All About Bladder Cancer

Ryan P. Smith, MD and Christine Hill-Kayser, MD
Updated by: Karen Arnold-Korzeniowski, BSN RN
Abramson Cancer Center of the University of Pennsylvania
Last Modified: January 20, 2016

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What is the bladder?

The bladder is an organ located in the lower abdominal area near the pelvic bones that acts as a reservoir 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. Because of the bladder’s ability to expand and contract it is thought of as a muscular balloon. Ureters, which are the two tubes connecting the kidneys to the bladder, empty urine into the bladder. The urethra, a tube connected to the bladder, releases urine to the outside of the body.

The bladder wall consists of 4 main layers of tissues. The innermost lining is called the urothelium, or transitional epithelium, and is made up of cells known as 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 connective 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 or malignant. Although benign tumors may grow in an uncontrolled fashion sometimes, they do not spread beyond the part of the body where they started (metastasize) 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, usually through the blood stream or through the lymphatic system where the lymph nodes are located. Over time, the cells within a malignant tumor become more abnormal and appear less like normal cells. This change in the appearance of cancer cells is called the tumor grade, and cancer cells are 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 types of cells from which they arise. Bladder cancers arise almost exclusively from the innermost lining of the bladder, so they are referred to as 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 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 invasive (invading into tissues) or noninvasive (not invading into tissues at all), and hence not having a risk for distant spread, as long as it is treated. In addition, there can be precancerous lesions in the bladder, 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. 

What causes bladder cancer and am I at risk?

It is estimated that in 2015 in the United States there will be 74,000 new cases of bladder cancer, resulting in 16,000 deaths. It is the sixth most common cancer diagnosis in the United States, being the third most common in men and eleventh most common in women. In the US, bladder cancer tends to affect older men more frequently; 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. It is estimated that about half of bladder cancers are caused by cigarette smoking. The risk of being diagnosed with bladder cancer is increased two to four times if you are a smoker. Other risk factors for developing bladder cancer include, family history, genetic mutations, 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, 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?

There are no standard screening tests used for bladder cancer in people who have not had bladder cancer. Cystoscopy and urine cytology may be used in people with a history of bladder cancer.

What are the signs of bladder cancer?

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). 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 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. 

How is bladder cancer diagnosed?

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. 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.

Anyone with 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 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 involvement of these structures with the 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 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 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 of 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.

When a diagnosis of bladder cancer is made, 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.

How is bladder cancer staged?

The staging of a cancer describes how much the cancer has grown and invaded, 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, 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 patient, and the pathologic stage, which is determined after the tumor is resected, or taken out surgically and lymph nodes evaluated.

American Joint Committee on Cancer (AJCC) TNM Staging for Bladder Cancer (7th ed., 2015)
The TNM breakdown is quite technical, but is provided here for your reference. Your healthcare provider will use the results of the diagnostic work up to assign the TNM result.

 

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

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

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 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 has not invaded into the muscle. The extent of disease is based mainly on findings during 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. Following initial treatment with a TUR procedure a patient will 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.

For some, the treatment of superficial bladder cancer may continue beyond a TUR and intravesicular chemotherapy. Some patients may also receive intravesicular therapy with a drug called Bacillus Calmette-Guerin (BCG) for a minimum of one year. 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 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.

Often, chemotherapy may be used in addition to surgery, 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). 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, 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.

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. 

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 some 15 million cancer survivors in the US 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/

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. 2015. Found at: http://www.cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-key-statistics

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 Comprehensive Cancer Center Network. Bladder Cancer. Version 2.2015. Found at: http://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf

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