Bladder Cancer Workup

Urine studies include the following:

• Urinalysis with microscopy
• Urine culture to rule out infection, if suspected
• Voided urinary cytology
• Urinary tumor marker testing

Urinalysis is performed to detect hematuria or infection. Microscopic hematuria from bladder cancer may be intermittent; therefore, a repeat negative result on urinalysis does not exclude the diagnosis.

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. Endoscopic biopsies are used to establish the diagnosis and determine the extent of the cancer.

A study by Cha et al found that immunocytology outperforms urine cytology and increases the accuracy of predictive models by a statistically and clinically significant margin for patients with painless hematuria.^[46]

Newer molecular and genetic markers may help in the early detection and prediction of urothelial carcinoma. However, at this time, no urinary assay has been shown to effectively replace urine cytology and cystoscopy, with or without biopsy, for the diagnosis of bladder cancer. However, they may be useful adjuncts to urine cytology and cystoscopy.

Cystoscopy is the criterion standard for detecting bladder cancer, but it is invasive and relatively expensive.^[47] Moreover, visibility can be reduced by bleeding, and flat urothelial lesions such as carcinoma in situ (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.

Because cytology is the most reliable urine test for detecting bladder cancer, a positive cytology finding should be treated as indicating 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.

Most patients with CIS have coexisting papillary cancer. In general, the papillary tumor is diagnosed initially, and CIS is discovered during the evaluation and treatment of the papillary tumor. In only 10% of patients with bladder cancer is there a pure CIS. The combination of CIS and papillary transitional cell carcinoma (TCC) is associated with a higher risk of recurrence and progression.

In cases of pure CIS, urine cytology may lead to the diagnosis. CIS exfoliates cells that have an unusual appearance and are easy to identify via cytologic examination, prompting further evaluation. Unfortunately, even findings from urine cytology may be normal in some patients, in whom the diagnosis is made only when the urologist maintains a high level of suspicion for CIS and obtains random bladder biopsy specimens from patients with worrisome symptoms. However, if the urinary cytology is performed properly, this should happen rarely.

Strittmatter et al found that the quality of urinary cytology is impacted by the individual learning curve. Specificity of cytology and sensitivity for low-grade tumors significantly changed when performed by a local cytologist at the beginning of the learning period. This suggests that in the diagnosis of bladder cancer, the impact of the individual learning curve on the clinical value of urinary cytology is important.^[48]

No blood tests are specific for bladder cancer. In patients with CIS, however, 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.

Liver function should be evaluated. One of the intravesical agents used to treat CIS is bacillus Calmette-Guérin (BCG) vaccine, and systemic absorption of this agent can produce acute hepatitis. Performing baseline liver function tests before initiating therapy and repeating these tests during the course of therapy help prevent serious adverse events and determine when therapy should be stopped. In patients with possible metastatic spread to liver and bone, liver function tests and measurement of the bony fraction of alkaline phosphatase are indicated in the evaluation.

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.

This routine test is used to evaluate for the presence of RBCs, WBCs, and protein and to assess for urinary tract infection.

The presence of RBCs in the urine mandates 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.

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.

Less than 20% of bladder cancer cases are identified on the basis 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 3 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."^[49]

Prior to performing an endoscopic examination or initiating any therapy, the urine should be free of evidence of infection.

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. Exfoliated urothelial cells are viewed using microscopy. In some urothelial cancers, cellular clumping, a high nuclear-to-cytoplasmic ratio, nucleoli, and atypia are seen. 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.

At least 100 mL of a freshly voided specimen is usually sufficient for urine cytology. The first morning sample should not be used, because 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 (ie, barbotage). 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.^[50]

Unfortunately, the sensitivity of cytology is low, with various studies reporting values between 11% and 76%.^[51] 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.^[52] 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.^[53] Urine cytology is associated with a significant false-negative rate, especially for low-grade carcinoma (10-50% accuracy rate). The false-positive rate is 1-12%, but it has a 95% accuracy rate for diagnosing high-grade carcinoma and carcinoma in situ (CIS). Urine cytology is often the test used for diagnosis of CIS. Suggestive urine cytology findings encourage the urologist to perform a bladder biopsy. With a properly collected urine sample that is promptly placed into fixative, CIS is detected in 70-75% of patients.

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.

Perform urine cytology at the same time as cystoscopy, although its routine use for screening is controversial. With a normal finding on cystoscopic examination, further evaluate a positive cytology result on urine study with an upper-tract study and random biopsies of the bladder. Obtain biopsy samples of the prostatic urethra in men.

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%.

Noninvasive urine markers can offer an alternative to the standard means of detecting bladder cancer or can be used as an adjunct to cystoscopy.^[54] Over 30 urinary biomarkers have been reported for use in bladder cancer diagnosis, but only a few are commercially available.^[1]

The 2011 update of the European Association of Urology (EAU) guidelines on non–muscle-invasive urothelial carcinoma of the bladder states that most of these tests are more sensitive than cytology but less specific.^[55] The National Comprehensive Cancer Network's (NCCN) Clinical Practice Guidelines in Oncology: Central Nervous System Cancers, also published in 2011, support the EAU guidelines but add that these tests may not offer any additional information for detection and management of non–muscle-invasive bladder tumors.^[56]

See Urine Tumor Markers in Bladder Cancer Diagnosis for more information on this topic.

Cystoscopy is the primary modality for the diagnosis of bladder carcinoma because of its low risk and because biopsy specimens can be taken and papillary tumors resected during a single procedure. The 2011 EAU guidelines on non–muscle-invasive bladder cancer state that cystoscopy should be performed in all patients with symptoms of possible bladder cancer and that no non-invasive test can take its place.^[55] However, cystoscopy may be an embarrassing procedure for the patient because of exposure and handling of the genitalia. The procedure must therefore be performed with respect, and the patient should remain exposed only as long as necessary to complete the evaluation. Men are most easily evaluated with a flexible cystoscope. In women, cystoscopy can be performed as described for men, using the flexible cystoscope, or a rigid cystoscope may be used because of the relatively straight female urethra. See Cystoscopy for more information on this topic.

In the setting of negative cystoscopy findings, negative urine cytology findings, and positive fluorescent in situ hybridization (FISH) findings, 2 possible scenarios arise. This result either is falsely positive or 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 1).

Table 1. Clinical Findings and Recommended Action (Open Table in a new window)

More than 90% of bladder cancers are transitional cell carcinomas (TCCs), approximately 5% are squamous cell carcinomas (SCCs), and less than 2% are adenocarcinoma.

Carcinoma in situ

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.

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.

For more information, see Pathologic Findings in Squamous Cell Bladder Carcinoma and Pathologic Findings in Small Cell Bladder Carcinoma.

Upper-tract imaging is necessary for the hematuria workup. The imaging modality chosen should be able to visualize both the kidneys and the urothelium. American Urologic Association Best Practice Policy recommends CT scanning of the abdomen and pelvis with contrast, with pre-infusion and post infusion phases. This evaluation is ideally performed with CT urography, using multidetector CT, or it can be performed with a single-detector CT study followed by an excretory radiographic study of the kidneys, ureters, and bladder (KUB) to obtain images similar to those produced with intravenous pyelography (IVP).

Two commonly used alternative studies are IVP and renal ultrasonography. The IVP is the traditional standard for upper-tract urothelium imaging; however, it is poor for evaluating the renal parenchyma. Few centers in the United States perform IVPs today, although IVPs are still included in the 2011 NCCN guidelines as an acceptable modality for imaging the upper tract collecting system.^[56] The EAU 2011 guideline update recommends CT urography as more informative than IVP for upper urinary tract tumors.^[55]

Ultrasonography is also commonly used; however, urothelial tumors of the upper tract and small stones are easily missed. The 2011 EAU guideline update states that ultrasonography is useful for identifying obstruction in patients with hematuria. It can detect renal masses, hydronephrosis, and bladder intraluminal masses. The guideline supports the statement that ultrasonography cannot be used to rule out tumors in the upper urinary tract.^[55]

Conduct retrograde pyelography in patients in whom contrast CT scanning cannot be performed because of azotemia or a severe allergy to intravenous contrast.

The bladder urothelium is not well visualized with routine imaging studies, including CT scanning or MRI. 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. 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.

The International Union Against Cancer and the American Joint Committee on Cancer Staging developed the tumor, node, and metastases (TNM) staging system, which is used to stage bladder cancer (see below).^[57] Ta and T1 tumors and CIS were once considered superficial bladder tumors. T2, T3, and T4 tumors were traditionally described as invasive bladder cancer. However, urologic oncologists now recommend avoiding the term superficial bladder cancer to describe Ta, T1, and CIS tumors because it is a misnomer and tends to group patients who may require different treatments and who may have differing prognoses.

Urothelial carcinoma is histologically graded as low grade (formerly graded 1-2) or high grade (formerly graded 3). CIS is characterized by full mucosal thickness and high-grade dysplasia of the bladder epithelium and is associated with a poorer prognosis.

The following is the TNM staging system for bladder cancer:

• CIS - Carcinoma in situ, high-grade dysplasia, confined to the epithelium
• Ta - Papillary tumor confined to the epithelium
• T1 - Tumor invasion into the lamina propria
• T2 - Tumor invasion into the muscularis propria
• T3 - Tumor involvement of the perivesical fat
• T4 - Tumor involvement of adjacent organs such as prostate, rectum, or pelvic sidewall
• N+ - Lymph node metastasis
• M+ - Metastasis

More than 70% of all newly diagnosed bladder cancers are non–muscle invasive, 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.

Clinically stage a patient who has muscle-invasive disease with CT scanning of the abdomen and pelvis,^[58] chest radiography, and serum chemistries. If the patient is asymptomatic with normal calcium and alkaline phosphatase levels, a bone scan is unnecessary.

As many as 50% of patients with muscle-invasive bladder cancer 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.

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.

In 2004, the International Society of Urologic Pathologists and World Health Organization eliminated grade 2 and adopted low-grade or high-grade designations. Papillary urothelial neoplasia of low malignant potential (PUNLMP) has also been added as a designation.

An exception to the above concept is in the case of CIS. 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. If left untreated, however, 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.

By definition, CIS is confined to the epithelial surface of the urinary tract and has no other official stage definition. It is a flat carcinoma that grows along the inner surface of the bladder. As such, it is considered to be a form of nonmuscle invasive bladder cancer (NMIBC), but this specific designation is reserved for papillary or solid transitional cell cancers.

In another commonly used staging system, tumors are Ta or T0 if they are confined to the epithelial layer and T1 if present in the lamina propria. However, CIS is just CIS. If there is evidence of tumor cell invasion into the lamina propria or deeper into the muscle, the cancer is considered to be a TCC and the designation of CIS is no longer used.