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

Carcinoma In Situ of the Urinary Bladder: Workup

Author: Stanley A Brosman, MD, Clinical Professor, Department of Urology, University of California at Los Angeles Medical School
Contributor Information and Disclosures

Updated: Oct 9, 2007

Workup

Laboratory Studies

The laboratory evaluation involves urinalysis to detect hematuria or infection, cytology, urinary tumor marker testing, and bladder biopsies.

• Urinalysis
  • This routine test is used to evaluate for the presence of RBCs, WBCs, and protein and to assess for urinary tract infection.
  • RBCs in the urine require either a repeat study or an evaluation by a urologist to investigate for any serious disease. Gross hematuria always requires a careful assessment with imaging studies of the entire urinary tract (CT urography) and cystoscopy. Patients with bladder cancer may have gross or microscopic hematuria, and this often resolves spontaneously. This lulls the patient and the clinician into erroneously believing that no significant entity is present.
  • Men do not usually have RBCs in their urine, and any number should lead to further urologic testing. In women, RBCs can frequently be found in a voided specimen, but persistent microhematuria warrants further testing, as does a voided urine sample containing 3 or more RBCs per high-power microscopy field.
• Urine for culture and sensitivity: Prior to performing an endoscopic examination or initiating any therapy, the urine should be free of evidence of infection.
• Urine cytology
  • An extremely valuable study, urine cytology is often the test used for diagnosis; suggestive urine cytology findings encourage the urologist to perform a bladder biopsy. With a properly collected urine sample that is promptly placed into fixative, the presence of carcinoma in situ (CIS) is detected in 70-75% of patients.
  • At least 100 mL of a freshly voided specimen, not an overnight sample, is usually sufficient. Cells sitting in the urine overnight tend to become distorted and are difficult to analyze. If the urine is very dilute, the number of cells may be insufficient, necessitating a larger urine volume. Bladder washings can be obtained by placing a catheter into the bladder and vigorously irrigating with saline. The advantage of bladder washing is that larger numbers of cells can be obtained.
  • As with any type of cytologic examination, the experience and skill of the cytopathologist is extremely important. Many hospital laboratories lack the skills and technology necessary to accurately perform this type of study. Good reference laboratories are available if local facilities cannot provide this service.
  • Cytoimmunologic techniques have been developed using cytokeratin 20 as a target molecule. This assay may be more sensitive than conventional cytology, although the ability to detect low-grade tumors tends to be poor in all cytologic examinations, whereas the positive predictive value in patients with CIS tends to be around 75%.
• Urine tumor markers
  • Numerous molecular tumor markers have been identified in the urine of patients with bladder cancer. The 4 available tests approved by the US Food and Drug Administration (FDA) for bladder cancer evaluation include the BTA stat ([bladder tumor antigen] Polymedco; Redmond, Wash), NMP22 (Matritech; Newton, Mass), DD23, and fluorescence in situ hybridization (FISH). These tests have been studied primarily in patients with papillary cancer, but the results from patients with high-grade tumors correlate with those obtained from persons with CIS. The FISH assay seems to be the most accurate and reliable of this group and is being used more frequently in the clinical setting. However, it remains very expensive.
  • Several cytokeratin markers have been studied. Bladder cancer antigen (BCA) testing measures cytokeratins 8 and 18, while CYFRA 21-1 testing detects cytokeratin 19. Cytokeratin 20 seems to have a higher sensitivity and positive predictive value than standard cytology.
  • In 2001, Sánchez-Carbayo et al compared cytology, BCA, CYFRA 21-1, and NMP22. Voided or bladder-wash specimens from 187 patients with CIS or papillary cancers were collected and analyzed. They noted that BCA had a sensitivity of 69.4%, a specificity of 91.3%, and a positive predictive value of 85%. CYFRA 21-1 had a sensitivity of 67.3%, a specificity of 88.4%, and a positive predictive value of 80.5%. NMP22 had a sensitivity of 61.2%, a specificity of 89.9%, and a positive predictive value of 81.1%. Cytology (positive or negative) had a sensitivity of 35.4%, a specificity of 97.2%, and a positive predictive value of 85.2%.¹
  • Other markers include telomerase, epithelial growth factor, fibrinogen products, and p53. Currently, these have not gained wide acceptance in clinical practice because they do not have the requisite high level of sensitivity and negative predictive value to substitute for currently accepted methodologies.
  • Van Rhijn and coworkers reviewed the literature for urine markers that would be useful for surveillance and reported on their findings. They found 18 markers that had enough data for evaluation. The highest median sensitivities were reported for CYFRA21-1 (85%), cytokeratin 20 (85%), and microsatellite analysis (89%). The highest specificities were reported for cytology (94%), BTA (92%), and microsatellite analysis (89%). They concluded that microsatellite analysis, ImmunoCyt, NMP22, CYFRA21-1, LewisX and FISH were the most promising, but none can replace cystoscopy with or without biopsy.²  Currently, a reasonable approach would be to use standard cytology or office-based NMP22 routinely with yearly ImmunoCyt or FISH testing.
  • Research to identify urine markers that could help in the diagnosis of TCC and could help determine the effectiveness of intravesical therapy is currently underway.
  • No blood tests are specific for this disease, but a general evaluation is necessary prior to initiating therapy with intravesical BCG vaccine.
  • With regard to the CBC count, the presence of anemia or an elevated WBC count warrants further investigation for an explanation.
• Chemistry panel
  • Liver function should be evaluated. One of the intravesical agents used to treat CIS is BCG vaccine. Systemic absorption of this agent can produce acute hepatitis. Knowing the findings of liver function tests prior to initiating therapy and repeating these tests during the course of therapy help prevent serious adverse events and determine when therapy should be stopped.
  • Patients with abnormal findings from liver function studies must be observed closely if they are to receive intravesical BCG vaccine. One of the adverse effects of this agent is hepatic toxicity.
• Renal panel
  • Kidney function should be evaluated prior to the initiation of therapy because patients with marginal or abnormal renal function may have an obstruction or some type of renal disease that may worsen with intravesical therapy. Renal function can be evaluated with serum creatinine measurements or technetium scans of the kidneys.
  • Intravesical therapy can produce significant inflammatory changes in the bladder, with edema of the ureteral orifices. Patients with coexisting papillary tumors growing into the muscle layer of the bladder may have ureteral obstruction.

Imaging Studies

CIS is not apparent on any imaging studies; however, when it coexists with papillary TCC, the entire urinary tract must be evaluated.

• CT urography
  • This is the most commonly used imaging technique, and it is usually performed with and without contrast. Compared with intravenous urography (IVP), CT urography is becoming the preferred imaging modality for studying the urinary tract. Patients undergoing IVP are often poorly prepared, and obtaining an optimal study is more difficult than with CT urography.
  • CT urography combines a CT scan with intravenous contrast to provide anatomic details of the kidneys, regional lymph nodes, and other abdominal organs that may be affected by this disease. Again, the study is usually performed with and without contrast.
• Intravenous urography
  • Occasionally, IVP is performed. This study involves the intravenous injection of contrast with a series of radiographic images of the abdomen.
  • IVP has been the study of choice for many years, but it is currently being supplanted by CT urography, which provides much better and more complete information.
• Ultrasonography
  • Ultrasonography is of limited value in assessing the upper urinary tract but can help identify bladder wall thickening and bladder diverticula.
  • The study is useful to detect obstruction and large tumors, but it does not provide the detail necessary to assess the presence or extent of a neoplasm within the renal pelvis or the ureters. Bladder wall thickening, a finding suggestive of TCC, may be detected.
• Retrograde pyelography
  • This is necessary only infrequently, but, in some patients, it may be the best study to identify tumors in the ureters, renal pelvis, and infundibula and to evaluate the response to therapy. Injecting dilute contrast into the ureters may be the only way to identify small tumors.
  • Retrograde pyelography can provide excellent detail of the renal pelvis and ureters, but it has largely been supplanted by the other studies.
• Magnetic resonance imaging
  • MRI can help define small tumors in the renal pelvis and ureter.
  • It also provides good anatomic detail and can help determine if tumor has invaded the wall of the bladder or the serosa.
  • MRI urography with gadolinium is being used more often, especially in patients with allergies to intravenous contrast agents.
• Positron emission tomography scanning: This has been of limited value in the evaluation of patients with TCC, and results have not been reliable. It is usually used to assess for the presence of metastatic disease.

Diagnostic Procedures

CIS is definitively diagnosed using cystoscopy with bladder biopsies. This is generally performed with the patient under general anesthesia, but obtaining good local anesthesia by instilling anesthetic agents into the bladder is possible.

The urologist generally obtains multiple bladder biopsy specimens from various locations in the bladder to help establish the diagnosis and to determine the extent of the tumor. A process known as bladder mapping is used for this purpose. Biopsy specimens, which are submitted in separate containers, are obtained from different areas using a punch biopsy forceps. The pathologist provides a report for each location from where a specimen was taken.

In order to detect invasion into the lamina propria or muscle, the biopsies should be deep, and the pathologist should record the presence or absence of these areas. At the time of this procedure, the bladder can be lavaged with saline and the specimen can be sent for cytology. The specimen should be labeled as a bladder washing or lavage to assist the pathologist in evaluation, as specimens from washings tend to have larger clumps of cells than simple voided urine.

Histologic Findings

The typical visual appearance of CIS is that of a flat carcinoma extending along the surface of the bladder. This is in contrast to a papillary tumor, which extends on a stalk into the lumen of the bladder. CIS, by definition, does not invade through the basement membrane into the lamina propria. When it does, the cancer is considered to behave as an aggressive TCC and is managed accordingly.

When first diagnosed, as many as 20% of patients with CIS may have unrecognized invasion. Thus, they may not respond to intravesical therapy. This emphasizes the need for repetitive cytology/markers and biopsies.

The histologic pattern of CIS is characterized by bizarre, abnormal cells in the epithelial layer. The cells appear to be high-grade cancers; thus, they are readily detected in cytology specimens.

The pathologist may have difficulty distinguishing between cellular atypia and CIS. A consultant should review the slides if the pathologist is uncertain or diagnoses atypia. Upon further review, these cases usually prove to be CIS. The distinction is important because CIS requires therapy and atypia can be managed with observation. Finally, some pathologists attempt to grade CIS; however, CIS is not graded. An associated papillary tumor would be graded as low or high grade.

Staging

By definition, CIS is confined to the epithelial surface of the urinary tract, which makes this a Ta tumor, although no specific stage designation is assigned.

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