Key Terms: Analgesic, Arylamine, Benign, Biopsy, Bladder, Catheter, Chromosomes, Creatinine, Immunotherapy, Papilloma, Tumor.
Definition
Transitional cell carcinoma (TCC) is a type of cancer that usually originates in the kidney, bladder, or ureter (the tube that carries urine from the kidney to the bladder). It has also been recently recognized as a sub-type of ovarian cancer.
Description
A transitional cell is intermediate between the flat squamous cell and the tall columnar cell. It is restricted to the epithelium (cellular lining) of the urinary bladder, ureters (tubes that carry urine from the kidneys to the bladder), and the pelvis of the kidney (that portion of the kidney collecting the urine as it leaves the kidneys and enters the ureters). Transitional cell carcinomas have a wide range in their gross appearance depending on their locations. Some of these carcinomas are flat in appearance, some are papillary (small elevation), and others are in the shape of a node. Under the microscope, however, most of these carcinomas have a papillary-like look. There are three generally recognized grades of transitional cell carcinoma. The grade of the carcinoma is determined by particular characteristics found in the cells of the tumor. Transitional cell carcinoma typically affects the mucosa (the moist tissue layer that lines hollow organs or the cavity of the body) in the areas where it originates.
The most common site of transitional cell carcinoma is in the urinary bladder. Transitional cell carcinoma is the form of cancer in about 90% of cancers found in the bladder. The highest grade of transitional cell carcinoma is very likely to spread to other parts of the body. There are two primary ways that transitional cell carcinoma spreads into the surrounding structures. The first is by way of epithelial cells that line the body cavity and many of the passageways that exit the body. The other means of spread is through the lymphatic (network that resembles the circulatory system but transports proteins, salts, water, and other substances) system.
Demographics
Most patients who develop transitional cell carcinoma are older than 40 years of age; the peak age of incidence is 60–70 years of age. The male:female ratio for this type of cancer is about 5:2. About 93% of all bladder cancers in North American are of the transitional cell carcinoma type. Only 8% of all renal cancers are of the transitional cell carcinoma type. According to the American Cancer Society (ACS), 60,240 Americans will be diagnosed with bladder cancer in 2004 and 12,710 will die from the disease.
Causes and Symptoms
The causes and mechanisms of transitional cell carcinoma, like all forms of cancer, are not entirely known or understood. However, researchers have isolated several factors that have been associated with an increased risk for developing this carcinoma.
Cigarette smoking is the strongest risk factor for transitional cell carcinoma. Researchers have found smoking increases the risk for developing this condition by three to seven times. In men with bladder cancer, 50% to 80% have a history of smoking cigarettes. Other methods of using tobacco, such as cigar and pipe smoking and chewing tobacco, have been shown to increase the risk of developing this carcinoma but at a reduced rate compared with smoking.
Individuals who have undergone long-term exposure to industrial chemicals, such as the class of compounds known as arylamines, are known to have an increased risk of developing transitional cell carcinoma. One of the most dangerous of these chemicals is one known as 2-naphthylamine. Individuals who develop these carcinomas usually do so anywhere from 15 to 40 years following the first exposure to these chemicals. Arsenic is another chemical that has been recently implicated in the development of TCC.
Individuals who have used analgesics for many years, or have used them excessively in the short-term, are at an increased risk for developing transitional cell carcinoma. Many of these patients have suffered at least some damage to the kidneys before developing the carcinoma. Drugs given to patients to treat an earlier cancer, such as the commonly used cyclophosphamide, increase the risk of developing transitional cell carcinoma at a later time.
Researchers believe these factors somehow alter genes that are important in the development of transitional cell carcinoma. These changes most often involve the deletions of certain chromosomes but also may result from mutations.
The most common symptom of transitional cell carcinoma is blood in the urine without accompanying pain. There may also be changes in the urge for the patient to urinate and in the frequency of urination. In some cases, urine may be partially obstructed by a tumor in the ureter. Rarely, pain occurs in the pelvic region. Physicians rarely detect a tumorous mass by touch during the first examination.
Diagnosis
There are a variety of ways that can be used to help diagnose transitional cell carcinoma. Many of these involve the use of imaging studies. In some cases, traditional x rays may be used to image upper urinary tract tumors. One of the things that physicians look for in patients suspected of having transitional cell carcinoma is the abnormal filling of structures in the urinary system. A type of imaging called excretory urography can help detect such flaws in the system. A different imaging method called retrograde urography can help physicians image the process of urinary collection and detect irregularities. Computed tomography (CT), more commonly called the CAT scan, is a very useful tool in the imaging of tumors in the upper tract of the urinary system. CT is more sensitive than traditional x rays. In some cases, however, small tumors can be missed using this method.
Ultrasound may also be used to help tell the difference between tumors and normal structures in this region. Magnetic resonance imaging, more commonly referred to as MRI, has not been found to have any significant advantage over computed tomography in the diagnosis of transitional cell carcinoma.
Cystoscopy is the examination of the bladder using a cystoscope, an instrument that allows the interior imaging of the ureter and bladder. Cystoscopy is usually mandatory in patients suspected of having transitional cell carcinoma and can be helpful in determining the origin of the bleeding in these patients. Patients who are suspected of having transitional cell carcinoma, or other type of cancer in the upper urinary tract, need to have laboratory analysis of the cells in the suspected mass. This cell analysis tells the physician what type and stage of cell is present.
The easiest but least accurate way to study these cells is to have the patient provide urine samples. Patients who have a low-grade tumor in the upper urinary tract will have normal results in up to 80% of cases when urinalysis is used. However, such urinalysis can be more effective in diagnosis of bladder tumors. Obtaining urine samples from the upper urinary tract using a catheter can provide more accurate analysis of upper urinary tract tumors.
A technique called the brush biopsy involves the placing of a tiny brush into a catheter. The catheter is then placed in the ureter and moved into the upper urinary tract where the brush scrapes off cells for later analysis. More modern techniques of imaging and sampling use tiny tubes with attached videocameras called endoscopes. These tubes can be moved into the upper urinary tract to locate bleeding and tumors and can be used to obtain biopsy samples.
Treatment Team
The treatment team that treats the patient with suspected and confirmed transitional cell carcinoma usually involves a primary care physician who refers to a specialist, a specialist such as a urologist or nephrologist (kidney specialist), a radiologist who performs the imaging, a pathologist who studies the sampled cells, an oncologist who monitors the overall course of the cancer, and a surgeon who performs the surgical removal of the carcinoma.
Clinical Staging, Treatments, and Prognosis
The International Society of Urological Pathology has developed a classification scheme for grading transitional cell carcinoma. These four grades are urothelial papilloma, urothelial neoplasms of low malignant potential, low-grade urothelial carcinoma, and high-grade carcinoma. Papilloma is usually seen in younger patients and is rare. Neoplasms of low malignant potential are sometimes difficult to differentiate from low-grade urothelial carcinomas. These tumors rarely become invasive to nearby tissue. Low-grade urothelial carcinoma tends to appear in the form of papillomas as well. These tumors can invade nearby tissue but usually do not progress. High-grade carcinomas are flat, papillary, or both. These tumors are larger and are more likely to invade nearby muscle tissue.
The most common means to treat papillary transitional cell carcinoma in the bladder is with surgery. When these tumors are classified as low grade, they can typically be removed completely. Unfortunately, these carcinomas recur 50% to 70% of the time. Because of this high rate of cancer recurrence, patients with transitional cell carcinoma have to be carefully monitored following surgery with cystoscopy and regular urinalysis.
Other types of therapy called immunologic therapy (immunotherapy) and chemotherapy are often used in treating bladder carcinoma. These methods use agents that are directly applied to the bladder. The most commonly used agent in these therapies is called bacillus Calmette-Gueérin (BCG). When BCG is placed in the bladder, the body begins an immune response that sometimes destroys the tumor. Patients usually receive one treatment per week for six weeks. After this period, a maintenance program involving three-week BCG courses of treatment for up to two years is used. The most common chemotherapy used for transitional cell carcinoma in the past is a combination of the drugs cisplatin, adriamycin, vinblastine, and methotrexate. Newer and less toxic drugs, such as celecoxib, bortezomib, ixabepilone, and gallium maltolate are being tested to replace these older agents. A combination regimen of chemotherapy and radiation is being considered as a therapy when the carcinoma invades the muscle surrounding the bladder. The effectiveness of this method has not been studied yet in research studies. Radiation therapy alone is not an effective treatment.
Transitional cell carcinoma in the upper urinary tract is also treated with surgical procedures. Affected areas in this region, including the kidney, are sometimes removed. Part or all of the ureter and parts of the bladder are also removed, in some cases.
The noninvasive papilloma rarely recurs once removed. If urothelial neoplasms of low malignant potential recur, they are usually benign tumors. However, in about 3% to 5% of cases, these recurrences are of a higher grade. These carcinomas rarely become invasive, and patients with them have a one-year survival rate of 95% to 98%. Low-grade urothelial carcinomas often show signs of invasion during diagnosis, but are not associated with a high risk for malignancy. High-grade carcinomas have considerable invasiveness into nearby tissue, particularly muscle, and are associated with a very high risk for metastasis (movement of cancer cells from one part of the body to another).
Those with superficial, noninvasive, or nonmalignant disease should receive a cystoscopy and a thorough examination every three months for two years followed by a regimen every six months for an additional two years. In those with advanced disease but who did not receive complete bladder removal, a cystoscopy with a thorough examination should be performed every three months for two years, followed by every six months for an additional two years, and then one per year. These patients should also receive a computed tomography (CT) scan of the pelvis and abdomen every six months for two years. Chest x rays, liver function tests, and serum creatinine tests should also be performed on this schedule. Those who had bladder removal should have chest x rays, liver function tests, computed tomography scan of abdomen and pelvis, and serum creatinine tests performed every six months for two years. In addition, an endoscopy of the newly formed bladder structure should be performed.
Coping With Cancer Treatment
A variety of issues need to be considered when the patient is receiving cancer treatment. One of the most important of these issues is the ability to cope with the emotion of having cancer in the first place. Several techniques, such as relaxation training, meditation, and bio-feedback, may be beneficial to the patient in reducing anxiety. Other issues such as missed work and other daily activities need to be planned before the treatment period to reduce emotional stress. The patient needs to consider worst-case scenarios, such as side effects from chemotherapy, when planning these future events. Participation in cancer support groups helps many patients with the stress of the treatment period.
There are physical issues as well during this period. Pain following surgery can be a significant problem. Fortunately, there are many effective pain medications available to handle most pain events. Nausea and hair loss (alopecia) are two of the more notable effects of chemotherapy. Nausea can be effectively treated with drugs in most cases. Hair loss is only a temporary event, but it often has significant psychological effects that can be somewhat alleviated through social support.
Clinical Trials
As of 2004 the National Cancer Institute (NCI) lists 46 clinical trials in progress for treating bladder cancer. Several new drugs are being tested, as well as various combinations of drugs, surgery, and BCG therapy. The best way to obtain the most current information is to call the Cancer Information Service at (800) 4-CANCER. The Cancer Information Service is part of CancerNet, a service of the National Cancer Institute. It can also be accessed at
Questions to Ask the Doctor
- What type of type of tests are necessary to make an accurate diagnosis?
- Are these tests painful?
- How long will it take to get results?
- If the tests are positive for cancer, what happens then?
- If it is transitional cell carcinoma, is the tumor invasive?
- Has the carcinoma spread to other tissues?
- What stage is the carcinoma?
- What treatment alternatives are there?
- If surgery is necessary, what will the surgery entail?
- What is the recuperation period like after the surgery?
- How long will I be in the hospital?
- If radiation is necessary, what sort of side effects are common?
- If chemotherapy or immunotherapy is necessary, what side effects are common?
- Will chemotherapy cause my hair to fall out?
- Are there any clinical trials that I can participate in?
- What type of surveillance schedule will I be on following the initial surgery and therapy?
Prevention
Cigarette smoking is a major risk factor for the development of transitional cell carcinoma. Cigarette smoking has been associated with 25% to 65% of all cases of bladder cancer. Smokers are two to four times more likely to develop transitional cell carcinoma than nonsmokers. Smoking increases the risk of developing tumors that are at a higher grade, in greater number, and of larger size. Those individuals who have abused analgesics are at an increased risk for developing transitional cell carcinoma. Exposure to the human papilloma-virus type 16 also increases the risk of developing transitional cell carcinoma. Petroleum, dye, textile, tire, and rubber workers are at increased risk for developing this carcinoma. Exposure to chemicals, such as 2-naphthylamine, benzidine, 4-amino-biphenyl, nitrosamines, or O-toluidine can also increase the risk of developing transitional cell carcinoma. Eliminating exposure to these substances substantially reduces the risk of developing transitional cell carcinoma.
Resources
Books
Beers, Mark H., MD, and Robert Berkow, MD, editors. "Bladder Cancer." Section 17, Chapter 233 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2002.
Beers, Mark H., MD, and Robert Berkow, MD, editors. "Ovarian Cancer." Section 18, Chapter 241 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2002.
Ellis, William J. "Malignant Tumors of the Urogenital Tract." Rakel: Conn's Current Therapy 2000. Philadelphia: Saunders, 2000.
Ferri, Fred F., et al., editors. "Bladder Cancer." In Ferri's Clinical Advisor. St. Louis: Mosby, 2001.
Tierney, Lawrence M., et al., editors. "Cancers of the Ureter and Renal Pelvis." In Current Medical Diagnosis & Treatment. New York: Lange, 2001.
Periodicals
Bazarbashi, S., et al. "Prospective Phase II Trial of Alternating Intravesical Bacillus Calmette-Guérin (BCG) and Interferon Alpha IIB in the Treatment and Prevention of Superficial Transitional Cell Carcinoma of the Urinary Bladder: Preliminary Results." Journal of Surgical Oncology 74 (2000).
Eichhorn, J. N., and R. H. Young. "Transitional Cell Carcinoma of the Ovary: A Morphologic Study of 100 Cases with Emphasis on Differential Diagnosis." American Journal of Surgical Pathology 28 (April 2004): 453–463.
Hayashida, Y., K. Nomata, M. Noguchi, et al. "Long-Term Effects of Bacille Calmette-Guérin Perfusion Therapy for Treatment of Transitional Cell Carcinoma in situ of Upper Urinary Tract." Urology 63 (June 2004): 1084–1088.
Karagas, M. R., T. D. Tosteson, J. S. Morris, et al. "Incidence of Transitional Cell Carcinoma of the Bladder and Arsenic Exposure in New Hampshire." Cancer Causes and Control 15 (June 2004): 465–472.
Konety, Badrinath R., MD, and Georgi Pirtskhalaishvili, MD. "Transitional Cell Carcinoma, Renal." eMedicine November 10, 2004.
Maluf, F.C., and D.F. Bajorin. "Chemotherapy Agents in Transitional Cell Carcinoma: the Old and the New." Seminars in Urologic Oncology 19 (2001).
Organizations
American Cancer Society. 1599 Clifton Rd. NE, Atlanta, GA 30329-4251. (800) 227-2345.
National Cancer Institute. National Institutes of Health. Bethesda, MD 20892. (800) 422-6237.
Other
American Cancer Society (ACS). Cancer Facts & Figures 2004.
American Pain Society. 4700 West Lake Ave., Glenville, IL 60025. (847) 966-5595.
—Mark Mitchell, M.D.; Rebecca Frey, Ph.D.
