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EDITORIAL: SURVEILLANCE OF SUPERFICIAL BLADDER CANCER— TRADITION AND INNOVATION
0022-5347/99/1626-1957/0 THE JOURNAL OF UROLOGY® Copyright © 1999 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Vol. 162, 1957–1958, December 1999 Printed in U.S.A.
EDITORIAL: SURVEILLANCE OF SUPERFICIAL BLADDER CANCER— TRADITION AND INNOVATION KEY WORDS: bladder neoplasms; follow-up studies; recurrence; disease progression; tumor markers, biological
Followup of patients with low grade and low stage bladder cancer is routine for most urologists. Patients undergo cystoscopy quarterly for 1 or 2 years, semiannual examinations for a similar interval and annual surveillance thereafter. Recurrence restarts the cycle. Concomitant urinary cytology facilitates detection of high grade lesions that are not always visually detectable (bladder carcinoma in situ and upper tract transitional cell). In our practice these office procedures with local anesthesia take 5 to 10 minutes and are relatively inexpensive. The 1999 Medicare reimbursement is $135 for office cystoscopy and $33 for cytology. With use of the flexible cystoscope discomfort is modest and tolerable for most men. In their update of the natural history of low grade and low stage transitional cell carcinoma Leblanc et al (page 1946) reexamine the rationale for standard long-term, careful followup. Of 152 patients followed for a mean of 76 months 55% had recurrence, including 30% after an initial 2 to 10-year tumor-free interval. Risk of progression in grade (20%) and stage (6%) was constant throughout followup and independent of tumor-free interval. Of 83 patients with recurrence 12 had progression more than 5 years after initial diagnosis and 5 (6%) had invasive disease. These findings are similar to those reported in 1973 by Greene et al.1 Of 100 similar patients followed for 15 years 73% had recurrence and 10% had progression to invasion with an 8-year mean interval from diagnosis to progression. Clearly the biology of low grade and low stage disease, and the surveillance strategy have remained constant with time. Because of the high risk and our inability to predict recurrence in individual cases the entire population is monitored closely. Since cytology is so insensitive to low grade disease, cystoscopy remains essential. In recent years investigators have focused on multiple urinary tumor markers for transitional cell carcinoma to identify reliable noninvasive adjuncts to traditional surveillance techniques. BTA,* NMP22† and fibrin degradation products have been approved by the Food and Drug Administration, and many other urinary markers continue to be examined in research settings. Despite this flurry of activity, no marker has general, widespread acceptance in routine urological practice. Why? Stents, recent manipulations, stones, infection, bowel interposition and prostatitis are common in bladder cancer cases and create false-positive results in at least 2 of the approved assays, making them difficult to use across-the-board.2 Disagreement among the experts is also confusing to practitioners. When 1 group reported success for NMP22 in a recent issue of the Journal,3 shortly thereafter others responded by strongly disagreeing with the conclusions of the primary report, citing several studies supporting their viewpoint.4 Clearly, much more clinical research is needed for a consensus to emerge defining extended exclusion criteria for individual assays, and to document reproducibility of sensitivity and specificity before these assays become everyday clinical tools. In this issue of the Journal 2 helpful studies add to the growing information base in this area. Sanchez-Carbayo et al (page 1951) examine the sensitivity and specificity of NMP22 to detect transitional cell carcinoma * Bard Diagnostics, Redmond, Washington. † Matritech, Cambridge, Massachusetts.
in various clinical settings. They also investigate an experimental battery of urinary cytokeratins to elucidate whether combined determination of these markers with NMP22 enhances standard assay usefulness for bladder cancer detection. To examine comparable sensitivity of the various markers they used a unique approach of setting cutoffs such that all were 95% specific in a reference population of individuals at risk for bladder tumor recurrence but with no evidence of disease. This is precisely the patient population in which such assays would be used clinically. To achieve this high level of specificity the NMP22 cutoff was increased from the recommended 10 to 14.6 U./ml. Under these nonstandard conditions the NMP22 assay demonstrated no false-positive results in patients with stones or malignancies other than bladder cancer as long as those with potentially confounding urinalyses positive for nitrites and leukocytes were excluded from analysis. Given these exclusions and even with this elevated cutoff, sensitivity was 80% for grades II and III tumors, and 76% for grade I lesions compared to the 30 to 40% sensitivity expected for cytology in such tumors. Combining NMP22 with either of 2 cytokeratin markers increased overall sensitivity to 86 to 88% but adversely affected specificity as well. This information is useful and if confirmed by others suggests that given appropriate exclusions NMP22 may be equivalent to cytology to detect high grade and better to detect low grade lesions. On a practical note, Medicare reimburses NMP22 at about $16 in our district and urinary cytology at $33, and so its use is also cost-effective. The addition of cytokeratins would probably add substantially to the cost but not enhance sensitivity anywhere approaching the 100% level of cystoscopy, which is the gold standard. The study by Jung et al (page 1900) is a far more basic investigation attempting to define a population at increased risk for recurrence by examination of chromosomal changes. They sample the urothelium at cystoscopy by bladder irrigation to obtain cell rich specimens for study. Using fluorescent in situ hybridization, a technique available at most tertiary medical centers or potentially via reference laboratories, they examined the association of chromosome 9 monosomy with future tumor recurrence and found it to be essentially equivalent to the presence of visible tumor in predicting future disease. No data regarding progression are presented. These data are exciting in that they examine fundamental changes in the genome which, as the authors suggest, may be associated with a critical event in tumorigenesis detectable well in advance of phenotypic expression as a tumor visible through the cystoscope. If so, such changes would potentially be highly specific and less likely than other assays to yield false-positive results when environmental factors, such as stents, calculi and so forth, stimulate cellular proliferation. Although they are a long way from any direct clinical application, these findings certainly justify further investigation. I believe that we are living in a transitional decade during which innovative laboratory investigations will produce results that will filter into the clinical arena to improve traditional methods of bladder cancer surveillance. Repeat evaluation of currently approved assays and evaluation of new assays as they are introduced will require time, patience and a critical eye on the part of clinicians as they examine studies
1957
1958
SURVEILLANCE OF SUPERFICIAL BLADDER CANCER
of these evolving techniques and fit them appropriately into day-to-day practice. Thomas H. Stanisic Affiliated Urology Specialists Peoria, Illinois REFERENCES
1. Greene, L. F., Hanash, K. A. and Farrow, G. M.: Benign papilloma or papillary carcinoma of the bladder? J. Urol., 110: 205, 1973.
2. Sharma, S., Zippe, C. D., Pandrangi, L., Nelson, D. and Agarwal, A.: Exclusion criteria enhance the specificity and positive predictive value of NMP22 and BTA STAT. J. Urol., 162: 53, 1999. 3. Zippe, C., Pandrangi, L. and Agarwal, A.: NMP22 is a sensitive, cost-effective test in patients at risk for bladder cancer. J. Urol., 161: 62, 1999. 4. Casella, R., Lehmann, K. and Gasser, T. C.: RE: NMP22 is a sensitive, cost-effective test in patients at risk for bladder cancer. J. Urol., 162: 500, 1999.
Vol. 162, 1957–1958, December 1999 Printed in U.S.A.
EDITORIAL: SURVEILLANCE OF SUPERFICIAL BLADDER CANCER— TRADITION AND INNOVATION KEY WORDS: bladder neoplasms; follow-up studies; recurrence; disease progression; tumor markers, biological
Followup of patients with low grade and low stage bladder cancer is routine for most urologists. Patients undergo cystoscopy quarterly for 1 or 2 years, semiannual examinations for a similar interval and annual surveillance thereafter. Recurrence restarts the cycle. Concomitant urinary cytology facilitates detection of high grade lesions that are not always visually detectable (bladder carcinoma in situ and upper tract transitional cell). In our practice these office procedures with local anesthesia take 5 to 10 minutes and are relatively inexpensive. The 1999 Medicare reimbursement is $135 for office cystoscopy and $33 for cytology. With use of the flexible cystoscope discomfort is modest and tolerable for most men. In their update of the natural history of low grade and low stage transitional cell carcinoma Leblanc et al (page 1946) reexamine the rationale for standard long-term, careful followup. Of 152 patients followed for a mean of 76 months 55% had recurrence, including 30% after an initial 2 to 10-year tumor-free interval. Risk of progression in grade (20%) and stage (6%) was constant throughout followup and independent of tumor-free interval. Of 83 patients with recurrence 12 had progression more than 5 years after initial diagnosis and 5 (6%) had invasive disease. These findings are similar to those reported in 1973 by Greene et al.1 Of 100 similar patients followed for 15 years 73% had recurrence and 10% had progression to invasion with an 8-year mean interval from diagnosis to progression. Clearly the biology of low grade and low stage disease, and the surveillance strategy have remained constant with time. Because of the high risk and our inability to predict recurrence in individual cases the entire population is monitored closely. Since cytology is so insensitive to low grade disease, cystoscopy remains essential. In recent years investigators have focused on multiple urinary tumor markers for transitional cell carcinoma to identify reliable noninvasive adjuncts to traditional surveillance techniques. BTA,* NMP22† and fibrin degradation products have been approved by the Food and Drug Administration, and many other urinary markers continue to be examined in research settings. Despite this flurry of activity, no marker has general, widespread acceptance in routine urological practice. Why? Stents, recent manipulations, stones, infection, bowel interposition and prostatitis are common in bladder cancer cases and create false-positive results in at least 2 of the approved assays, making them difficult to use across-the-board.2 Disagreement among the experts is also confusing to practitioners. When 1 group reported success for NMP22 in a recent issue of the Journal,3 shortly thereafter others responded by strongly disagreeing with the conclusions of the primary report, citing several studies supporting their viewpoint.4 Clearly, much more clinical research is needed for a consensus to emerge defining extended exclusion criteria for individual assays, and to document reproducibility of sensitivity and specificity before these assays become everyday clinical tools. In this issue of the Journal 2 helpful studies add to the growing information base in this area. Sanchez-Carbayo et al (page 1951) examine the sensitivity and specificity of NMP22 to detect transitional cell carcinoma * Bard Diagnostics, Redmond, Washington. † Matritech, Cambridge, Massachusetts.
in various clinical settings. They also investigate an experimental battery of urinary cytokeratins to elucidate whether combined determination of these markers with NMP22 enhances standard assay usefulness for bladder cancer detection. To examine comparable sensitivity of the various markers they used a unique approach of setting cutoffs such that all were 95% specific in a reference population of individuals at risk for bladder tumor recurrence but with no evidence of disease. This is precisely the patient population in which such assays would be used clinically. To achieve this high level of specificity the NMP22 cutoff was increased from the recommended 10 to 14.6 U./ml. Under these nonstandard conditions the NMP22 assay demonstrated no false-positive results in patients with stones or malignancies other than bladder cancer as long as those with potentially confounding urinalyses positive for nitrites and leukocytes were excluded from analysis. Given these exclusions and even with this elevated cutoff, sensitivity was 80% for grades II and III tumors, and 76% for grade I lesions compared to the 30 to 40% sensitivity expected for cytology in such tumors. Combining NMP22 with either of 2 cytokeratin markers increased overall sensitivity to 86 to 88% but adversely affected specificity as well. This information is useful and if confirmed by others suggests that given appropriate exclusions NMP22 may be equivalent to cytology to detect high grade and better to detect low grade lesions. On a practical note, Medicare reimburses NMP22 at about $16 in our district and urinary cytology at $33, and so its use is also cost-effective. The addition of cytokeratins would probably add substantially to the cost but not enhance sensitivity anywhere approaching the 100% level of cystoscopy, which is the gold standard. The study by Jung et al (page 1900) is a far more basic investigation attempting to define a population at increased risk for recurrence by examination of chromosomal changes. They sample the urothelium at cystoscopy by bladder irrigation to obtain cell rich specimens for study. Using fluorescent in situ hybridization, a technique available at most tertiary medical centers or potentially via reference laboratories, they examined the association of chromosome 9 monosomy with future tumor recurrence and found it to be essentially equivalent to the presence of visible tumor in predicting future disease. No data regarding progression are presented. These data are exciting in that they examine fundamental changes in the genome which, as the authors suggest, may be associated with a critical event in tumorigenesis detectable well in advance of phenotypic expression as a tumor visible through the cystoscope. If so, such changes would potentially be highly specific and less likely than other assays to yield false-positive results when environmental factors, such as stents, calculi and so forth, stimulate cellular proliferation. Although they are a long way from any direct clinical application, these findings certainly justify further investigation. I believe that we are living in a transitional decade during which innovative laboratory investigations will produce results that will filter into the clinical arena to improve traditional methods of bladder cancer surveillance. Repeat evaluation of currently approved assays and evaluation of new assays as they are introduced will require time, patience and a critical eye on the part of clinicians as they examine studies
1957
1958
SURVEILLANCE OF SUPERFICIAL BLADDER CANCER
of these evolving techniques and fit them appropriately into day-to-day practice. Thomas H. Stanisic Affiliated Urology Specialists Peoria, Illinois REFERENCES
1. Greene, L. F., Hanash, K. A. and Farrow, G. M.: Benign papilloma or papillary carcinoma of the bladder? J. Urol., 110: 205, 1973.
2. Sharma, S., Zippe, C. D., Pandrangi, L., Nelson, D. and Agarwal, A.: Exclusion criteria enhance the specificity and positive predictive value of NMP22 and BTA STAT. J. Urol., 162: 53, 1999. 3. Zippe, C., Pandrangi, L. and Agarwal, A.: NMP22 is a sensitive, cost-effective test in patients at risk for bladder cancer. J. Urol., 161: 62, 1999. 4. Casella, R., Lehmann, K. and Gasser, T. C.: RE: NMP22 is a sensitive, cost-effective test in patients at risk for bladder cancer. J. Urol., 162: 500, 1999.