BLADDER CANCER MARKERS: Current availability and the future standard of care.
The current standard of care for bladder cancer has been staging and grading of pathologic urinalysis and cystoscopy. These evaluations have been used to diagnose bladder cancer, predict patient survival, select the best treatment approach, and predict recurrence and progression of TCC. However, these procedures are either invasive or lack sensitivity and specificity. Consequently, more sensitive and specific urinary bio-markers are urgently needed to detect, monitor, and predict the prognosis of TCC. For optimal patient care, simple, reliable, and preferably noninvasive diagnostic tools must be made available for the easy identification and monitoring of these initial, superficial forms of bladder cancer as well as its signs of progression and recurrence. It is essential to be able to determine which invasive bladder cancers will metastasize.
To meet these criteria, substantial research has focused on developing a variety of potential biomarkers, including nuclear matrix protein, fibrin/fibrinogen product, bladder tumor antigen, telomeric repeat amplification protocols (TRAP), tumor-associated antigens, hyaluronic acid, and hyaluronidase. Several investigations are currently trying to determine possible clinical application of these biomarkers. In this review, some of the most promising and available biomarkers for bladder cancer are discussed. Use of the current biomarkers as adjunct modalities can potentially improve our ability to diagnose and monitor bladder cancer. A better understanding of the pathophysiology of bladder cancer is essential for developing even better biomarkers for this disease.
The standard staging system for classifying bladder cancer is done according to tumor, node, and metastasis (TNM). At the time of diagnosis, approximately 75% of patients with bladder cancer have superficial (Tis, Ta, or T1) disease; 20% have invasive disease (T2/T3), and 5% have a metastasized tumor (see Table 1 for explanation of abbreviations of tumor classification). Fortunately, two-thirds of the superficial lesions are confined to the mucosa (stage Ta); however, as previously stated, recurrence and progression are the major problems with superficial bladder cancer. The recurrence rate for superficial disease is more than 60%; and within 10 years, tumors progress to a higher stage or grade for 42% of patients. 
Grading is also a very important factor for prognosis. The grade of the tumor is based on the histological characteristics of the bladder cancer (see Table 2). The higher the tumor grade, the more likely the tumor is to recur and/or progress to a more aggressive form. Progression in grade-1 tumors was 2-10% (recurrence = 63%); progression in grade 2 was 11-19% (recurrence = 67%), and progression in grade 3 was 33-45% (recurrence = 71%) .
Until recently, determination and monitoring of tumor stage and grade were the most reliable variables for evaluating risk of recurrence and progression. For example, 4% of patients at stage Ta progressed to a higher stage (risk of recurrence = 52%), while the probability of progression for patients with T1 lesions was 30% (risk of recurrence = 77%). Carcinoma in situ (Tis) lesions are flat, epithelial tumors confined to the superficial mucosa. Most are high grade, thought to be particularly virulent, and progress in as many as 60% of cases.
Current standard of care
As previously stated, detection, recurrence, and progression are the main problems of bladder cancer. Established techniques for detecting and monitoring bladder cancer include cystoscopy, cytology of urine, and urinalysis, which includes both dipstick and microscopic exam to detect microscopic hematuria. The initial diagnosis of bladder cancer can be problematic because the most common presenting symptoms on initial exam are painless hematuria and irritative voiding, which are nonspecific. For example, hematuria is the most prevalent presenting symptom, and it occurs in only 4-10% of bladder cancers. Although urinalysis and microscopic exam are accurate for detecting microhematuria, both lack sensitivity and specificity for bladder cancer.
Cytology. Exfoliated malignant cells, which are present in urine sediment, have large and eccentric nuclei with a higher ratio of nucleus to cytoplasm and irregular, coarse chromatin. Although urine cytology has a specificity of more than 90% for diagnosis, because the incidence of bladder cancer in patients with hematuria is only 4-10%, it is not cost effective to perform this procedure for every patient with hematuria. In addition, despite its specificity, cytology has many shortcomings.
First, results are always subjective because pathologists differ as to the exact definitions of normal and abnormal cellular morphology. Second, rapid turnaround time for results is rare. The biggest drawback, however, is poor sensitivity (20-40%) for the most common low-grade lesions, regardless of the manner of collection. This poor sensitivity exists because cells in the urine sample for cytological exam appear normal despite the existence of a tumor. This is true because the most common well-differentiated tumors (low-grade) are more cohesive, which makes these cells less likely to be shed into the urine.
In an attempt to increase the sensitivity of cytology, a clinician can collect urine specimens other than voided urine. For example, to increase the number of actual bladder cells observed, urine can be obtained from bladder washings after the patient is catheterized.
Another drawback, however, is that false-positive cytology results can occur in as many as 12% of patients because of inflammation, urothelial atypia, and (most important) changes caused by chemo- or radiation therapy. Additionally, urine cytology results are false negative in 20% of patients with high-grade tumors. Thus, despite its high specificity, the low overall accuracy of urine cytology relegates this procedure to use as an adjunct for endoscopic diagnosis by cystoscopy.
Cystoscopy. Classically, bladder tumors are diagnosed using cystoscopy, which is the visual examination of the urinary tract with a cystoscope designed specifically for bladder exams. This method provides the most valuable information for detecting and monitoring bladder cancer, with sensitivity at approximately 70%, and allows the characterization of any tumors present as to number, multifocality, size, and appearance. Obviously, cystoscopy is indispensable for resection and provides specimens that yield the most important prognostic information, such as tumor stage and grade. However, cystoscopy is also an invasive and costly procedure, and one that again is subject to human interpretation. Furthermore, current standards for patients found to have abnormalities require cystoscopic follow-up at least every 3 months or more often depending on the stage and grade of any tumor detected. Thus, the traditional approaches to detect and monitor bladder cancer can be invasive, and none are sufficiently predictive i n the individual patient. Improved methods are needed to diagnose superficial bladder cancer, provide prognosis, and monitor therapy.
Rationale for biomarkers
Biomarkers may improve the screening and diagnosis of bladder cancer and determine its malignant potential and prognosis. Ideally, specimens for tests using biomarkers should be easily obtained using noninvasive methods. Procedures for biomarker testing should be inexpensive, easy to use and interpret, and provide results rapidly. The results should be accurate, with high sensitivity and specificity. Target groups of patients for whom these markers would be used could include those who are at high risk for bladder cancer, especially patients who:
* are older than 65 years
* have a history of smoking or another type of exposure to carcinogenic substances
* experience symptoms of bladder cancer: hematuria or irritable urinary symptoms such as urgency and frequency
* are being monitored after bladder cancer diagnosis or treatment.
Furthermore, if a biomarker is developed and the incidence of bladder cancer justifies the cost, it could be evaluated for use as routine bladder cancer screening in the elderly population in the same way that PSA is used to screen men of a certain age or risk group for prostate cancer.
The value of biomarkers must be measured by their ability to differentiate pathologic stage and grade of bladder tumors because those factors increase the probability of recurrence and progression. Currently,. a variety of markers have been developed, and the following have been approved by the Food and Drug Administration to monitor patients with bladder cancer: bladder tumor antigen (BTA), fibrin/fibrinogen degradation product (FDP), and nuclear matrix protein (NMP22). Recently, NMP22 also was approved as a screening test for bladder cancer.
FDA-approved biomarkers for monitoring bladder cancer Bladder tumor antigen. The BTA test (C.R. Bard Inc., Murray Hill, NJ) detects the presence of basement membrane complexes in the urine. Patient urine samples are mixed with latex particles coated with human IgG and agents for blocking unspecific cross-reactions. If proteolyte degradation products (basement membrane complexes) are present, they combine with latex particles and agglutinate. This reaction produces a color change, which differentiates positive from negative results on a test strip. A positive result means complexes are present and the patient has bladder cancer; the higher the stage of the tumor, the higher is the sensitivity of the test. The loss of these basement membrane proteins into the urine correlates with tumor stage and grade. 
Because original BTA test sensitivity (approximately 40%) was no better than that of cytology, several assay modifications were introduced, including the BTA stat and BTA TRAK. These assays detect a human complement factor H-related protein (hCFHrp) produced by several human bladder cancer cells but not healthy epithelial cells. The function and structure of hCFHrp is similar to the human complement factor H (hCFH). The latter inhibits the alternative complement pathway, and thus inhibits lysis of foreign cells. Like hCFH, the bladder tumor antigen interrupts the complement cascade and may confer a selective growth advantage to cancer cells in vivo by allowing them to evade the patient's immune system.
The qualitative, single-step immunochromatographic BTA stat test is a point-of-care dipstick test that can be performed in the physicians' office and provides results within 5 minutes. Sensitivity of the BTA stat test for low-grade lesions is higher than that of cytology (grade 1 BTA stat: 50%). However, sensitivity of the BTA stat test for high-grade lesions is lower than that of cytology (BTA stat: grade 2 = 29-66%, grade 3 = 40-83%). [6,7] Specificity of the BTA stat test is lower than cytology (BTA stat: 72-95%; cytology: [greater than] 90%). Specificity regardless of tumor grade is 75-95%. The newest BTA test (BTA TRAK) measures the levels of hCFHrp. False-positive limitations of these BTA tests include hematuria and benign disease, such as inflammation, urothelial trauma, kidney stones, and other genitourinary malignancies.
Fibrin/fibrinogen degradation product (FDP). The qualitative FDP test (AuraTek FDP, Per Immune Inc., Rockville, MD) is based on the recognition that increased FDP levels in the urine are associated with the presence of malignant bladder tumors. This flow immunoassay uses monoclonal antibodies to detect FDP and is a rapid point-of-care dipstick test with an overall sensitivity of 82.1% for all stages of bladder cancers.  This sensitivity is much higher than that of cytology. Sensitivity for grading the tumors was 63.2% for grade-1, 88.2% for grade-2, and 95.0% for grade-3 disease.
The specificity is 96% for healthy subjects, 86% for patients with urological disease other than bladder cancer, and 80% for patients being monitored for bladder cancer but who have a negative cystoscopic examination at the time of the assay.  However, it should be noted that the manufacturer has currently withdrawn the assay from the market due to its short half-life. 
Nuclear matrix protein (NMP22). Cancer-specific nuclear matrix proteins (NMPs) have been identified in colon, breast, bone, and urothelium; NMP22 was recognized as a potential urothelial-specific cancer marker.  Malignancy causes these NMPs to be shed from the cell nucleus into the urine by an active form of cell death termed "apoptosis." To quantitate NMP22 in voided urine, the NMP22 test kit (Matritech, Inc., Newton, MA) is an immunoassay that uses monoclonal antibodies specific for NMP22.
Clinical research demonstrated significant differences in NMP22 levels in voided urine from healthy volunteers compared with levels from patients with active TCC. In a recent study, urinary NMP22 was measured in 267 patients, 187 of whom had TCC, using an enzyme-linked immunosorbent assay (ELISA); and results showed a sensitivity of 78.2% and a specificity of 95.5%.  In 1996, the FDA approved the NMP22 assay to detect occult or rapidly recurring disease after transurethral resection. Several studies reported sensitivities for the NMP22 test ranging from 68%  to l00%,  without significant differences.
Conversely, assay specificity differs immensely between authors, with reported specificities of 61%  and 85%,  depending on the cutoff value for units of detected NMP22 (6.4 units/mL for patients previously diagnosed with bladder cancer; 10 units/mL for patients with only micro- and macrohematuria and voiding symptoms) that mark the difference between benign and malignant bladder disease. Others report high false-positive rates for urolithiasis (50%), benign prostate hyperplasia (15.6%), benign urological diseases (25.6%), and renal diseases (25.6%)  Interestingly, sensitivity and specificity are not affected with respect to stage and grade of disease as much as other assays or cytology.
Biomarkers still in research Telomerase, the TRAP assay. Telomeres are the short ends of chromosomes; and in somatic cells, these telomeres degrade as the cell ages. With every round of replication, the cell loses more telomeres [16,17] until after losing a specific number of telomeres, the cells start to lose significant sequences of the parent DNA. The chromosomes then become unstable and finally die.  Germ cells survive these multiple replications by producing telomerase, an enzyme that maintains their telomeres.  Previous reports showed a strong telomerase activity in different cancer cells, [20,21] including bladder cancers that express telomerase activity in voided urine. 
In one study, telomerase assays showed varying sensitivity for detecting different grades of tumors, with sensitivity at grade 1 = 100%, grade 2 = 92%, and grade 3 = 83%.  The detection rate for bladder cancer in later studies was more than 85%, where telomeric repeat amplification protocols were used. [24,25] However, these very promising results were not supported by other investigations that used voided urine specimens and yielded sensitivities that were 60-70%.  In another report, the specificity of the telomerase assay was 80%.  False-positive results in 23.3% of cases were caused by kidney stone disease, inflammation, benign prostatic hyperplasia, and other benign urologic diseases. 
A comparison was recently published that evaluated the sensitivity and specificity for urine cytology, BTA stat, NMP22, FDP, telomerase, chemiluminescent hemoglobin, and hemoglobin dipstick tests.  Results indicated that urinary telomerase had the highest combination of sensitivity (70%) and specificity (99%) for bladder cancer screening and was extremely useful for identifying low-grade tumors and Tis.  However, this assay is not yet available for clinical use.
Hyaluronic acid and hyaluronidase.
Hyaluronic acid is a free, nonsulfated glycosaminoglycan formed in connective tissue, body fluids, and extracellular matrix. In the presence of one of several human cancers (e.g., breast, colon, or bladder) the concentration of hyaluronic acid in urine is elevated, and this acid helps malignant cells to migrate and escape immune surveillance. Metastatic cells produce enzymes and enzyme products, including 2 types of hyaluronidases that dissolve the cellular matrix, also allowing malignant cells to migrate toward blood vessels.  Two types of hyaluronidases and hyaluronic acid fragments are also present in the urine of patients with bladder cancer and can be detected in the urine by an ELISA.
It has been reported that hyaluronic acid was elevated 5 to 7 times in all patients with bladder cancer, regardless of tumor grade, whereas hyaluronidase was elevated only in higher-grade bladder cancers.  Reported sensitivity and specificity for both markers have ranged from 86-92%.  In a recent study, researchers screened 513 urine samples (261 from patients with TCC and 243 from control subjects) and found that hyaluronic acid levels were 2.5 to 6.5 times higher for patients with bladder cancer, compared with healthy controls (P [less than] 0.001). Hyaluronidase levels were 3 to 7 times elevated for patients with grade 2-3 TCC (P [less than] 0.001). Combining inferences of hyaluronic acid and the hyaluronidase assays yielded a sensitivity of 91.2% and specificity of 84.4%.  It is still too early to recommend the hyalurondase assay as a standard test for bladder cancer; additional multicenter clinical trials are still needed.
Cell-surface antigen. ImmunoCyt (Diagnocure Inc., Saint-Foy, Quebec, Canada) uses 3 fluorescent monoclonal antibodies to detect cell-surface antigens (M344, LDQ10, and 19A211) that are specific for TCC. Using a combination of immunofluorescence and cytology on 1 slide, ImmunoCyt had an initial reported sensitivity of 95% for low-grade lesions (Ta, T1) Results from one study (n = 264) revealed 86.1% sensitivity and 79.4% specificity for ImmunoCyt alone and 89.9% sensitivity in combination with cytology.  However, this cell-surface antigen test yields a substantial number of false-positive results and thus has a lower specificity compared with traditional cytologic evaluations.
The future of biomarkers
Regardless of cytology's recognized specificity ([greater than] 90%) for bladder cancer, cytology's low sensitivity (20-40%) prevents its use as a replacement for cystoscopy. Comparison studies involving the different screening techniques for bladder cancer are definitely needed. Prospective standardized multicenter trials are essential to determine if one of the new biomarkers might replace cystoscopic studies. Tumor stage and grade based on pathological characteristics, in addition to other risk factors mentioned previously, can help the clinician differentiate between patients who are at high risk for recurrence from those who are at lower risk. Biomarkers could then be used in combination with cytology or alone to modify the intervals between cystoscopies to monitor patient progress.
For example, patients with low NMP22 values can be monitored by using office-based cystoscopies performed under local intraurethral anesthesia. Conversely, patients with high values for NMP22 would prompt a definitive treatment tailored to their diagnosis. Furthermore, normal NMP22 values may indicate that the time intervals between cystoscopies could be increased. In contrast, high NMP22 values would require shorter intervals between cystoscopic evaluations. This type of tailored treatment could improve compliance and hopefully reduce the cost of management.
During the last few years, research has intensified for new biomarkers that can detect bladder cancers early as well as monitor patients' treatment and prognoses. Of the tests discussed here, the NMP22, BTA, TRNP, and ImmunoCyt tests are easy to use, but currently only NMP22 and the BTA tests are FDA approved and clinically available in the US. Although providing a higher sensitivity, currently available biomarkers cannot replace established methods, such as cystoscopy and cytology, but have the potential to increase sensitivity and specificity of this testing when used as adjuncts for conventional procedures. Recent studies provided promising results for biomarkers for bladder cancer such as telomerase, hyaluronic acid and hyaluronidase, cell-surface antigen, blood group-related antigens, and tumor-associated antigens, as well as proliferating antigens, oncogenes, growth factors, cellular adhesion molecules, and cell cycle regulatory proteins, not discussed here. Further evaluation of these new tools and ot her biomarkers that might be developed in the future could help improve our ability to screen for, detect, and monitor various forms of bladder cancer. Once proven, bladder cancer biomarkers have the potential to be useful for screening high-risk groups, such as the growing population of elderly patients. This paradigm would be comparable to the use of colonoscopy, mammography, or PSA as well-known and widely accepted screening tests in other high-risk groups.
Authors are affiliated with the Department of Urology, College of Physicians and Surgeons, Columbia University, New York, NY.
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1997 Tumor, node, and metastasis (TNM) staging system for urinary bladder cancer Stage Description Primary Tumor (T) Tx Primary tumor cannot be assessed TO No evidence of primary tumor Ta  Noninvasive papillary carcinoma Tis  Carcinoma in situ T1  Tumor invades subepithelial connective tissue T2  Tumor invades muscle T2a Tumor invades superficial muscle T2b Tumor invades deep muscle T3  Tumor invades perivesical tissue T3a Microscopically T3b Macroscopically (extravesical) T4  Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall T4a Tumor invades prostate, uterus, vagina T4b Tumor invades pelvic wall, abdominal wall Regional lymph nodes (N) Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node, [less than or equal to] 2 cm in greatest dimension N2 Metastasis in a single lymph node, [greater than] 2 cm but not [greater than] 5 cm in greater dimension, or multiple lymph nodes, none [greater than] 5 cm in greatest dimension N3 Metastasis in a lymph node [greater than] 5 cm in greatest dimension Distant metastasis (M) Mx Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis (1.)superficial disease (2.)invasive disease (3.)metastasized tumor Grouping Stage Tumor Node Metastasis Stage Oa Ta N0 M0 Stage Ois Tis N0 M0 Stage I T1 N0 M0 Stage II T2a-2b N0 M0 Stage III T3a-3b N0 M0 T4a-4b N0 M0 Stage IV Any T N1-3 M0 Any T Any N M1 Source: Adapted from Sobin LH, Wittekind Ch, eds. TNM Classification of Malignant Tumors. 5th ed. New York: Wiley-Liss; 1997. Tumor grading system for urinary bladder cancer Grade Description Gx Grade of tumor differentiation cannot be assessed G1 Tumor is well differentiated G2 Tumor is moderately differentiated G3-4 Tumor is poorly differentiated/undifferentiated
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|Author:||Sawczuk, Ihor S.; Burchardt, Tatjana; Shabsigh, Ahmad; Taille, Alexandre de la; Burchardt, Martin|
|Publication:||Medical Laboratory Observer|
|Date:||Mar 1, 2000|
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