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Staging and Grading
Treating a bladder cancer, like many other cancers, requires a complete pathologic knowledge of its characteristics. Its appearance under a microscope, its size and the degree to which it has spread all affect your risk and help your doctor select the best treatment. Each cancer is unique, and so a grading system has been carefully developed to assist in evaluating them. The grading system contains four categories:
- The degree to which the cancer resembles the tissue from which it grew.
- The depth and size that it has spread locally.
- The number and the location of the lymph nodes to which it has spread.
- Whether it has seeded and spread to sites (called metastases) elsewhere in the body.
In category 1, the less the cancer resembles its tissue of origin, the more likely it is to cause trouble. The World Health Organization (WHO) recognizes three different grades of bladder cancer: well differentiated, moderately differentiated and poorly differentiated. The grade, as determined by the pathologist, gives an idea of how fast the cancer is growing. High-grade cancers grow faster and spread earlier than low-grade cancers. The current system uses these three grades. However, some doctors use a four-level grading system (I, II, III and IV). Both are acceptable.
Well-differentiated means the cancer looks more like normal bladder tissue; it is less aggressive and does not grow or spread quickly. Poorly differentiated tumors are more aggressive, do not look like normal bladder tissue and usually grow quickly and spread to other tissues earlier. Moderately differentiated are in the middle.
Category 2 deals with how far into the wall or depth of invasion into the bladder that the tumor has grown. This determination is made by biopsies taken during cystoscopy. The bladder has a three-layered wall. How many layers the cancer has penetrated determines whether the cancer is in Stage 0, I, II or III.
Category 3 deals with spread of the cancer into the local lymph nodes. Lymph nodes are the first retaining wall that infections and cancers must overcome before reaching the rest of the body. At surgery, and usually not before, a collection of lymph nodes surrounding the bladder are harvested and examined under a microscope for cancer cells. The number of these nodes that contain cancer cells helps predict the extent of the disease, risk of progression and the likelihood of cure. Usually this process is all done while you are asleep in the operating room. The surgeon waits for the results of the microscopic exam from the pathologist before deciding what surgical procedure to do. That's because the doctor doesn't want to do the kind of "radical" surgery to cure the cancer if it has spread past the point of being curable by surgery.
Category 4 definitely precludes surgical cure, except in very rare cases where the removal of a single cancer metastasis in a special location has produced long-term survival.
A combination of these categories gives the cancer a total score from which good estimates can be made of your chances of survival.
An older system of grading bladder cancers, known as the Jewett-Strong-Marshall system, uses four categories -- A, B, C and D. A means the cancer has not extended beyond the inner lining of the bladder. B tumors have passed through the basement membrane and have invaded the next layer -- the bladder muscle. C tumors have reached the fat (serosa) that surrounds the bladder, and D tumors have spread beyond the bladder to lymph nodes or distant sites. The newer American Joint Committee on Cancer (AJCC) staging system for bladder cancer consists of five stages -- (0), I, II, III, IV
Predicting the future of your cancer
If your cancer is stage 0 (the tumor is very superficial), you have a 90 percent chance of surviving the next five years. In Stage I, you have a 75 percent chance or higher of being alive in five years. Stage II gives you a 55 percent to 90 percent chance of a 5-year survival rate depending on grade of the cancer. Stage III is 20 percent to 60 percent. And Stage IV, 50 percent die within one year and 80 percent have a five-year survival rate of less than 5 percent. Fortunately, three-quarters of all bladder cancers are found in Stage I. Only 5 percent of patients have metastases when their bladder cancer is discovered. The grade of your cancer helps fine-tune the predictions based on the stage of your cancer.
Treatment of localized disease
If you are among the majority whose cancer is confined to the bladder, the chances of curing you through surgery are good. There are two scenarios:
If the cancer is confined to the innermost layer of the bladder, a high rate of cure can be achieved by local removal followed by the instillation of one of several agents, called intravesical therapy. Curiously, chemotherapy drugs such as thiotepa and doxorubicin appear less effective than the immunization used against tuberculosis (TB). This modified TB germ, known as bacillus Calmette-Guerin (BCG), creates an immune response that spills over and attacks the cancer cells as well. The mode of treatment is called immunotherapy. BCG is completely effective in more than 70 percent of superficial tumors and carcinoma in situ (a very early stage of cancer). It reduces cancer recurrence by 40 percent to 45 percent, whereas chemotherapy produces only an 8 percent to 18 percent reduced rate. Each agent has its occasional side effects that must be anticipated and addressed.
The second scenario applies to cancers that have invaded the outer layers of the bladder. In this case more extensive surgery is required with the intention of curing the disease. Ten percent of these cases have a cancer that is isolated to a piece of bladder wall that can be removed without taking the whole bladder with it. If your cancer is not among these fortunate few, you must suffer the removal of your entire bladder and most of the organs nearby. But the surgeon will not perform this type of surgery if he or she thinks he cannot remove all the cancer. He or she may not know until you are on the operating table, asleep and opened up. At that point the surgeon looks around as much as possible inside you to find all evidence of the cancer. If it appears that all of it can be removed, your chances of a cure may be about 50 percent with "radical" surgery depending on the pathology grade (how advanced the tumor is).
But what happens to my urine when I don't have a bladder?
Although the urinary bladder is not a vital organ like the heart or brain, its function is certainly necessary to your health and well-being. Arrangements have to be made. There are four possibilities:
- Ureters, which carry urine to the bladder, may be reconnected directly to the intestines so that urine flows into them and out with bowel movements. This plan produces complications with chemicals in the urine that the intestines doesn't handle well and is generally not done.
- Ureters can be diverted to an opening in the skin called an ostomy, over which a pouch is placed to catch the urine that continuously dribbles out. The connection requires the ureters be extended by creating a tube of small intestine, so that they are long enough to reach a convenient place on the front of the abdomen.
- A pouch made of intestine and separated from the rest of the bowel can be constructed and made to hold urine until you can empty it yourself. This way you don't have to wear a bag. Instead, you insert a tube (catheter) into the pouch through a hole in your skin whenever it needs emptying.
- The most desirable arrangement, and the most difficult to accomplish, is to rebuild from a piece of intestine a bladder that functions the same way the original bladder did. This is called an orthotopic bladder substitute. It requires a number of lucky conditions, including a cancer that can be removed without damaging the other structures needed to allow you to urinate normally.
Treatment of disease that has spread
Because bladder cancer has a high rate of recurrence, even advanced cases may benefit from radical surgery. In these cases, surgery is followed by more treatment, either chemotherapy with a variety of agents, or radiation, or both. Bladder cancer is relatively sensitive to anti-cancer chemicals; so a certain number of them, about 20 percent, can be cured using several drugs at once.
Even if radical surgery is not recommended, some sort of surgery may be necessary, perhaps to relieve an obstruction to the flow or urine or to remove the bulk of a cancer so that radiation or chemotherapy will be more effective.
There is much research currently in progress to determine the best treatment for each stage and grade of bladder cancer.
Recurrences
Initial cure is only part of the necessary treatment, however, since somewhere between 30 percent and 80 percent of patients suffer a return of the disease in another part of the bladder. This is why intravesical therapy is so important. Not only does it help cure the initial cancer, it helps suppress the appearance of new cancers elsewhere in the bladder.
New horizons and Investigational Drugs
There may be chemicals easily found in the urine or blood that indicate the presence of cancer in the bladder, just as prostatic specific antigen (PSA) is useful to screen for prostatic cancer. One chemical called the nuclear matrix protein (NMP22) is being investigated and may be useful in early detection of recurrence, although it is not yet useful in screening for the disease in the general population.
In addition to fine-tuning the currently available treatments and trying other anti-cancer drugs, there are more possible treatments for bladder cancer that show promise, although they are still considered experimental. One of these is called photodynamic therapy (PDT). PDT can be used on any tissue that can be exposed to light, and is approved by the Food and Drug Administration for cancer of the esophagus and lung. After administering a chemical that sensitizes tissue to light, the light can produce enough of a "sunburn" to destroy the tissue. It is possible to concentrate the sensitizing chemical in the cancer tissue to some extent, but you still run the risk of getting a sunburn from the sun.
A similar experimental treatment is a more direct application of heat called hyperthermia. Microwave, radiofrequency, X-ray and just plain hot salt water have been used to burn these cancers up. Alcohol also has been tried. So far not enough cases have been tested to allow firm recommendations to be made. But, as mentioned earlier, research and experimentation is very active because there are 61,400 new cases of bladder cancers diagnosed every year just in the United States alone.
Because of the significant success of immunotherapy with BCG in reducing bladder cancer, other agents are being tried to stimulate the body's immune mechanisms to fight off this cancer. Among these agents are: keyhole limpet hemocyanin, interferons and interleukin 2.
Attempts also are being made to determine in the laboratory which chemical treatments a given cancer is sensitive to. A sample of your cancer is grown in a test tube and exposed to various drugs to see which appears to work best. This approach has not yet yielded results good enough to make it part of the routine treatment.
Treating Bladder Cancer
Immunotoxins are antibodies or smaller fragments of antibodies manufactured in the laboratory that recognize specific substances (receptors or antigens) on the surface of cancer cells. Once the immunotoxins recognize a cancer cell, they deliver a powerful toxin attached to the antibody that enters and kills the cell. Early studies of immunotoxins used in bladder cancer treatment are in progress.
Gene therapy is a promising new method being tested against bladder cancer. Mutations in genes that normally suppress tumors (the p53 gene for example) can cause bladder cells to grow abnormally. Researchers are studying ways to infect bladder cancer cells with genetically engineered viruses that contain a normal p53 gene in order to restore normal growth control. Clinical trials of this therapy are underway. Experimental genetic DNA attempts are also being tested.
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External Sources
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Dollinger M, Rosenbaum, EH, Tempero M., et al. Everyone's Guide to Cancer Therapy, Fourth Edition, Kansas City, Missouri: Andrews McMeel Publishing, 2002.
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National Cancer Institute.
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This article was reviewed and updated June 2007.
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