. Bladder cancer that has progressed to the point of organ invasion and metastasis eventually may cause the patient to lose weight and strength. Anemia (low red blood cell count) and uremia (high blood levels of urea and other metabolic by-products; often due to urinary tract obstruction) are further indications of late-stage bladder cancer.

What are the causes and risks of the condition?

Cigarette Smoking
Cigarette smoking is, by far, the single greatest risk factor for bladder cancer. There is a significant "dose-response" relationship between the number of pack-years smoked and bladder cancer risk. In comparison to nonsmokers, smokers may have a two- to ten-fold increased risk of bladder cancer, depending upon the amount smoked over time. Individuals who quit smoking reduce their risk of developing bladder cancer.

The type of tobacco used appears to have some effect upon bladder cancer risk. Cigarettes made from "black," or dark tobaccos produce the highest risk, whereas the risk is less for cigarettes made from "blonde," or light tobaccos (as in most American-made cigarettes). The risk of bladder cancer appears to be small in cigar and pipe smokers and in users of smokeless tobacco products (snuff, chewing tobacco). No direct relationship has been established between bladder cancer and exposure to secondhand smoke ("passive smoking").

How does smoking cause bladder cancer? This question has not yet been answered, but the most likely cause is the toxic mix of chemicals found in tobacco smoke. The major cigarette smoke chemicals that have been studied with respect to bladder cancer are polycyclic aromatic hydrocarbons (PAHs), aromatic amines, unsaturated aldehydes, nicotine, nicotine by-products, and tobacco-specific nitrosamines (TSNAs). Of these, the PAHs largely have been ruled out, since they are released into the urine in inactive forms. Likewise nicotine, nicotine by-products, and TSNAs don't appear related to the development of bladder cancer. However, there is a great deal of evidence that the aromatic amines in cigarette smoke -- especially 4-aminobiphenyl (4-ABP) and o-toluidine -- are associated with bladder cancer. In addition, cigarette smoke's unsaturated aldehydes (such as acrolein) are toxic, mutagenic (cause mutations in test tube studies), and possibly carcinogenic (cause cancer in animals and/or humans).

Occupational Exposure
Another source of risk is occupational exposure to carcinogens (cancer-causing substances). Research suggests that one in four cases of bladder cancer can be linked to industrial carcinogen exposure. Workers are particularly vulnerable in industries involving the manufacture or use of dyes (especially aniline dyes), textiles, and rubber. However, many other occupations are associated with increased risk of bladder cancer

Schistosomiasis (Bilharzia)
Schistosomiasis is a condition caused by infection with the parasite Schistosoma haematobium, a blood fluke (flat worm) that is widespread in places such as Egypt. In man, S. haematobium infection results from contact with contaminated water. The flukes deposit their eggs within the wall of the bladder. Such deposits bring about a response that results in cystitis (bladder inflammation) and hematuria (bloody urine). Over time, the chronic inflammatory response from schistosomiasis leads to changes in the bladder lining, especially if the person is reinfected. The normal transitional epithelium of the inner bladder then is converted to squamous metaplastic epithelium - a form of tissue in which the cells proliferate, or reproduce, more rapidly (see also What Is Bladder Cancer?). A large proportion of individuals with chronic schistosomiasis eventually develop squamous cell carcinoma (SCC), rather than transitional cell carcinoma (TCC), the most common histologic (tissue) type of bladder cancer (see also Types of Bladder Cancer).

Chronic Cystitis
Bladder cancer -- in particular, squamous cell carcinoma (SCC) -- also may be caused by chronic cystitis (bladder inflammation) due to long-term urinary tract infection (UTI), an indwelling catheter (a tube that passes through the urethra into the bladder to drain urine into a bag outside the body), or urinary calculi, or "stones" (mineral deposits within the urinary tract). It is estimated that approximately 2% to 10% of paraplegics with indwelling catheters develop bladder cancer, as do many women with recurrent UTIs. As with schistosomiasis, researchers suspect that chronic inflammation is associated with increased cell reproduction and changes in the bladder lining that eventually may become cancerous.

Pelvic Radiation Therapy
Women who have undergone pelvic irradiation for uterine/cervical cancer have a two- to four-fold increased risk of developing transitional cell carcinoma (TCC) of the bladder. The increased risk is most apparent among patients who have received radiation doses between 30 and 60 Gy. And, unfortunately, radiation-associated cancers usually are high-grade and show locally advanced growth at the time of diagnosis. Therefore, the possibility of a bladder tumor should be considered in all persons who experience hematuria after pelvic irradiation, even though such hematuria often is attributed to radiation cystitis (radiation-related bladder inflammation).

Chemotheraputic Agents
Some medications designed to combat cancer actually have been linked to bladder cancer development. For example, the drug chlornaphazine originally was produced as an anticancer chemotherapeutic agent, but its use was soon discontinued after a large number of patients developed bladder cancer within a short period of time. Similarly, physicians have seen up to a nine-fold increase in bladder cancer among patients treated with the chemotherapeutic medication cyclophosphamide (Cytoxan®). The metabolic by-product of cyclophosphamide -- acrolein -- may be the chemical that truly is responsible for inflammation and eventual bladder cancer in exposed patients (latent period = 6 to 13 years). However, researchers believe that the use of medications like mesna (sodium 2-mercaptoethanesulfonate; Mesnex®) may reduce the risks for people who require chemotherapy with cyclophosphamide.

Nitrosamines
Nitrosamines are a group of chemicals that are widespread in the environment. They also can be formed in the body by certain chemical reactions (e.g., nitrosation reactions of secondary amines under acidic conditions, such as in the urine). Since some nitrosamines cause bladder cancer in animals, it has been suggested that they also may be carcinogens in humans. To date, though, there is no established association between nitrosamine exposure and bladder cancer.

Other Factors
Over the past 20 years, suspicions have been raised about the possible carcinogenicity (cancer-causing activity) of both caffeine (found in coffee, tea, and other foods) and artificial sweeteners (saccharin, cyclamates); however, recent findings indicate that these dietary substances do not significantly contribute to bladder cancer risk. Unfortunately, bladder cancer studies have been complicated by the fact that coffee/tea, artificial sweeteners, and cigarettes often are used in association with each other. Therefore, potential carcinogenic effects have been difficult to distinguish.

Types

In contrast to some other organs (for example, the lungs), which may develop more histologic (tissue) types of cancer, most bladder cancers (about 98%) occur within the transitional epithelium, or surface layer of tissue that lines the bladder. Approximately 90% of bladder cancers are transitional cell carcinomas (TCC). It is not uncommon for different tumor types to occur within the same bladder; however, all epithelial tumors are thought to begin in transitional epithelium. Papillary TCC with flat carcinoma in situ (CIS or TIS) is the most widespread combination of bladder tumors. In addition, invasive TCC often is seen with squamous cell carcinoma (SCC) or, less frequently, with adenocarcinoma

Transitional Cell Carcinoma(TCC)
As already mentioned, transitional cell carcinoma (TCC) is the most common form of bladder cancer. TCC usually occurs as a superficial (surface), papillary (wart-like), exophytic (outward-growing) mass upon a stalk-like base. In some cases, though, TCC may be attached on a broad base or it may appear ulcerated (within an indented lesion).

Papillary TCCs
Papillary TCCs - make up the bulk (about 70%) of all TCCs. They usually are: low-grade and noninvasive at the time of appearance, and are characterized by multiple recurrences.>

Papillary TCCs often start out as areas of hyperplasia (abnormal increase in the number of cells) that later "dedifferentiate," or lose individual cell characteristics. Only about 10% to 30% of papillary TCCs develop into invasive cancers.

By contrast, nonpapillary forms of TCC are more likely to become invasive. As noted, such TCCs may appear ulcerated or flat. Flat, nonpapillary TCC that is made up of anaplastic (undifferentiated) epithelium is classified as carcinoma in situ (CIS or TIS). The tissue of CIS contains cells that are large, have noticeable nucleoli (round body within a cell; involved in protein synthesis), and lack normal polarity.

Carcinoma In Situ (CIS, TIS)

The symptoms of bladder CIS may be mistaken for urinary tract infection, prostate disease, or neurogenic bladder incontinence (leaky bladder due to defects in the nervous system, which conducts urination signals between the bladder and the brain). CIS may involve nearby organs such as the urethra, periurethral glands (glands around the urethra), and prostate. In fact, because CIS can be dangerously silent within the prostate, many doctors recommend routine biopsy of the prostate in male CIS patients.

In some instances, bladder CIS may have features of Paget's disease, an inflammatory form of cancer that affects organs such as the breast. Pagetoid CIS may cause the bladder lining to flake off or slough. In other cases, CIS may involve groups of bladder cells known as von Brunn's nests. Association with von Brunn's nests is important, as it may influence the type of treatment chosen by the physician.

Cancers that are not composed of transitional cells -- that is, nontransitional cell carcinomas -- make up the last 10% or so of bladder tumors. Such cancers include squamous cell carcinoma (SCC), adenocarcinoma, undifferentiated carcinoma, mixed carcinoma, and rare cancers.

Squamous Cell Carcinoma (SCC)
In the American population, squamous cell carcinoma (SCC) accounts for roughly 8% of all bladder cancers. It is more common in individuals who have experienced long-term bladder irritation due to:

• catheter use

• bladder stones

• bladder diverticula (abnormal pouches)

• infection

• long history of cigarette smoking

Up to 80% of paraplegics with an indwelling catheter (a tube that passes through the urethra into the bladder to drain urine into a bag outside the body) show squamous (scaly) changes in their bladder tissue. About 5% eventually develop SCC. The staging and diagnosis of SCC usually is the same as TCC. Unfortunately, SCC tends to be aggressive, with early invasion of the lymph nodes. It generally is treated by radical cystectomy -- total removal of the bladder -- with or without radiation therapy.

In areas of the world where Schistosoma haematobium (Bilharzia) infection is epidemic, SCC of the bladder occurs more frequently. Such cancer is referred to as "bilharzial bladder cancer." Bilharzial bladder cancer affects individuals who are, on average, 10 to 20 years younger than patients with transitional cell carcinoma (TCC). Unlike other bladder SCCs, most bilharzial cancers are low-grade and they do not tend to invade the lymph nodes or to metastasize readily.

Overall, the outcome is poor for bladder SCC, since most patients have advanced, widespread disease at the time of diagnosis.

Adenocarcinoma
Adenocarcimomas may occur as solid tumors, or they may be papillary (wart-like) in nature. Most produce a mucus-like substance that may be seen in the urine. Fewer than 2% of all bladder cancers are adenocarcinomas. When bladder adenocarcinoma does occur, it can be grouped into one of three categories:

• Primary vesical (involving the bladder proper)

• Urachal involving the urachus, an outer, fetal bladder canal)

• Metastatic (cancer cells that have broken away from the original tumor to grow within the bladder)

Primary Vesical Adenocarcinoma commonly affects either the bladder base or dome. Like SCC, primary vesical adenocarcinoma may arise after long-term irritation and inflammation, and it may occur in some individuals who have been infected with Schistosoma haematobium. In addition, primary vesical adenocarcinoma is the most frequent form of bladder cancer in persons who have the inherent bladder defect known as "exstrophic" bladder (hereditary absence of the front wall of the bladder). Most primary vesical adenocarcinomas are locally aggressive and invasive. Patients often have poor prognoses and do not respond well to radiation therapy or chemotherapy because their tumors are diagnosed too late. One treatment plan is preoperative radiation (2,000 rads) followed by radical cystectomy - total removal of the bladder- and urinary diversion to re-route the urine from the kidneys.

Urachal carcinoma is a rare tumor that affects the outside of the bladder. It may be composed of tissue classified as adenocarcinoma, squamous cell carcinoma (SCC), or even sarcoma. Urachal tumors may cause mucous or bloody discharges in the urine, and they may produce dotted or "stippled" images on X-ray. Like primary vesical adenocarcinomas, urachal carcinomas usually do not respond well to radiation therapy, chemotherapy, or surgical therapy. Urachal tumors often are wider and deeper than expected, and they tend to metastasize and/or recur.

Metastatic adenocarcinoma is a rare bladder tumor caused by cancer cells that have broken off from a primary cancer somewhere else in the body. The most likely primary cancer sites are the rectum (lower large intestine), stomach, endometrium (lining of the womb), breast, prostate, lung, and ovary. Before metastatic adenocarcinoma is treated, the patient must be evaluated to detect the primary cancer and any other metastatic tumors that may be present.

Undifferentialted Carcinoma
Another rare tumor is undifferentiated carcinoma, which accounts for fewer than 1% of all bladder cancers. Undifferentiated carcinomas show no mature epithelial (bladder lining) cells. Some forms have "small cell" elements that look like the small cell cancers that may occur in the lungs. Actual small cell carcinomas of the bladder may be identified by specific tissue stains (for example, a stain known as neuron-specific enolase). If small cell carcinoma of the bladder is confirmed, the patient should be evaluated for a primary lung cancer. Primary small cell carcinoma of the lung may have metastasized to the bladder and may look like undifferentiated carcinoma.

How is this condition diagnosed?

As previously noted, individuals with bladder cancer may not notice any symptoms other than occasional bouts of hematuria (bloody urine). But if the physician suspects bladder cancer, he or she may perform a number of tests and procedures to aid in the diagnosis

History

To help diagnose the cause of a person's bladder complaints, the physician first will obtain a careful medical history, followed by a physical examination. In particular, the physician will ask about:

• Previous urinary tract infections (UTIs) or episodes of bladder irritation

• Unusual voiding symptoms

• Bladder stones

During the medical history, the physician may also ask about smoking habits and exposures to harmful occupational or environmental substances. If the patient reports workplace exposure to chemicals such as benzidine, 2-naphthylamine, or MBOCA, the physician may want to perform a dipstick test for microhematuria (AMH) -- that is, a test to detect small, invisible amounts of blood in the urine. In addition, the physician will seek information about previous treatments with chemotherapeutic medications or radiotherapy.

The physical examination is, of course, necessary to rule out other coexistent diseases or conditions. In the vast majority of people with bladder cancer, routine physical examination is unremarkable. However, in persons with advanced disease, physical examination may uncover abnormalities such as abdominal tenderness, a palpable (detectable by touch) tumor mass, or an induration or hard spot.

If the physician suspects bladder cancer -- for example, in a low-risk patient with AMH -- then he or she may decide to perform a limited urologic workup, including tests such as:

• Urine erythrocyte morphology - an examination of the shape of red blood cells in the urine

• Urine cytology - an examination of cells in the urine

• Urinalysis/culture - urine testing to see whether infectious organisms are present to rule out UTI

• Abdominal ultrasound - visual imaging of internal, lower body organs by means of ultrasound echoes

High-risk individuals may require a more in-depth, formal workup, including tests such as (X-ray visualization of the urinary tract during voiding), cystoscopy (visual examination of the urinary tract with a cystoscope -- a thin, telescope-like tube with a tiny attached camera that is inserted into the bladder through the urethra), and urine cytology.

Urine Cytology
Urinary cytology is the study of cells from the bladder. Bladder cells are obtained from voided urine or from lavage ("washing") fluid. In bladder lavage, fluid such as a saline (salt) solution is repeatedly placed into the bladder via catheterization (passing a hollow tube through the urethra into the bladder) and is then withdrawn. Usually, three specimens are acquired for analysis. Specimens from bladder lavage can be submitted to flow cytometry for further analysis. Urine cytology is especially useful in diagnosing transitional carcinoma in situ (TIS) and high-grade transitional cell carcinoma (TCC). In fact, urine cytology is positive in roughly 95% of patients with high-grade tumors (see Bladder Cancer Staging). Unfortunately, though, urine cytology does not detect low-grade lesions very well, since cellular changes often are very subtle in early malignancy; only about one-third of all cytologic findings for low-grade lesions are positive. Urine cytology features that suggest cancer include:

• Increased nuclear to cytoplasmic ratio (the cell center is very large in size in comparison to the rest of the cell body)

• Irregular nuclear border (the cell center has an uneven edge)

• Hyperchromasia (dark coloration of the cell center, due to filling with chromatin, or genetic material)

• Irregular clumping of chromatin

• Abnormal location of the nucleus (cell center)

• No cytoplasmic vacuolization (spaces within the cell fluid)

In addition, a small percentage (1% to 12%) of cytology findings are "false positive" -- that is, they imply cancer when none, in fact, exists. False-positive cytologic results may be caused by factors such as inflammation or changes brought on by radiation therapy or chemotherapy.

Urinalysis/Culture
Urinalysis and urine culture are tests to determine whether infectious organisms are present in the urine. The symptoms of cystitis and urinary tract infection (UTI) are very similar to those of bladder cancer. Therefore, the physician will want to rule out infection before making a diagnosis, although some bladder cancer patients also have UTIs due to microorganism growth on the rough the surfaces of their tumors. However, if urinalysis indicates sterile pyuria —- that is, no microorganisms are present but there is "pus-like" matter in the urine -- then cancer or tuberculosis are suspected until further tests are performed. Sterile pyuria is caused by cancer cells that flake off into the urine and resemble pus. A Papanicolaou stain (Pap stain) also may be used to detect any cancer cells in the urine.

Flow Cystometry
Flow cytometry uses cells from bladder washings to assess DNA (genetic) material within cells. Specifically, cytometry can measure the number of sets of chromosomes (DNA threads) within cells -— or the cell ploidy. Bladder washing samples that contain cells with more than 15% aneuploidy (abnormal number of chromosome sets) are "suspicious" and are associated with malignant transitional cell carcinoma (TCC) in over 80% of cases. Unfortunately, though, flow cytometry is not a valuable diagnostic tool unless it is conducted and interpreted by a trained cytopathologist, who is an expert in cell disease.

Intravenous Pyelogram (IVP)
The intravenous pyelogram (IVP) -— an X-ray of the kidneys and ureters after injection of contrast material -— is performed to detect defects in the urinary tract. All patients with hematuria should have an IVP. The physician will use the IVP to rule out hematuria due to kidney disorders, for example, kidney stones, tuberculosis, or tumors.

Cystoscopy
Cystoscopy (also known as cystourethroscopy) is a procedure that lets the physician see the inside of the bladder, bladder neck, and urethra. Usually performed in the doctor's office or outpatient facility, cystoscopy is perhaps the most powerful diagnostic tool for bladder cancer diagnosis. During the procedure, a thin, telescope-like hose with a tiny attached camera called a cystoscope is inserted into the bladder through the urethra (the tube that passes urine from the bladder out of the body). A local anesthetic jelly is used during the procedure. The physician maneuvers the cystoscope to detect any abnormalities in the urinary tract. Special attention is paid to the opening of the ureter into the bladder (ureteral opening), where many tumors begin to grow. The physician will inspect the bladder from numerous angles and may press on the abdomen to view areas such as the bladder dome.

After cystoscopy, the physician may want to perform other diagnostic tests such as excretory urography, computed tomography, and bone scans to thoroughly evaluate the upper urinary tract and to identify or rule out distant metastases.

Excretory Urography
Excretory urography is a form of radiography (X-ray) that is performed after the administration of contrast medium, which is voided into the urine. Since excretory urography is not the best method for detecting bladder tumors, especially if they are small in size, it is more useful as a screening tool to locate other tumors that may be present in the upper urinary tract. During excretory urography, some large bladder cancer tumors may appear as bladder filling defects. Bladder tumors that cause blockages in the ureters, the two tubes that pass urine out of the kidneys and into the bladder, are frequently muscle-invasive in nature.

Computed Tomography and Magnetic Resonance Imaging
Computed tomography (CT scan) and magnetic resonance imaging (MRI) are imaging methods that create cross-sectional pictures of the internal organs. Both methods rely upon computer analysis. CT scans or MRIs of the pelvis and bladder are used by physicians to assess large (greater than 5 cm) bulky tumors, lymphatic involvement, and the response of tumors to radiation or chemotherapy. But neither method can distinguish between surface bladder tumors and those that invade deep muscle tissue. CT scans may be difficult to interpret in patients who have had urethral surgery or radiation therapy. In addition, CT scans and MRIs cannot diagnose microscopic metastatic disease; for example, they only depict cancerous lymph nodes that are 1 cm or larger in size. However, MRIs, in contrast to CT scans, are able to distinguish blood vessels from lymph nodes.

Ultrasonography
Ultrasonography—visual imaging of internal organs using echos from high-frequency (ultrasound) sound waves—is a technique that is rapidly being developed to classify, or "stage," bladder cancers before surgical removal. At the present time, ultrasonography for bladder cancer can be conducted via three routes:

1. Transabdominal - through the abdomen

2. Transrectal - through the rectum (end of the large intestine)

3. Transurethral - through the urethra (the tube that passes urine from the bladder out of the body)

Transurethral ultrasonography is the most accurate of all of the ultrasound methods; however, this approach is invasive—that is, it involves entry into the body through the urethra—and it requires a miniature transducer (power converter) that is not widely available in many health care centers.

Bone Scans and Other Procedures
If the physician suspects that a bladder cancer has metastasized - that is, cancerous cells have broken away from the original tumor to grow within other parts of the body - then tests such as bone scans, liver function tests, or chest X-rays may be ordered. If any of these tests indicate metastasis, then further testing should be performed to confirm the diagnosis, usually by the least invasive means possible, such as fine-needle aspiration biopsy in which a fine, hollow needle attached to a syringe is inserted into the suspicious mass and the needle is pushed back and forth to free some cells, which are aspirated (drawn up) into the syringe and are smeared on a glass slide for analysis. The bones, liver, and lungs are common sites of cancer metastasis.

New Diagnostic Tests
Over the past few years, a number of new tests have been devised to aid the diagnosis of bladder cancer. These tests include the bladder-tumor-associated antigen test (BTATM), the BTA stat test, the BTA TRAK® test, the fibrin/fibrinogen degradation products test (FDPTM), and the NMP22TM assay. All of these tests can be performed on urine samples.

BTA test
The BTA® test was designed to detect proteins that are released by reproduction of bladder tumor cells, and its interpretation does not require a technician or specialist. The BTA® test significantly identifies superficial (surface) bladder tumors by changing color. The top of the BTA® test strip turns yellow when positive for bladder cancer, and it turns green when negative. The BTA stat test is an immunologic assay that can be used to identify recurrent bladder cancer. The FDP® test detects the breakdown products of blood-clotting proteins (fibrin, fibrinogen), which are increased in the urine in the presence of bladder cancer. Both the BTA stat and FDP® tests are superior to voided urine cytology, especially for low-stage and low-grade disease.

NMP22TM assay
The NMP22TM assay measures specific proteins from the nuclear matrix (cell center). It can detect transitional cell carcinoma (TCC) with a sensitivity of roughly 67%, meaning that 67% of existing TCCs are detected. But, perhaps more importantly, the NMP22TM assay it is able to predict the recurrence of bladder cancer after transurethral resection (TUR) for invasive cancer with an overall sensitivity of 70% (see also Treatment of Bladder Cancer). The BTA TRAK® test measures the levels of a specific protein (human complement factor H-related protein, or hCFHrp) that is detected by the BTA stat test.

There are a number of other potentially useful "markers" for bladder cancer diagnosis, including blood group antigens, inducers of immune response which may help to predict the invasive potential of surface tumors; and urine markers, such as M344 antigen, autocrine motility factors, glycosaminoglycans, scatter factor, telomerase activity, and microsatellite analysis.

Unfortunately, when TCC is treated by TUR alone, bladder cancer may reappear in up to 90% of all patients. Therefore, other treatment methods have been developed to decrease the likelihood of cancer recurrence. Intravesical therapy includes both chemotherapy (chemical therapy) and immunotherapy (therapy by immune system stimulation). During this procedure, the medication (chemotherapeutic drug or immune vaccine) is placed intravesically - that is, directly within the bladder. Intravesical therapy concentrates the medication at the tumor site to reduce the survival of any tumor tissue that is overlooked after TUR. The most frequently used drugs for intravesical therapy are the immunotherapeutic agent Bacillus Calmette-GuČrin (BCG), thiotepa, mitomycin C, doxorubicin hydrochloride, and epirubicin.

Bacillus Calmette-GuČrin (BCG)
BCG vaccine is a nonspecific immune stimulant. BCG acts by binding to the bladder tissue and starting an immune response that hampers tumor growth. During treatment, BCG is dissolved in normal saline (salt solution). The solution is instilled (administered by slow drip) into the bladder through a urethral catheter for 2 hours weekly for 6 or more weeks. BCG is a very effective form of intravesical therapy, especially for carcinoma in situ (CIS, TIS), which can be aggressive despite its surface location on the bladder wall. BCG decreases the frequency of tumor recurrence in over half of all CIS patients, and it reduces invasive potential in individuals with high-grade tumors. BCG therapy may cause side effects such as bladder irritation, hematuria, flu-like symptoms and, rarely, fever or sepsis (infection). However, most patients are able to tolerate BCG therapy, and flu and fever symptoms can be reduced by simultaneous use of the antituberculosis drug isoniazid (INH).

As previously noted, the most common intravesical chemotherapeutic drugs are thiotepa, mitomycin C, doxorubicin hydrochloride, and epirubicin.

Thiotepa
Thiotepa (triethylenethiophosphoramide) is an alkylating agent that is chemically related to nitrogen mustard. It stops cancer growth by causing cross-links between vital nucleic acids and proteins within the tumor. The usual dose of thiotepa is 30 to 60 mg in distilled water weekly for 6 weeks, followed by monthly treatments. Thiotepa therapy alone produces complete responses in only one third of patients. Thiotepa therapy after TUR increases disease-free survival at 12- and 20-month periods.

Mitomycin C
Mitomycin C, like thiotepa, also causes cross-links in substances that are essential for tumor growth. It may be beneficial for patients who have failed thiotepa therapy, and, because it is not readily absorbed through the bladder, bodily side effects are uncommon (skin rash, especially of the palms, has been noted in some patients). The customary dose of mitomycin is 20 to 60 mg weekly for 8 weeks.

Doxorubicin hydrochloride
Doxorubicin hydrochloride (Adriamycin®) is a toxic antibiotic that disrupts tumor cell function. It is given in 30 to 90 mg doses over different time frames. Some studies have shown increased tumor-free survival with doxorubicin at 18 months of follow-up. Doxorubicin hydrochloride is not as well absorbed through the bladder and is less toxic to the system than thiotepa.

Epirubicin
Epirubicin (4'-epidoxorubicin) is a new drug that is related to doxorubicin and has similar effects upon tumor growth. Dosages range from 30 to 80 mg weekly for up to 8 weeks.

A number of new drugs and techniques have been investigated for use as intravesical therapy. Such options may be especially helpful for patients who are unresponsive to BCG or other agents. They include interferons, immune system stimulants and modulators, photodynamic therapy with laser light, and gene therapy.

• Interferons are naturally occurring compounds that exert many beneficial anticancer effects, such as the slowing of tumor cell growth and antiviral activity. The recombinant interferon a2b (rINFa-2b) is a particularly good second-line option for patients who do not tolerate or respond to BCG or chemotherapy.

• Bropirimine is an oral immunomodulator that causes the body to produce interferon as well as other beneficial cancer-fighting substances (for example, interleukin-1, tumor necrosis factor, cytokines, etc.).

• Keyhole-limpet hemocyanin (KLH), a shellfish-based compound, is a nonspecific immune system stimulant. KHL causes few side effects and may prove advantageous for the prevention of recurrent tumors.

• Photodynamic Therapy (PDT) is a two-step process that selectively destroys the rapidly dividing cells of bladder cancers. PDT is begun by intravenous treatment with a photosensitizer (for example, the chemical Photofrin), which makes the bladder lining tissue light-sensitive. Next, "intrevesical activation" of the bladder lining is achieved by laser therapy with visible light. PDT causes cancer cell destruction and vascular damage; however, PDT also may produce severe side effects, such as cystitis-like syndrome ("post-PDT syndrome"), bladder contracture (shrinkage), and prolonged sensitivity to sunlight.

• Gene Therapy includes treatments that use genes to (1) correct faulty genetic information or (2) selectively destroy cancerous tissue. In the second category, vaccinia virus (a pox virus) has been genetically modified to express an antitumor response in the bladder.

  

Staging this disease

Once the physician has determined that a tumor exists, the next step is to clarify the tumor's status. Several questions will have to be answered: Is the tumor large or small? Does it lie within the lining of the bladder or has it extended into the surrounding tissue? Has the tumor spread to nearby lymph nodes? Has the tumor metastasized to distant sites within the body?

Fortunately, a number of systems have been developed to answer these questions. The most common of these -- the TNM (tumor, node, metastasis) system -- allows tumors to be classified, or "staged," according to their overall characteristics. A biopsy is removed and sent to a histopathologist for examination under a microscope. The pathologist then assigns a stage and a grade to the tissue sample.

The stage refers to the physical location of the tumor within the bladder or, more specifically, the tumor's depth of penetration. In general, tumor stage is confined to one of two categories: (1) superficial, surface tumors, or (2) invasive, deep-spreading tumors. Superficial tumors affect only the bladder lining. They grow up and out from the lining tissue and extend into the bladder's hollow cavity. Invasive tumors grow down into the deeper layers of bladder tissue, and they may involve surrounding muscle, fat, and/or nearby organs. Invasive tumors are more dangerous than superficial tumors, since they are more likely to metastasize.

The grade is an estimate of the speed of tumor growth as suggested by cell features seen under a microscope. Most systems are based upon the degree of tumor cell anaplasia - that is, the loss of cellular "differentiation," the distinguishing characteristics of a cell. The World Health Organization (WHO) grading system groups transitional cell carcinomas (TCCs) into three grades that correspond to well-, moderately, and poorly differentiated cells. The International Union Against Cancer (UICC) has devised a four-grade system that considers Grade 1 tumors to be well-differentiated, Grade 2 to be moderately differentiated, and Grades 3 or 4 to be poorly differentiated. Both systems are widely used and can be summarized as follows:

• Grade 1 (well-differentiated)

• Grade 2 (moderately differentiated)

• Grade 3 or Grade 4 (poorly differentiated)

There is a continuing debate about the classification of benign bladder lesions known as papillomas. The WHO defines papilloma as a single papillary (wart-like) growth with 8 or less cell layers in normal-looking surface tissue. By contrast, many pathologists and urologists classify papilloma as a Grade 1 TCC because of its tendency to recur and not to invade muscle.

There is a strong correlation between tumor stage and tumor grade. Nearly all superficial tumors are low grade; that is, they are Grade 1 tumors, with cells that are distinctly specialized and well-differentiated, whereas nearly all muscle-invasive tumors are high grade; that is, they are Grade 3 or 4 tumors, with cells that are nonspecialized and poorly differentiated. More importantly, there is a strong correlation between tumor stage and prognosis (the probable outcome of a disease), with superficial tumors having the most chance of a favorable result.

What are the treatments?

The treatment of bladder cancer depends upon many factors. The most important of these factors are the type of tumor that is present and its stage. (see also Bladder Cancer Staging and Types of Bladder Cancer).

SURGICAL THERAPY

Bladder cancers that are no longer confined to the surface lining and have grown into surrounding tissue usually require surgical therapy. Specifically, Stage T2 to T3a tumors—that is, tumors that have invaded the muscle or fatty tissue around the bladder—need surgical management. In men, a standard surgical procedure is cystoprostatectomy (removal of the bladder and prostate) with pelvic lymphadenectomy (removal of the lymph nodes within the hip cavity). Bladder surgery, which usually involves removal of the seminal vesicles (semen-conducting tubes), can be performed in a manner that preserves sexual function in some men. In addition, new surgical methods of urinary diversion (re-routing of urine through a surgical channel) may eliminate the need for an external urinary appliance.

Radical Cystectomy
In women with T2 to T3a tumors, a standard surgical procedure is radical cystectomy (cutting away of the entire bladder and associated tissues) with pelvic lymphadenectomy. Radical cystectomy in women includes removal of the uterus (womb), tubes, ovaries, anterior vaginal wall (front of the birth canal), and urethra (the tube that passes urine from the bladder out of the body). Preoperative radiation therapy may have some merit when combined with bladder surgery, although radiation therapy alone usually is unsuccessful.

Segmental Cystectomy
Segmental cystectomy (partial removal of the bladder)—a bladder-preserving or "salvage" form of surgery—is appropriate only in a limited selection of male or female patients (for example, patients with squamous cell carcinomas or adenocarcinomas that arise high in the bladder dome). When segmental cystectomy is performed, it may be preceded by radiation therapy (see also Radiation Therapy).

Urinary Tract Diversion
Until recently, most bladder cancer patients who underwent cystectomy (bladder removal) needed an ostomy (surgical creation of an artificial opening) and an external bag to collect their urine. Now, reconstructive surgical methods have been developed to replace the cancerous bladder. The continent urinary reservoir is the newest form of urinary diversion. With this technique, a piece of colon (large intestine) is removed and used to form an internal pouch to store urine. The pouch is specially refashioned to prevent back-up of urine into the ureters (one of two tubes that pass urine out of the kidneys and into the bladder) and kidneys. The patient—whether male or female—can urinate as before, without the need for an external bag or collection device. The urinary reservoir procedure is associated with some complications, such as bowel (intestine) obstruction, blood clots, pneumonia (lung inflammation), ureteral reflux (back-flow), and ureteral blockage.

Ileal Conduit
The ileal conduit is a small urine reservoir that is surgically created from a small piece of the patient's bowel. During this procedure, the ureters are attached to one end of the bowel piece; the other end is brought out onto the surface of the body to make a stoma. The patient then attaches an external, urine-collecting bag to the stoma. This bag needs to be worn at all times. Complications of the ileal conduit procedure include bowel obstruction, urinary tract infection (UTI), blood clots, pneumonia, upper urinary tract damage, and skin breakdown around the stoma.

Systemic Chemotherapy
Many individuals with late-stage bladder tumor(s) and/or metastases have a poor prognosis. Therefore, researchers have begun a number of clinical trials to test the effectiveness of systemic (in the vein) chemotherapy with multiple drugs. In particular, combinations of agents such as cisplatin, methotrexate, and vinblastine, with or without doxorubicin (CMV or M-VAC), have produced some encouraging responses in late-stage patients. In addition, the combination of cisplatin, cyclophosphamide, and doxorubicin (CISCA) has shown some activity, although the responses have not been as great as those reported for CMV or M-VAC treatments. In metastatic bladder cancer, other chemotherapeutic agents that have produced some benefits are: paclitaxel, ifosfamide, gallium nitrate, and gemcitabine. Whenever possible, individuals should be encouraged to participate in such trials. Multi-agent chemotherapeutic trials for metastatic bladder cancer have produced response rates of up to 70%, and survival times may be increased.

 

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