Ryan P. Smith, MD and Christine Hill-Kayser, MD
Modified By: Lara Bonner Millar, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: February 6, 2013
The bladder serves as a reservoir for urine in our bodies. It permits the storage of urine for a period of time before releasing it as we urinate. It can be thought of as a muscular balloon; it is a flat structure when there is no urine (immediately after a person urinates), but is able to fill up to a liter or so of urine when needed (though this would be very uncomfortable). Normally, as the bladder nears 500 cc (1/2 of a liter), we feel the urge to urinate. The muscular structure of the bladder also helps other pelvic muscles push the urine out when it is released. The bladder is located deep in the pelvis, just above the pubic symphysis, which is a bone that can be felt in the midline on the front of the pelvis. In fact, when the bladder is over distended, it can be felt by a physician. Ureters empty urine into the bladder from the kidneys, and the urethra leads out from the bladder, emptying urine out of our bodies.
A tumor is a mass of abnormally growing cells. Tumors can be either benign or malignant. Benign tumors may grow in an uncontrolled way, but without any invasion into normal tissues and without any risk of spreading to distant parts of the body. Tumors are malignant (or "cancer") when cells gain the propensity to invade tissues and spread locally as well as to distant parts of the body. In this sense, bladder cancer occurs when cells in the lining of the bladder grow uncontrollably and form tumors that can invade normal tissues and spread to other parts of the body.
Cancers are described by the types of cells from which they arise. Bladder cancers arise almost exclusively from the lining of the bladder. In the United States, 98% of bladder cancers are called transitional cell carcinomas. This simply means that the cancer started in the lining of the bladder, which is made up of transitional cells that appear elliptical under the microscope. Less commonly, other types of cancers can arise from the lining of the bladder, called adenocarcinomas, squamous cell carcinomas and small cell carcinomas.
Commonly, bladder cancers grow in a "papillary" growth pattern. When a bladder cancer grows this way, it can be noninvasive, i.e., not invading into tissues at all, and hence not having a risk for distant spread (as long as it is treated). In addition to other invasive cancers, patients are sometimes diagnosed with precancerous lesions, called carcinoma-in-situ. Carcinoma-in-situ occurs when the lining of the bladder undergoes changes similar to cancerous changes without any invasion into the deeper tissues. Hence, while the cells themselves have cancer-like qualities, no invasion has occurred. However, both papillary bladder cancers and cancer-in-situ may become invasive, so treatment is very important.
Bladder cancer is the fourth most common cancer in men and the eighth most common cancer in women. It is estimated that in 2012 there will be 73,510 new cases of bladder cancer diagnosed in the United States, with over 14,800 deaths. Internationally, the incidence of transitional cell bladder cancer varies substantially, with highest rates in Europe and North America. In Northern Africa, where infection with a type of parasite called Schistosoma haematobium is common squamous cell carcinomas of the bladder are more common. Classically, in the US, bladder cancer is thought of as a disease that affects older men, with men affected more than women by a 3:1 ratio and 2/3 of the cases diagnosed in people over the age of 65.
Cigarette smoking is the largest risk factor for bladder cancer (yet another reason to stop smoking). Smokers have 2-4 times the risk of having bladder cancer, and it contributes to up to 50% of all bladder cancers that are diagnosed. Chronic bladder irritation, from either stones or long-term catheter use, may increase risk of bladder cancer. Occupational exposures, such as polychromatic hydrocarbons (benzene, benzidine), can increase risk of bladder cancer. Recently, an association has been made between chlorinated drinking water and bladder cancer. Though there have been suggestions of saccharin and high intake of dietary fat and cholesterol being causative for bladder cancer, these have yet to be substantiated. The previously mentioned Schistosoma haematobium infections may also increase risk of squamous cell carcinoma of the bladder; this parasite is present mainly in regions of North Africa such as Egypt.,
Smoking is the strongest risk factor associated with the development of bladder cancer. Therefore, smoking cessation is the best way to prevent bladder cancer. Additionally, reducing the exposure to carcinogenic compounds should decrease the risk of developing bladder cancer. Other than these preventative measures, decreasing the risk of bladder cancer relies on early detection of symptoms and possibly screening high-risk individuals.
The goal of screening tests is to detect cancers early so that treatment can be initiated when the cancer is in an early stage, or even before it becomes invasive. Cytologic examination of urine (looking for abnormal cells in urine) has been the most commonly tested screening tool. It involves testing urine for the presence of abnormal cells, which would indicate the possibility of a cancer. This method is fairly inexpensive and without risk to the patient. If abnormal cells are seen, over 95% of the time it accurately predicts the presence of bladder cancer. However, a fair amount of cancers can be missed using this method. Also, the incidence of preclinical (too small to cause any symptoms) bladder cancer in the general population is likely too low for cytologic examination of urine to be useful as a mass screening tool. Routine urinalysis, performed as part of normal health maintenance, will detect any presence of blood in the urine. If blood is detected and is not due to another cause (such as infection), further tests should be carried out.
By far the most common sign of bladder cancer is the presence of blood in the urine, called hematuria. The blood in the urine can either be noticeable by the naked eye, called gross hematuria, or noted only when the urine is analyzed in a laboratory, called microscopic hematuria. Either gross hematuria or microscopic hematuria is present in over 80% of cases of bladder cancer. Therefore, when someone is noted to have blood in the urine, further testing is very important.
Other signs of bladder cancer could include symptoms of urinary irritation, such as increased frequency of urination, a feeling of urgency to urinate, pain (burning) with urination, and the feeling of incomplete bladder emptying. These are all caused by irritation of the bladder wall by the tumor.
In advanced cases of bladder cancer, the tumor can actually obstruct either the entrance of urine into the bladder or the exit of urine from the bladder. This causes severe flank pain, infection, and damage to the kidneys.
Anyone with either gross or microscopic hematuria should undergo a work-up to insure the symptoms are not from bladder cancer. Often, the first thing that is done is a urine cytology, which as mentioned above, is looking at the urine under a microscope to detect cancerous appearing cells. Again, if these cells are seen, a diagnosis of cancer may be made. However, the test does not detect all cases of bladder cancer. X-ray imaging of the upper urinary tract (including the ureters and kidneys) may be performed to diagnose bladder cancer, or after a diagnosis of bladder cancer to rule out any involvement of these structures with cancer. Ultrasound can be used to study the kidneys, and a CT scan is often very good at studying the entire length of the urinary tract. One of the traditional methods of studying the (upper) urinary tract is with an intravenous pyelogram (IVP). This involves administering a dye through a patient's vein and taking a regular x-ray a short time later. The dye can be seen in the x-ray, showing the full extent of the kidney collecting system, ureters, and often the bladder.
Though the above tests are useful, the mainstay of diagnosis and staging is endoscopic evaluation with cystoscopy. This involves placing a fiberoptic camera into the bladder via the urethra. Cystoscopy allows for direct visualization of the entire bladder and also allows for biopsy for any suspicious lesions. If the biopsy reveals cancer, a repeat cystoscopy and resection (called a transurethral resection (TUR)) is done to completely evaluate the tumor and the extent and depth of disease.
With a diagnosis of bladder cancer obtained, a complete physical examination is done as well as the previously mentioned radiologic studies to fully evaluate the urinary tract, the local extent of disease, and any metastatic disease.
The staging of a cancer describes how much is the cancer has grown and invaded before the diagnosis has been made, documenting the extent of disease. Bladder cancer often presents at an early stage, as it produces hematuria early in the course of the disease. More than 70% of bladder cancers are diagnosed at the Ta (non-invasive) or T1 (superficially invasive) stage (see below). Unfortunately, sometimes bladder cancer can advance to invasive disease prior to causing symptoms. Before the staging systems are introduced, we will explain some background on the ways in which cancers grow and spread, and therefore advance in stage.
Cancers cause problems because they spread and can disrupt the functioning of normal organs. Bladder cancers often begin very superficially, involving only the lining of the bladder. Eventually, however, bladder cancers can invade into the bladder wall, involving the muscular layers of the wall. If a bladder cancer is allowed to grow, it may eventually invade the entire way through the wall and into the fat surrounding the bladder or even into other organs (prostate, uterus, vagina). This local extension is the most common way bladder cancer spreads.
Cancer can also spread by accessing the lymphatic system. The lymphatic circulation is a complete circulation system in the body (somewhat like the blood circulatory system) that drains into various lymph nodes. When cancer cells access this lymphatic circulation, they can travel to lymph nodes and start new sites of cancer. This is called lymphatic spread. Bladder cancer can spread this way. If it does, it usually first spreads to the lymph nodes, in the pelvis, surrounding the bladder (perivesicular lymph nodes). From there, it can spread to lymph nodes that are in close proximity to the external iliac and internal iliac arteries and veins, which are the very large blood vessels that run into the leg and into pelvis, respectively. The presence of lymph node spread is best evaluated by CT scan or at surgical exploration.
Bladder cancer can also spread through the bloodstream. Cancer cells gain access to distant organs via the bloodstream and the tumors that arise from cells' travel to other organs are called metastases. Cancers of the bladder generally spread locally or to lymph nodes before spreading distantly through the bloodstream, though this is not always the case. If spread through the bloodstream does occur, the lungs and bones are the most common sites to be involved.
The staging system used to describe bladder tumors is the "TNM system", as described by the American Joint Committee on Cancer. The TNM systems are used to describe many types of cancers. They have three components: T-describing the extent of the "primary" tumor (the tumor in the bladder itself); N-describing the spread to the lymph nodes; M-describing the spread to other organs (i.e.-metastases).
There are two "T" stages that are often reported: the clinical stage, which is based on the physical exam of the physician, and the pathologic stage, which is noted after the tumor is resected, or taken out surgically.
Above are considered "superficial"
The "N" stage is as follows:
These are the lymph nodes closest to the bladder.
These lymph nodes are located further from the bladder than lymph nodes in the pelvis.
The "M" stage is as follows:
The overall stage is based on a combination of these T, N, and M parameters.
II: T2aN0M0 and T2bN0M0
III: T3aN0M0 and T3bN0M0 and T4aN0M0
IV: T4bN0M0 and Any T N1-3 M0 and Any T Any N M1
Though complicated, these staging systems help physicians determine the extent of the cancer, and therefore make treatment decisions regarding a patient's cancer. The stage of cancer, or extent of disease, is based on information gathered through the various tests done as the diagnosis and work-up of the cancer is being performed. An important distinction in bladder cancer is between superficial disease (Ta, Tis, T1) or muscular invasive disease. It has large implications for treatment, as will be discussed below.
Superficial bladder cancer is that which has not invaded at all into the muscle. As noted above, the extent of disease is based mainly on the transurethral resection (TUR). Likewise, the primary treatment for superficial disease is the TUR. Since the cancer is superficial, all of the tumor may be able to be removed by the TUR. Although TUR is almost always used to treat superficial bladder cancers, bladder tumors will recur (grow back) in about 50-70% of cases after TUR alone. For this reason, other treatments may be used in addition to TUR. The most common treatment is a compound known as BCG. BCG is placed into the bladder several times over 1-2 months. BCG is often used in addition to TUR for patients with high grade tumors, large tumors, multiply recurrent superficial tumors, or tumors that invade into the lining of the bladder (T1 tumors). Though BCG is effective, it is not without side effects-causing bladder spasm and irritation, often with every instillation.
The standard of care in treating more advanced cancers may involve surgically removing the entire bladder in a procedure called a cystectomy. A large concern in performing this surgery is how to divert the urine so that the patient can still excrete it. In the past, this was done using an "ileal conduit", where the urine drained through a portion of the small intestine and out through the skin into a bag. More recently, techniques for bladder reconstruction have developed. This allows the ureters to be implanted into the newly created bladder and the urethra to lead out of the new bladder. These techniques may allow the patient to be continent and excrete urine normally. Often, chemotherapy may be used in addition to surgery, either before the surgery or after the surgery. Recent data has demonstrated that use of chemotherapy may prolong survival and decrease risk of cancer recurrence; the combination of cisplatin and gemcitabine either before or after cystectomy has been shown to be as effective but less toxic than the old standard regimen "MVAC" (methotrexate, vinblastine, doxorubicin, cisplatin) . In patients unable to receive cisplatin chemotherapy, other chemotherapy agents such as 5-FU and mitomycin C may be used.
Sometimes, radiation and chemotherapy may be used to allow the patient to avoid cystectomy; this is referred to as a "bladder-preservation approach." The best candidates for this treatment approach are those with cancer limited to just one area of the bladder, less than 5cm of disease, no blockage of the ureter or kidney, and good bladder function (since those with poor bladder function would be better off with a cystectomy). Regimens that have the best results all start with maximum resection of the bladder tumor via TUR, just like with superficial bladder cancers.
The patient then starts a treatment course of radiation with chemotherapy, usually cisplatin, for 4-5 weeks. The chemotherapy is used as a "radiosensitizer" which means it helps make the cancer cells more sensitive to the radiation. Patients are then re-evaluated by a repeat cystoscopy to determine if the chemotherapy and radiation have caused the tumor completely disappear. If the tumor is no longer present by examination, further chemotherapy and radiation is given for an additional 2-3 weeks. This method has comparable survival rates to cystectomy and has the advantage of allowing the patient to keep his or her bladder. If invasive disease remains after chemotherapy and radiation, the patient may be advised to undergo cystectomy, despite efforts to avoid this. If superficial disease remains after chemotherapy and radiation, either BCG or a cystectomy may be considered.
Cystectomy is performed for patients who do not have adequate response to chemotherapy and radiation in order to eliminate the cancer and reduce the risk of death from the cancer. Even when patients do not need to undergo cystectectomy, they may experience significant side effects from radiation and chemotherapy. The most concerning of these are decreased bladder capacity (leading to more frequent urination), bladder spasm, chronic burning or pain with urination, and hematuria from the damage done by the chemotherapy and radiation.
In summary, there are different treatment methods available for bladder cancer with curative potential. As is true for many other sites of cancer, regimens have been developed that allow for a higher quality of life after the treatment is completed. The exact method of treatment should be chosen individually by the patient, after discussing it with a team of physicians adept at treating bladder cancer, to maximize chance of cure and adequate bladder function.
Advanced Bladder Cancer Meta-Analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 2003;361:11927-1934.
Coppin C, Gospodarowicz M, James K, et al. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada clinical trials group. J Clin Oncol 1996; 14:2901-2907
Edge S, Byrd D, Compton B, eds. AJCC Cancer Staging Manual, 7th ed, New York, Springer; 2010.
Holmäng S, Hedelin H, Anderström C, et al. The relationship among multiple recurrences, progression and prognosis of patients with stages Ta and T1 transitional cell cancer of the bladder followed for at least 20 years. J Urol 1995;153 (6): 1823-6; discussion 1826-7.
Feb 3, 2011 - Frequency of tumor recurrence is a predictor of subsequent stage progression in patients diagnosed with nonmuscle invasive bladder cancer, according to a study published in the February issue of The Journal of Urology.
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