Ask the MD What Causes Bladder Cancer

Michael O’Donnell, MD
Director of Urologic Oncology, Department of Urology
University of Iowa Hospitals and Clinics

Bladder cancer is the fourth most common new cancer in men and the tenth in women. About 70,000 new cases of bladder cancer will be diagnosed this year.

What causes bladder cancer?
No one knows the exact causes of bladder cancer, but research continues to find answers and, with continued progress, will eventually find a cure.

Many studies have found the following risk factors for bladder cancer.

Age. The chance of getting bladder cancer increases with age. Bladder cancer affects primarily people in their sixties and seventies. People younger than 40 rarely get this disease, but it does happen occasionally.

Cigarette smoking. Cigarette smoking is directly responsible for most cases of bladder cancer, causing about half of all bladder cancer deaths in men and about one-third of those in women.

Working in certain industries. Some workers have a higher risk of getting bladder cancer because of carcinogens (cancer-causing agents) in the workplace. Workers in the rubber, dye, chemical, and leather industries are at increased risk as are hairdressers, machinists, metal workers, printers, painters, textile workers, and truck drivers.

Race. Whites get bladder cancer twice as often as African Americans and Latinos. The lowest rates are among Asians.

Gender. Men are three times more likely than women to develop bladder cancer. Women are more likely to die from the disease, however, because they are often not diagnosed in the early stage.

Family history. People with family members who have bladder cancer are more likely to get the disease. Researchers are studying changes in certain genes that may increase the risk of bladder cancer.

What should women know about bladder cancer?

It can happen to you.

The most common sign is blood in the urine, but other urinary symptoms (frequency, urgency, and burning pain) can also be signs of the disease.

Women are more likely to have the disease diagnosed later than men (and thus have worse disease and a higher mortality rate) because most primary care and OB/GYN physicians don’t think about the possibility and often inappropriately treat women for months with antibiotics for a presumed urinary tract infection or with drugs for cystitis.

Smoking and permanent hair dyes are known risk factors.

Reconstructive options that can preserve the uterus and the ovaries and internal pouches or neobladders are available for women who are diagnosed with advanced forms of the disease.

The disease is very rare in women under the age of 40 who are nonsmokers.

Can women be screened for bladder cancer?

Yes, women can be screened, but it is appropriate only if there is unexplained blood in the urine or other bladder symptoms that don’t go away as expected.

Bladder cancer does tend to run in families, but it is not passed on as some traits are, suggesting this may be more related to similar exposure to cancer-causing agents rather than strict genetics. The highest-risk group for this disease consists of women with visible, painless blood in the urine who are over the age of 50 and who happen to have smoked for 20 or more years. In these cases an X-ray test (such as a computed tomography [CT] urogram or an intravenous pyelogram [IVP]) would be appropriate together with a scoping procedure called cystoscopy, which involves look ing directly into the bladder. A urine Pap test—also known as a urine cytology—is an important part of the evaluation, but a normal cytology does not rule out bladder cancer. If all these tests are negative, however, the chance of unsuspected bladder cancer is well under 1 percent.

How does bladder cancer develop?

Nearly 80 percent of bladder cancers remain within the bladder lining, or mucosa. This type of bladder cancer is called superficial bladder cancer, or carcinoma in situ (CIS), and often comes back after treatment.

In invasive cases, the cancer extends through the bladder wall and may grow into bones and other organs, including lymph nodes, reproductive organs, lungs, liver, and the pelvis.

What are the symptoms of bladder cancer?

The most common symptoms of bladder cancer include:

  • Blood in the urine (making the urine slightly rusty to deep red)
  • Pain during urination
  • Frequent urination or feeling the need to urinate without being able to

Having these symptoms does not necessarily mean a person has bladder cancer. Infections, benign tumors, bladder stones, or other problems also can cause these symptoms. Anyone with these symptoms should see a doctor so that the problem can be caught early.

How is bladder cancer diagnosed?

If a patient has symptoms that suggest bladder cancer, the doctor will give the patient a complete physical exam and order lab tests. The person may have one or more of the following procedures.

Physical exam. The doctor feels the abdomen and the pelvis for tumors. The physical exam may include a rectal or vaginal exam.

Urine tests. The laboratory checks the urine for blood, cancer cells, and other signs of disease. The most common urine test for bladder cancer is a urine cytology, similar to a Pap test.

Intravenous pyelogram. During an IVP, the doctor injects dye into a blood vessel. The dye collects in the urine, making the bladder and the kidneys show up on X-rays.

Cystoscopy. The doctor uses a thin, lighted tube called a cystoscope to look directly into the bladder. The doctor inserts the cystoscope through the urethra to examine the lining of the bladder. The patient may need anesthesia for this procedure.

The doctor can remove samples of tissue with the cystoscope. A pathologist then examines the tissue under a microscope. The removal of tissue to look for cancer cells is called a biopsy. In many cases, a biopsy is the only sure way to tell whether cancer is present. For a small number of patients, the doctor removes the entire cancerous area during the biopsy. For these patients, bladder cancer is diagnosed and treated in a single procedure.

How is bladder cancer staged?

If bladder cancer is diagnosed, the doctor needs to know the stage, or extent, of the disease to plan the best treatment. Staging is a careful attempt to find out whether the cancer has invaded the bladder wall, whether the disease has spread, and, if so, to what parts of the body. In a sense it is a measure of the depth and the extent of the disease.

The doctor may determine the stage of bladder cancer at the time of diagnosis, or the patient may need to undergo further testing. Such tests may include imaging tests—CT scan, magnetic resonance imaging (MRI), sonogram, IVP, bone scan, or chest X-ray. Sometimes staging is not complete until the patient has surgery.

The following are the main features of each stage of the disease.

  • Stage 0. Cancer cells are found only on the surface of the inner lining of the bladder; this stage is known as superficial cancer. One particularly aggressive form is the surface-spreading case of high-grade cancer called carcinoma in situ.
  • Stage I. Cancer cells are found deep in the inner lining of the bladder but not in the muscle of the bladder. While technically invasive, this stage is still considered superficial bladder cancer because it can be removed through cystoscopic surgery.
  • Stage II. Cancer cells have spread to the muscle of the bladder.
  • Stage III. Cancer cells have spread through the muscular wall of the bladder to the layer of tissue surrounding the bladder. At this stage the cancer may also have spread to the reproductive organs.
  • Stage IV. Cancer extends to the abdomen or pelvis. At this stage the cancer may have also spread to the lymph nodes and even as far away as the lungs.

How do doctors rate the aggressiveness of bladder cancer?

In addition to knowing the extent of the disease, it is important to know whether the disease has intrinsic aggressive potential. Under the microscope, the pathologist can usually determine this by looking at the individual cancer cells. Bladder cancer has traditionally been graded on a 3- to 4-point scale, where grade 1 signifies a less aggressive (low-grade) cancer, grade 2 is intermediate, and grades 3 to 4 signify a highly aggressive (high-grade) cancer.

The grade of the cancer is probably the single most important predictor of prognosis for superficial bladder cancers. Unfortunately, by the time the cancers have reached Stages II to IV, grade is less important because almost all of them are of the high-grade type. By definition, CIS is always high-grade.

How is bladder cancer treated?

Treatments for bladder cancer include surgery, radiation therapy, chemotherapy, and immunological therapy.

Surgery. Surgery is a common treatment for bladder cancer. The type of surgery depends largely on the stage and the grade of the tumor.

Transurethral resection. The doctor may treat early-stage (superficial) bladder cancer with transurethral resection (TUR). During TUR, a cystoscope is inserted into the bladder through the urethra. A small wire loop on the end is used to remove the cancerous area and to burn away any remaining cancer cells with an electric current.

Radical cystectomy. For invasive bladder cancer (and when superficial cancer involves a large part of the bladder), the most common type of surgery is radical cystectomy, during which the entire bladder, the nearby lymph nodes, part of the urethra, and the nearby organs that may contain cancer cells—all are removed. In men the prostate, seminal vesicles, and part of the vas deferens are removed. In women the uterus, ovaries, fallopian tubes, and part of the vagina are often removed. If the entire bladder is removed, the patient may undergo another procedure to create a pouch to hold urine.

Occasionally, small, localized, muscle-invasive bladder cancers can be removed, sparing the remaining normal bladder in a procedure referred to as partial cystectomy.

When bladder cancer has spread beyond the bladder, the goal of surgery is often not to remove the cancer itself but to relieve the symptoms of the disease. Additional forms of therapy are then used to treat the cancer.

Radiation therapy. Also called radiotherapy, this technique uses high-energy rays to kill cancer cells in one specific area. Radiation therapy can also be used to shrink a tumor before surgery to make it easier to remove, or, after surgery, to kill any cancer cells that may have been left behind.

External radiation. This is usually done at least several days per week on an outpatient basis for several weeks. The high-energy rays are concentrated on the cancerous area from outside the body.

Internal radiation. This is done by placing a small container of a radioactive substance into the bladder through the urethra or through an incision in the abdomen and requires a hospital stay. Once the implant is removed, no radioactivity is left in the body.

Chemotherapy. Chemotherapy uses drugs to kill cancer cells. A single drug or a combination of drugs may be used.

For patients with superficial bladder cancer, intravesical (inside the bladder) chemotherapy may be used after TUR. A catheter (tube) is placed through the urethra and into the bladder and used to fill the bladder with liquid forms of the drug(s) used. The drugs are left in the bladder for several hours. This treatment is usually done once a week for several weeks and can then be continued once or several times a month for up to a year.

For cancer that has spread to other parts of the body, chemotherapy drugs may be given intravenously (through a vein that carries the drugs throughout the body). The drugs are usually given in cycles so that a recovery period follows every treatment period. Occasionally, chemotherapy is also given before bladder surgery (cystectomy) as a means to facilitate surgery by reducing the tumor bulk. This is known as neoadjuvant therapy and has demonstrated survival benefit for many patients needing a radical cystectomy.

Immunological therapy. Also known as immunotherapy and biological therapy, this approach uses the body’s natural ability (immune system) to fight cancer and is most often used after TUR for superficial bladder cancer to prevent the cancer from coming back. It is usually begun within a few weeks after any superficial tumor is surgically removed by TUR.

Bacillus Calmette-Guerin (BCG). This is the most common form of immunotherapy. BCG solution contains live, weakened bacteria related to cow tuberculosis that stimulate the immune system to kill cancer cells in the bladder. The bladder is filled with the solution through a catheter and left for about two hours. Patients generally undergo this treatment once a week for about six weeks.

Interferon. This is another form of biologic therapy, which involves the administration of large amounts of a synthetic protein normally made by the body to activate and energize the immune system. Recent studies suggest that a combination of BCG plus interferon may be particularly active against aggressive or refractory superficial bladder cancer, especially CIS.

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