All About Bladder Cancer

Ryan P. Smith, MD and Christine Hill-Kayser, MD
Updated by: Karen Arnold-Korzeniowski, BSN RN
Last Modified: October 12, 2017

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, so they are called transitional cell or urothelial cancer. In the United States, more than 9 out of 10 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. Less commonly, other types of cancers can arise from the lining of the bladder, including adenocarcinomas, squamous cell carcinomas and small cell carcinomas.

Bladder cancers can be invasive (invading into tissues) or noninvasive (not invading into tissues at all). In addition, precancerous lesions can occur in the bladder, called carcinoma-in-situ. Carcinoma-in-situ occurs when the lining of the bladder undergoes changes similar to cancer, without any invasion into the deeper tissues. However, both bladder cancers and carcinoma-in-situ may become invasive, so treatment is very important.

What causes bladder cancer and am I at risk?

In 2017, it is estimated that there will be 79,030 new cases of bladder cancer in the United States. In the US, bladder cancer tends to affect older men more frequently; with an expected 60,490 men being diagnosed per year compared with 18,540 women. The average age at diagnosis is 73. 

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 smoke than a non-smoker. Other risk factors for developing bladder cancer include: family history, occupational exposure to chemicals (especially those processed in paint, dye, metal and petroleum 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 as mentioned above, is looking at the urine under a microscope to detect abnormal 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 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) is 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 TUR) 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 previously mentioned 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 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, 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 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 for 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 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 (TUR). 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. Following initial treatment with a TUR procedure, a patient will often undergo intravesicular chemotherapy. Intravesicular chemotherapy involves the instillation of chemotherapy directly into the bladder so that any remaining cancer cells can be eradicated. Mitomycin C is the most commonly used chemotherapy used for this treatment.

Some patients may also receive intravesicular therapy with a medication called Bacillus Calmette-Guerin (BCG) for a minimum of one year. BCG is a type of virus, which works to stimulate the immune system to destroy any cancer cells in the area. Patients will also be monitored for relapse or recurrence of tumors.

Muscle Invading Bladder Cancer

Cystectomy, or the surgical removal of the entire bladder, is the standard of care for treating more advanced cancers. 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 been 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 urinate normally.

Chemotherapy is often used in addition to surgery in these cancers, either before or after the surgery. 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, transurethral resection (TUR), in combination with radiation and chemotherapy may be used to allow the patient to avoid cystectomy. This is referred to as a "bladder-preservation approach" and is also known as tri-modal therapy. The best candidates for this treatment approach are those with cancer limited to just one area of the bladder that is less than 5cm in size, with no blockage of the ureter or kidney, and good bladder function (since those with poor bladder function would be better off with a cystectomy). This typically starts 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 to completely disappear. If the tumor is no longer present, 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 cystectomy, they may experience 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.

Some patients with locally advanced or metastatic disease may not be able to tolerate chemotherapy, or all chemotherapy options have been exhausted. For these patients, immunotherapy medications may be an option for treatment. Immunotherapy medications use the person's own immune system to kill cancer cells. Atezolizumab, nivolumab, avelumab, pembrolizumab, and durvalumab have all been approved for use in bladder cancer for these patients. 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 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.

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 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

After treatment is complete you will be watched closely by your providers. Those who have had bladder cancer are at high risk of developing a second bladder cancer. Therefore, at your follow up appointments, your provider will ask you if you are having any problems and may do testing such as cystoscopy, urine cytology and imaging testing to monitor for recurrent disease. If you completed treatment and had no signs of disease, you will most likely see your provider every 3 to 6 months. Your provider will continually assess you and any side effects your may have had from your treatments. 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 sover 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 (7.2010)

Primary Tumor- (T)

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Ta

Noninvasive papillary carcinoma

T1s

Carcinoma in situ: "flat tumor"

T1

Tumor invades subepithelial connective tissue

T2

Muscle invades muscularis propria

pT2a

Tumor invades superficial muscularis propria (inner half)

pT2b

Tumor invades deep muscularis propria (outer half)

T3

Tumor invades perivesical tissue

pT3a

Microscopically

pT3b

Macroscopically (extravesical mass)

T4

Tumor invades any of the following: prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall

T4a

Tumor invades prostatic stroma,, uterus, vagina

T4b

Tumor invades pelvic wall, abdominal wall

Regional Lymph Nodes (N)
Regional lymph nodes include both primary and secondary drainage regions. All other nodes above the aortic bifurcation are considered distant lymph nodes.

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Single regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac, or presacral lymph node)

N2

Single regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac, or presacral lymph node)

N3

Lymph node metastasis to the common iliac lymph nodes

Distant Metastasis (M)

M0

No distant metastasis

M1

Distant metastasis to organs other than those near the bladder like the prostate, uterus, or vagina.

Anatomic Stage/Prognostic Groups

The T, N, and M are then combined to determine a stage.

Stage 0a

Ta

N0

M0

Stage 0is

Tis

N0

M0

Stage I

T1

N0

M0

Stage II

T2a
T2b

N0
N0

M0
M0

Stage III

T3a
T3b
T4b

N0
N0
N0

M0
M0
M0

Stage IV

T4b
Any T
Any T

N0
N1-3
Any N

M0
M0
M1

References

Advanced Bladder Cancer Meta-Analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 2003;361:11927-1934.

American Cancer Society. Bladder Cancer. 2017. Found at: https://www.cancer.org/cancer/bladder-cancer/about.html

Bladder Cancer Treatment (PDQ ®). PDQ Cancer Information Summaries. National Cancer Institute. 01 Oct 2015.

Edge S, Byrd D, Compton B, eds. AJCC Cancer Staging Manual, 7th ed, New York, Springer; 2010.

Lerner S, Raghavan D. Overview of the initial approach and management of urothelial bladder cancer. Up To Date. 2015.

National Cancer Institute Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets: Bladder Cancer. 2015. Found at: http://seer.cancer.gov/statfacts/html/urinb.html

National Cancer Institute. Bladder Cancer Treatment PDQ. 2017. Found at: https://www.cancer.gov/types/bladder/patient/bladder-treatment-pdq#section/_134

National Cancer Institute. FDA Approves Immunotherapy Drugs for Patients with Bladder Cancer. 2017. Found at: https://www.cancer.gov/news-events/cancer-currents-blog/2017/approvals-fda-checkpoint-bladder

National Comprehensive Cancer Center Network. Bladder Cancer. Version 5.2017. Found at: https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf

National Institutes of Health. Smoking and Bladder Cancer. 2011. Found at: https://www.nih.gov/news-events/nih-research-matters/smoking-bladder-cancer

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