eMedicine Specialties > Urology > Cancer, Bladder, Penis, and Urethra

Surveillance for Recurrent Bladder Cancer

David A Levy, MD, Assistant Professor of Surgery (Urology), Glickman Urologic and Kidney Institute, Cleveland Clinic Foundation
J Stephen Jones, MD, FACS, Chairman, Department of Regional Urology, Cleveland Clinic Glickman Urological and Kidney Institute; Associate Professor of Surgery (Urology), Cleveland Clinic Lerner College of Medicine at Case Western Reserve University School of Medicine

Updated: Nov 21, 2008

Introduction

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. Therefore, the foci of this article include the management of noninvasive bladder cancer and the strategies for surveillance of tumor recurrence and progression.

The American Cancer Society predicts that 68,810 new cases of bladder cancer will be diagnosed in the United States in 2008, and 14,100 people will die of the disease. The vast majority of patients diagnosed with bladder cancer present with noninvasive disease.¹

For more information on bladder cancer, see Medscape’s Bladder Cancer Resource Center.

History of the Procedure

Nitze's cystoscope allowed endoscopic visualization of bladder tumors, but Dittel first published the finding in 1885, a year before the inventor documented his results. Beer described the first endoscopic destruction of a bladder tumor soon thereafter, using the Oudin high-frequency current. Keyes subsequently used the more efficient d'Arsonval current, followed by Kidd's diathermy electrode with its "massive ball electrode." By the 1920s, the Stern-McCarthy resectoscope allowed tissue removal without destruction, permitting pathological examination of the specimen.

The history of posttreatment surveillance for bladder cancer recurrence is not well documented, but the practice of monitoring tumors with serial endoscopy appears to have arisen with the emergence of cystoscopy in the 20th century. The recommendation for cystoscopic tumor surveillance every 3 months dates back to at least 1936, apparently based on the fact that substantial numbers of patients with bladder cancer experience tumor recurrence. Early recommendations for initial monthly surveillance have largely been abandoned.

The origin of the traditional timing beginning 3 months following bladder tumor removal is not clear. One theory is that it may have arisen as the timeframe believed to be required for healing after tumor resection. Cystoscopic findings prior to this time would have been difficult to interpret because of numerous factors, including incomplete healing and edema, among others. Nevertheless, the author has queried colleagues known for subspecialization in bladder cancer and has failed to determine the origin of this practice.

Bladder cancer surveillance standards arose based primarily on expert opinion rather than as an evidence-based standard. The American Urological Association recommends surveillance every 3-6 months for 3 years and at least yearly thereafter.² The US National Comprehensive Cancer Network has made similar recommendations.³

Although sequential cystoscopy for surveillance of bladder tumor recurrence is a routine practiced by almost every urologist, the major texts do not fully address the topic and barely acknowledge that the routine might be challenged.

Problem

According to the US National Cancer Institute, bladder cancer affects approximately 500,000 people in America. Because most still have an intact bladder, the number of patients under surveillance approaches this figure.

Although the incidence of bladder cancer is less than that of prostate cancer, expenditures are almost twice as high for bladder cancer because of its chronic nature and the need for long-term surveillance. According to the Agency for Health Care Policy and Research of the US Public Health Service, annual expenditures are $2.2 billion for bladder cancer versus $1.4 billion for prostate cancer. This suggests a close assessment of surveillance techniques and standards is appropriate.

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 noninvasive bladder cancer should be used and qualified with the appropriate American Joint Committee on Cancer stage (ie, Ta, T1, Tis). Seventy percent of noninvasive bladder cancers occur as stage Ta, 20% occur as T1, and 10% occur as Tis. Note that invasion refers to muscularis propria involvement and not lamina propria involvement. Therefore, stage T1 cancer invades lamina propria but is classified as noninvasive.

Patients whose cancer progresses while under surveillance may have a worse prognosis than those who present with invasive disease.

Frequency

The American Cancer Society predicts that 68,810 new cases of bladder cancer will be diagnosed in the United States in 2008, and 14,100 people will die of the disease. Bladder cancer is more common in males than in females, with a male-to-female ratio of approximately 3:1 (51,230 cases in males and 17,580 cases in females). Accordingly, more males than females are expected to die of bladder cancer in 2008, with 9,950 mortalities in males versus 4,150 mortalities in females.¹

The vast majority of individuals with newly diagnosed bladder cancer have noninvasive disease at the time of diagnosis, but these individuals are at risk for disease recurrence. While most of these patients are at low risk for cancer progression or death, monitoring is required to identify the need for further intervention. White persons are more likely to develop bladder cancer, but African Americans appear to have a worse prognosis.

Etiology

Tobacco use is by far the most common cause of bladder cancer in the United States. The likelihood of bladder cancer in smokers is 4 times that in nonsmokers.

Aromatic amines, aniline dyes, pelvic radiation, oxazaphosphorine chemotherapeutic agents (eg, cyclophosphamide, iphosphamide), and numerous occupations (eg, auto work, truck driving, plumbing, leather and apparel work, rubber and metal work) have been associated with an increased risk for bladder cancer. In addition, 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, have been reported to have an increased risk. Occupational exposure is presumed to be the cause of bladder cancer up to 25% of cases.

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.

In many underdeveloped countries, particularly in the Middle East, Schistosoma haematobium infection causes most cases of squamous cell carcinoma. Tobacco abuse in these countries may be changing the ratio as more patients develop transitional cell carcinoma as a consequence of smoking.

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. Specific DNA alterations known to be involved are discussed in Genetic pathophysiology.

Transitional cell carcinoma is the most common histological type of bladder cancer in developed countries, accounting for approximately 90% of cases. It is the only cell type commonly associated with successful organ-sparing therapy (except the rare urachal carcinoma, which may be removed with partial cystectomy of the dome and urachal remnant). With a high recurrence rate following local therapy, these patients constitute the surveillance population on whom this article is focused.

Squamous cell carcinoma is the second most common cell type associated with bladder cancer in developed countries. Many of these patients are thought to develop disease due to chronic irritation, including from indwelling catheters, bladder stones, and, possibly, infections.

Many urothelial tumors are primarily composed of transitional cell carcinoma but contain small areas of squamous differentiation, squamous cell carcinoma, or adenocarcinoma.

Adenocarcinoma of the bladder is rare and is 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. Except lymphoma, which may be effectively treated with chemotherapy or radiation, these tumors are associated with a poor prognosis.

Stage and grade are particularly important to the likelihood of cancer recurrence and progression in persons with bladder cancer who are treated with local therapy. Using the American Joint Committee on Cancer staging system combined with grade, tumors may be classified using a T-G system of labeling. For example, a Ta tumor that is grade 2 (intermediate differentiation) is described as Ta-G2. The extremes are Ta-G1 (low stage, low grade) to T1-G3 (invading lamina propria, high grade), with correspondingly favorable or unfavorable prognoses.

An anomaly to the above concept is in the case of CIS (see Carcinoma In Situ of the Urinary Bladder). CIS is defined as flat, high-grade, noninvasive cancer. Although some are tempted to consider CIS a premalignant condition, in reality, it is an aggressive form of cancer that is detected prior to invasion. Therefore, correspondingly aggressive management and surveillance are warranted. Likewise, the opportunity to affect CIS-associated mortality is significant because this type of cancer may respond to conservative therapy. However, if left untreated, CIS eventually becomes invasive and progresses. In addition, a move is developing toward classifying such cancers as either high grade or low grade instead of as multiple levels, which has been used in the past. Regardless, the correlation between stage and grade is significant.

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).

Presentation

Most patients with bladder cancer present with gross painless hematuria involving the complete voiding phase. Any adult presenting with this finding should be considered to have bladder cancer until proven otherwise. Less than 20% of patients are diagnosed with bladder cancer based on identification of microscopic hematuria. Routine care visits or employment screens may be the setting for such a finding.

According to the American Urological Association Guidelines Committee, "the recommended definition of microscopic hematuria is three or more red blood cells per high-power microscopic field in urinary sediment from two of three properly collected urinalysis specimens. This definition accounts for some degree of hematuria in normal patients, as well as the intermittent nature of hematuria in patients with urologic malignancies."

Occasionally, cases of bladder cancer are identified because of irritative voiding symptoms. Urgency, frequency, nocturia, and/or urge incontinence is typical. CIS is especially likely to cause such symptoms; therefore, patients presenting with unexplained or refractory irritative symptoms should be considered for cystoscopy and cytological examination of urine. The threshold for doing so should be especially low in persons who smoke and in other persons considered to be at risk.

Physical examination findings are otherwise uncommon with localized bladder cancer. Rarely, a mass is palpable during abdominal, pelvic, rectal, or bimanual examination. A bimanual examination may be considered part of the staging of such lesions.

Indications

Among most patients with bladder cancer who present with noninvasive disease, most remain clinically indolent with even a modicum of urologic intervention. However, some progress, and most experience recurrence at least once in the follow-up period, creating the need for accurate tumor surveillance.

According to the National Comprehensive Cancer Network, the probability of recurrence following local therapy is at least 50% for all stages and grades, whereas 70-90% of patients with T1-G3 tumors experience recurrence. The traditional surveillance protocol involves the following schedule for cystoscopy after removal of the typical noninvasive tumor:

• From 0-2 years - Every 3 months
• From 2-4 years - Every 6 months
• From 5 years and beyond - Every year

This sequence traditionally begins following the removal of a bladder tumor. Therefore, the schedule is restarted (ie, every 3 mo) following each recurrence.

Although most relapses occur within the first 5 years, late recurrence can occur at any time; therefore, lifetime surveillance is considered the standard.

Although the benefit is not clearly demonstrated, many urologists obtain cytology results at the time of cystoscopy in most, if not all, occasions. The roles for this and other bladder cancer detection tests are discussed in Lab Studies.

Relevant Anatomy

Cystourethroscopy is familiar to all urologists. Findings from flexible cystoscopy are as accurate as those from rigid cystoscopy, and flexible cystoscopy is much better tolerated in male patients. Women experience similar levels of discomfort with rigid or flexible cystoscopy.

Viscous lidocaine may somewhat decrease the discomfort for men, but lubrication appears to be more important for patient tolerance. The use of lidocaine has shown little benefit in women in randomized controlled trials.

The entire lower urinary tract urothelium should be inspected endoscopically, noting changes in the urethra and in the bladder. Obstructing benign prostatic hyperplasia should be noted because it may suggest an increased risk of perioperative urinary retention.

Contraindications

• Acute infection
• Intolerance of pain: Although rare, this may necessitate the use of general anesthesia in the operating room.
• Urethral stricture: This could indicate the presence of carcinoma, and a biopsy should be performed if carcinoma is even remotely possible or if the overlying urothelium appears abnormal.
• Lidocaine or latex sensitivity: These should be considered, and, if present, lidocaine and/or latex should be avoided.

Workup

Laboratory Studies

• Dipstick and microscopic examination of the urine allows detection of hematuria or infection. Hematuria suggests the likelihood of bladder cancer recurrence.
• Infection should delay instrumentation because of the risk of sepsis and because of the concern that inflammatory changes might further complicate evaluation of the urothelium.
• Conventional urine cytology has been deemed the criterion standard to detect tumor markers, but its role has been questioned.
  • According to a recent review, the value of conventional cytology appears to have diminished in the last decade. The cause for this decline is unclear and does not appear to be a change in the criteria for determining malignancy through cytological examination because specificity did not change appreciably during the interval. The authors theorized that a decrease in the specialization of cytopathologists reading urine specimens might be responsible.
  • Irrespective of the cause, the sensitivity of cytology in the published literature has diminished, as is shown in the following data reported by Halling and associates in their review of the literature. The sensitivity of conventional cytology for grade 1 tumors was 37% before 1990 but only 11% afterward. Similarly, the sensitivity for grade 2 tumors fell from 75% to 31%.⁴
  • Of concern is that, although it is widely believed that cytology might miss low-grade tumors but is the criterion standard for high-grade tumors, this has apparently changed. Based on the Halling et al review of the literature, cytology found 94% of grade 3 tumors in the earlier era, but, after 1990, cytology reportedly detected only 60% of even high-grade tumors.⁴
  • Fortunately, although the sensitivity of cytology has clearly declined, the specificity remains high and approaches 100%. Therefore, a positive cytology result should be regarded as a true positive; aggressive investigation for occult disease in both the lower and upper urinary tract should ensue.
  • A host of newer tumor markers and molecular diagnostic indicators has been used, as follows:
    • DNA ploidy and image analysis
    • Chromosomal aneuploidy or polysomy
    • Bladder tumor–associated antigen/analytes
    • Nuclear matrix proteins⁵
    • ImmunoCyt
    • Hyaluronic acid and hyaluronidase
    • Fibrin/fibrinogen degradation product
    • Telomerase⁶
    • Microsatellite instability
    • Phenotypic antigens, including Lewis X, M344, DD23, and T138Ag
    • Growth factors and receptors, including epidermal growth factor receptor, autocrine motility factor, basic fibroblast growth factor
    • Oncogene and tumor suppressor genes
    • Survivin antibody
    • Molecular cytology (FISH)

Imaging Studies

• The bladder urothelium is not well visualized with routine imaging studies, including CT scanning, MRI, or pelvic ultrasonography. Small tumors are easily missed on images produced by these modalities, and suggestive findings are commonly related to incomplete bladder filling leaving an irregular area that appears as a filling defect.
• Cystography is useful to evaluate for trauma or to help detect ureteral reflux, but the contrast obliterates visualization of small tumors, obviating its value in the evaluation of malignancy.
• CIS is not visible on images from any current radiographic study.
• Virtual cystoscopy can help detect many bladder tumors, but it is more expensive than cystoscopy and has lower sensitivity and specificity; therefore, it does not play a role in surveillance at this time.
• Upper urinary tract surveillance is as follows:
  • Transitional cell carcinoma is a field change disease, meaning that the entire field of transitional cells is prone to the DNA changes leading to cancer. Therefore, the entire urothelium should be monitored, especially in higher-risk individuals.
  • Because of the association of upper tract transitional cell carcinoma with bladder cancer, the upper tract urothelium should be evaluated radiographically at least upon initial presentation.
  • No standard has been set for the frequency of upper tract surveillance imaging, but most patients present with hematuria and therefore undergo imaging during the original investigation, regardless of bladder cancer status. Following treatment, the frequency of upper tract imaging is still not standardized. However, many authors recommend annual urography, especially in high-risk patients.
  • Patients at high risk should undergo intermittent evaluations during the surveillance period. Patients with positive urine cytology results or positive findings from FISH or other bladder tumor indicators who have no tumor identified in the bladder to explain the positive test result should undergo repeat upper tract evaluation.
  • Excretory urography (ie, intravenous pyelography), retrograde pyelography, and ureterorenoscopy can help detect upper tract synchronous or metachronous tumors. The accuracy of these tests increases in the order listed, with radiographic imaging missing up to three fourths of small upper tract tumors in some series if read by a radiologist instead of the urologist present in the operating room during retrograde contrast injection. Office-based cystourethroscopy has a role in some patients with upper tract transitional cell carcinoma treated with nephron-sparing surgery.
  • CT urography using digital reconstruction of CT images to create a view of the ureters is promising technology that potentially can blend the advantages of CT (ie, speed, visualization of renal parenchyma, visualization of nonurological structures) with the advantages of excretory or retrograde urography (ie, visualization of the upper tract lumen). A few centers currently have the ability to perform this modality, and evaluations are being conducted to assess its role.
• Some centers also use CT intravenous pyelography. Kidney-ureter-bladder (KUB) imaging is performed, followed by a noncontrast CT scan of the abdomen and pelvis. Contrast is then injected intravenously, followed by vascular and excretion-phase CT abdominopelvic imaging. The patient then undergoes anteroposterior and oblique abdominal radiography and postvoid radiography.

Other Tests

• Sensitivity and specificity of commonly available tumor markers: A recent review reported these sensitivities and specificities for commonly available tumor markers.
  • BTAstat yields a sensitivity of 57-83% and a specificity of 46-73%.
  • Nuclear matrix proteins yield a sensitivity of 47-100% and a specificity of 60-70%.
  • Immunocyt yields a sensitivity of 86% and a specificity of 79%.
  • Accu-Dx yields a sensitivity of 52-81% and a specificity of 75-90%.
• FISH molecular cytology: Detection of specific DNA alterations known to be associated with bladder cancer is possible using multitarget FISH. DNA probes (stains) hybridize with abnormal chromosomal sites and may be visualized using fluorescence microscopy.
  • According to several recently published articles, molecular diagnostic testing has improved the previously noted bladder tumor markers. FISH (molecular cytology) has significantly greater sensitivity than conventional cytology while maintaining the known high specificity of cytology.
  • The DNA probes chosen for available FISH testing are based on the highest-yielding combination of chromosomal abnormalities. Three of these are centromeric enumeration probes, which allow rapid determination of aneuploidy of chromosomes 3, 7, and 17, the most commonly related to bladder cancer. The fourth probe is used to label the 9p21 locus, known to be the site of a significant tumor suppressor gene. Loss of this tumor suppressor gene is also related to cancer recurrence and progression.
  • Among patients with bladder cancer in whom cytology results were negative, atypical, and suggestive, FISH detected 60%, 89%, and 100%, respectively, allowing identification of cancer in most patients in whom cytology failed to detect cancer recurrence.
  • Data from the Mayo Clinic indicate that a conversion of FISH results from positive to negative during bacillus Calmette-Guérin (BCG) therapy indicates a response, whereas a failure to convert indicates a high likelihood of cancer persistence following BCG therapy.

Diagnostic Procedures

• Cystourethroscopy is performed in all patients undergoing bladder cancer surveillance, theoretically on the schedule noted in Indications. However, only 40% of patients actually adhere to such recommendations. Failure to undergo standard surveillance has been due to numerous issues. Advanced age and lower-risk tumors are associated with a failure to follow guidelines, as are lower economic status and urban dwelling.

Treatment

Medical Therapy

American Urological Association Guidelines Panel Recommendations

In 1999, the American Urological Association issued evidence-based guidelines for the management of noninvasive bladder cancer. In December 2007, a revision of the guidelines was published based on a comprehensive review of the available literature, as well as individual Panel member experience.⁷ Thus, some of the published recommendations are not evidence-based but a product of practitioner experience. The Panel determined 5 index-patient scenarios for which recommendations could be formulated.

The Panel defined standard guideline statements for which (1) the health outcomes of the alternative interventions are sufficiently well known to permit meaningful decisions and (2) there is virtual unanimity about which intervention is preferred. They defined recommendation guidelines for which (1) the health outcomes of the alternative interventions are sufficiently well known to permit meaningful decisions and (2) an appreciable but not unanimous majority agrees on which intervention is preferred. Finally, they defined option guidelines for which (1) the health outcomes of the interventions are not sufficiently well known to permit meaningful decisions or (2) preferences are unknown or equivocal. Options can exist because of insufficient evidence or because patient preferences are divided and may or should influence choices made.

• For all index patients: Standard: The physician discusses treatment options with the patient, including advantages and disadvantages and adverse effects of intravesical treatment, especially in regard to each particular agent.
• Index patient no. 1: This is a patient who presents with an abnormal growth of the urothelium prior to the establishment of a cancer diagnosis.
• Standard
• A biopsy specimen is obtained for pathologic analysis.
• Under most circumstances, all visible tumor should be completely eradicated.
• If bladder cancer is confirmed, surveillance cystoscopy should be implemented; however, no ideal interval or duration for surveillance cystoscopy has been determined.
• Option: An initial single dose of intravesical chemotherapy may be administered immediately following tumor resection. (Immediate use of an intravesical agent is an option rather than a standard because of the lack of pathologic confirmation of disease at the time of resection, as well as potential side effects, costs, and patient preference. Additionally, intravesical agents are not of benefit in the setting of muscle-invasive disease.)
• Index patient no. 2:This is a patient with small-volume low-grade Ta bladder cancer.
• Recommendation: An initial single dose of intravesical chemotherapy may be administered immediately postoperatively. (The published guidelines explain that single-dose mitomycin C resulted in 17% fewer recurrences than tumor resection alone when all risk groups were considered, but the risk of recurrence and disease progression in individuals with low-grade Ta disease is "relatively low... and there is no evidence that multiple adjuvant instillations of either BCG or chemotherapy have additional benefit in patients at initial diagnosis of Ta Grade 1 bladder cancer.")
• Index patient no. 3:This is a patient with multifocal and/or large-volume, histologically confirmed, low-grade Ta disease or a patient with recurrent low-grade Ta bladder cancer.
• Recommendation: An induction course of intravesical therapy with BCG or mitomycin C is recommended with the goal being prevention or delay of recurrence. (The published guidelines reported a decreased probability of recurrence with either BCG or mitomycin C compared with tumor resection alone. Additionally, the report indicated no statistical advantage of either agent with respect to the incidence of tumor recurrence.)
• Option: Maintenance BCG or mitomycin C may be considered. (The guidelines listed that, while maintenance BCG or mitomycin C is more effective in decreasing recurrence than induction alone, one must consider side effects, discomfort, lack of a uniform dosing schedule, and cost factors that may outweigh the benefits of this approach.)
• Index patient no. 4:This is a patient with initial histologically confirmed high-grade Ta, T1, and/or Tis bladder cancer.
• Standard: For patients with lamina propria invasion (T1) but without muscularis propria in the specimen, repeat resection should be performed prior to additional intravesical therapy.
• Recommendation: An induction course of BCG followed by maintenance therapy is recommended as treatment in these patients. In high-risk patients, BCG has proven superior to mitomycin C in terms of disease-free intervals, regardless of maintenance therapy. No significant data indicate any benefit in terms of disease progression.
• Option: Cystectomy should be considered for initial therapy in select patients. No data indicate an advantage of intravesical therapy with regard to disease progression; thus, clinical factors, including tumor size, multifocality, grade, presence of CIS, angiolymphatic invasion, and prostatic urethral involvement, are all factors to be considered in this option.
• Index patient no. 5:This is a patient with high-grade Ta, T1, and/or CIS bladder cancer that has recurred after prior intravesical therapy.
• Standard: In patients with lamina propria invasion (T1) but without muscularis propria in the specimen, repeat resection should be performed prior to additional intravesical therapy.
• Recommendation: Cystectomy should be considered as a therapeutic alternative in these patients. (High-risk individuals in whom initial intravesical therapy fails are at an high risk of progression to invasive disease, and definitive therapy may be in their best interest.)
• Option: Further intravesical therapy may be considered for these patients. (Repeat intravesical therapy may be indicated in individuals with late recurrence after previous complete response to an intravesical agent. Data are insufficient regarding the role of combined agent therapy regimens.)

Chemotherapy for bladder cancer is covered in detail in Bladder Cancer. In brief, patients with low-grade, low-stage disease may receive expectant treatment or may benefit from BCG or other intravesical therapies. In contrast, patients with T1-G3 disease or CIS are advised to undergo BCG therapy or chemotherapy because of the substantial risk of disease progression.

Smoking cessation decreases the risk of tumor recurrence and progression and improves overall health.

Increased water intake has been advocated because it may help dilute carcinogens and decrease their exposure to the urothelium. Conclusive benefit has not been shown.

Multivitamin or vitamin A supplementation has also been advocated, but data do not fully support this practice.

Surgical Therapy

Transurethral resection of bladder tumor

Complete eradication of tumor is the first step. Most tumors are papillary and are easily removed by endoscopically transecting their narrow stalk or base. Following this, biopsy of the base is performed to ensure complete removal and the absence of invasion. Muscle tissue (or fat) must be present in the base biopsy specimen to ensure accurate staging. Without this, accurate staging cannot be ensured.

Medium and large tumors are resected piecemeal prior to transection of the stalk in order to ensure that large segments do not remain that might be too large to evacuate through the resectoscope.

Cystectomy

This is rarely indicated for noninvasive disease. Exceptions are patients with (1) tumor bulk so substantial that complete eradication of tumor is not feasible endoscopically and (2) CIS or T1-G3 tumor persistence despite adequate intravesical management.

Patients with T1-G3 cancer in association with diffuse CIS are at especially high risk of progression, and they might be treated with early cystectomy based on a decision made by the physician and patient.

Random biopsies

The role of random bladder biopsies is controversial. The minimal benefit of identifying unsuspected CIS must be weighed against the risk of increasing tumor implantation plus the risk of additional bleeding or bladder perforation. However, CIS is often not visible and may be underdetected without bladder biopsies of normal-appearing urothelium.

CIS may not be reasonably removed in total because of its diffuse nature. Therefore, the diagnosis is established and adjuvant therapy is instituted. Obvious areas of CIS may also be fulgurated, but the benefits of this have not been proven.

Resection and management of invasive bladder cancer is also covered in Bladder Cancer.

Preoperative Details

Patients scheduled for cystoscopy or anesthetic cystoscopy with transurethral resection of bladder tumor (or bladder biopsies) must have sterile urine documented prior to instrumentation. This is usually presumed by a microscopic urinalysis showing no bacteria or WBCs. A urine culture is ideal but not always feasible for surveillance cystoscopy.

The risk of urinary tract infection with instrumentation is approximately 1%. Therefore, the author recommends a single dose of fluoroquinolone for patients undergoing cystoscopy and a dose of intravenous antibiotics (ie, cefazolin, gentamicin) for patients in the operating room. Allergies may prompt the use of alternative antibiotic regimens.

Some patients need additional antibiotics based on a history of valvular heart disease. The American Heart Association guidelines recommend prophylaxis in these patients to prevent endocarditis. Administer 2 g of ampicillin intravenously or intramuscularly at least 30 minutes before the procedure (or 2 g of amoxicillin orally at least 1 h before the procedure) in moderate-risk patients. Vancomycin at 1 g intravenously over 1-2 hours completed at least 30 minutes before the procedure may be substituted in patients allergic to penicillin. High-risk patients also receive 120 mg of gentamicin parenterally 30 minutes before the procedure, and they receive a second dose of ampicillin or amoxicillin 6 hours later.

Patients with prosthetics may merit additional antibiotics based on the clinical scenario.

Intraoperative Details

Transurethral Resection of Bladder Tumor

General or regional anesthesia can be used.

Smaller and more friable tumors may be removed at least partially by knocking off fragments with the cutting loop of the resectoscope without the electricity turned on. This sometimes allows partial removal with less risk of bladder perforation.

Pulling the cutting loop away from the tumor is generally much safer than pushing it toward the tumor. Lifting the tumor away from the surrounding normal bladder tissue using the cutting loop is also advisable.

Continuous-irrigation resectoscopes concern some surgeons regarding fluid absorption. However, continuous infusion lessens the bladder wall movement that occurs during filling and emptying and thereby may decrease the risk of bladder perforation. Overfilling also stretches and thins the detrusor, which is another risk factor.

Transurethral resection syndrome due to fluid absorption is uncommon unless the tumor being resected is particularly large. If this is a concern, glycine prevents hemolysis, but not hyponatremia.

Overuse of cautery at the base of the tumor increases cautery artifact, which can complicate pathological determination of muscle invasion status.

In select patients, office-based fulguration of small tumors allows control of low-risk lesions without incurring the cost and inefficiencies of the operating room.⁸

Patient comfort with surveillance cystoscopy should be paramount. As noted, intraurethral lidocaine may be beneficial in men, but not significantly so in women. Adequate lubrication, gentle technique, and facilitation of patient relaxation are the most effective measures to allow tolerance of the procedure.

Cystoscopy is an embarrassing procedure to the patient. Exposure and handling of the genitalia must be performed with respect. The patient remains exposed only as long as is necessary to complete the evaluation.

Men are most easily evaluated with a flexible cystoscope. Modern versions have superior optics and allow easy visualization of the entire bladder. Miniaturization of the instruments also allows for biopsy and fulguration through the flexible cystoscope.

The latest development in surveillance involves advances that integrate video chip technology on the end of flexible cystoscopes, as with the Endo-EYE from Olympus America Inc (see Image 5). (Olympus and Endo-EYE are registered trademarks of the Olympus Corporation, Olympus America Inc, or their affiliated entities.)

Different techniques are described, including "painting" the bladder with multiple passes in and out. The author prefers a "sweeping" technique when using fiberoptic scopes.

The scope is advanced through the urethra under direct visualization, asking the patient to relax his "bottom" while passing through the external urinary sphincter. Immediately upon bladder entry, the scope is advanced to its greatest depth while using the thumb to retroflex it against the bladder dome.

Irrigation is turned off to minimize bladder overdistension. This is more comfortable for the patient and minimizes the amount of mucosal surface area that must be inspected. It may be restarted if distention is inadequate or if debris or blood impairs visualization.

Secondary deflection from the scope angling off the detrusor easily allows a bird's-eye view of the bladder base, which is the most common site of primary occurrences. In this position with slight left and right rotation, more than half the bladder is visible. If a lesion is identified, the scope may be advanced closer for a magnified view.

The scope is then pulled back to the bladder neck and directed to view the floor by thumb control. Once the floor is fully visible, the scope is swept toward the patient's right side.

Minor movement in and out at the bladder neck (taking care to not drag the scope over the bladder neck mucosa) allows complete visualization as the scope is swept 270°.

When the scope reaches the 3-o'clock position (patient's left side), the surgeon's wrist cannot complete the circle so the scope is brought back to the base of the bladder and the procedure is repeated in reverse.

Any suggestive areas are inspected carefully, confirming the healthiness of the mucosa or noting any lesions that require further investigation or intervention.

In contrast to the sweeping technique, which is most effective with fiberoptic scopes, the vastly superior optics of modern digital chip technology scopes allow visualization of the entire bladder in most patients by moving minimally in either direction when the tip of the scope sits just inside the bladder neck. After seeing the upper half or more of the bladder, the scope may be advanced into the retroflexed position and can easily visualize the basilar (or trigonal) half or more of the bladder. This offers more completeness of the examination and is better tolerated by the patient.

Cystoscopy techniques for women

Female cystoscopy can be performed as described for men, using the flexible cystoscope, or, because of the relatively straight female urethra, using a rigid cystoscope.

In actuality, the female urethra also dips slightly down; therefore, placement of the rigid scope is more comfortable if the scope (with an obturator in place to create a smooth tip) is pointed dorsally as it enters the urethra and then redirected ventrally prior to entering bladder neck, following the natural, slightly upward curve of the urethra.

In order to remove the obturator without spilling urine, the scope may be placed gently against the back wall of the bladder while switching the obturator for a lens, although the surgeon must be careful to avoid causing irritation that could mimic CIS. Note that the trigone is the most sensitive part of the bladder, so placing the scope against the back wall instead of the trigone is requisite.

Once the 70° lens is in place, the bladder may be swept similarly by angling the surgeon's end of the scope away from the side of interest. In doing so, the scope (eyepiece) essentially ends up creating a conical motion, with the tip or pivot point being the urethra. The 30° degree lens is then able to visualize the entire bladder with effort, but the 70° degree lens can easily visualize the entire bladder unless the bladder is overfilled.

Use of a video camera system is helpful for education of both residents and patients and allows documentation of findings. Monitoring is not usually required for patients undergoing office-based cystourethroscopy. Some urologists also believe their diagnostic accuracy is improved with the magnification and optics of the camera system.

Digital chip endoscopy may be performed as easily in women as it is in men. See Cystoscopy techniques for men for a description.

Postoperative Details

Patients may prefer to redress themselves prior to discussing the findings or allowing family members to enter the examination room.

Follow-up

Patients must understand that minor hematuria or dysuria is normal and expected following instrumentation. Irritative symptoms may be treated with phenazopyridine. Less commonly, anticholinergic agents may help relieve detrusor contractions.

Obstructive symptoms in men usually resolve within a few hours, but urinary retention occasionally occurs. Alpha-blocking agents may be useful if administered prior to complete retention. Patients with preexisting obstructive symptoms may be given preemptive treatment.

Patient Education:

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center, Kidneys and Urinary System Center, and Procedures Center. Also, see eMedicine's patient education articles Bladder Cancer, Blood in the Urine, and Cystoscopy.

Complications

Complications of surveillance cystoscopy are as follows:

• Urinary tract infection
• Dysuria
• Hematuria
• Urethral stricture
• Pain

A specific concern is in a patient with spinal cord injury. Autonomic dysreflexia can occur as a response to bladder distention, leading to potentially life-threatening hypertension. This may be prevented with nifedipine or terazosin in some cases, but careful monitoring is requisite. Any signs of headache, tremors, or hypertension should lead to immediate cessation of the procedure and emptying of the distended bladder. For this reason, most patients with spinal cord injury should probably undergo cystoscopy in the operating room with anesthesia monitoring.

Complications of transurethral resection of bladder tumor are as follows:

• Bladder perforation
• Ureteral obstruction
• Hematuria
• Urinary retention
• Transurethral resection syndrome
• Urinary tract infection
• Dysuria
• Hematuria
• Urethral stricture
• Pain

Outcome and Prognosis

The prognosis of bladder cancer is primarily related to tumor grade and stage. In addition, multiplicity or rapid recurrence following an initial transurethral resection of bladder tumor is associated with greater recurrence rates (although early recurrence may also be related to incomplete initial resection or failure to detect a satellite lesion).

Estimates vary, but low-risk cancers (ie, Ta-G1) recur in at least half of all patients and progress in approximately 5%. In contrast, high-risk cancers carry a correspondingly worse prognosis. T1-G3 cancers usually recur, and they progress in approximately half of all patients. T1-G3 cancers found in association with CIS frequently progress, and these patients may be considered for immediate cystectomy.

Future and Controversies

Although many urologists believe that cystoscopy is infallible in their hands (or eyes), some concerning findings challenge this opinion.

Instilling 5-aminolevulinic acid into the bladder a few hours prior to cystoscopy allows accumulation in malignant sites often not visible during white-light (normal) cystoscopy. When illuminated with a light ranging from 375-445 nm, up to one fourth of small malignant areas may be missed during routine cystoscopy. This has been proven by biopsy studies.

Of concern is that these areas may be more likely to harbor higher-grade cancer than those identified otherwise. CIS is missed by conventional cystoscopy 22% of the time.

Halling et al similarly found a significant number of cancers that cystoscopy failed to definitively identify.⁴ This draws into question whether early recurrences are truly recurrent cancer or simply incompletely removed cancer.

Artificial neural networks using various tumor markers similar to those described by Parekattil et al may be more cost effective for detecting recurrence and progression than the current screening protocol of cystoscopy and conventional cytology at predetermined intervals.⁵ Using more effective markers may allow scheduling of cystoscopy on a more logical and targeted schedule than is currently the default.

Nonlinear surveillance strategies have been shown in at least one model to actually decrease the time to detection of tumor recurrence while optimizing the utilization of resources.

A fresh look at surveillance strategies is in order based on the lack of evidence on which current standards are based and on new findings regarding the ability to predict cancer recurrence using neural networks, prediction models, and improved diagnostic tests, including molecular diagnostic evaluations. As this process progresses, the conventional surveillance protocol will likely change. Using tumor stage and grade in conjunction with improved surveillance methods, resources may be focused on patients at risk of recurrence and progression.

Specific concepts likely to help focus surveillance in the near future include improved endoscopic techniques that can identify otherwise imperceptible malignancy and molecular diagnostic tests that can identify malignant change prior to anatomic transformation. However, until such time, cystoscopy in conjunction with some form of cytology (either conventional or molecular cytology, ie, FISH) is likely to remain the mainstay in surveillance at currently accepted intervals.

Multimedia

Media file 1: The classic appearance of carcinoma in situ as a flat, velvety patch. However, using special staining techniques such as 5-aminolevulinic acid, it has been shown that significant areas of carcinoma in situ are easily overlooked by conventional cystoscopy. Courtesy of Abbott and Vysis Inc.

Media file 2: Papillary bladder tumors such as this one are typically of low stage and grade (Ta-G1). Courtesy of Abbott and Vysis Inc.

Media file 3: Sessile lesions as shown usually invade muscle, although occasionally a tumor is detected at the T1-G3 stage prior to muscle invasion. Courtesy of Abbott and Vysis Inc.

Media file 4: Flexible cystoscopes such as this one facilitate endoscopic tumor surveillance with minimal morbidity and excellent visualization of the urothelium. Courtesy of Olympus America Inc.

Media file 5: The latest development in surveillance involves advances that integrate video chip technology on to the end of flexible cystoscopes. Courtesy of Olympus America Inc.

Media file 6: Rigid cystoscopes such as this one allow biopsy collection via in-office fulguration of small tumors. Such fulguration may be performed using electrocautery or laser. Courtesy of Olympus America Inc.

Media file 7: Resection of all visible tumors is possible using modern resectoscopes. Courtesy of Olympus America Inc.

Media file 8: Photograph in which fluorescence in situ hybridization centromere staining identifies aneuploidy of chromosome 3. Multiple instances of overexpression of the chromosome (note the multiple red dots, which identify centromeres of this chromosome) prove aneuploidy.

References

1. American Cancer Society. Cancer Fascts and Figures. 2008. Atlanta.

2. Morey SS. American Urological Association issues guidelines on the management of bladder cancer. Am Fam Physician. Jun 15 2000;61(12):3734, 3736. [Medline].

3. Scher H, Bahnson R, Cohen S, et al. NCCN urothelial cancer practice guidelines. National Comprehensive Cancer Network. Oncology (Huntingt). Jul 1998;12(7A):225-71. [Medline].

4. Halling KC, King W, Sokolova IA, et al. A comparison of cytology and fluorescence in situ hybridization for the detection of urothelial carcinoma. J Urol. Nov 2000;164(5):1768-75. [Medline].

5. Parekattil SJ, Fisher HA, Kogan BA. Neural network using combined urine nuclear matrix protein-22, monocyte chemoattractant protein-1 and urinary intercellular adhesion molecule-1 to detect bladder cancer. J Urol. Mar 2003;169(3):917-20. [Medline].

6. Halling KC, King W, Sokolova IA, et al. A comparison of BTA stat, hemoglobin dipstick, telomerase and Vysis UroVysion assays for the detection of urothelial carcinoma in urine. J Urol. May 2002;167(5):2001-6. [Medline].

7. Hall MC, Chang SS, Dalbagni G, Pruthi RS, Seigne JD, Skinner EC, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol. Dec 2007;178(6):2314-30. [Medline].

8. Donat SM, North A, Dalbagni G, Herr HW. Efficacy of office fulguration for recurrent low grade papillary bladder tumors less than 0.5 cm. J Urol. Feb 2004;171(2 Pt 1):636-9. [Medline].

9. Brown FM. Urine cytology. It is still the gold standard for screening?. Urol Clin North Am. Feb 2000;27(1):25-37. [Medline].

10. Herts BR. The current status of CT urography (2002). Crit Rev Comput Tomogr. 2002;43(3):219-41. [Medline].

11. Jones JS. DNA-based molecular cytology for bladder cancer surveillance. Urology. Mar 2006;67(3 Suppl 1):35-45; discussion 45-7. [Medline].

12. Karnes R, Halling K, Lieber M. Urine fluorescence in situ hybridization analysis during bacillus Calmette-Guerin treatments in urothelia carcinoma. Presented at: Society of Urologic Oncology Fourth Annual Meeting: Extraordinary Opportunities for Discovery. Bethesda, Md; December 13-14, 2002:. Poster abstr.

13. Kent DL, Nease RA, Sox HC, et al. Evaluation of nonlinear optimization for scheduling of follow-up cystoscopies to detect recurrent bladder cancer. The Bladder Cancer follow-up Group. Med Decis Making. Oct-Dec 1991;11(4):240-8. [Medline].

14. Kipp BR, Karnes RJ, Brankley SM, et al. Monitoring intravesical therapy for superficial bladder cancer using fluorescence in situ hybridization. J Urol. Feb 2005;173(2):401-4. [Medline].

15. Koch MO, Smith JA Jr. Natural history and surgical management of superficial bladder cancer (stages Ta/T1/CIS). In: Vogelzang N, Miles BJ, eds. Comprehensive Textbook of Genitourinary Oncology. Baltimore, Md: Williams & Wilkins; 1996:415.

16. Lokeshwar VB, Soloway MS. Current bladder tumor tests: does their projected utility fulfill clinical necessity?. J Urol. Apr 2001;165(4):1067-77. [Medline].

17. Malkowicz SB. Management of superficial bladder cancer. In: Walsh PC, Retik AB, Vaughan ED, Wein AJ, eds. Campbell's Urology. 8^th ed. Philadelphia, Pa: WB Saunders; 2003:2785.

18. Ries LAG, Eisner MP, Kosary CL. SEER Cancer Statistics Review, 1975-2000. Available at: http://seer.cancer.gov/csr/1975_2000/. Bethesda, Md: National Cancer Institute. [Full Text].

19. Schrag D, Hsieh LJ, Rabbani F, et al. Adherence to surveillance among patients with superficial bladder cancer. J Natl Cancer Inst. Apr 16 2003;95(8):588-97. [Medline].

Keywords

surveillance for recurrent bladder cancer, non-invasive bladder cancer, noninvasive bladder cancer, bladder cancer, bladder cancer surveillance, bladder tumor surveillance, superficial bladder cancer, carcinoma in situ, CIS bladder cancer, papillary bladder cancer, urologic cancer, transitional cell carcinoma, TCC, squamous cell carcinoma, SCC, cystoscope, TURBT, transurethral resection of bladder tumor, TUR syndrome, transurethral resection syndrome, bladder cancer recurrence, bladder tumor recurrence, leiomyosarcoma, rhabdosarcoma, carcinosarcoma, lymphoma, small cell carcinoma, adenocarcinoma

Contributor Information and Disclosures

Author

David A Levy, MD, Assistant Professor of Surgery (Urology), Glickman Urologic and Kidney Institute, Cleveland Clinic Foundation
David A Levy, MD is a member of the following medical societies: American Association of Clinical Urologists, American Urological Association, and Society of Urologic Oncology
Disclosure: Nothing to disclose.

Coauthor(s)

J Stephen Jones, MD, FACS, Chairman, Department of Regional Urology, Cleveland Clinic Glickman Urological and Kidney Institute; Associate Professor of Surgery (Urology), Cleveland Clinic Lerner College of Medicine at Case Western Reserve University School of Medicine
J Stephen Jones, MD, FACS is a member of the following medical societies: Academy of Medicine Cleveland/Northern Ohio Medical Assn, American College of Surgeons, American Urological Association, International Continence Society, Society of Urologic Oncology, and Southwest Oncology Group
Disclosure: Abbott Honoraria Speaking and teaching; cook Honoraria Consulting; endocare Honoraria Speaking and teaching; pfizer Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Martin I Resnick, MD †, Former Lester Persky Professor and Chair, Department of Urology, Former Professor, Department of Oncology, Case Western Reserve University School of Medicine
Martin I Resnick, MD † is a member of the following medical societies: American College of Surgeons, American Federation for Medical Research, American Institute of Ultrasound in Medicine, American Medical Association, American Society for Bone and Mineral Research, American Society for Reproductive Medicine, American Society of Andrology, American Surgical Association, American Urological Association, Association for Academic Surgery, Endocrine Society, National Kidney Foundation, Ohio Urological Society, and Pan American Medical Association
Disclosure: Nothing to disclose.

CME Editor

J Stuart Wolf Jr, MD, FACS, David A Bloom Professor of Urology, Director of Division of Minimally Invasive Urology, Department of Urology, University of Michigan
J Stuart Wolf Jr, MD, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Catholic Medical Association, Endourological Society, Society for Urology and Engineering, Society of Laparoendoscopic Surgeons, Society of University Urologists, and Society of Urologic Oncology
Disclosure: Terumo Corporation Consulting fee Consulting; Gyrus-ACMI Honoraria Speaking and teaching

Chief Editor

Bradley Fields Schwartz, DO, FACS, Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine
Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Association of Military Osteopathic Physicians and Surgeons, Endourological Society, Society of Laparoendoscopic Surgeons, and Society of University Urologists
Disclosure: Nothing to disclose.

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