Hans Boman

FOUR BLADDER TUMOR MARKERS HAVE A DISAPPOINTINGLY LOW SENSITIVITY FOR SMALL SIZE AND LOW GRADE RECURRENCE

PURPOSE We determine the sensitivity and specificity of 3 bladder tumor markers in urine, including NMP22 assay (Matritech, Newton, Massachusetts), BTA stat test (Bion Diagnostic Sciences, Inc., Redmond, Washington) and UBC antigen (IDL Biotech, Sollentuna, Sweden), and bladder wash cytology for new and recurrent bladder cancer. We examine whether tumor size, grade, and stage influence sensitivity and specificity of the markers. MATERIALS AND METHODS A total of 304 samples in 250 patients were studied. There were 174 patients who had a history of bladder cancer, including 93 with and 81 without recurrent tumor at cystoscopy. The other group of patients consisted of 66 with newly diagnosed bladder tumor and 64 investigated for microscopic hematuria that was found to be idiopathic. BTA stat was assayed according to manufacturer instructions. NMP22 and UBC were measured in urine with an enzyme-linked immunosorbent assay. A cutoff level of 4 for NMP22 and 1 for UBC was chosen to get the same specificity for new tumors as BTA stat (75%) RESULTS There was a highly significant difference (p <0.001) in all markers between patients with new bladder tumors and those without. The difference was less pronounced for tumor recurrence for NMP22, UBC and BTA stat (p=0.002, 0.016 and 0.244, respectively). The difference between new and recurrent tumors disappeared when corrected for tumor size, grade and stage. The sensitivity for new tumors was 65%, 75% and 60% for NMP22, BTA stat and UBC, respectively. Cytology had a sensitivity of 41% for new tumors at a specificity of 94%. The specificity for recurrence was 64% for NMP22, 54% BTA stat and 72% UBC. The sensitivity was 45% for NMP22, 55% BTA stat and 40% UBC. CONCLUSIONS Tumor size, grade and stage have a strong impact on sensitivity, and specificity for all 3 tested tumor markers as well as bladder wash cytology. The tumor markers or any combination of them cannot replace followup cystoscopy, mainly because most recurrences are small. The role of the markers for screening high risk populations and as a complement to followup cystoscopy remains to be evaluated.

Institutional variability in the accuracy of urinary cytology for predicting recurrence of transitional cell carcinoma of the bladder

To assess the contemporary inter‐institutional accuracy of urinary cytology in predicting the recurrence of transitional cell carcinoma (TCC) of the bladder, in a large multi‐institutional cohort from four continents, as cystoscopy and urinary cytology represent the ‘gold standards’ for surveillance of TCC recurrences, but the ability of cytology to predict recurrence varies.

Newly diagnosed bladder cancer: The relationship of initial symptoms, degree of microhematuria and tumor marker status

PURPOSE We recorded initial symptoms and evaluated the frequency and intensity of hematuria in patients with newly diagnosed bladder cancer. We also evaluated and compared the sensitivity of bladder wash cytology, NMP22 (Matritech, Newton, Massachusetts), BTA Stat (Bion Diagnostic Sciences, Redmond, Washington) and UBC antigen (IDL Biotech, Sollentona, Sweden) with hematuria dipsticks and flow cytometry for determining the size of erythrocytes in urine. MATERIALS AND METHODS Urine samples were collected from 92 patients with newly diagnosed bladder cancer, 64 with idiopathic microhematuria and 42 with nephritis. Urine was analyzed for NMP22, BTA Stat, UBC and erythrocytes size using flow cytometry. Bladder wash cytology was done at cystoscopy. Urine was analyzed for microhematuria with hematuria dipsticks at home for 7 consecutive days immediately before the operation and in the hospital on the day of surgery. RESULTS Sensitivity was 75% for NMP22, 78% for BTA Stat, 64% for UBC and 61% for flow cytometry at 73% specificity. Cytology had 42% sensitivity at 97% specificity. Tumor size, grade and stage had a statistically significant influence on NMP22, BTA Stat, UBC and cytology. Of the patients 75% had microhematuria on the day of the operation and 75% had hematuria at least 1 of 7 days when tested at home the last week before transurethral bladder resection. The 70% of all patients with macroscopic hematuria as the initial symptom did not seem to differ from those without the condition in tumor size, grade, stage or tumor marker levels. CONCLUSIONS Flow cytometry was not well enough able to distinguish patients with bladder cancer from controls. The sensitivity of all tested markers, including hematuria dipsticks, was high for large and high grade, high stage tumors. Further studies are needed to evaluate whether a marker could be used to determine priority among patients referred due to microhematuria.

Screening for bladder tumours in men aged 60-70 years with a bladder tumour marker (UBC) and dipstick-detected haematuria using both white-light and fluorescence cystoscopy.

Objective. To investigate the relevance of bladder tumour screening using haematuria dipsticks and a bladder tumour marker in a random selection of men, age 60–70 years, from a well-defined geographical area using both fluorescence and white-light cystoscopy. Material and methods. A total of 2000 randomly selected men, age 60–70 years, were invited by mail to participate in a screening for bladder tumours by having their urine tested with a dipstick for haematuria and a bladder tumour marker (UBC). Men with 5–10 red blood cells (RBC)/µl and an International Prostate Symptom Score (IPSS) of >10 and all men with ≥25 RBC/µl and/or elevated UBC levels underwent both white-light and fluorescence cystoscopy. Results. A total of 1096 men (55%) responded and were included in the study. The incidence of 5–10 RBC/µl was high: 14%. A tumour was detected in one of the 62 men with 5–10 RBC/µl and an IPSS of >10. Among the 10% of men (n=112) with ≥25 RBC/µl, four bladder tumours were detected. Another two tumours were detected in men without haematuria (positive UBC test). No tumours were observed using only fluorescence cystoscopy. Conclusions. Fluorescence cystoscopy and the UBC test were of no use in this screening situation. The incidence of haematuria (≥5–10 RBC/µl) was so high (1:4) that this borderline for bladder tumour screening appears unrealistic. The incidence of ≥25 RBC/µl was 1:10 and one of 28 cystoscopies revealed a bladder tumour. All seven tumours were detected in men who were or had been smokers. A haematuria-based screening among older male smokers with ≥25 RBC/µl on dipstick testing is thus an option that should be considered.

Urinary cytology and nuclear matrix protein 22 in the detection of bladder cancer recurrence other than transitional cell carcinoma

To assess the value of nuclear matrix protein‐22 (NMP22), compared with urinary cytology, in predicting the recurrence of bladder cancer that is not transitional cell carcinoma (non‐TCC).

The results of routine evaluation of adult patients with haematuria analysed according to referral form information with 2-year follow-up

OBJECTIVE With the principal aim of determining how often investigation of haematuria results in a malignancy diagnosis, the referrals (n = 581) during one year to a department of urology (catchment area 250,000 inhabitants) where haematuria was mentioned in the referral form have been registered and analysed. The case records were evaluated after two years. RESULTS The tumours detected were mainly bladder tumours (n = 43) and prostate cancers (n = 31). Only three upper urinary tract tumours were diagnosed. The incidence of malignancies was high in patients with macroscopic haematuria (24%), especially if it was asymptomatic (32%). The incidence was lower in microscopic haematuria (9%), especially if it was asymptomatic (5%). The incidence of malignancies was strongly age- and sex-related; in no female under 70 years and in no male under 45 years of age with microscopic haematuria was a malignant tumour detected. CONCLUSION Macroscopic haematuria, especially in older patients, is often associated with a malignancy and the investigation must be given high priority. The incidence of malignant tumours in patients with symptomatic microscopic haematuria also warrants an investigation. In the case of asymptomatic microhaematuria. the risk is so low, especially in women that the need for a work-up must be strongly questioned.

Relationships between lower urinary tract symptoms, the bother they induce and erectile dysfunction.

Objective. To study the relationships between lower urinary tract symptoms (LUTS), LUTS-induced bother, age and erectile dysfunction. Material and methods. A survey consisting of two questionnaires, the International Prostate Symptom Score (IPSS) (reflecting LUTS) and the International Index of Erectile Function (IIEF)-5 (reflecting erectile function), together with instructions on how to perform timed micturition, was sent to 2000 randomly selected men (age range 60–70 years) living in the five counties surrounding our hospital. The IPSS questionnaire included a question concerning the degree of bother induced by LUTS. Results. The survey was answered by 1096 men; after the exclusion of incomplete answers, 924 surveys were evaluated. Of these 924 men, 725 (78%) were sexually active and included in the analyses. The prevalence of moderate-to-severe LUTS (IPSS ≥ 8) was 45%. The prevalence of erectile dysfunction (ED), defined as an IIEF-5 score of ≤ 20, was 44%. IPSS correlated significantly with timed micturition, but not with age. IPSS was also, as expected, strongly correlated with LUTS-induced bother (correlation coefficient [c.c.] 0.76). The IIEF-5 score was correlated with timed micturition and age. There was a significant correlation between the IIEF-5 score and IPSS (c.c. −0.29; p<0.001). The IIEF-5 score was also correlated with LUTS-induced bother (c.c. −0.30; p<0.001). In a multivariate analysis, the presence of ED (IIEF-5 score ≤ 20) was significantly correlated with IPSS, LUTS-induced bother and age, but not with timed micturition. Men who were more severely bothered by LUTS more often had ED than those who were less bothered by them. Conclusions. LUTS and the bother it induces were independently significantly correlated with ED, as reflected by the IIEF-5 score. The relationships were, however, rather weak and we recommend further studies, preferably of a longitudinal and/or qualitative character, to gain a more profound understanding of the interaction, probably multifactorial, between LUTS, the bother it induces and ED. Such studies are necessary not only in order to better understand the possible causality but also to evaluate whether the relationships are of any practical value regarding the management of individual patients.

Urine tissue-polypeptide-specific antigen (TPS) as a marker for bladder cancer.

Objectives: To determine the sensitivity and specificity of urine tissue-polypeptide-specific antigen (TPS) for bladder carcinomas and to evaluate whether urine TPS is influenced by tumour size, number, grade and stage. Patients and methods: A total of 260 patients entered the study, one group (n = 151) with known bladder cancer disease (79 with recurrent tumour and 72 with no tumour at cystoscopy). The other group (n = 109) consisted of patients without previously known bladder tumour disease, 55 with newly detected bladder tumour(s) and 54 investigated for microhematuria found to be idiopathic. TPS in urine was measured using an ELISA-kit, a solid phase two-site immunosorbent assay with polyclonal antibodies against cytokeratin 18. Results: Urine TPS was significantly higher in patients with bladder tumours (p < 0.001). There was a significant correlation between TPS and tumour size (p = 0.004), grade (p = 0.001) and stage (p = 0.001). Tumour number was not significantly correlated to urine TPS (p = 0.75). With TPS 42 as a cut-off level, the sensitivity was 73% for newly detected tumours and 50% for recurrences; the specificity was 70% and 63% respectively. With a 95% specificity, the sensitivity for newly detected tumours was 33% and for recurrences 18%. The lower sensitivity and specificity for recurrences was mainly explained by differences in tumour size, grade and stage between the recurrences and the newly detected tumours. Conclusions: Urine TPS is a marker for bladder carcinoma correlated to size, grade and stage. The sensitivity and specificity for newly detected tumours are quite comparable with other markers. Its clinical usefulness is however not established and it appears less useful in the follow-up of patients with known bladder tumour disease.OBJECTIVES To determine the sensitivity and specificity of urine tissue-polypeptide-specific antigen (TPS) for bladder carcinomas and to evaluate whether urine TPS is influenced by tumour size, number, grade and stage. PATIENTS AND METHODS A total of 260 patients entered the study, one group (n = 151) with known bladder cancer disease (79 with recurrent tumour and 72 with no tumour at cystoscopy). The other group (n = 109) consisted of patients without previously known bladder tumour disease, 55 with newly detected bladder tumour(s) and 54 investigated for microhematuria found to be idiopathic. TPS in urine was measured using an ELISA-kit, a solid phase two-site immunosorbent assay with polyclonal antibodies against cytokeratin 18. RESULTS Urine TPS was significantly higher in patients with bladder tumours (p < 0.001). There was a significant correlation between TPS and tumour size (p = 0.004), grade (p = 0.001) and stage (p = 0.001). Tumour number was not significantly correlated to urine TPS (p = 0.75). With TPS 42 as a cut-off level, the sensitivity was 73% for newly detected tumours and 50% for recurrences; the specificity was 70% and 63% respectively. With a 95% specificity, the sensitivity for newly detected tumours was 33% and for recurrences 18%. The lower sensitivity and specificity for recurrences was mainly explained by differences in tumour size, grade and stage between the recurrences and the newly detected tumours. CONCLUSIONS Urine TPS is a marker for bladder carcinoma correlated to size, grade and stage. The sensitivity and specificity for newly detected tumours are quite comparable with other markers. Its clinical usefulness is however not established and it appears less useful in the follow-up of patients with known bladder tumour disease.

Four bladder tumor markers have a disappointingly low sensitivity for small size and low grade recurrence.1: J. Urol 2002;167:80–83.

Abstract Purpose: We determined the sensitivity and specificity of three bladder tumor markers in urine, including NMP22 assay (Matritech, Newton, Massachusetts), BTA stat test (Bion Diagnostic Sciences, Inc., Redmond, Washington) and UBC antigen (IDL Biotech, Sollentuna, Sweden), and bladder wash cytology for new and recurrent bladder cancer. We examine whether tumor size, grade, and stage influence sensitivity and specificity of the markers. Materials and Methods: A total of 304 samples in 250 patients were studied. There were 174 patients who had a history of bladder cancer, including 93 with and 81 without recurrent tumor at cystoscopy. The other group of patients consisted of 66 with newly diagnosed bladder tumor and 64 investigated for microscopic hematuria that was found to be idiopathic. BTA stat was assayed according to manufacturer instructions. NMP22 and UBC were measured in urine with an enzyme-linked immunosorbent assay. A cutoff level of 4 for NMP22 and 1 for UBC was chosen to get the same specificity for new tumors as BTA stat (75%) Results: There was a highly significant difference ( P p = 0.002, 0.016, and 0.244, respectively). The difference between new and recurrent tumors disappeared when corrected for tumor size, grade and stage. The sensitivity for new tumors was 65%, 75%, and 60% for NMP22, BTA stat, and UBC, respectively. Cytology had a sensitivity of 41% for new tumors at a specificity of 94%. The specificity for recurrence was 64% for NMP22, 54% BTA stat, and 72% UBC. The sensitivity was 45% for NMP22, 55% BTA stat, and 40% UBC. Conclusions: Tumor size, grade, and stage have a strong impact on sensitivity, and specificity for all three tested tumor markers as well as bladder wash cytology. The tumor markers or any combination of them cannot replace followup cystoscopy, mainly because most recurrences are small. The role of the markers for screening high risk populations and as a complement to follow-up cystoscopy remains to be evaluated.