Bladder cancer typically refers only to Transitional Cell Carcinoma (or TCC) of the bladder. This type of cancer makes up 90-95% of all bladder cancers. Squamous cell carcinoma makes up only about 5% of bladder cancers. Adenocarcinoma occurs only about 2% of the time.
Since transitional cell is the most common cell type and presents about 70,000 new cases a year with 14,000 deaths in 2010, this article will only deal with Transitional Cell Carcinoma.
The empty bladder is a hollow, potential space organ similar to an empty balloon in the pelvis. Its function is to store urine between urinations. The bladder, as well as the ureters, is lined with a tissue type called transitional cells. This name comes from the fact that the bladder lining or urothelium is 7 layers of cells thick. The bottom layers are rounder and transition (or change) into flatter cells at the surface of the bladder.
The lamina propria is the layer just beneath the bladder mucosa or urothelium. (When you pull the skin off the chicken, the thin white layer that you see underneath the chicken’s skin is pretty much what we’re talking about.) This thin layer attaches the urothelial layer to the deeper underlying muscle layer. The muscle layer is the layer that contracts to allow the urine to flow out from the bladder at the time of urination.
Signs and Symptoms of TCC
The most common sign of bladder cancer is hematuria. Hematuria is the presence of blood in the urine. This may be visible to the naked eye as gross hematuria or microscopic and can be detected by your doctor upon urinalysis. Hematuria itself does not mean that you have cancer but does warrant an evaluation. While infection, stones, and prostate enlargement are more common than cancer, it is most important to find a cancer early.
Frequent urination may be a sign of bladder cancer. When this is new in onset and coupled with blood in the urine, tests for cancer are ordered.
Painful urination or pain in the pelvic area may also occur.
Dysuria or burning on urination may occur without infection or kidney stones.
Causes of Bladder Cancer
The kidneys eliminate waste products. These waste products are held in the bladder between urinations. The longer the urine is held the longer it is kept in contact with the urothelium.
Tobacco exposure is the most common cause of bladder cancer accounting for over 50% of all cases in the USA. The most literature available on this particular cancer deals with smoking. There is literature to support that tobacco in any form can initiate the formation of bladder cancer. Chewing tobacco and snuff are not safe alternatives to smoking. The ratio of men to women with TCC is about 3:1. Many people feel that secondhand smoke is also a cause for TCC.
Chemical exposure in industry is the next most common cause. Most of this is due to hydrocarbon exposure. Most commonly, this occurs in any form of mechanical work.
Solvents made from oil are another source of exposure. Benzene and Naphthalene are known bladder carcinogens.
The tire and rubber industry utilizes oil in their manufacturing process. Even the handling of the finished product without gloves over long periods of time may cause cancer.
People in industries using dyes have an increased risk of developing bladder cancer. The worst dyes are called aniline dyes. Dyes used in the leather industry, textile industry, paint industry, and hair dye industries have been implicated.
Prior radiation exposure to the pelvis in the treatment of prostate, colon, and GYN cancers has been reported to increase the later risk of developing bladder cancer.
Chemotherapy exposure to cyclophosphamide has been shown to increase the risk of bladder cancer.
Age over 80 years is apparently an independent risk factor, even in the absence of any chemical or tobacco exposure.
Bladder stones, chronic urinary catheters, and a Middle Eastern parasite, schistosomiasis, are all risks for squamous cell bladder carcinoma.
Prevention of Bladder Cancer
You may have heard that you should drink 2 liters of water a day, but water contained in the foods you eat counts as part of that fluid intake. So, the most correct way is to tell you to eat and drink enough fluid to produce two liters of urine a day. Doing this keeps the urine diluted and decreases the time that any of the known carcinogens are in contact with the bladder lining.
Wearing appropriate barriers, when handling these chemicals, significantly reduces the risk of developing cancer. Gloves, respirators, and protective clothing requirements when handling chemicals are available in every work place in the MSDS (Material Safety Data Sheet) file required by OSHA (Occupational Safety and Health Administration).
Stopping all use of tobacco for 5-10 years reduces the risk of smokers to that of a non-smoker.
Thus far, large studies have not found any conclusive evidence that any dietary supplement decreases your risk of bladder cancer.
Healthy eating habits with foods low in fat and red meat but high in fruits and vegetables as well as weight loss have been shown to lower the risk of all cancers.
Once hematuria (or blood in the urine) is documented, a thorough history looks at occupational and tobacco exposure risk factors.
X-rays look for abnormalities of the lining of the kidneys, ureters, and bladder. The older x-ray was the intravenous pyelogram. The newer x-ray is the CT (computed tomography) urogram. Both require the injection of an iodine containing contrast. The contrast is excreted in the urine and outlines the internal collecting system of the kidney, ureters, and bladder. The CT can also evaluate the bladder wall thickness and look for any signs of a tumor spreading to the pelvic lymph nodes. IVP only looks at the collecting system and not the lymph nodes or adjacent pelvic structures.
Cystoscopy is the telescopic visual inspection of the inside of the bladder. This finds tumors that are too small to see on an x-ray evaluation. So far, we have not been able to find a substitute for this direct visual inspection of the bladder.
Ureteroscopy is the visual evaluation of the inside of the ureters for a tumor. This is done when the x-rays suggest abnormalities in the ureters and/or kidneys. About 3% of TCC is found in the upper urinary tract above the bladder.
Urinary cytology is the microscopic inspection of the urinary sediment. The urine is concentrated in a centrifuge, and the last drop is stained with the Pap (Papanicolaou) stain. This is the same process as for cervical Pap smear stains in women. The pathologist then evaluates the slide visually looking for cancer cells. Slow growing TCC sheds normal looking cells and may be missed. Sometimes the pathologist simply notes too many cells to be normal. The cytology is better at looking for the high-grade or more malignant cancers.
Tumor markers such as NMP-22, BTA STAT, and FISH assay may sometimes be helpful. They have not yet to date found a reliable enough tumor marker to replace the cystoscopy.
Rectal exam in men and pelvic exam in women evaluate for thickening of the pelvic tissues or fixation to the surrounding tissues that might suggest a more advanced tumor stage.
Initial staging or clinical staging of bladder cancer is done through physical findings and x-ray findings. The pathologist then evaluates the type of cancer and depth of bladder wall invasion using the TNM (tumor nodes metastasis) staging system to find the pathologic stage.
Staging of primary bladder cancer tumors (T)
- Ta: Noninvasive papillary carcinoma
- Tis: CIS (anaplastic “ﬂat tumor” conﬁned to urothelium)
- T1: Tumor invades lamina propria
- T2: Tumor invades muscularis propria
- T2a: Invades superﬁcial muscularis propria
- T2b: Invades deep muscularis propria
- T3: Tumor invades perivesical fat
- T3a: Invades microscopic perivesical fat
- T3b: Invades macroscopic perivesical fat (extravesical mass)
- T4: Tumor invades prostate, uterus, vagina, pelvic wall or abdominal wall
- T4a: Invades adjacent organs (uterus, ovaries, prostate stoma)
- T4b: Invades pelvic wall and/or abdominal wall
Grading of Bladder Tumors
The pathologist determines the tumor grade.
Grade 1, or a low-grade tumor, has fairly normal looking cells still trying to form normal layers. These often form finger-like projections on stalks similar but finer than on a head of a broccoli floret. Frequently these tumors have a small stalk-like attachment to the bladder with a larger head of tumor on the end of that stalk. These often have 6-7 layers like normal transitional cell layers.
Grade 2, or moderately differentiated tumor cells, is more abnormal than grade 1. This often forms stubbier fingers with fewer layers. They in general have a broader base attachment to the bladder than does the grade 1 tumor.
Grade 3 tumors are classified as aggressive or poorly differentiated tumors. These are also referred to as high-grade tumors. They have very abnormal looking cells under the microscope. These are more likely to be multi-focal and low growing with a large, wide base. They generally are flatter tumors seen on cystoscopy.
Treatment of Bladder Cancer
The initial treatment is the TURBT or transurethral resection of the bladder tumor. This provides tissue for the pathologist to evaluate for tissue cell type, grade of the tumor, and depth of invasion or pathologic stage of the tumor. Bladder biopsies of the right, left, posterior bladder, bladder dome and trigone, and possibly the prostatic urethra in men are obtained to evaluate the remainder of the “normal” looking bladder for signs of pre-cancerous changes.
Mitomycin C may be placed in the bladder at the time of tumor resection in an attempt to reduce tumor recurrence.
Stage 1 tumors or T0, Ta, and Tis are localized to the top layer of the bladder lining and are removed by surgery and may require nothing more than close follow-up. They usually do not require any topical or intravesical chemotherapy.
Stage 2 or T1 tumors begin to invade the lamina propria or connective tissue layer below the urothelium but are not deep enough to penetrate into the bladder muscle. These have a higher recurrence rate and progression to higher-grade tumors and are usually treated with liquid chemotherapy introduced into the bladder by way of a catheter.
Stage 3 or T2 tumors invade into the muscle and are at risk for local or even wide spread systemic metastasis. This is currently treated with pre-op chemotherapy and bladder removal or cystectomy.
Stage 4 tumors have invaded through the bladder and into the fat surrounding the bladder or have spread to the pelvic lymph nodes or beyond. This is usually treated with IV chemotherapy and radiation.
Cystectomy and Urinary Diversion for Bladder Cancer
Once the bladder is removed, the urine must still be collected and disposed of. There are 3 main operations for this.
Ureterosigmoidostomy was the first attempt to divert the urine. The ureters were simply sewn into the distal colon. Most people had 3-6 loose bowel movements per day, but were continent of urine. This was discontinued when it was found that after 10 years or so these people developed colon cancer due to the interaction of the urine and the bacteria housed in the normal bowel movement.
Ileal conduit construction goes back to the 1950’s. This is constructed by disconnecting a segment from the bowel as an isolated segment. This utilizes a 6-8 inch segment of small bowel to bring the urine to the skin. The urine is then collected in an ostomy bag.
Neo bladder is the construction of a new bladder-like pouch that is connected to the urethra and allows for some semblance of normal voiding.
Orthotopic neobladders are new bladder pouches not sewn to the urethra but brought out of the skin through a catheterizable stoma.
Intravesical Therapy for Bladder Cancer
The introduction of chemotherapy or immunotherapy into the bladder in an attempt to decrease the rate of recurrence and progression to a higher stage of tumor is considered intravesical therapy.
Thiotepa was used until the 1980’s. It was replaced by chemotherapy after it was found to suppress bone marrow production in 13% of those patients.
Mitomycin, Adriamycin, and Doxorubicin are true chemo therapeutic agents used in the bladder.
BCG (Bacillus Calmette-Guerin) is a form of immunotherapy introduced in the 1980’s. It uses the introduction of a weakened strain of bovine tuberculosis to stimulate your own immune system to fight the cancer and reduce the chances of recurrence of a tumor. The side effects are flu-like symptoms, burning on urination, and frequent urination. It significantly reduces the rate of recurrence.
Intravenous Chemotherapy for Bladder Tumors
Until the introduction of IV chemotherapy, once the tumor had spread, the average life expectancy was about 18 months. With the introduction of MVAC, this began to climb.
A= Adriamycin or Doxorubicin
Most recently, Gemzar or Gemcitabine and Cisplatin have replaced MVAC. This combination has a lower side effect profile than MVAC.
Carboplatin may be used if the renal function is decreased and Cisplatin cannot be used.
Long-Term Follow-Up After Bladder Cancer
Most patients need 5-10 years of long-term follow-up. This includes cystoscopy every 3 months for 1-2 years, then every 6 months for 1 year, and then yearly for 10 years for tumors localized to the bladder and treated with BCG.
Cystectomy patients with neobladders and orthotopic pouches need scope evaluations yearly.
Cystectomy and IV chemotherapy patients may be followed with CT scans, MRI (magnetic resonance imaging), and bone scans.