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

Bladder Cancer: Follow-up

Author: Gary David Steinberg, MD, FACS, Professor and Vice Chairman of Urology, Director of Urologic Oncology, Section of Urology, Department of Surgery, The University of Chicago Cancer Research Center
Coauthor(s): Mark H Katz, MD, Fellow in Urologic Oncology and Minimally Invasive Surgery, University of Chicago Medical Center; Kush Sachdeva, MD, Southern Oncology and Hematology Associates, South Jersey Healthcare, Fox Chase Cancer Center Partner; Brendan Curti, MD, Director, Genitourinary Oncology Research, Robert W Franz Cancer Research Center, Earle A Chiles Research Institute, Providence Cancer Center; Bagi RP Jana, MD, Assistant Professor, University of Central Florida College of Medicine; Attending Physician, Department of Medicine, Florida Hospital Cancer Institute, Orlando
Contributor Information and Disclosures

Updated: Jul 27, 2009

Follow-up

Further Outpatient Care

For more information, see Surveillance for Recurrent Bladder Cancer.

The high rate of disease recurrence and progression in non–muscle invasive bladder cancer underscores the need for careful follow-up studies. Surveillance for these patients includes cystoscopy and bladder wash cytologies every 3 months for 2 years, then every 6 months for 2 years, and then at least yearly.

Cystoscopy

Cystoscopy is the primary diagnostic modality for the diagnosis of bladder carcinoma because it confers low risk and can be performed in the physician's office. Although it is the criterion standard for detecting bladder cancer, cystoscopy is invasive and relatively expensive.³ Moreover, visibility can be reduced by bleeding, and flat urothelial lesions such as CIS may be difficult to distinguish from normal bladder tissue. Thus, cytologic analysis of voided urine is frequently used as an adjunctive test to aid in identifying occult cancers.

Cytology

Voided urine cytology is the standard noninvasive method for diagnosis in the detection of bladder carcinoma. Cytology is used to assess morphologic changes in intact cells. Unfortunately, however, the sensitivity of cytology is low, with various studies reporting values between 11% and 76%.⁴ Sensitivity depends largely on the degree of tumor differentiation. High-grade tumors with marked pleomorphism and distinctly abnormal nuclear features are identified more accurately.

Small and/or well-differentiated tumors are less likely to exfoliate cells because intercellular attachments are better preserved and the degree of morphological departure from normal is smaller, complicating cytologic recognition.⁵ This results in poor sensitivity in low-grade and early-stage cancers. Several other factors affect the sensitivity of cytology, including specimen quality, number of exfoliated cells, and pathologist expertise. The overall low sensitivity of cytology is due to its low sensitivity in detecting low-grade bladder tumors.⁶

In addition, instrumentation may cause reactive cellular changes, contributing to variability in interpretation. False-positive reports of malignant cells are uncommon, but ambiguous reports of atypical cells are frequent. Bladder wash cytology yields more tumor cells in the sample and is more sensitive in identifying cancer, especially for high-grade tumors, but it also yields a higher false-positive rate than voided urine cytology.⁷

Noninvasive urine markers can offer an alternative to the standard means of detecting bladder cancer or can be used as an adjunct to cystoscopy.⁸

Genetic aberrations

The study of genetic aberrations commonly associated with urothelial carcinoma provides a more objective assessment for diagnosing and detecting recurrent disease. Homozygous loss of chromosome band 9p21, the site for the tumor suppressor gene p16, is a known early genetic event in the development of papillary carcinoma and urothelial CIS.⁹

Increased chromosomal instability and aneuploidy have been implicated in tumor progression. A study by Sokolova et al of 9 genetic markers for detecting urothelial carcinoma showed that polysomy of chromosomes 3, 7, and 17 and deletion of 9p21 were the most sensitive and specific markers, detecting 95% of recurrent urothelial carcinoma.¹⁰ Halling et al established that a threshold of 5 or more cells with polysomy was 84% sensitive and 92% specific for detecting recurrent urothelial cancer.⁹

Fluorescence in situ hybridization

A commercial FISH assay (UroVysion), which includes probes for the centromeres for chromosomes 3, 7, and 17 and has a locus-specific probe for 9p21, was developed to screen for recurrent urothelial carcinoma and was recently approved by the US Food and Drug Administration (FDA) for diagnostic studies.

Initial comparisons of urine cytology with FISH for detecting bladder cancer recurrence showed that FISH yielded a greater sensitivity.¹¹ FISH is 42-83% sensitive for detecting pTa and pT1 lesions and 92-100% sensitive for pT2-4 invasive lesions in patients with known bladder cancer, while urine cytology yields sensitivities of 24-50% for pTa and pT1 lesions and 78-85% for pT2-4 invasive lesions.¹² For suspected new cases of urothelial carcinoma, cytology yields a reported diagnostic sensitivity of 48%, while no data are available for FISH evaluation of these cases.¹³

Laudadio et al compared the diagnostic sensitivity of FISH with concurrent biopsy and cytological assessments.¹⁴ FISH analysis was found to yield a high sensitivity for detecting new cases of urothelial carcinoma, as well as recurrences. Their study showed FISH detected 95% of cases with high-grade carcinoma, while cytology detected 41% of such cases. FISH yielded an overall specificity of 65%, compared to 93% with cytology. From this data, the authors concluded that FISH is considerably more sensitive and only slightly less specific than cytology in diagnosing urothelial carcinoma. They recommended FISH as a useful initial diagnostic tool in patients suspected of both new and recurrent bladder cancer.

Nuclear matrix protein-22

Nuclear matrix, first described in 1974, is the nonchromatin structure that supports nuclear shape and organizes DNA. It also takes part in DNA replication and transcription, as well as RNA processing.^15,16,17 NMP-22 is involved in the proper distribution of chromatin to daughter cells during cell division and is found in the nuclear matrix of all cell types. NMP-22 is thought to be released from the nuclei of tumor cells after they die and can be detected in the urine. Research has found that persons with bladder cancer may have urinary NMP-22 levels up to 25 times that in healthy persons.¹⁸

The NMP-22 BladderChek test is an in vitro immunoassay intended for the qualitative detection of NMP-22 in urine. It determines whether NMP-22 is present in urine and provides an absolute positive or negative test result, much in the same manner as a pregnancy test. The NMP-22 assay detects elevated amounts of nuclear mitotic apparatus protein, a component of the nuclear matrix essential for cell division that is released into the urine during cell death. Unlike cytologic examinations and FISH-based tests, detection of NMP-22 protein does not depend on the recovery of intact cells. It is a painless and noninvasive assay that provides results within 30 minutes and is the only in-office test approved by the FDA for the diagnosis of bladder cancer.

Grossman et al compared the NMP-22 BladderChek test with cystoscopy and voided urine cytology for surveillance of recurrent bladder cancer.⁵ Initial cystoscopy alone detected 91% of the cancers. The combination of the NMP-22 test with cystoscopy increased overall sensitivity to 99% (P =0.005). The NMP-22 test was significantly more sensitive than cytologic analysis of voided urine. The authors concluded that, when combined with cystoscopy, the NMP-22 test improves the detection of recurrence in patients with a history of bladder cancer. Unlike cytologic analysis, this test does not require expert analysis or laboratory time, does not depend on intact cells, and provides unambiguous results. In addition, the NMP-22 test provides results during the patient visit, and its cost is less than half that of cytology.

Of concern with the NMP-22 assay is its variability of performance in detecting bladder cancer. A report by Shariat et al assessed the variability in the diagnostic performance of NMP-22 for detecting recurrence and progression in patients with Ta, T1, and/or CIS TCC of the bladder.¹⁹ NMP-22 voided urine levels were measured in 2,871 patients who underwent office cystoscopy for monitoring previous stage Ta, T1, and/or CIS bladder cancer at 12 institutions. Their results showed that the manufacturer cutoff of 10 U/mL detected 57% of cases with a 19% false-positive rate. For each NMP-22 cutoff assessed, NMP-22 had a higher sensitivity for detecting grade III and stage T2 or greater bladder cancer than for detecting any cancer.

No optimal cutoffs for detecting any or aggressive bladder cancer could be derived based on NMP-22 values. The authors concluded that there is a substantial degree of heterogeneity in the diagnostic performance of NMP-22 applied to populations from different institutions. There was no clearly defined NMP-22 cutoff, but there was a continuum of risk for recurrence and progression.

Conclusions

Several reviews have been performed to assess the myriad urine markers proposed for bladder cancer surveillance. They note that none of the markers has been proven sensitive and specific enough to replace cystoscopy.²⁰ While FISH and NMP-22 are promising, the clinical evidence is insufficient to warrant the substitution of the cystoscopic follow-up scheme with any of the currently available urine marker tests.²¹

If FISH and NMP-22 are considered to have some utility when used to complement or replace cytology, a dilemma arises when their results conflict with each other. Of particular interest is how to treat a patient with positive cytology and/or FISH findings when cystoscopy findings are negative.

Because cytology is the most reliable urine test for detecting bladder cancer, a positive cytology finding should be treated as cancer until proven otherwise. If cystoscopy findings are negative in the setting of positive cytology findings, further evaluation of the urinary tract is required. The upper urinary tract should be evaluated with contrast imaging. Cystoscopy with bilateral retrograde pyelography and bilateral ureteral washings should be performed. At the time of this procedure, ureteroscopy may also be performed if possible upper tract disease is suspected. The urinary tract distal to the bladder—the shorter urethra in women or the longer urethra in men, with its prostatic, bulbar, and penile portions—must also be assessed during cystoscopy. If the findings of all of these examinations remain negative, one must maintain a heightened suspicion and perform routine surveillance with more regularity.

In the setting of negative cystoscopy findings, negative urine cytology findings, and positive FISH findings, 2 possible scenarios arise. This result is either falsely positive, or it may be an anticipatory positive result, meaning that such patients have a 30% chance of developing a bladder tumor over 2 years, despite having negative cytology and cystoscopic evaluation findings. Patients in this category should also undergo surveillance with increased frequency (see Table 2).

Table 2. Clinical Findings and Recommended Action

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Patients who have undergone radical cystectomy require routine surveillance to monitor for local recurrence or the development of metastatic disease. Abdominal and pelvic CT scanning and chest radiography should be performed annually. Some patients with more adverse pathology at the time of cystectomy (eg, locally advanced disease, lymph node metastases) may require more frequent imaging.

The retained male urethra is at risk for cancer recurrence after radical cystoprostatectomy. Urethral recurrence occurs in approximately 7% of patients after cystoprostatectomy.

• Cancer involving the prostate (urothelium or stroma) at the time of cystoprostatectomy is the most significant risk factor for urethral recurrence.
• Monitoring the retained urethra has historically included periodic urethral cytology with subsequent biopsy, if indicated. However, some small studies have suggested monitoring with urethral washings does not confer a survival benefit.²²
• Gross hematuria or bloody urethral discharge requires immediate workup.
• A positive urethral cytology or biopsy finding warrants immediate urethrectomy.

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 radical cystectomy 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 small-bowel obstruction and ureteroenteric stricture (see Table 3).
• Table 3. Most Common Complications of Radical Cystectomy

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  Table

  Early Complications	Rate, %	Late Complications	Rate, %
  Ileus	5.9	Small bowel obstruction	7.4
  Wound infection	5.5	Ureteroenteric stricture	7.0
  Sepsis	4.9	Renal calculi	3.9
  Pelvic abscess	4.7	Acute pyelonephritis	3.1
  Hemorrhage	3.4	Parastomal hernia	2.8
  Wound dehiscence	3.3	Stomal stenosis	2.8
  Bowel obstruction	3.0	Incisional hernia	2.2
  Enterocutaneous fistula	2.2	Fistula	1.3
  Rectal injury	2.2	Rectal complications	<1

  Early Complications	Rate, %	Late Complications	Rate, %
  Ileus	5.9	Small bowel obstruction	7.4
  Wound infection	5.5	Ureteroenteric stricture	7.0
  Sepsis	4.9	Renal calculi	3.9
  Pelvic abscess	4.7	Acute pyelonephritis	3.1
  Hemorrhage	3.4	Parastomal hernia	2.8
  Wound dehiscence	3.3	Stomal stenosis	2.8
  Bowel obstruction	3.0	Incisional hernia	2.2
  Enterocutaneous fistula	2.2	Fistula	1.3
  Rectal injury	2.2	Rectal complications	<1

• Radical cystectomy
  • The reported overall early and late complication rate associated with radical cystectomy is approximately 25%-30%. However, this may be an underestimation of the true complication rate because of a lack of standardized reporting in published studies.
  • 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 in patients older than 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

• 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 metastatic urothelial 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.
• 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).
• Non–muscle invasive bladder cancer
  • 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 – 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.

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, Intravenous Pyelogram, and Cystoscopy.

Miscellaneous

Medicolegal Pitfalls

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

• Search for CME/CE on This Topic »

• Surveillance for Recurrent Bladder Cancer (Urology)
• Cystectomy, Radical (Urology)
• Lymph Node Dissection, Pelvic (Urology)
• Carcinoma In Situ of the Urinary Bladder (Urology)

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• Bladder Cancer Overview
• Bladder Cancer Causes
• Bladder Cancer Symptoms
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• Kidneys and Urinary System Center
• Blood in Urine Overview
• Cystoscopy Introduction
• Bladder Cancer Treatment

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• Epigenetic Biomarkers in Urothelial Bladder Cancer
• Role of Human Papillomavirus Types 16, 18, and 52 in Recurrent Cystitis and Urinary Bladder Cancer Among Egyptian Patients

• Bladder Cancer Resource Center