Approach Considerations
Any patient with gross or microscopic hematuria should undergo urologic evaluation, as hematuria is the most common clinical manifestation in patients presenting with bladder cancer. [64] All patients with gross hematuria should undergo a hematuria workup consisting of a cystoscopy, computed tomography (CT) urogram, and cytology. In patients with microscopic hematuria (≥3 red blood cells per high-power field), the American Urological Association (AUA) guideline recommends stratification as low, intermediate, or high risk to determine the workup strategy. High-risk patients undergo the standard evaluation of cystoscopy with CT urogram. Intermediate-risk patients are evaluated with cystoscopy and renal ultrasound. Low-risk patients undergo repeat urinalysis in 6 months. [65]
Urine studies
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
All patients with gross hematuria should undergo cystoscopy, upper tract imaging, and urinary cytology (preferably barbotage urine for cytology). It is no longer recommended to use urine cytology in the initial evaluation of patients with microscopic hematuria unless the patient has risk factors for carcinoma in situ (CIS). Additionally, cytology can be used in patients with microhematuria who have irritative urinary symptoms after a negative workup. [65]
Urinary cytology is most helpful in diagnosing high-grade tumors and 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. [66]
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. [67]
Findings
Because cytology is the most reliable urine test for detecting bladder cancer, a positive cytology finding should be treated as indicating cancer somewhere in the urinary tract 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 and possibly ureteroscopy. Cystoscopy with bilateral retrograde pyelography and bilateral ureteral washings should be performed. Additionally, in men the prostatic urethra should be examined.
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 one of the first tests that should be completed in a patient presenting with signs and symptoms suspicious for bladder cancer. Unfortunately, one study found that only 13% of patients with hematuria and risk factors for bladder cancer underwent cystoscopy. [65] Drawbacks of the procedure are that it is invasive and relatively expensive. [68] In addition, flat urothelial lesions such as CIS may be difficult to distinguish from normal bladder tissue, and bleeding caused by the procedure can reduce visibility.
Use of adjunctive endoscopic techniques, such as blue light cystoscopy with hexaminolevulinic acid (HAL), may improve the accuracy of cystoscopy. HAL is instilled intravesically and remains in the bladder for one hour before cystoscopy. This allows malignant cells, which have higher intracellular accumulation of the photoactive porphyrins, to appear pink or red while the nonmalignant tissue appears blue. [64] 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.
For more information, see Cystoscopy in Bladder Carcinoma.
Imaging studies
Imaging studies of the upper urinary tract are an integral part of the hematuria workup. CT scans of the abdomen and pelvis with contrast are recommended. Two commonly used alternative techniques are magnetic resonance imaging (MRI) and renal ultrasonography. A retrograde pyelogram can also be done to assess the upper tracts. [64]
Intravenous pyelography (IVP) was 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 National Comprehensive Cancer Network (NCCN) guidelines as an acceptable modality for imaging the upper tract collecting system. [1] European Association of Urology (EAU) guidelines recommend CT urography as more informative than IVP for upper urinary tract tumors. [69]
The bladder urothelium is not well visualized with routine imaging studies, including CT 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.
Biomarker testing
Newer molecular and genetic markers, including detection of mutations in genes such as RAS, FGFR3,PIK3CA, and TP53, and methylation pathways in urinary sediment, [70] 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.
However due to high cost and low specificity, use of urine-based tumor markers is not recommended by the AUA or the EAU as part of the microhematuria workup. [64] NCCN guidelines state that urinary markers may be useful during surveillance of bladder cancer, but whether these markers are helpful in the detection and management of non–muscle-invasive bladder tumors remains unclear. [1]
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).
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. Although BCG is administered intravesically, 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 is important to help prevent serious adverse events and to determine when therapy should be stopped. In patients with suspected metastasis to liver or bone, liver function tests and measurement of the bony fraction of alkaline phosphatase should be performed.
Kidney function should be evaluated prior to the initiation of therapy because patients with marginal or abnormal kidney function may have an obstruction or some type of renal disease that may worsen with intravesical therapy. Kidney function can be evaluated with serum creatinine measurements or technetium scans of the kidneys.
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 an evaluation by a urologist to investigate for any serious disease. American Urological Association (AUA) guidelines recommend against relying on dipstick testing alone to diagnose microhematuria, and instead advise following up a positive dipstick test with a formal evaluation; the AUA defines microhematuria as “≥3 red blood cells per high-power field on microscopic evaluation of a single properly collected urine specimen." Workup of microhematuria should be based on history and physical exam findings while taking into consideration the patient's individual risk factors for genitourinary malignancy. [65]
Gross hematuria always requires a careful assessment with imaging studies of the entire urinary tract (CT urography) and cystoscopy. However, 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. Although microhematuria may be present in healthy persons, 13-34.5% of patients with gross hematuria and 0.5-10.5% of patients with microscopic hematuria will be diagnosed with bladder cancer on initial evaluation. [65]
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. [71]
Sensitivity and specificity
Unfortunately, the sensitivity of cytology is low, with various studies reporting values between 11% and 76%. [72] 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. [73] 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. [74] 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 cases.
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. [75]
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%.
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. [76] Over 30 urinary biomarkers have been reported for use in bladder cancer diagnosis, but only a few are commercially available. [77]
The EAU guidelines on non–muscle-invasive bladder cancer state 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. [69] NCCN guidelines generally agree with the EAU guidelines but note that urinary biomarker tests approved by the FDA may be considered for use in monitoring for recurrence; however, this is a category 2B recommendation (ie, based on lower-level evidence). [1]
See Urine Tumor Markers in Bladder Cancer Diagnosis for more information on this topic.
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 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. [69]
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.
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
|
*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 UCs. 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 transitional cell carcinoma (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.
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 Urological Association Best Practice Policy recommends CT scanning of the abdomen and pelvis with contrast, with preinfusion and postinfusion phases. [78] 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 intravenous pyelography.
Conduct retrograde pyelography in patients in whom contrast CT scanning cannot be performed because of azotemia or a severe allergy to intravenous contrast.
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. For patients who are unable to receive contrast, NCCN guidelines state that a renal ultrasound can be used in addition to retrograde ureteropyelogram as a substitute to CT with contrast. [1] EAU guidelines state that ultrasonography is useful for identifying obstruction in patients with hematuria. It can detect renal masses, hydronephrosis, and bladder intraluminal masses but cannot rule out all potential causes of hematuria. It cannot reliably exclude the presence of upper tract urothelial carcinomas and cannot replace CT urography. [69]
Staging
The tumor, node, and metastasis (TNM) system developed by the International Union Against Cancer and the American Joint Committee on Cancer Staging is used to stage bladder cancer. [79] 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 or high grade. CIS is characterized by full mucosal thickness and high-grade dysplasia of the bladder epithelium and is associated with a poorer prognosis. Ta, T1, and CIS are categorized as non–muscle invasive while T2-T4 are muscle invasive. [1]
Primary tumor (T) classification for bladder cancer is as follows:
-
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: T2a, superficial muscularis propria; T2b, deep muscularis propria
-
T3 - Tumor involvement of the perivesical fat: T3a, microscopic invasion; T3b, macroscopic invasion
-
T4 - Tumor involvement of adjacent organs: T4a, invasion of prostatic stroma, seminal vesicles, uterus, or vagina; T4b, invasion of pelvic or abdominal wall
Node (N) classification for bladder cancer is as follows:
-
N0: No regional lymph node metastasis
-
N1: Metastasis in a single lymph node in true pelvis
-
N2: Metastasis in multiple regional lymph nodes in true pelvis
-
N3: Metastasis in common iliac lymph node(s)
Distant metastasis (M) classification for bladder cancer is as follows:
-
M0: No distant metastsis
-
M1a: Non regional lymph nodes
-
M1b: Other distant 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 25% of affected patients have muscle-invasive disease at diagnosis. Approximately 5% of patients present with metastatic disease, which commonly involves the lymph nodes, lung, liver, bone, and central nervous system.
In order to clinically stage a patient with muscle-invasive bladder cancer the following needs to be completed: CT or MRI of the abdomen and pelvis, chest imaging, CBC, and chemistry panel with alkaline phosphatase. [80] Bone imaging is recommended only if there is concern for bone metastasis, which could be indicated by bone pain or an elevated alkaline phosphatase. [1] Currently, routine PET scanning is not recommended during the initial staging workup. [80]
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 and around 5% will have distant metastasis at the time of initial diagnosis. [80] 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. Metastasis can occur through lymphatic spread, most commonly affecting the pelvic lymph nodes, or through hematogenous spread to the liver, lung, or bone. [80]
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.
In 2004, the International Society of Urologic Pathologists and World Health Organization adopted low-grade or high-grade designations. Papillary urothelial neoplasia of low malignant potential (PUNLMP) has also been added as a designation. [5]
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 can lead to an invasive bladder cancer.
-
In an ileal conduit, a small segment of ileum is taken out of continuity with the gastrointestinal tract but is maintained on its mesentery. Ureters are anastomosed to one end of this ileal segment, and the other end is brought out as a stoma to the abdominal wall.
-
In an Indiana pouch, a urinary reservoir is created from detubularized right colon and an efferent limb of terminal ileum. Terminal ileum is plicated and brought to the abdominal wall. The continence mechanism is the ileocecal valve.
-
In an orthotopic neobladder, a segment of ileum is used to construct a neobladder, which is connected to the urethra. Orthotopic neobladder most closely restores the natural storage and voiding function of the native bladder.
-
Bladder cancer. The classic appearance of carcinoma in situ is 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.
-
Bladder cancer. Papillary bladder tumors such as this one are typically of low stage and grade (Ta-G1). Courtesy of Abbott and Vysis Inc.
-
Bladder cancer. 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.
-
Bladder cancer. 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.
-
Bladder cancer. Cross-section through the bladder, uterus, and vagina with squamous cell carcinoma of the bladder infiltrating through the bladder wall into the vaginal wall.
-
Bladder cancer. High power, Pap stain showing high grade urothelial carcinoma on a bladder wash cytology.
-
Bladder cancer, Intermediate power, H&E stain of urothelial carcinoma in situ. The superficial cells shed into the urine and correlate with those seen in cytologic bladder washing or urine cytology.
-
Bladder cancer. High power, H&E stain of high grade urothelial carcinoma. This tumor is now invasive into the muscularis propria (smooth muscle seen in center of image).
-
Bladder cancer. Histopathology of bladder shows eggs of Schistosoma haematobium surrounded by intense infiltrates of eosinophils and other inflammatory cells.
-
Bladder cancer. (A) When infused into the bladder, the optical imaging agent hexaminolevulinate (Cysview) accumulates preferentially in malignant cells. (B) On blue-light cystoscopy, the collection of hexaminolevulinate within tumors is visible as bright red spots. Courtesy of Gary David Steinberg, MD, FACS.
Tables
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
|
*FISH - Fluorescent in situ hybridization. †Negative predictive value 95%. ‡Positive predictive value 30%. |
|||
Stage |
Recurrence, % |
Progression, % |
Ta |
55 |
11 |
T1 |
61 |
31 |
CIS |
45 |
23 |
G1 |
61 |
2-4 |
G2 |
56 |
5-7 |
G3 |
50-70 |
30-40 |
Early Complications |
Rate, % |
Late Complications |
Rate, % |
Ileus |
10 |
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 |
