Bladder Cancer 

Bladder cancer is a common urologic cancer. Almost all bladder cancers originate in the urothelium, which is a 3- to 7-cell mucosal layer within the muscular bladder.

In North America, South America, Europe, and Asia, the most common type of urothelial tumor diagnosed is transitional cell carcinoma (TCC); TCC constitutes more than 90% of bladder cancers in those regions. TCC can arise anywhere in the urinary tract, including the renal pelvis, ureter, bladder, and urethra, but it is usually found in the urinary bladder. Carcinoma in situ (CIS) is frequently found in association with high-grade or extensive TCC.

Squamous cell carcinoma (SCC) is the second most common cell type associated with bladder cancer in developed countries. In the United States, around 5% of bladder cancers are SCCs.^[1] Worldwide, however, SCC is the most common form of bladder cancer, accounting for 75% of cases in developing nations (see Epidemiology).

In the United States, the development of SCC is associated with persistent inflammation from long-term indwelling Foley catheters and bladder stones, and, possibly, infections. In underdeveloped nations, SCC is often associated with bladder infection by Schistosoma haematobium (see Etiology).

Approximately 2% of bladder cancers are adenocarcinomas. Nonurothelial primary bladder tumors are extremely rare and may include small cell carcinoma, carcinosarcoma, primary lymphoma, and sarcoma (see Pathophysiology). Small cell carcinoma of the urinary bladder accounts for only 0.3-0.7% of all bladder tumors.

The clinical course of bladder cancer carries a broad spectrum of aggressiveness and risk. Low-grade, superficial bladder cancers have minimal risk of progression to death; however, high-grade non–muscle-invasive cancers frequently progress and muscle-invasive cancers are often lethal (see Prognosis).

The classic presentation of bladder cancer is painless gross hematuria, which is seen in approximately 80-90% of patients. Physical examination results are often unremarkable (see Clinical Presentation). Cystoscopy, cytology, and biopsy when necessary are the principal diagnostic tests (see Workup).

Upon presentation, 55-60% of patients have low-grade noninvasive disease, which is usually treated conservatively with transurethral resection and periodic cystoscopy. The remainder have high-grade disease, of which 50% is muscle invasive and is typically treated with radical cystectomy (see Treatment and Management).

Carcinoma in situ (CIS) is managed by instilling chemotherapeutic or immunotherapeutic agents—most commonly bacillus Calmette-Guérin (BCG) vaccine—into the bladder via catheter. These intravesical treatments are not effective in the 20% of patients in whom cancer has invaded the bladder wall; those cases require cystectomy or a combination of radiation therapy and chemotherapy (see Treatment and Management).

Bladder cancer has the highest recurrence rate of any malignancy. Although most patients with bladder cancer can be treated with organ-sparing therapy, most experience either recurrence or progression, creating a great need for accurate and diligent surveillance (see Treatment and Management).

For more information on bladder cancer, see the following:

• Urine Tumor Markers in Bladder Cancer Diagnosis
• Cystoscopy
• Pathologic Findings in Squamous Cell Bladder Carcinoma
• Pathologic Findings in Small Cell Bladder Carcinoma
• Bacillus Calmette-Guérin in the Treatment of Bladder Cancer
• Treatment of Carcinoma In Situ
• Transurethral Resection of Bladder Tumors
• Surveillance for Recurrent Bladder Cancer

The bladder is an extraperitoneal muscular urine reservoir that lies behind the pubis symphysis in the pelvis. At the dome of the bladder lies the median umbilical ligament, a fibrous cord that is anchored to the umbilicus and that represents the obliterated urachus. This ligament contains vessels that must be ligated when divided.

The ureters, which transport urine from kidney to bladder, approach the bladder obliquely and posterosuperiorly, entering at the trigone. The intravesical ureteral orifices are roughly 2-3 cm apart and form the superolateral borders of the trigone. The trigone consists of the area between the interureteric ridge and the bladder neck. The bladder neck serves as an internal sphincter, which is sacrificed during a radical cystectomy.

In males, the seminal vesicles, vas deferens, ureters, and rectum border the inferoposterior aspect of the bladder. Anterior to the bladder is the space of Retzius, which is composed of fibroadipose tissue and the prevesical fascia. The dome and posterior surface of the bladder are covered by parietal peritoneum, which reflects superiorly to the seminal vesicles and is continuous with the anterior rectal peritoneum. In females, the posterior peritoneal reflection is continuous with the uterus and vagina.

The vascular supply to the bladder arrives primarily via the internal iliac (hypogastric) arteries, branching into the superior, middle, and inferior vesical arteries, which are often recognizable as lateral and posterior pedicles. The arterial supply also arrives via the obturator and inferior gluteal artery and, in females, via the uterine and vaginal arteries. Bladder venous drainage is a rich network that often parallels the named arterial vessels, most of which ultimately drain into the internal iliac vein.

Initial lymphatic drainage from the bladder is primarily into the external iliac, obturator, internal iliac (hypogastric), and common iliac nodes. Following the drainage to these sentinel pelvic regions, spread may continue to the presacral, paracaval, interaortocaval, and para-aortic lymph node chains.

Almost all bladder cancers originate in the urothelium, which is a 3- to 7-cell mucosal layer within the muscular bladder. Squamous cell carcinoma of the bladder can involve multiple sites; however, the lateral wall and trigone are more commonly involved by this tumor. All small cell carcinomas of the urinary system identified so far have been located in the urinary bladder, most commonly in the dome and vesical lateral wall.^[2]

Bladder cancer is often described as a polyclonal field change defect with frequent recurrences due to a heightened potential for malignant transformation. However, bladder cancer has also been described as resulting from implantation of malignant cells that have migrated from a previously affected site. This occurs less often and may account for only a small percentage of cases.

Use of the common term superficial bladder cancer should be discouraged. The term implies a harmless nature, which is misleading in many instances. Because it was used to describe the disparate disorders of low-grade papillary bladder cancer and the markedly more aggressive form, carcinoma in situ (CIS), the World Health Organization has recommended it be abandoned.

In its place, the term non–muscle-invasive bladder cancer should be used and qualified with the appropriate American Joint Committee on Cancer stage (ie, Ta, T1, Tis). Stage T1 cancer invades lamina propria but not the muscle of the bladder.

The World Health Organization classifies bladder cancers as low grade (grade 1 and 2) or high grade (grade 3). Tumors are also classified by growth patterns: papillary (70%), sessile or mixed (20%), and nodular (10%).

Transitional cell carcinoma

Transitional cell carcinoma (TCC) arises from stem cells that are adjacent to the basement membrane of the epithelial surface. Depending on the genetic alterations that occur, these cells may follow different pathways in the expression of their phenotype.

The most common molecular biologic pathway for TCCs involves the development of a papillary tumor that projects into the bladder lumen and, if untreated, eventually penetrates the basement membrane, invades the lamina propria, and then continues into the bladder muscle, where it can metastasize. Nearly 90% of transitional cell bladder tumors exhibit this type of behavior. This progression only occurs with high-grade cancers. Low-grade cancers rarely, if ever, progress and are thought to have a distinct molecular pathway, different from the high-grade cancers and CIS.

The remaining 10% of TCCs follow a different molecular pathway and are called CIS. This is a flat, noninvasive, high-grade urothelial carcinoma tumor that spreads along the surface of the bladder and, over time, may progress to an invasive form of cancer that behaves the same as invasive TCC.

Many urothelial tumors are primarily composed of TCC but contain small areas of squamous differentiation, squamous cell carcinoma (SCC), or adenocarcinoma.

Squamous cell carcinoma

SCC of the urinary bladder is a malignant neoplasm derived from bladder urothelium with pure squamous phenotype.^{[3, 4, 5]} SCC of the bladder is essentially similar to squamous cell tumors arising in other organs. Because many urothelial carcinomas contain a minor squamous cell component, a diagnosis of SCC of the bladder should be rendered only when the tumor is solely composed of squamous cell components, with no conventional urothelial carcinoma component.

Reportedly, SCC has less of a tendency for nodal and vascular distant metastases than urothelial carcinoma.^{[6, 7]}

Rare forms of bladder cancer

Adenocarcinomas account for less than 2% of primary bladder tumors. These tumors are observed most commonly in exstrophic bladders and are often associated with malignant degeneration of a persistent urachal remnant.

Other rare forms of bladder cancer include leiomyosarcoma, rhabdosarcoma, carcinosarcoma, lymphoma, and small cell carcinoma. Carcinosarcomas are highly malignant tumors that contain both mesenchymal and epithelial elements. Primary bladder lymphomas arise in the submucosa of the bladder. Leiomyosarcoma is the most common sarcoma of the bladder. Rhabdomyosarcomas most commonly occur in children. Except for lymphomas, all these rare bladder cancers carry a poor prognosis.

Small cell carcinoma of the urinary bladder is a poorly differentiated malignant neoplasm that originates from urothelial stem cells and has variable expression of neuroendocrine markers. Morphologically, it shares the same features of small cell carcinoma of other organs, including small cell carcinoma of the lung.

Genetic pathophysiology

As with all cancers, bladder cancer is associated with oxidative DNA genetic changes in the host cells, leading to abnormal and potentially uncontrolled growth. The TP53 tumor suppressor gene and band 9p21, a locus known to be the site of a significant tumor suppressor gene, are two of the most common and significant missing or mutated gene/gene sites in many patients with bladder cancer.

In addition, tumor suppressor genes P15 and P16 on chromosome 9, the RB tumor suppressor gene, the erb -b2 oncogene, and the p21-ras, c-myc, and c-jun genes may be mutated. Aneuploidy of chromosomes 3, 7, and 17 is also present in many patients with bladder cancer and may be readily detected using fluorescent in situ hybridization (FISH).

See the image of chromosome 3 aneuploidy below.

Up to 80% of bladder cancer cases are associated with environmental exposure. Tobacco use is by far the most common cause of bladder cancer in the United States and is increasing in importance in some developing countries. Smoking duration and intensity are directly related to increased risk.^{[8, 9, 10]} Compared with nonsmokers, smokers have a 2-6 times increased risk of developing bladder carcinoma. The risk appears to be similar between men and women.^[11] Nitrosamine, 2-naphthylamine, and 4-aminobiphenyl are possible carcinogenic agents found in cigarette smoke.

Occupational exposure to aromatic amines or aniline dyes is presumed to be the cause of bladder cancer in up to 25% of cases. Numerous occupations associated with diesel exhaust, petroleum products, and solvents (eg, auto work, truck driving, plumbing, leather and apparel work, rubber and metal work) have been associated with an increased risk of bladder cancer. Increased risk has also been reported in persons who work with organic chemicals and dyes, such as beauticians, dry cleaners, painters, paper production workers, rope and twine industry workers, dental workers, physicians, and barbers.

People living in urban areas are more likely to develop bladder cancer. The etiology is thought to be multifactorial, potentially involving exposure to numerous carcinogens.

Several medical risk factors are associated with bladder cancer. Patients who have undergone radiation treatment of the pelvis have an increased risk of bladder cancer. Chemotherapy with cyclophosphamide increases the risk of bladder cancer via exposure to acrolein, a urinary metabolite of cyclophosphamide.^[12] Patients with spinal cord injuries who have long-term indwelling catheters have a 16- to 20-fold increased risk of developing SCC of the bladder.

In many underdeveloped countries, particularly in the Middle East, Schistosoma haematobium infection causes most cases of squamous cell carcinoma. In one study from Egypt, 82% of patients with bladder carcinoma harbored S haematobium eggs in the bladder wall.^[13] In egg-positive cases, the tumor developed in younger age groups, with predominantly squamous cell carcinoma, relative to egg-negative persons. A higher degree of adenocarcinoma has also been reported in schistosomal-associated bladder carcinomas.^[13]

Three pathogenic species responsible for the disease in humans are S haematobium, S mansoni, and S japonicum. The eggs reside in the pelvic and mesenteric venous plexus. In the bladder, a severe inflammatory response and fibrosis secondary to the deposition of Schistosoma eggs is common.

The eggs are found embedded in the lamina propria and muscularis propria of the bladder wall. Many of the eggs are destroyed by host reaction and calcified, resulting in a lesion commonly known as sandy patch, which appears as a granular, yellow-tan surface lesion. It has been reported that S haematobium total antigen induces increased proliferation, migration, and invasion and decreases apoptosis of normal epithelial cells.^[14]

Keratinous squamous metaplasia has been associated with the increased risk of developing squamous cell carcinoma, with approximately one half of the cases arising subsequent to the metaplasia.^{[15, 16]} The majority of the cases will arise in the setting of chronic cystitis.^[17] Chronic irritation secondary to lithiasis,^{[3, 4]} urinary retention, and indwelling catheters has also been linked to the development of squamous cell carcinoma.^[4]

Having bladder diverticula may render an increased chance of developing squamous cell carcinoma in individuals.^[18] Rarely, bacillus Calmette-Guerin (BCG) treatment for carcinoma in situ has been reported to lead to development of squamous cell carcinoma.^[19] Development of bladder cancer at a younger age has been associated with bladder exstrophy.^{[20, 21, 22, 23]} Squamous cell carcinoma has also been described in urachal remnants.^{[24, 25, 26, 27, 28]}

Coffee consumption does not increase the risk of developing bladder cancer. Early studies of rodents and a minority of human studies suggested a weak connection between artificial sweeteners (eg, saccharin, cyclamate) and bladder cancer; however, most recent studies show no significant correlation.

Although no convincing evidence exists for a hereditary factor in the development of bladder cancer, familial clusters of bladder cancer have been reported. Several genetic mutations have been identified in bladder cancer. Mutations of the tumor suppressor gene p53, found on chromosome 17, are associated with high-grade bladder cancer and CIS. Mutations of the tumor suppressor genes p15 and p16, found on chromosome 9, are associated with low-grade and superficial tumors. Retinoblastoma (Rb) tumor suppressor gene mutations are also noted. Bladder cancer is associated with increased expression of the epidermal growth factor gene and the erb- b2 oncogene and mutations of the oncogenes p21-ras, c-myc, and c-jun.

United States statistics

The American Cancer Society predicted that 70,530 new cases of bladder cancer would be diagnosed in the United States in 2010 and that 14,680 people would die of the disease.^[29]

Incidence of bladder cancer increases with age, with the median age at diagnosis being 68 years, and is about 4 times higher in men than in women. Over the past 2 decades, the rate of bladder cancer has been stable in men but has increased in women by 0.2% a year.^[30] The male predominance in bladder cancer in the United States reflects the prevalence of transitional cell carcinoma (TCC). With SCC—in contrast to TCC—the male-to-female incidence ratio is 1:2.

Bladder cancer is the fourth most common cancer in men in the United States, after prostate, lung, and colorectal cancer, whereas bladder cancer is not even among the top 10 cancers in women. Accordingly, more males than females are expected to die of bladder cancer in 2010, with 10,410 deaths in males versus 4,270 in females.^[29] Nevertheless, women generally have a worse prognosis than men.

The incidence of bladder cancer is twice as high in white men as in black men in the United States. However, blacks have a worse prognosis than whites.^{[30, 31]}

Limited data indicate that small cell carcinoma of the urinary bladder probably has the same epidemiological characteristics as urothelial carcinoma. Patients are more likely to be male and older than 50 years.^{[32, 33]}

International statistics

Worldwide, bladder cancer is diagnosed in approximately 275,000 people each year, and about 108,000 die of this disease. In developed countries, 90% of bladder cancers are TCC. In developing countries—particularly in the Middle East and Africa—the majority of bladder cancers are SCCs, and most of these cancers are secondary to Schistosoma haematobium infection. Recent studies report that urothelial carcinoma is the most common urologic cancer in China.

In Africa, the highest incidence of SCC has been seen in schistosomal-endemic areas, notably Sudan and Egypt, where SCC ranges from two thirds to three quarters of all malignant tumors of the bladder. In recent years, a few studies from Egypt have shown a reversal of this trend due to the better control of schistosomiasis in the region, whereas in other parts of Africa the association is unchanged.^{[7, 34, 35]} Increased smoking incidence is believed to have contributed to the shift toward TCC in Egypt, which has a stronger smoking association.

The recurrence rate for superficial transitional cell cancer (TCC) of the bladder is high. As many as 80% of patients have at least one recurrence.

The most significant prognostic factors for bladder cancer are grade, depth of invasion, and the presence of CIS. To date, there is no convincing evidence of genetic factors affecting outcome.^[36]

Non–muscle invasive bladder cancer has a good prognosis, with 5-year survival rates of 82-100%. The 5-year survival rate decreases with increasing stage, as follows:

• Ta, T1, CIS – 82-100%
• T2 – 63-83%
• T3a – 67-71%
• T3b – 17-57%
• T4 – 0-22%

Prognosis for patients with metastatic urothelial cancer is poor, with only 5-10% of patients living 2 years after diagnosis.

The risk of progression, defined as an increased tumor grade or stage, depends primarily on the tumor grade. The risk of progression increases with tumor grade, as follows:

• Grade I – 2-4%
• Grade II – 5-7%
• Grade III – 33-64%

Prognosis in carcinoma in situ

CIS alone, or in association with Ta or T1 papillary tumor, carries a poorer prognosis and a recurrence rate of 63-92%. Diffuse CIS is an especially ominous finding, with 78% of cases progressing to muscle-invasive disease in one study.

Prognosis in squamous cell carcinoma

Tumor stage, lymph node involvement, and tumor grade have been shown to be of independent prognostic value in SCC.^{[37, 38]} However, pathologic stage is the most important prognostic factor.^[36] In one relatively larger series of 154 cases, the overall 5-year survival was 56% for pT1 and 68% for pT2 tumors. However, the 5-year survival for pT3 and pT4 tumors was only 19%.

Several studies have demonstrated grading to be a significant morphologic parameter in SCC.^[36] In one series, 5-year survival rates for grade 1, 2, and 3 squamous cell carcinoma was 62%, 52%, and 35%, respectively.^[36] In the same study of patients undergoing cystectomy, the investigators suggested that a higher number of newly formed blood vessels predicts unfavorable disease outcome.^[36]

In SCC, the survival rate appears to be better with radical surgery than with radiation therapy and/or chemotherapy. In locally advanced tumors, however, neoadjuvant radiation improves the outcome.^[39]

Sex and age have not been prognostically significant in SCC.^[36]

Prognosis in small cell carcinoma

Patients with small cell carcinoma of the bladder usually have disease in an advanced stage at diagnosis, and they have a poor prognosis.^{[40, 41, 42]} The overall median survival is only 1.7 years. The 5-year survival rates for stage II, III, and IV diseases are 64%, 15%, and 11%, respectively.^[43]

Recurrent bladder cancer

Bladder cancer has the highest recurrence rate of any malignancy (ie, 70% within 5 y). Although most patients with bladder cancer can be treated initially with organ-sparing therapy, most experience either recurrence or progression. The underlying genetic changes that result in a bladder tumor occur in the entire urothelium, making the whole lining of the urinary system susceptible to tumor recurrence.

Risk factors for recurrence and progression include the following^{[44, 45]} :

• Female sex
• Larger tumor size
• Multifocality
• Larger number of tumors
• High tumor grade
• Advanced stage
• Presence of CIS

The time interval to recurrence is also significant. Patients with tumor recurrences within 2 years, and especially with recurrences within 3-6 months, have an aggressive tumor and an increased risk of disease progression.

For patient education information, see the Cancer and Tumors Center, Kidneys and Urinary System Center, and Procedures Center, as well as Bladder Cancer, Blood in the Urine, Intravenous Pyelogram, and Cystoscopy.