Chapter 72. Bladder Cancer

A 68-year-old man, who is a retired painter and in good health, comes to the office at the insistence of his wife. He reports that his urinary stream is smaller and he has occasional dysuria. He has no major medical problems, although he continues to smoke one pack of cigarettes per day. His urinalysis in the office shows microscopic hematuria and an irregular mass is seen in the bladder on CT scan (Figure 72-1). Cystoscopy shows a bladder tumor (Figure 72-2). Complete endoscopic resection is performed and confirms transitional cell carcinoma.

Bladder cancer is a malignant neoplasm of the bladder, almost exclusively urothelial (transitional cell) carcinoma.

• In 2008, there were approximately 398,329 men and 139,099 women alive in the United States who had a history of cancer of the urinary bladder.1
• Almost 70,000 new cases (52,020 men and 17,230 women) were diagnosed and approximately 14,990 deaths occurred from bladder cancer in 2011.1 Mean age at diagnosis is 73 years.
• The age-adjusted incidence rate (based on 2004 to 2008 data) was 21.1 per 100,000 men and women per year with a male-to-female ratio of approximately 4:1. Among men, bladder cancer is more prevalent in whites than in blacks or Hispanics (ratio of 2:1) and more prevalent in whites than in Asian/Pacific Islander or American Indian/Alaska Natives (ratio 2.4:1); for white women, incidence rates are also higher but the differences are not as great.1

• Ninety percent to 95% are transitional cell cancers and the remainder are nonurothelial neoplasms, including primarily squamous cell, adenocarcinoma, and small cell carcinoma2,3 (Figures 72-1, 72-2, and 72-4). Rare forms include nonepithelial neoplasms (approximately 1%), including benign tumors, such as hemangiomas or lipomas, and malignant tumors, such as angiosarcomas.3
• Transitional cells line the urinary tract from the renal pelvis to the proximal two-thirds of the urethra. Ninety percent of transitional cell tumors develop in the bladder and the others develop in the renal pelvis, ureters, or urethra.2
• Most tumors are superficial (75% to 85%).4 At diagnosis, approximately 51% are in situ and 35% are localized (confined to primary site) with an additional 7% of cases having regional spread and 4% having distant metastases at diagnosis (3% unknown).2
• Multiple tumors are seen in 30% of cases.4
• Bladder tumor cells are also graded based on their appearance and behavior into well differentiated or low grade (grade 1), moderately well differentiated or moderate grade (grade 2), and poorly differentiated or high grade (grade 3).
• The most common sites of hematogenous spread are lung, bone, liver, and brain. Superficial lesions do not metastasize until they invade deeply and may remain indolent for years.2

• Risk factors include smoking (odds ratio increased by 3- to 4-fold; 50% attributable risk) and exposure to pelvic radiation,5 the drugs phenacetin and chlornaphazine, external-beam radiation, and chronic infection, including Schistosoma haematobium and genitourinary tuberculosis.2,3
• There is an increased risk in certain occupations, particularly those involving exposure to metals (e.g., aluminum), paint and solvents, polycyclic aromatic hydrocarbons, diesel engine emissions, aniline dyes (e.g., workers in chemical plants exposed to benzidine or o-toluidine),2 and textiles.6
• An increased risk was also seen with drinking tap water (odds ratio [OR] for >2 L/day vs. ≤0.5 L/day was 1.46 [1.20 to 1.78]), with a higher risk among men (OR = 1.50, 1.21 to 1.88).7
• Familial cases indicate a genetic predisposition.8

Clinical Features

• Hematuria in 80% to 90%; with microscopic hematuria approximately 2% have bladder cancer and with gross hematuria approximately 20% have bladder cancer.3
• Irritative symptoms (i.e., dysuria, frequency) are the most common presentation.
• Obstructive symptoms may occur if the tumor is located near the urethra or bladder neck.

Laboratory

• Urine microscopy and culture to rule out bladder infection.3
• Urine cytology (high specificity [90% to 95%] but low sensitivity [23% to 60%]), CT scan of the pelvis (Figures 72-1, 72-3, and 72-4) or intravenous urography (IVU), and cystoscopy with biopsy (Figure 72-2) comprise the basic work-up.2 Fluorescence cystoscopy (use of photosensitizer instilled into the bladder, can enhance detection of flat neoplastic lesions like carcinoma in situ (CIS).4 When CIS is found in a cystectomy specimen, 9% to 13% of patients have upper urinary tract disease.4
• Bladder wash cytology during cystoscopy detects most CIS.3
• A complete blood count, blood chemistry tests (including alkaline phosphatase tests), liver function tests, CT or MRI of the chest or abdomen and a bone scan may be needed for suspected metastatic disease.2,3 Bone scanning may be limited to patients with bone pain and/or elevated levels of serum alkaline phosphatase.4
• Tumor markers such as fluorescence in situ hybridization (FISH) analysis and nuclear matrix protein (NMP) 22 identify changes in cells in the urine and are more sensitive than urine cytology for low-grade tumors with equivalent sensitivity for high-grade tumors and CIS.9 As specificity is low, tumor markers should not be used for diagnosis.

Imaging

• For pretreatment staging of invasive bladder cancer, the American College of Radiology (ACR) recommends a chest X-ray (with chest CT if equivocal), CT of the abdomen and pelvis (without and with contrast) or MRI of the pelvis (especially in cases where patients are unable to undergo contrast injection), and possibly IVU; contrast-enhanced MRI is preferred over CT for local staging.4 SOR C
• The European Association of Urology (EAU) recommends multidetector-row CT (MDCT) of the chest, abdomen, and pelvis as the optimal form of staging for patients with confirmed muscle-invasive bladder cancer, including MDCT urography for examination of the upper urinary tracts.9 If MDCT is not available, alternatives are excretory urography and a chest X-ray. SOR B
• EAU recommends renal and bladder ultrasonography, and IVU or CT prior to transurethral resection for presumed invasive bladder cancer.10 SOR B ACR agrees that ultrasound is useful for local tumor staging.4 For patients with verified invasive bladder cancer, EAU recommends either MRI with fast dynamic contrast-enhancement or MDCT with contrast enhancement for patients considered suitable for radical treatment. SOR B

Biopsy

• Diagnosis is made by cystoscopy, biopsy, and histology.

• Among adult patients with microscopic hematuria, most patients have benign pathology, such as urinary tract infection, with 25% having prostate cancer and only 2% having bladder cancer.2
• Among adult patients with gross hematuria, 22% have benign cystitis and 15% to 20% have bladder cancer.2

Medications

Neoadjuvant cisplatin-containing combination chemotherapy (administered prior to main treatment) improves overall 5-year survival by 5% to 7% and should be considered in muscle-invasive bladder cancer irrespective of definitive treatment.9,11 SOR A It is not recommended for patients with performance status of 2 or more and impaired renal function or for primary therapy for localized bladder cancer.9

• The role of adjuvant chemotherapy (usually administered after surgery) for invasive bladder cancer is under debate. A Cochrane review based on 6 small trials (N = 491) found a 25% relative reduction in the risk of death for chemotherapy compared to control patients (hazard ratio for survival 0.75; 95% CI 0.60, 0.96), suggesting a benefit for these patients.12
• Cisplatin-containing combination chemotherapy is first-line therapy for patients with metastatic disease and treated patients can achieve a median survival of up to 14 months.9,13  SOR A

Surgical

Depends on the extent (depth and grade) or spread of the disease (Table 72-1). Recommendations have been provided by the American Urological Association (AUA, 2007)13 and the EAU (2009)9 as given below:

• Non-muscle-invasive disease (70% to 75% of cases)—Complete endoscopic resection with or without intravesical treatment (bacille Calmette-Guérin [BCG] weekly for 6 weeks or interferon or mitomycin C). SOR C Low-grade tumors (Ta tumors) can be treated with resection alone or with a single postoperative dose of intravesical chemotherapy. SOR B In a metaanalysis of three trials, tumor recurrence was significantly lower with intravesical BCG but there was no difference in disease progression or survival.14 SOR B BCG treatment causes urinary frequency (71%), cystitis (67%), hematuria (23%), fever (25%),15 and, rarely, systemic granulomatous infection requiring antituberculosis treatment.
• For Ta, Tis, or T1 tumors that are initially histologically confirmed as high grade, the AUA recommends repeat resection and additional intravesical therapy (induction course of BCG followed by maintenance therapy).13 SOR A A Cochrane review based on five small trials found that immunotherapy with intravesical BCG following surgery benefits patients with medium/high risk Ta or T1 bladder cancer on delaying tumor recurrence.15 Additional Cochrane reviews found intravesical BCG more effective than intravesical epirubicin or mitomycin C in reducing tumour recurrence (the latter only for patients at high risk of recurrence) 16,17; mitomycin C, however, was equivalent to BCG for disease progression and survival. SOR A
• Persistent or recurrent superficial disease—Repeat resection with an induction course of BCG; maintenance BCG or mitomycin C is recommended or consideration of intravesical chemotherapy (valrubicin or gemcitabine). SOR B For treatment failure of patients with non-muscle-invasive bladder tumors, EAU recommends radical cystectomy for those with high-grade tumors and cystectomy for other patients with T1 tumors.9 SOR B Delay in cystectomy for these patients increases the risk of progression and cancer-specific death.9
• Recurrent high-grade T1 tumors or invasive-muscle disease (extends to muscle or lymph nodes)—Radical cystectomy and pelvic lymphadenectomy with or without systemic chemo­therapy.2,9 SOR C In men, radical cystectomy includes removal of the prostate, seminal vesicles, and proximal urethra resulting in impotence. In women, the uterus, ovaries, and anterior vaginal wall are removed. Most patients receive cutaneous reservoirs (bowel or orthotopic neobladder) drained by intermittent self-catheterization.
• Chemotherapy is not used for nonurothelial cancers, such as squamous cell carcinoma or adenocarcinoma, which are primarily treated with cystectomy.2
• Upper urinary tract recurrence—Radical nephroureterec­tomy. SOR B

Other Therapy

• In a Cochrane review of three trials comparing radical radiotherapy followed by surgery (salvage cystectomy) versus radical cystectomy, overall survival was better with radical cystectomy.18 SOR A
• External-beam radiotherapy alone is considered an option for patients unfit for cystectomy or to stop the bleeding from a tumor when local control can't be achieved by transurethral manipulation because of extensive local tumor growth.9  SOR C

Eliminate active and passive smoking.9  SOR C

• Most recurrences are also superficial tumors with only approximately 10% to 15% of tumors progressing to invasive disease.4
• Performance status, ranging from 0 (fully active) to 4 (completely disabled), and the presence or absence of visceral metastases are independent prognostic factors for survival.
• The EAU working group suggests use of a weighted scoring system to estimate recurrence and progression risk.19 Factors include number, size, category, and grade of tumors; recurrence; and concomitant CIS. Scores range from 0 to 17 for recurrence and 0 to 23 for progression. These scores are translated into probabilities for 1-year and 5-year recurrence (15% and 31%, respectively, for a score of 0, and 61% to 78%, respectively, for a score of 10 to 17) and 1-year and 5-year progression (0.2% and 0.8%, respectively, for a score of 0, and 17% to 45%, respectively, for a score of 14 to 23).
• Risk of disease progression by tumor grade: 10% to 15% progress with grade 1 tumors, 14% to 37% with grade 2, and 33% to 64% with grade 3 tumors.20
• Five-year survival rates for superficial disease are 90%; infiltrating (stage II or III), 35% to 70%; metastatic disease (stage IV), 5.4% to 20% (see Table 72-1).1 Long-term disease-free survival is reported in approximately 15% of patients with nodal disease and good performance status.

• Recurrence rates overall are 50% with a median recurrence at 1 year (0.4 to 11 years), and 5% to 20% progress to a more advanced stage. Patients should be seen every 3 months for the first year. SOR C The ACR and EAU recommend stopping oncologic surveillance after 5-years of normal follow-up to be replaced by functional surveillance (e.g., renal function).4,9
• For patients with high-grade Ta and T1 disease, cystoscopy, urinalysis and urine cytology are recommended every 3 months for 2 years, then every 6 months for 2 years, then annually. Imaging of the upper tract collecting system is performed every 1 to 2 years.2,4
• For patients with muscle-invasive disease, laboratory tests (liver function test, creatinine clearance, electrolyte panel) in addition to a chest X-ray are recommended every 6 to 12 months with imaging of upper urinary tract, abdomen, and pelvis for recurrence every 3 to 6 months for 2 years, and then as clinically indicated.3
• For patients undergoing bladder-sparing surgery, urine cytology with or without biopsy is conducted every 3 months for 1 year, then at increasing intervals.3
• For patients undergoing cystectomy, urine cytology is conducted every 6 to 12 months, and for those undergoing cystectomy and cutaneous diversion, urethral wash cytology is recommended every 6 to 12 months.3
• For patients with cystectomy and continent orthotopic diversion, vitamin B12 level should be checked annually.3,21
• Bladder tumor markers from voided urine will likely improve detection of recurrence in the future, but data are still insufficient to warrant substitution of cystoscopic follow-up.4,22

• The most important primary prevention for muscle-invasive bladder cancer is to eliminate active and passive smoking.
• Tumor recurrence and progression risk can be estimated from clinical and pathologic factors;4 this information may help in joint decision-making for primary treatment and follow-up intervals.

Patient Resources

• www.nlm.nih.gov/medlineplus/bladdercancer.html.
• http://cancerhelp.cancerresearchuk.org/type/bladder-cancer/about/.
• http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Bladder/Bladdercancer.aspx.

Provider Resources

• SEER Cancer Statistics Review—http://seer.cancer.gov/statfacts/html/urinb.html.