All About Bladder Cancer

What is the bladder?

The bladder is an organ found in the lower part of the belly near the pelvic bones. It 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. They empty urine from the kidneys into the bladder. The urethra is a tube that connects the bladder to the outside of the body and releases urine.

The bladder wall consists of 4 main layers of tissue. 

• The innermost layer is called the urothelium, or transitional epithelium. It is made up of cells called urothelial or transitional cells. 
• Beneath the urothelium is a thin layer called the lamina propria, made up of connective tissue, blood vessels, and nerves. 
• The next layer is called the muscularis propria, 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. Once enough cells are made to replace the old ones, normal cells stop dividing. Tumors occur when there is an error and cells continue to grow in an uncontrolled way. Tumors can either be benign (not cancer) or malignant (cancer). Benign tumors do not spread beyond the part of the body where they started and do not invade (grow) into surrounding tissues. Malignant tumors can invade and damage other tissues around them. They also may spread to other parts of the body, called metastasis. 

Over time, the cancer cells in the tumor become more abnormal and appear less like normal cells. How a cancer cell looks is called the tumor grade. The grade is described as being well-differentiated, moderately-differentiated, poorly-differentiated, or undifferentiated. Well-differentiated cells are quite normal appearing and look like the normal cells they started from. 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 almost always start in the innermost lining of the bladder. These are called transitional cell carcinoma (TCC) or urothelial cancer and account for about 90% of bladder cancers. Squamous cell carcinoma accounts for about 4%, adenocarcinoma accounts for about 2% of cases, and other less common types make up the rest. 

Bladder cancers can be invasive (invading into tissues and muscle layers) or noninvasive or non-muscle invasive (have only invaded the first layer of the 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?

Each year, about 83,730 new cases of bladder cancer will be diagnosed in the United States. It affects more men than women and the average age at diagnosis is 73.

Cigarette smoking is the biggest risk factor for bladder cancer. About half of all bladder cancers are caused by cigarette smoking. 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, the medication pioglitazone, exposure to arsenic (especially in well water), aristolochic (a Chinese herb), bladder infections caused by schistosoma haematobium, not drinking enough fluids, a genetic condition called Lynch Syndrome, a mutation of the retinoblastoma (RB1) gene or the PTEN gene. and neurogenic bladder and the overuse of indwelling catheters.

How can I prevent bladder cancer?

Stopping smoking is the best way to prevent bladder cancer. You should also reduce your exposure to cancer-causing agents to help prevent bladder cancer. Other than these measures, decreasing your risk of invasive bladder cancer relies on early detection of symptoms and possibly screening if you are high-risk.

What screening tests are used for bladder cancer?

It is not standard to screen for bladder cancer. Bladder cancer screening may be used in people who are considered high risk. If you have a history of bladder cancer, a history of a birth defect of the bladder, or have been exposed to certain chemicals at work, you may be considered high-risk. You should ask your provider if screening tests are right for you.

Testing the urine for blood, abnormal cells, and tumor markers can help find some bladder cancers early but the results vary. Not all bladder cancers are found, and some people may have changes in their urine but do not have bladder cancer. These tests can be used in those who already have signs of bladder cancer or if the cancer has returned. However, more research is needed to determine how useful testing the urine is as a screening test. 

What are the signs of bladder cancer?

The most common sign of bladder cancer is blood in the urine, called hematuria. Gross hematuria is blood that can be seen in the urine. Your urine can be pink, red, or dark red. In some cases, urine can only be seen with a microscope, called microscopic hematuria. Other signs of bladder cancer 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 feeling like your bladder is not empty. 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 stop (obstruct) urine from entering the bladder, or from exiting the bladder. This may cause severe flank (lower back) pain, infection, and damage to the kidneys. Other signs of advanced bladder cancer are loss of appetite, weight loss, feeling tired, bone pain, and swelling in the feet. 

How is bladder cancer diagnosed?

Anyone with blood in the urine (either gross or microscopic hematuria) should have other testing done. Often, the first thing that is done is a urine cytology, which looks at the urine under a microscope to find 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.

• An X-ray of the upper urinary tract (including the ureters and kidneys) may be done to diagnose bladder cancer or to see if these structures contain cancer. 
• Ultrasound can be used to study the kidneys. 
• A CT scan is used to look at the entire urinary tract. 
• An intravenous pyelogram (IVP) can be used to study the urinary tract. An IVP puts a dye into a patient's vein and then an x-ray is done a short time later. The dye exits the body via the kidneys and urine and can be seen on the x-ray, showing 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. A fiberoptic camera is placed into the bladder, going through the urethra. Cystoscopy allows the provider to see the entire bladder and biopsy any suspicious lesions. If the biopsy reveals cancer, a repeat cystoscopy and resection (called a transurethral resection or TURBT) is done to see the whole tumor and if it has started to spread.

If you are diagnosed with cancer, you will also have a complete physical done. Your provider will tell you what tests you need to have done to help determine the extent of the cancer and if it has spread. 

How is bladder cancer staged?

Cancer staging describes how much the cancer has grown and invaded the area, explaining the extent of the disease. Bladder cancer is often found at an early stage, as hematuria starts early in the course of the disease. Sometimes bladder cancer can advance to invasive disease before causing symptoms. To best understand staging, you need to know how cancer spreads and advances in stage.  

Cancers can spread and disrupt how normal organs work. Bladder cancers often begin very superficially, involving only the lining of the bladder. Bladder cancers can invade the bladder wall, involving the muscular layers of the wall. As bladder cancer grows it can 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.

When cancer spreads to another area in the body, that area is called metastasis. Cancer can also spread through the lymph system and the bloodstream. Bladder cancer often spreads 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.

Cancer can also spread through the lymph system. The lymph system includes lymph nodes and several organs found 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 around 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 can be found through a CT scan or during surgery. Bladder cancer can also spread through the bloodstream. Cancer cells gain access to distant organs via the bloodstream. 

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 found at the end of this article. 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 workup of the cancer is being done. An important distinction in bladder cancer is between superficial or non-invasive disease (Ta, Tis, T1) or muscle invasive disease. This can help determine your treatment plan.

How is bladder cancer treated?

Treatment for bladder cancer will depend on the stage and type of cancer you have. Your provider will talk to you about treatment options and which plan of care is best for you. 

Superficial Bladder Cancer 

Superficial bladder cancer is bladder cancer that has not invaded into the muscle. It is often treated with surgery and intravesicular therapy. 

Surgery

A TURBT (transurethral resection of the tumor) is a surgical treatment in which a surgeon removes the bladder tumor using a tool placed into the body through the urethra. The extent of the disease is based mainly on findings during this test. TURBT is the main treatment for superficial disease since all of the tumor is often able to be removed. After a TURBT, you may have intravesicular therapy to prevent the cancer from coming back. 

Intravesicular Therapy 

Intravesicular therapy is when chemotherapy or immune therapy is injected directly into the bladder. This treatment destroys any remaining cancer cells. Both immunotherapy and chemotherapy medications can be used in intravesicular therapy. 

Bacillus Calmette-Guerin (BCG) is an immunotherapy medication that is used. BCG is a type of virus that works to stimulate the immune system to destroy any cancer cells in the area. You will likely be given this medication multiple times. After treatment, you will have regular cystoscopies to monitor for any reoccurrence or new tumor development. 

Mitomycin C and gemcitabine are chemotherapies that can be used in intravesicular therapy. How often you receive it will depend on your specific case. Because the chemotherapy is given in the bladder and not into the bloodstream there tend to be fewer side effects than with systemic (intravenous or oral) chemotherapy. 

Muscle Invading Bladder Cancer

In some cases, bladder cancers can be invasive. This means that they have grown into tissues and muscle layers. These cancers can be treated in many ways and your provider will talk to you about your options. 

Surgery

There are a few different surgeries that can be used in the treatment of invasive bladder cancer. A cystectomy is the partial or complete removal of the bladder. 

• 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 of metastatic disease, the surgeon will also remove other nearby organs.

If the whole bladder is removed, the surgeon must create a way for urine to leave the body. This is called urinary diversion. There are 3 basic types of urinary diversion:

• Ileal or colonic conduit – The surgeon will 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 (opening). The stoma will have a bag attached to the outside of your body to collect the urine as it drains from your kidneys. You can empty the bag as needed. 
• Internal continent pouch or reservoir – These include the Kock pouch and the Indiana pouch. These pouches use a piece of the 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 inserting a catheter (flexible tube) into the stoma.
• Neobladder – This is like the internal continent pouch because 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 for close to normal urination. You will need 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 

Chemotherapy is often used in addition to surgery in stage III, IV, and recurrent cancer, either before or after the surgery. Standard treatment regimens include a combination of cisplatin and gemcitabine, DDMVAC (dose-dense methotrexate, vinblastine, doxorubicin, cisplatin), and CMV (cisplatin, methotrexate, and vinblastine. Some patients can’t receive cisplatin and in those cases, they will receive other chemotherapies such as carboplatin, paclitaxel, ifosfamide, and doxorubicin.

Bladder Preservation Therapy

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 radiation/chemotherapy. If the tumor is gone, the patient can be monitored and keep their bladder.

Radiation and Chemoradiation

Radiation is the use of high-energy x-rays to kill cancer cells. Radiation therapy can be used in some cases to shrink the tumor or treat lymph nodes. In most cases, chemotherapy is given with radiation therapy, which is called chemoradiation. In this method, chemotherapy is used as a "radiosensitizer" which means it helps make the cancer cells more sensitive to 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.

Immunotherapy

Immunotherapy can be a treatment option if you can’t tolerate chemotherapy or if your cancer has returned after treatment. Immunotherapy medications use your own immune system to kill cancer cells. Nivolumab, avelumab, pembrolizumab, erdafitinib, and enfortumab vedotin-ejfv, are all 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. 

Clinical Trials

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 the 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. 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 keep your appointments and to speak with your provider about any new or recurrent issues you are having.

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, 8^th Edition

 AJCC Prognostic Groups