Bladder Cancer Workup

Updated: Apr 15, 2019
  • Author: Gary David Steinberg, MD, FACS; Chief Editor: Bradley Fields Schwartz, DO, FACS  more...
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Workup

Approach Considerations

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.

Cytology

Urinary cytology is extremely valuable and is often the test used for diagnosis; suggestive urine cytology findings should encourage the urologist to perform a cystoscopy and possibly bladder biopsy. All patients with gross hematuria and many with significant microscopic hematuria should undergo a cystoscopy and urinary cytology (preferably barbotage urine for cytology).

Urinary cytology is most helpful in diagnosing high-grade tumors and carcinoma in situ (CIS). Low-grade, noninvasive tumors may be missed by routine cytologic analysis.

Endoscopic biopsies are used to establish the diagnosis and determine the extent of the cancer. However, 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. [62]

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 cytologist’s level of experience has an important impact on the clinical value of urinary cytology. [63]

Findings

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 first, and CIS is discovered during the evaluation and treatment of the papillary tumor. Only 10% of patients with bladder cancer have 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, urinary 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 these cases 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.

Cystoscopy

Cystoscopy is the criterion standard for detecting bladder cancer, but it is invasive and relatively expensive. [64] Moreover, visibility can be reduced by bleeding, and flat urothelial lesions such as CIS may be difficult to distinguish from normal bladder tissue. Use of adjunctive endoscopic techniques, such as blue light cystoscopy with 5-aminolevulinic acid, may improve the accuracy of cystoscopy. Cytologic analysis of voided urine is frequently used as an adjunctive test to aid in identifying occult cancers.

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.

Imaging studies

Imaging studies of the upper urinary tract are an integral part of the hematuria workup. Computed tomography (CT) scans of the abdomen and pelvis with contrast are recommended. Two commonly used alternative techniques are magnetic resonance imaging (MRI) and renal ultrasonography. Few US centers still perform intravenous pyelography (IVP) for upper tract imaging.

The bladder urothelium is not well visualized with routine imaging studies, including CT scanning and MRI. Small tumors are easily missed on images produced by these modalities. Irregular areas on images, which may appear to represent mucosal abnormalities, are often artifacts of incomplete bladder filling; delayed images following contrast administration can better visualize actual filling defects. CIS is not visible on images from any current radiographic study.

Other tests

Markers

Newer molecular and genetic markers, including detection of mutations in genes such as RAS, FGFR3,PIK3CA, and TP53, and methylation pathways in urinary sediment, [65] may help in the early detection and prediction of urothelial carcinoma. At this time, however, no urinary assay has been shown to effectively replace urine cytology and cystoscopy, with or without biopsy, for the diagnosis of bladder cancer. Nevertheless, marker assays may be useful adjuncts to urine cytology and cystoscopy.

Blood tests

No blood tests are specific for bladder cancer. In patients with CIS, however, a general evaluation is necessary prior to initiating therapy with intravesical bacillus Calmette-Guérin (BCG) vaccine.

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Complete Blood Count and Chemistry Panel

On the complete blood count (CBC), the presence of anemia or an elevated white blood cell (WBC) count warrants further investigation for an explanation.

The chemistry panel should include liver function studies. One of the intravesical agents used to treat CIS is BCG vaccine, but 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 to prevent serious adverse events and to determine when therapy should be stopped. Liver function tests, as well as measurement of the bony fraction of alkaline phosphatase, are also indicated in patients with possible metastasis to liver or bone.

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.

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Urinalysis and Urine Culture

Urinalysis is used routinely to evaluate for the presence of red blood cells (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. Prior to performing an endoscopic examination or initiating any therapy, a urine culture should be performed to confirm that the urine is free of evidence of infection.

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." [66]

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Urine 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. 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 personnel 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. [67]

Sensitivity and specificity

Unfortunately, the sensitivity of cytology is low, with various studies reporting values between 11% and 76%. [68] 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 morphologic departure from normal is smaller, complicating cytologic recognition. [69] 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. However, the overall low sensitivity of cytology is due to its low sensitivity in detecting low-grade bladder tumors. [70] 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%, although cytology has a 95% accuracy rate for diagnosing high-grade carcinoma and 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.

Improving accuracy

Perform urine cytology at the same time as cystoscopy, although its routine use for screening is controversial. If the cystoscopic examination yields normal findings but the urine cytology result is positive, further evaluation should include an upper tract study and random biopsies of the bladder. Obtain biopsy samples of the prostatic urethra in men.

Fluorescence in situ hybridization (FISH) may improve the sensitivity and specificity of routine cytology. The US Food and Drug Administration (FDA) has approved a FISH assay for the detection of recurrent bladder cancer in voided urine specimens from patients with a history of bladder cancer, as well as for the detection of bladder cancer in voided urine specimens from patients with gross or microscopic hematuria but no previous history of bladder cancer. [71]

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. In contrast, the positive predictive value in patients with CIS tends to be around 75%.

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Urine Tumor Markers

Noninvasive urine markers can offer an alternative to the standard means of detecting bladder cancer or can be used as an adjunct to cystoscopy. [72] Over 30 urinary biomarkers have been reported for use in bladder cancer diagnosis, but only a few are commercially available. [73]

The 2013 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 are less specific, and none have been accepted for diagnosis or follow-up in routine urologic practice or in guidelines. [74] The National Comprehensive Cancer Network's (NCCN) 2015 Clinical Practice Guidelines in Oncology: Bladder Cancer generally agree with the EAU guidelines but note that urinary biomarker tests approved by the U.S. Food and Drug Administration may be considered for use in monitoring for recurrence; however, this is a category 2B recommendation (ie, based on lower-level evidence). [75]

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

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Cystoscopy

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 noninvasive test can take its place. [74]

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 a flexible cystoscope, although, because the female urethra is relatively straight, a rigid cystoscope may be used instead.

See Cystoscopy for more information on this topic.

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Diagnostic Strategy

In the setting of findings that are negative for cystoscopy and urinary cytology but positive for FISH, 2 possible scenarios arise. One is that the FISH result is falsely positive. The other is that it is an anticipatory positive result; in such cases, the patient has a 30% chance of developing a bladder tumor over 2 years. Patients in this category should undergo surveillance with increased frequency (see Table 1, below).

Table 1. Clinical Findings and Recommended Action in Patients with Negative Cystoscopy (Open Table in a new window)

Cystoscopy Findings

Urine Cytology Findings

FISH* Findings

Action

Negative

Negative

Negative†

Routine follow-up

Negative

Negative

Positive‡

Increased frequency of surveillance, whether FISH findings are false positive or anticipatory positive

Negative

Positive

Negative or positive

Cancer until proven otherwise

  • Upper tract imaging with contrast

  • Cystoscopy with retrograde pyelography, washings, and/or ureteroscopy

  • Evaluate urethra

  • Increased frequency of surveillance upon negative findings

*FISH - Fluorescent in situ hybridization.

†Negative predictive value 95%.

‡Positive predictive value 30%.

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Histologic Findings

In North America, South America, Europe, and Asia, more than 90% of bladder cancers are TCCs. Approximately 5% are squamous cell carcinomas (SCCs), and less than 2% are adenocarcinomas.

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 those of high-grade cancer; 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 while 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 Pathology of Urinary Bladder Squamous Cell Carcinoma and Pathologic Findings in Small Cell Bladder Carcinoma.

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Computed Tomography Scanning

Upper tract imaging is necessary for the hematuria workup. The imaging modality chosen should be able to visualize the kidneys and the urothelium.

American Urologic Association Best Practice Policy recommends CT scanning of the abdomen and pelvis with contrast, with preinfusion and postinfusion phases. [76] This evaluation is ideally performed with CT urography, using multidetector CT, or it can be performed with a single-detector CT-scan study followed by an excretory radiographic study of the kidneys, ureters, and bladder (KUB) to obtain images similar to those produced with IVP.

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

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Intravenous Pyelography

IVP is the traditional standard for upper tract urothelium imaging; however, it is a poor modality for evaluating the renal parenchyma. Few centers in the United States perform IVP today, although the test is still included in the 2012 NCCN guidelines as an acceptable modality for imaging the upper tract collecting system. [75] The EAU 2011 guideline update recommends CT urography as more informative than IVP for upper urinary tract tumors. [74]

Renal Ultrasonography

Ultrasonography is also commonly used in the diagnosis of bladder cancer. 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. [74]

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Staging

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). [77] 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 together patients who may require different treatments and who may have different 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 the prostate, rectum, or pelvic sidewall

  • N+ - Lymph node metastasis

  • M+ - Metastasis

See Bladder Cancer Staging for more information on this topic.

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, [78] chest radiography, and serum chemistries. If the patient is asymptomatic with normal calcium and alkaline phosphatase levels, a bone scan is unnecessary.

Metastasis

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.

Grade

Stage and grade are critical 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 the 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.

CIS, which is defined as a flat, high-grade, noninvasive cancer, is an exception to the above concept. 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, 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 using the multiple-level classification that has been employed in the past. Regardless, the correlation between stage and grade is significant.

Designation of CIS

By definition, CIS is confined to the epithelial surface of the urinary tract and has no other official stage definition. It grows along the inner surface of the bladder and is therefore considered to be a form of non–muscle-invasive bladder cancer, but this specific designation is reserved for papillary or solid TCCs.

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.

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