All About Bladder Cancer
What is the bladder?
The bladder is an organ located in the lower abdominal area near the pelvic bones that acts as a holding area for urine. The bladder expands and can hold about half of a liter of urine, but a person usually feels the urge to urinate when the bladder is 25% full. The bladder will contract and become smaller when it is empty. The ureters are two tubes that connect the kidneys to the bladder, and empty urine from the kidneys, into the bladder. The urethra is a tube connected to the bladder that releases urine to the outside of the body.
The bladder wall consists of 4 main layers of tissue. The innermost layer is called the urothelium, or transitional epithelium, and is made up of cells called urothelial or transitional cells. Beneath this layer is a thin layer called the lamina propria, which is made up of connective tissue, blood vessels and nerves. The next layer is called the muscularis propria, which is made of muscle. The last layer is a layer of fatty tissue that separates the bladder from other surrounding organs.
What is bladder cancer?
Normally, cells in the body will grow and divide to replace old or damaged cells in the body. This growth is highly regulated, and once enough cells are produced to replace the old ones, normal cells stop dividing. Tumors occur when there is an error in this regulation and cells continue to grow in an uncontrolled way. Tumors can either be benign (not cancer) or malignant (cancer). Although benign tumors may grow in an uncontrolled fashion sometimes, they do not spread beyond the part of the body where they started and do not invade into surrounding tissues. Malignant tumors, however, will grow in such a way that they invade and damage other tissues around them. They also may spread to other parts of the body, which is called metastasis. Over time, the cells in a cancerous tumor become more abnormal and appear less like normal cells. The appearance of cancer cells is called the tumor grade, and the grade is described as being well-differentiated, moderately-differentiated, poorly-differentiated, or undifferentiated. Well-differentiated cells are quite normal appearing and resemble the normal cells from which they originated. Undifferentiated cells are cells that have become so abnormal that often we cannot tell what types of cells they started from.
Cancers are described by the type of cells from which they arise. Bladder cancers arise almost exclusively from the innermost lining of the bladder. These are called transitional cell carcinoma (TCC) or urothelial cancer. In the United States, more than 9 out of 10 bladder cancers are of this type. This simply means that the cancer started in the lining of the bladder. About 5% of bladder cancers are other types of cancers, including adenocarcinomas, squamous cell carcinomas and neuroendocrine (also referred to as small cell).
Bladder cancers can be invasive (invading into tissues and muscle layers) or noninvasive or non-muscle invasive (have only invaded the first layer of bladder wall or not invaded at all). Carcinoma-in-situ occurs when there is a flat cancerous growth on the lining of the bladder wall. While it does not invade the tissues, these are usually “high grade” and have the potential to spread quickly. All bladder cancers can become invasive, so treatment is very important.
What causes bladder cancer and am I at risk?
In 2019, it is estimated that there will be 80,470 new cases of bladder cancer in the United States. In the US, bladder cancer tends to affect older men more frequently; with an expected 61,700 men being diagnosed per year compared with 18,770 women. The average age at diagnosis is 73 with the large majority of people being over 55 years of age at diagnosis.
Cigarette smoking is the biggest risk factor for bladder cancer. It is estimated that about half of all bladder cancers are caused by cigarette smoking. The risk of being diagnosed with bladder cancer is four to seven times higher in a smoker than a non-smoker. Other risk factors for developing bladder cancer include: family history, occupational exposure to chemicals (especially those processed in paint, dye, plastics, leather and rubber products), previous cancer treatment with cyclophosphamide, ifosfamide, or pelvic radiation, exposure to arsenic (especially in well water), aristolochic (a Chinese herb), bladder infections caused by schistosoma haematobium, a genetic condition called Lynch Syndrome, and neurogenic bladder and the overuse of indwelling catheters.
How can I prevent bladder cancer?
Smoking cessation is the best way to prevent bladder cancer. Additionally, reducing the exposure to cancer causing agents should decrease the risk of developing bladder cancer. Other than these preventative measures, decreasing the risk of invasive bladder cancer relies on early detection of symptoms and possibly screening high-risk individuals.
What screening tests are used for bladder cancer?
It is not standard to screen for bladder cancer. At the healthcare provider's discretion, bladder cancer screening may be used in people with a history of bladder cancer, a history of a birth defect of the bladder, or for those who have been exposed to certain chemicals at their work.
Cytologic examination of urine (looking for abnormal cells in urine) has been the most commonly used 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. 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 the 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.
What are the signs of bladder cancer?
The most common sign of bladder cancer is the presence of blood in the urine, called hematuria. Blood in the urine may be seen by the naked eye (called gross hematuria), or found only when the urine is analyzed in a laboratory (called microscopic hematuria). Other signs of bladder cancer could include increased frequency of urination, a feeling of urgency to urinate, nocturia (waking up at night due to having to urinate), pain (burning) with urination, and the feeling of incomplete bladder emptying. These can all be caused by irritation of the bladder wall by the tumor, but can also be signs of infection or other bladder problems.
In advanced cases of bladder cancer, the tumor can actually obstruct the entrance of urine into the bladder, or the exit of urine from the bladder. This may cause severe flank (lower back) pain, infection, and damage to the kidneys.
How is bladder cancer diagnosed?
Anyone with blood in the urine (either gross or microscopic hematuria) should undergo a work-up to ensure the symptoms are not from bladder (or other) cancer. Often, the first thing that is done is a urine cytology, which is looking at the urine under a microscope to detect abnormal appearing cells. 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 to determine if these structures contain cancer. Ultrasound can be used to study the kidneys. A CT scan is often useful for studying the entire urinary tract. Intravenous pyelogram (IVP) can be used to study the urinary tract. This involves putting a dye into a patient's vein and taking a regular x-ray a short time later. The dye is excreted via the kidneys and urine, and can be seen on the x-ray, showing the full extent of the kidney collecting system, ureters, and often the bladder.
Though the above tests are useful, the most important test for diagnosis and staging is a cystoscopy. This involves placing a fiberoptic camera into the bladder, going through the urethra. Cystoscopy allows the provider to see the entire bladder and to biopsy any suspicious lesions. If the biopsy reveals cancer, a repeat cystoscopy and resection (called a transurethral resection or TURBT) is done to completely evaluate the tumor and the extent and depth of disease.
When a diagnosis of bladder cancer is made, a complete physical exam is done, as well as the above radiologic studies to fully evaluate the urinary tract, the local extent of disease, and any metastatic (spread of) cancer.
How is bladder cancer staged?
The staging of a cancer describes how much the cancer has grown and invaded the area, explaining the extent of disease. Bladder cancer is often found 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 appendix for staging information). 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, 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 lymph system. The lymph system includes lymph nodes and several organs, located all over the body. When cancer cells spread into the lymph system, they can travel to lymph nodes in other areas of the body 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 (called perivesicular lymph nodes). From there, it can spread to lymph nodes that are close to major blood vessels that run into the leg and pelvis. The spread of cancer to lymph nodes is best evaluated by CT scan or during surgery.
Bladder cancer can also spread through the bloodstream. Cancer cells gain access to distant organs via the bloodstream. When the cancer spreads to another area in the body, that area is called a metastasis. Cancers of the bladder generally spread locally or to lymph nodes before spreading distantly, though this is not always the case. The lungs and bones are the most common areas for metastases to develop. When bladder cancer spreads to another area, it is still bladder cancer. For instance, if it spreads to the lung, it is not called lung cancer, but bladder cancer that has metastasized to the lung. If we look at the affected lung tissue under a microscope, it will look like bladder cancer cells.
The staging system used to describe bladder tumors is the "TNM system". The TNM system is used to describe many types of cancers. It has three components: T-describing the extent of the "primary" tumor (the tumor in the bladder itself); N-describing if there is cancer in the lymph nodes; M-describing the spread to other organs (metastases).
There are two "T" stages that are often reported: the clinical stage, which is based on the physical exam of the patient, and the pathologic stage, which is determined after the tumor is removed during surgery, and the area lymph nodes evaluated.
The staging system is very complex, and the entire staging system is outlined at the end of this article. Though complicated, the staging system helps healthcare providers determine the extent of the cancer, and in turn, make treatment decisions. 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 or non-invasive disease (Ta, Tis, T1) or muscle invasive disease. It has large implications for treatment, as will be discussed below.
How is bladder cancer treated?
Superficial Bladder Cancer
Superficial bladder cancer is bladder cancer that has not invaded into the muscle. The extent of disease is based mainly on findings during the transurethral resection of the tumor (TURBT). Since the cancer is superficial, all of the tumor may be able to be removed by the TURBT and this is the main treatment for superficial disease.
Following initial treatment with a TUR procedure, a patient will often undergo intravesicular therapy. Intravesicular therapy involves the instillation of chemotherapy or an immune therapy directly into the bladder so that any remaining cancer cells can be destroyed.
Bacillus Calmette-Guerin (BCG) is an immunotherapy medication that is often used for intravesicular therapy. BCG is a type of virus, which works to stimulate the immune system to destroy any cancer cells in the area. BCG is given in “courses” which consist of one dose a week for 6 weeks initially – this is called induction. This is followed by a break and then one dose a week for 3 weeks – this is called maintenance therapy. You will likely have multiple rounds of maintenance therapy. These range from 1 year of therapy to 3 years, depending on your situation. After treatment, you will have regular cystoscopy to monitor for any recurrence or new tumor development. (Learn more about BCG.)
Intravesicular chemotherapy may be given after surgery. Mitomycin C is the most commonly used chemotherapy used for this treatment. It is given in a weekly dose for six weeks. Because the chemotherapy is given in the bladder and not into the bloodstream, the side effects are much less than what you typically think of with chemotherapy. (Learn more about mitomycin in the bladder.)
Muscle Invading Bladder Cancer
There are a few different surgeries that can be used in the treatment of bladder cancer. A partial cystectomy removes only part of the bladder, which can be an option when the tumor is limited to one area of the bladder. A radical cystectomy removes the entire bladder, nearby lymph nodes and part of the urethra (which carries urine from the bladder out of the body). In some cases, the surgeon will also remove other nearby organs.
If the bladder is removed entirely, the surgeon must create a way for the urine to leave the body. This is called urinary diversion. There are 3 basic types of urinary diversion:
- Ileal or colonic conduit – these use a small piece of bowel (ileum or colon) to create a reservoir for urine, which is attached to the abdominal wall to form a stoma. The stoma will have a bag attached to the abdominal wall to collect the urine as it drains.
- Internal continent pouch or reservoir – these include the Kock pouch and the Indiana pouch. These pouches use a piece of bowel to create a reservoir to collect urine. The end is attached to the abdominal wall to form a stoma. The end of the bowel has a valve on it to keep the urine from leaking out of the stoma. The pouch is drained by the patient periodically using a catheter inserted into the stoma.
- Neobladder – this is similar to the internal continent pouch in that it collects urine into a reservoir created from a piece of bowel. However, it is connected to the urethra instead of a stoma. This allows close to normal urination. This does require a significant amount of rehab / physical therapy to retrain the muscles to stop, start and control this urine flow. Many people never achieve complete continence and night-time incontinence is a common issue.
Chemotherapy and Radiation
Chemotherapy is often used in addition to surgery in stage III and IV or recurrent cancer, either before or after the surgery. Use of chemotherapy may prolong survival and decrease risk of cancer recurrence. Standard treatment regimens include a combination of cisplatin and gemcitabine and "DDMVAC" (dose-dense methotrexate, vinblastine, doxorubicin, cisplatin). In patients unable to receive cisplatin chemotherapy, other chemotherapy agents may be used such as gemcitabine, carboplatin, paclitaxel, ifosfamide and doxorubicin.
Bladder preservation therapy may be an option for some people with cancer limited to one area of the bladder. This treatment begins with transurethral resection (TURBT), followed by a combination of radiation and chemotherapy. The goal is to shrink the tumor, preventing the need for cystectomy. A cystoscopy is done after the radiation/chemo is complete and if the tumor has been eliminated, the patient can be monitored and keep their bladder.
Radiation therapy can be used in some cases to shrink the tumor or treat lymph nodes. In most cases, chemotherapy is given in conjunction with radiation therapy, which is called chemoradiation. In this method, the chemotherapy is used as a "radiosensitizer" which means it helps make the cancer cells more sensitive to the radiation. The side effects of radiation and chemotherapy include 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.
Some patients with locally advanced or metastatic disease may not be able to tolerate chemotherapy or the cancer has returned after treatment. For these patients, immunotherapy medications may be an option for treatment. Immunotherapy medications use the person's own immune system to kill cancer cells. Immunotherapies atezolizumab, nivolumab, avelumab, pembrolizumab, erdafitinib and durvalumab have all been approved for use in bladder cancer. Clinical trials are continuing to determine if these medications can be useful in treating bladder cancer at other stages as well.
In summary, there are different treatment methods available for bladder cancer. As is true for many other sites of cancer, regimens have been developed that allow for quality of life after the treatment is completed. The treatment should be chosen individually by the patient, after discussing it with a team of doctors very familiar with treating bladder cancer, to maximize chance of cure and adequate bladder function.
There are clinical research trials for most types of cancer, and every stage of the disease. Clinical trials are designed to determine the value of specific treatments. Trials are often designed to treat a certain stage of cancer, either as the first form of treatment offered, or as an option for treatment after other treatments have failed to work. They can be used to evaluate medications or treatments to prevent cancer, detect it earlier, or help manage side effects. Clinical trials are extremely important in furthering our knowledge of disease. It is through clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your provider about participating in clinical trials in your area. You can also explore currently open clinical trials using the OncoLink Clinical Trials Matching Service.
Follow-up Care and Survivorship
Follow-up care for bladder cancer varies widely, depending on the stage, grade and location of the tumor, and the treatments received. Your team will provide a plan for follow up care that will include physical exams, asking about symptoms, testing such as cystoscopy, urine cytology and imaging tests to monitor for recurrent disease. After treatment, you will most likely see your provider every 3 to 6 months to start. Visits may become less frequent as time goes on. Bladder cancer survivors are at high risk of developing a second bladder cancer, so it is important to not miss your appointments and to speak with your provider about any new or recurrent issues you are experiencing.
Fear of recurrence, financial impact of cancer treatment, employment issues and coping strategies are common emotional and practical issues experienced by bladder cancer survivors. Your healthcare team can identify resources for support and management of these practical and emotional challenges faced during and after cancer.
Cancer survivorship is a relatively new focus of oncology care. With over 15 million cancer survivors in the U.S. alone, there is a need to help patients transition from active treatment to survivorship. What happens next, how do you get back to normal, what should you know and do to live healthy going forward? A survivorship care plan can be a first step in educating yourself about navigating life after cancer and helping you communicate knowledgeably with your healthcare providers. Create a survivorship care plan today on OncoLink.
Resources for More Information
Bladder Cancer Advocacy Network
Offers education and support services, advances research and raises awareness about bladder cancer. Has an extensive online resource library for bladder cancer patients. http://www.bcan.org/
American Bladder Cancer Society
The site is intended to offer help, hope, and support to anyone affected by bladder cancer. Bladder cancer information, resources and a support forum are offered. http://bladdercancersupport.org/
Appendix: Complete Bladder Cancer Staging
American Joint Committee on Cancer, 8th Edition
Primary Tumor (T)
Primary tumor cannot be assessed
No evidence of primary tumor
Noninvasive papillary carcinoma
Carcinoma in situ: "flat tumor"
Tumor invades subepithelial connective tissue
Muscle invades muscularis propria
Tumor invades superficial muscularis propria (inner half)
Tumor invades deep muscularis propria (outer half)
Tumor invades perivesical tissue
Macroscopically (extravesical mass)
Tumor invades any of the following: prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall
Tumor invades prostatic stroma, uterus, vagina
Tumor invades pelvic wall, abdominal wall
Regional Lymph Nodes (N)
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Single regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac, or presacral lymph node)
Multiple regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac, or presacral lymph node)
Lymph node metastasis to the common iliac lymph nodes
Distant Metastasis (M)
No distant metastasis
Distant metastasis to organs other than those near the bladder like the prostate, uterus, or vagina.
Distant metastasis limited to lymph nodes beyond the common iliacs
Non lymph node distant metastasis
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