Bladder Cancer

INTRODUCTION

Background: Bladder cancer is a common urologic cancer. Most cases in the United States are transitional cell carcinoma (TCC), often described as polyclonal field change defects. Urothelium in the entire urinary tract may be involved, including the renal pelvis, ureter, bladder, and urethra.

To predict the clinical course of the disease and to determine the appropriate treatment, bladder cancer is categorized as low grade or high grade and as superficial or muscle invasive. Newer molecular and genetic markers may help in the early detection and prediction of TCC.

Nonurothelial primary bladder tumors are rare and may include small cell carcinoma, carcinosarcoma, primary lymphoma, and sarcoma.

Pathophysiology: No convincing evidence exists for a hereditary factor in the development of bladder cancer. Most patients have superficial disease, which usually is treated conservatively with transurethral resection and periodic cystoscopy.

Adenocarcinomas account for less than 2% of primary bladder tumors. These tumors are observed most commonly in exstrophic bladders and are poorly responsive to radiation and chemotherapy. Radical cystectomy is the treatment of choice.

Most squamous cell carcinomas of the bladder in the United States are associated with persistent inflammations from long-term indwelling Foley catheters and bladder stones.

Small cell carcinomas are thought to arise from neuroendocrine stem cells and are aggressive tumors that carry a poor prognosis.

Carcinosarcomas are highly malignant tumors that contain both mesenchymal and epithelial elements.

Primary bladder lymphomas arise in the submucosa of the bladder and are treated with radiation therapy.

Leiomyosarcoma is the most common sarcoma of the bladder.

Rhabdomyosarcomas most commonly occur in children and carry a poor prognosis.

Frequency:
　

• In the US: Bladder cancer is the fourth most common cancer in men, after prostate, lung, and colorectal cancer. This type of cancer is the eighth most common cancer in women. From 1984-1993, the number of patients diagnosed annually with bladder cancer increased by 36%. An annual cohort of 300,000?00,000 patients with bladder cancer is reported in the United States. The recurrence rate for superficial transitional cell cancer of the bladder is quite high, and as many as 80% of patients have at least one recurrence.

• Internationally: In developed countries, 90% of bladder cancers are TCC. In developing countries, 75% are squamous cell carcinomas, and most of these are secondary to Schistosoma haematobium infection.

Mortality/Morbidity: In 1998, an estimated 54,400 new patients were diagnosed with bladder cancer in the United States, and 12,500 of those patients died from the disease.

Race: Bladder cancer is more common in whites than blacks; however, blacks have a worse prognosis.

Sex: The male-to-female ratio is 3:1. Women generally have a worse prognosis than men.

CLINICAL

History:

• Bladder cancer classically presents as total, gross, painless hematuria.

• Approximately 80-90% of patients with bladder cancer present with hematuria.

• Consider all patients with gross hematuria to have bladder cancer, until proven otherwise.

• Suspect bladder cancer when any patient presents with unexplained microscopic hematuria.

Physical: Bladder cancer classically presents as painless hematuria. The hematuria may be gross or microscopic. With more advanced muscle-invasive disease or carcinoma in situ (CIS), irritative voiding symptoms may be present (eg, frequency, dysuria).

Causes:

• Bladder cancer is associated with the following environmental risk factors:

• Smoking accounts for approximately 50% of all bladder cancers. Nitrosamine, 2-naphthylamine, and 4-aminobiphenyl are possible carcinogenic agents found in cigarette smoke.

• Bladder cancer also is associated with industrial exposure to aromatic amines in dyes, paints, solvents, leather dust, inks, combustion products, rubber, and textiles.

• Prior radiation treatments to the pelvis and exposure to acrolein, a urinary metabolite of cyclophosphamide, increase the risk of bladder cancer.

• Coffee consumption does not increase the risk of developing bladder cancer.

• Early studies of rodents and a minority of human studies suggest a weak connection between artificial sweeteners (eg, saccharin, cyclamate) and bladder cancer; however, most recent studies show no significant correlation.

• Epidemiologic data presenting a strong link between bladder cancer and environmental exposures suggest that bladder cancer is a potentially preventable disease.

• The following genetic mutations are 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.

• Mutations of the rubidium (Rb) tumor suppressor gene also are noted.

• Bladder cancer is associated with increased expression of the epidermal growth factor gene and the erbB-2 oncogene, and mutations of the oncogenes p21 ras, c-myc, and c-jun.

WORKUP

Lab Studies:
　

• Urologic evaluation

• Conduct this evaluation on any patient with hematuria, whether gross or microscopic.

• Microscopic hematuria from bladder cancer may be intermittent; therefore, a repeat negative result on urinalysis does not exclude the diagnosis.

• Infection may cause hematuria and usually is associated with irritative voiding symptoms (eg, dysuria, frequency, urgency).

• Perform a urinalysis and culture to exclude urinary tract infection.

• Irritative voiding symptoms also may be caused by CIS or muscle-invasive bladder cancer.

• Further evaluate irritative voiding symptoms from a urinary tract infection that do not resolve with treatment.

• Urinary cytology may be helpful if results are positive, but a negative cytology result cannot be considered definitive. Urinary cytology for routine screening is controversial.

• Urine assay: Newer, voided urine assays (ie, bladder tumor antigen [BTA-Stat], nuclear matrix protein [NMP-22], fibrin/fibrinogen degradation products [FDP]) are being used for the detection and surveillance of TCC. These tests also have high false-positive and false-negative rates. In the future, other newer assays based on telomerase and microsatellite analysis may prove to be a better detection method than urinary cytology.

Imaging Studies:
　

• Intravenous pyelogram

• An intravenous pyelogram (IVP) is the criterion standard for upper-tract urothelium imaging.

• Many urologists believe that any patient with significant risk factors for bladder cancer who presents with hematuria should receive an IVP (eg, a 65-y-old person who smokes with gross hematuria should receive an IVP rather than a renal ultrasound).

• Conduct a retrograde pyelogram in patients where IVP cannot be performed because of azotemia or a severe allergy to IVP contrast.

• CT scan and ultrasound are employed commonly; however, they may miss urothelial tumors of the upper tract and small stones.

Procedures:
　

• Cystoscopy

• Obtain a biopsy of suspicious lesions during cytoscopy. Attempt to include the bladder muscle in the biopsy specimen. This allows the pathologist to determine whether the tumor is muscle invasive.

• Transitional cell tumors typically are papillary or sessile, and CIS may appear as an erythematous, velvety lesion. Unless the lesion is in a bladder diverticulum (pseudodiverticulum), attempt to resect the primary tumor completely.

• A bladder diverticulum lacks a surrounding muscle layer, and a deep biopsy of a lesion within a diverticulum risks perforating the bladder and extravesical extravasation of cancer cells.

• Because no muscle layer surrounds the bladder diverticulum, the next step in the progression of a superficial tumor is extravesical spread, requiring more aggressive surgical therapy (eg, partial cystectomy, open diverticulectomy) rather than a simple resection followed by surveillance.

• Further investigate efflux of blood from either ureteral orifice with a retrograde pyelogram and/or ureteroscopy.

• Urine cytology

• Perform this test at the same time as cystoscopy, although its routine use for screening is controversial.

• This procedure is associated with a significant false-negative rate, especially for low-grade carcinoma (eg, 10-50% accuracy rate).

• The false-positive rate is 1-12%, but it has a 95% accuracy rate for diagnosing high-grade carcinoma and CIS.

• With a normal finding on cystoscopic examination, further evaluate a positive result on urine study with an upper-tract study and random biopsies of the bladder. Obtain biopsies of the prostatic urethra in men.

Histologic Findings: More than 90% of bladder cancer cases are TCC, approximately 5% are squamous cell carcinoma, and less than 2% are adenocarcinoma. Both the stage and tumor grade correlate independently with prognosis.

• More than 70% of all newly diagnosed bladder cancers are superficial, approximately 50-70% are Ta, 20-30% are T1, and 10% are CIS.

• Approximately 5% of patients present with metastatic disease, which commonly involves the lymph nodes, lung, liver, bone, and central nervous system.

• Approximately 25% of affected patients have muscle-invasive disease at diagnosis.

• Muscle-invasive disease

• Clinically stage an affected patient with a CT scan of the abdomen and pelvis, chest x-ray, and serum chemistries.

• If the patient is asymptomatic with normal calcium and alkaline phosphatase, a bone scan is unnecessary.

• Of patients with muscle-invasive bladder cancer, as many as 50% may have occult metastases that become clinically apparent within 5 years of initial diagnosis.

• Most patients with overt metastatic disease die within 2 years, despite chemotherapy.

• Approximately 25-30% of patients with only limited regional lymph node metastasis discovered during cystectomy and pelvic lymph node dissection may survive beyond 5 years.

TREATMENT

Medical Care:

• Intravesical chemotherapy

  　

  • Valrubicin recently has been approved as intravesical chemotherapy for CIS that is refractory to BCG. In patients who do not respond to BCG, the overall response rate to valrubicin is approximately 20%, and some patients can delay a cystectomy for prolonged periods.

    　

  • Other forms of adjuvant intravesical chemotherapy for superficial bladder cancer include intravesical triethylenethiophosphoramide (Thiotepa), mitomycin C, doxorubicin, and epirubicin. Although these agents may increase the time to disease recurrence, no evidence indicates that these therapies prevent disease progression.

    　

  • No evidence suggests that these adjuvant therapies are significantly more effective than others or as effective as BCG.

• Muscle-invasive bladder cancer

  　

  • Neoadjuvant external beam radiation therapy has not improved the survival rate for muscle-invasive bladder cancer.

    　

  • To date, no study has demonstrated a significant survival benefit of neoadjuvant chemotherapy, prior to a radical cystectomy or external beam radiotherapy.

    　

  • In one small series, 45% of patients with T4 tumors responded to chemotherapy, making potentially curative cystectomy possible.

    　

  • Adjuvant systemic chemotherapy after a radical cystectomy is used in many US facilities.

    　

  • While no definite evidence of benefit exists, patients with P3-4 or N+ TCC typically are advised to receive chemotherapy.

    　

  • An ongoing multicenter trial, funded by the National Cancer Institute, is randomizing P2 bladder cancer patients by p53 gene status to chemotherapy versus observation.

    　

  • External beam radiation therapy is used in various other countries for T2-T3 TCC of the bladder with inferior results to radical cystectomy. The overall 5-year survival rate after treatment with external beam radiation is 20-40%.

• Vitamin A

  　

  • Some evidence suggests that vitamin A may have a protective effect against bladder cancer.

    　

  • Etretinate is a synthetic retinoid with a greater antitumor effect and fewer side effects than other forms of vitamin A (eg, trans-retinoic acid, 13-cis-retinoic acid). In some studies, this retinoid has decreased the recurrence rate for superficial papillary bladder tumors; however, long-term safety and tolerance of etretinate administration is unknown.

• Methotrexate, vinblastine, Adriamycin, and cisplatin combination

  　

  • The methotrexate, vinblastine, Adriamycin, and cisplatin (M-VAC) combination is the standard treatment of metastatic bladder cancer.

    　

  • TCC may be a chemosensitive cancer.

    　

  • M-VAC has objective response rates of 57-70%, complete response rates of 15-20%, and a 2-year survival rate of 15-20%.

• Other treatments

  　

  • Other vitamins and medications are being studied as chemopreventive agents for bladder cancer, including difluoromethyl ornithine (DFMO), Oltipraz, and cyclooxygenase-2 (COX-2) inhibitors.

    　

  • Cessation of smoking is thought to decrease bladder cancer recurrence rates; yet in contrast to lung cancer, the risk of development does not diminish.

    　

  • Several novel compounds have shown activity against transitional cell bladder cancer and now are being tested in combination chemotherapy trials. Some of these promising agents are ifosfamide, paclitaxel, docetaxel, gemcitabine, and carboplatin. In combination, these agents have the same response rate as the criterion standard regimen M-VAC but with less toxicity.

Surgical Care:

• Superficial bladder cancer (Ta, T1, CIS)

• Endoscopic resection and fulguration of the bladder tumor adequately treat superficial bladder cancer. No further metastatic workup may be indicated.

  　

• Because bladder cancer is a polyclonal field change defect, continued surveillance is mandatory.

• Radical cystoprostatectomy (men)

• In men, this is the criterion standard for organ-confined, muscle-invasive bladder cancer (eg, T2, T3).

  　

• Remove the bladder, prostate, and pelvic lymph nodes.

  　

• Perform a total urethrectomy for anterior urethral involvement, involvement of the prostatic stroma, or diffuse CIS involving the prostate.

• Anterior pelvic exenteration (women)

• Perform this procedure on women diagnosed with muscle-invasive bladder cancer.

  　

• The procedure involves removal of the bladder, urethra, uterus, ovaries, and anterior vaginal wall.

  　

• If no tumor involvement of the bladder neck is present, the urethra and anterior vaginal wall may be spared with the construction of an orthotopic neobladder.

MEDICATION

M-VAC is the standard treatment for metastatic bladder cancer. No proven role exists for adjuvant chemotherapy. When selecting therapy, the M-VAC combination has substantial toxicity and must be weighed against the expected benefit. The major dose-limiting toxicity is myelosuppression. The new combination regimens (eg, gemcitabine, cisplatin) show response rates and median survival comparable to M-VAC but with less toxicity.
　

Drug Category: Antineoplastic agents -- Inhibit cell growth and proliferation.

FOLLOW-UP

Further Outpatient Care:
　

• The high rate of disease recurrence and progression in superficial bladder cancer underscores the need for careful follow-up studies.

• Surveillance for patients with superficial transitional cell cancer includes cystoscopy and bladder wash cytologies every 3 months for 2 years, then every 6 months for 2 years, and then at least yearly.

Complications:
　

• The morbidity of untreated bladder cancer is significant and includes hematuria, dysuria, irritative urinary symptoms, urinary retention, incontinence, ureteral obstruction, and pelvic pain.

  　

• The perioperative mortality rate is 1-2%.

• The local recurrence rate is 5-10%; however, it increases to 15-25% for T3-T4 disease.

  　

• The 2 most common complications are wound infection and bowel obstruction (see Table 3).

  Table 3. Most Common Complications of Radical Cystectomy

  Complication	Rate %
  Wound infection	12.9
  Bowel obstruction	11
  Pyelonephritis	9.8
  Ureteral obstruction	6.8
  Pneumonia	5.0
  Cardiac arrhythmia or congestive heart failure	3.7
  Incisional hernia	3.4
  Prolonged ileus	3.3
  Renal calculus	2.6

  　

• Radical cystectomy

• The complication rate for a radical cystectomy is approximately 25%.

• Many patients undergo a radical cystectomy and have multiple comorbid health risk factors (eg, advanced age, cardiovascular disease, pulmonary disease).

• Despite these difficulties, this procedure may be performed safely on patients aged 70-80 years.

  　

• Following a radical cystectomy, all men are impotent if the parasympathetic nerves from the pelvic plexus (S2-S4) to the corpora cavernosum are not spared at the time of surgery; however, a nerve-sparing approach may reduce the impotency rate to approximately 40-50%.

• Orthotopic neobladder

• With the recent advances in surgical technique, this procedure is becoming the diversion of choice.

• Risk factors include daytime and nighttime urinary incontinence of approximately 10% and 15%, respectively.

• Urinary incontinence may develop from multiple factors, including injury to the external urethral sphincter, increased urine production from solute absorption, and relaxation of the external sphincter, which is greater at night.

Prognosis:
　

• Superficial bladder cancer has a good prognosis, with 5-year survival rates of 82-100%.

• The 5-year survival rates for pathologic T2, T3, and T4 tumors are 63-83%, 45-55%, and 0-22%, respectively (see Table 4).

  Table 4. 5-Year Survival Rates for Bladder Cancer

  Stage	5-Year Survival Rate %
  Ta, T1, CIS	82-100
  T2	63-83
  T3a	67-71
  T3b	17-57
  T4	0-22

  　

• Prognosis for metastatic transitional cell cancer is dismal, with only 5% of patients living 2 years after diagnosis.

• Early diagnosis and improvements in treatment of bladder cancer may be responsible for the improved survival rate of patients with TCC.

  　

• Further studies of molecular determinants of bladder cancer development and progression aid in prevention, earlier diagnosis, and treatment. Much progress has been made in the treatment of advanced bladder cancer; however, researchers must further elucidate optimal agents and regimens.

• 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 (ie, 70% within 5 y).

• Superficial bladder cancer

• The risk of progression, defined as an increased tumor grade or stage, depends primarily on the tumor grade.

• The risk of progression for grades I, II, and III TCC are approximately 10-15%, 14-37%, and 33-64%, respectively (see Table 5).

  Table 5. Risk of Progression of TCC of the Bladder

  Grade	Risk of Progression %
  Grade I	10-15
  Grade II	14-37
  Grade III	33-64

  　

• 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% progressing to muscle-invasive disease in one study.

• Other risk factors for recurrence and progression include the tumor size, multifocality, number of tumors, high tumor grade, advanced stage, the presence of CIS, and the time interval to recurrence.

  　

• Patients with tumor recurrences within 2 years, and especially with recurrences within 3 months, have an aggressive tumor and an increased risk of disease progression.

MISCELLANEOUS

Medical/Legal Pitfalls:
　

• Failure to obtain a workup for possible urothelial carcinoma for all patients with gross hematuria and persistent microscopic hematuria