A SIDE BY SIDE COMPARISON OF CYTOLOGY AND BIOMARKERS FORBLADDER CANCER DETECTION

GRETHCHEN L. SCHROEDER,* MARIA-FERNANDA LORENZO-GOMEZ,* STEFAN H. HAUTMANN,MARTIN G. FRIEDRICH, SINAN EKICI, HARTWIG HULAND AND VINATA LOKESHWAR†

From the Departments of Urology (GLS, M-FL-G, SE, VL) and Cell Biology and Anatomy (VL) and Sylvester Comprehensive CancerCenter (VL), University of Miami School of Medicine, Miami, Florida, and Department of Urology, University Hospital Hamburg-

Eppendorf, University of Hamburg (SHH, MGF, HH), Hamburg, Germany

ABSTRACT

Purpose: The identification of accurate bladder tumor markers/tests could improve diagnosis,recurrence monitoring and treatment in patients with bladder cancer. In this study we comparedthe efficacy of the hyaluronic acid (HA)-hyaluronidase (HAase), BTA-Stat (Bard/Bion Diagnos-tics, Redmond, Washington), Hemastix (Bayer Corp., Elkhart, Indiana) (hematuria detection)and UBC-Rapid (IDL Biotech, Borlanger, Sweden) tests, and cytology to detect bladder cancer.The HA-HAase test measures urinary HA and HAase levels, BTA-Stat detects complementfactor-H and H related protein in urine, the Hemastix hemoglobin dipstick detects hematuriaand UBC-Rapid detects cytokeratin 8 and 18 fragments in urine.Materials and Methods: A total of 138 urine specimens from 115 patients were collected at

University Hospital Hamburg-Eppendorf, including 59 with active bladder cancer and 79 with ahistory of bladder cancer (73) or with benign genitourinary conditions (6). Specimens wereassayed by the HA-HAase test, BTA-Stat, Hemastix (hemoglobin dipstick) and UBC-Rapid.Cystoscopy and histological findings were used to make the clinical diagnosis. Cytology resultswere available on 92 patients.Results: In a side by side comparison the HA-HAase test, cytology, BTA-Stat, Hemastix and

UBC-Rapid had 88.1%, 70.6%, 52.5%, 50.8% and 35.6% sensitivity, and 81%, 81%, 76.7%, 78.2%and 75% specificity, respectively. The accuracy, and negative and positive predictive values of theHA-HAase test were the highest (84.1%, 90.1% and 77.6%), followed by cytology (77.2%, 82.5%and 68.6%), Hemastix (66.4%, 67.8% and 63.8%), BTA-Stat (66.2%, 67.8% and 63.3%) andUBC-Rapid (57.8%, 60% and 52.5%), respectively.Conclusions: The HA-HAase test is superior to cytology, BTA-Stat, Hemastix and UBC-Rapid

for detecting bladder cancer recurrence. A side-by-side comparison of tumor markers should helpidentify a marker for monitoring bladder cancer recurrence.

KEY WORDS: bladder; bladder neoplasms; tumor markers, biological; cytology; hematuria

Cystoscopy is the primary diagnostic method for diagnos-ing bladder carcinoma. Although it is the gold standard fordetecting bladder cancer, it is invasive and relatively expen-sive.1 The standard noninvasive marker voided urine cytol-ogy is tumor specific with specificity reported in variousstudies as high as 90% to 95%.2 However, the sensitivity ofcytology is low and in various studies it was between 11% and76%.3 Several factors affect the sensitivity of cytology, includ-ing specimen quality, the number of exfoliated cells andpathologist expertise. The overall low sensitivity of cytologyis due to its low sensitivity to detect low grade bladdertumors.Noninvasive urine markers can offer an alternative to the

standard mode of detecting bladder cancer or they can beused as an adjunct to cystoscopy. Several noninvasive mark-ers have shown potential for detecting bladder cancer withhigher sensitivity, although they have lower specificity than

cytology.2–4 Of these markers hematuria detection is themost common marker for bladder cancer. Almost 85% ofpatients with bladder cancer have gross or microscopic he-maturia.5 However, many benign urological conditions alsocause hematuria. Thus, although hematuria may have highsensitivity for detecting bladder cancer, it has low specifici-ty.6BTA-Stat is a point-of-care test approved by the Food and

Drug Administration as an adjunct to cystoscopy for moni-toring bladder cancer recurrence (BTA-Stat product insert).The test is an immunoassay that qualitatively detects thepresence of a human complement factor H (hCFH) related(hCFH-r) protein in the urine of patients with bladder can-cer. The hCFH-r protein is similar to hCFH protein and it isproduced by bladder tumor cells.7 BTA-Stat detects hCFH-rand hCFH proteins (BTA-Stat product insert). In variousstudies the sensitivity and specificity of BTA-Stat was be-tween 50% and 85% (average 50% to 60%).3, 8, 9 Another pointof care test is UBC-Rapid, an immunoassay that detects thepresence of cytokeratin 8 and 18 fragments.10 In variousstudies the sensitivity of UBC-Rapid was between 33% and65%.10–13 However, the test may show a false-positive resultin individuals with a wide range of clinical disorders.10–13

The hyaluronic acid (HA)-hyaluronidase (HAase) urinetest is a combination of 2 enzyme-linked immunosorbentassay-like assays that measure urinary HA and HAase.3 HA

Accepted for publication March 19, 2004.Study received University of Miami institutional review board

approval.Supported by National Cancer Institute/National Institutes of

Health Grant RO1 CA-72821-06A2, American Cancer Society Flor-ida and German Research Society Grant DFG HA 2842/2-1.* Equal study contribution.† Correspondence: Department of Urology (M-800), University of

Miami School of Medicine, P. O. Box 016960, Miami, Florida 33101(telephone: 305-243-6321; FAX: 305-243-6893; e-mail: vlokesh@med.miami.edu).

0022-5347/04/1723-1123/0 Vol. 172, 1123–1126, September 2004THE JOURNAL OF UROLOGY® Printed in U.S.A.Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION DOI: 10.1097/01.ju.0000134347.14643.ab

1123

is a glycosaminoglycan, of which the concentration is in-creased in several tumors.14 HAase is an endoglycosidasethat degrades HA into angiogenic HA fragments.15, 16 HA andHAase levels are increased in bladder cancer tissues.17 TheHA-HAase test has shown 91.9% sensitivity and 84.3% spec-ificity for detecting bladder cancer.18, 19 In a recent study theHA-HAase test was found to be superior to BTA-Stat (87% vs64% accuracy).19 In the same study 60% of false-positivecases by the HA-HAase test had clinical recurrence in 4.7months.19 In this study we performed a side-by-side compar-ison of HA-HAase, BTA-Stat, Hemastix (hematuria detec-tion), UBC-Rapid and cytology to detect bladder cancer.

MATERIALS AND METHODS

Study patients. A total of 138 voided urine specimens werecollected from 115 patients seen at the Department of Urol-ogy, University Hospital clinic, University of Hamburg,Hamburg, Germany. Of the patients 23 provided 2 urinespecimens within the year of collection. Mean age of the 115patients was 64.3 years (range 44 to 90). In this cohort therewere 80 male (69.6%) and 35 female (30.4%) patients. Allpatients studied had primary tumors and did not receive anymedical therapy (ie instillation therapy or systemic chemo-therapy prior to the marker study). This also applies to the 23patients who were included in this study with 2 specimenscollected within 1 year. Of 138 specimens 70 were from pa-tients suspected of having bladder cancer who were sched-uled for cystoscopy. The remaining 68 specimens were frompatients who had a history of bladder cancer and were un-dergoing surveillance cystoscopies or who had benign urolog-ical conditions. All patients included in the study underwentcystoscopy following urine collection since they had at leastmicrohematuria.Of the 70 specimens collected from patients suspected of

having bladder cancer 59 showed active disease, as confirmedby cystoscopy, biopsy, pathological evaluation and cytology.Grade in the 59 bladder cancer positive cases was G1 to G3 in8, 26 and 23, respectively, and undetermined in 2. Undeter-mined grade refers to 2 patients in whom cytology resultsshowed malignant tumor cells, although cystoscopy revealeddysplasia. The stage distribution of bladder cancer positivecases was Ta in 28, T1 in 13, T2 in 9, carcinoma in situ (CIS)in 2, Ta � CIS in 2, T1 � CIS in 1, T2 � CIS in 2 andundetermined in 2. Of the 79 bladder cancer negative speci-mens there was prostate cancer in 2, cystitis in 2, benignhyperplasia in 1 and bladder leiomyoma in 1. Of the 138specimens cytology results were available on 92, of which 34were from patients with active disease and 58 were frompatients with results negative for bladder cancer.All urine specimens were stored at �80C until assay. Bi-

omarker assays (ie hematuria detection, BTA-Stat, UBC-Rapid and HA-HAase) were done in blinded fashion at thedepartment of urology, University of Miami and results werecompared to clinical findings collected by the University ofHamburg group. At the end of the study biomarker testresults were compared to clinical findings after breaking thecode by one of us (SHH).

Hematuria detection.Hemastix (hemoglobin dipstick) wereused. Each urine specimen was assayed according to manu-facturer instruction. Two of us (GLS and M-FL-G) read theresults independently and in blinded fashion.BTA-Stat test. For the BTA-Stat test (30 tests per kit) each

specimen was assayed according to manufacturer instruc-tions. Test results were read by 2 of us (GLS and M-FL-G)independently. As suggested by the manufacturer, any resultregardless of whether it was weakly or strongly positive atthe end of 5 minutes was considered positive.UBC-Rapid. For the UBC-Rapid test each specimen was

assayed according to manufacturer instruction. A band in thetest window, however weak or strong, was considered posi-tive. Two of us (M-FL-G and SE) read each result indepen-dently.HA-HAase test. Urinary HA and HAase levels were meas-

ured using the HA and HAase test, respectively.17–19 UrinaryHA and HAase levels were normalized to urinary protein andexpressed as ng HA/mg protein and mU HAase/mg protein.For the HA test urinary HA levels 500 ng/mg or greater(cutoff limit) represent a positive test. Urinary HAase levels10 mU/mg or greater represent a positive HAase test. Thecombined HA-HAase test is considered positive when the HAand/or HAase test is positive.Statistical analyses. The sensitivity, specificity, accuracy,

positive predictive value (PPV) and negative predictive value(NPV) of each test were calculated using 2 � 2 contingencytables (test positive/test negative and bladder cancer present/absent).3 For the HA-HAase test a positive result on the HAand/or HAase test was considered positive. Consequently afalse-positive result on the HA and/or HAase test was con-sidered false-positive.

RESULTS

Determination of sensitivity, specificity and other relatedparameters. In this study we tested the hypothesis that non-invasive tests are better than voided urine cytology for de-tecting bladder cancer. The study was not designed to detectbladder cancer recurrence since patients with primary tu-mors, those at risk for recurrence and those with other gen-itourinary conditions were included in the biomarker evalu-ation.Table 1 shows that the sensitivity of the HA-HAase test for

detecting bladder cancer was 35% to 53% better than that ofBTA-Stat, hematuria detection and UBC-Rapid. Although inthis study cytology results were available only on 34 of the 59specimens from patients with active disease, cytology had70.6% sensitivity for detecting bladder cancer. The specificityof all tests was comparable to one another and to cytology(table 1). The accuracy of the HA-HAase test (84.1%) was thehighest, followed by cytology, hematuria detection, BTA-Statand UBC-Rapid. Consequently the NPV and PPV of theHA-HAase test was also the highest, followed by cytology,BTA-Stat, hematuria detection and UBC-Rapid.Comparison of the sensitivity of cytology and various bi-

omarkers by tumor grade and stage. In this study there wereonly 8 patients with G1 bladder tumors, of whom cytology

TABLE 1. Sensitivity, specificity, accuracy, PPV and NPV of biomarkers and cytology

Category% (No./total No.)

HA-HAase BTA-Stat Hemastix UBC-Rapid Cytology

Sensitivity 88.1 (52/59) 52.5 (31/59) 50.8 (30/59) 35.6 (21/59) 70.6 (24/34)False-neg 11.9 (7/59) 47.5 (28/59) 49.2 (29/59) 64.4 (38/59) 29.4 (10/34)Specificity 81 (64/79) 76.7 (59/77) 78.2 (61/78) 75 (57/76) 81 (47/58)False-pos 19 (15/79) 25.3 (18/77) 21.8 (17/78) 25 (19/76) 19 (11/58)Accuracy 84.1 (116/138) 66.2 (90/136) 66.4 (91/137) 57.8 (78/135) 77.2 (71/92)NPV 90.1 (64/71) 67.8 (59/87) 67.8 (61/90) 60 (57/90) 82.5 (47/57)PPV 77.6 (52/67) 63.3 (31/49) 63.8 (30/47) 52.5 (21/40) 68.6 (24/35)

Of 79 NED specimens BTA-Stat specificity was available for 77, Hemastix specificity was available for 78, UBC-Rapid specificity was available for 76 andcytology results were available for 58, and of 59 bladder cancer specimens cytology results were available for 34.

COMPARISON OF CYTOLOGY AND BLADDER TUMOR MARKERS1124

results were available on 5. The biomarkers BTA-Stat, he-maturia detection and UBC-Rapid had 50% or less sensitiv-ity for detecting G1 tumors, whereas cytology and the HA-HAase test had 60% and 75% sensitivity, respectively. Thesensitivity of BTA-Stat, hematuria detection and UBC-Rapidfor detecting G2 bladder tumors was also comparable, al-though it was significantly less than that of cytology and theHA-HAase test (table 2). The HA-HAase test detected G3tumors with the highest sensitivity (95.7%), followed by BTA-Stat, cytology, hematuria detection and UBC-Rapid. Therewere 2 patients in whom cystoscopy and biopsy showed dys-plasia, although cytology was positive for malignant cells. Inthese 2 patients disease was detected by the HA-HAase test,while it was detected in 1 by UBC-Rapid and none by BTA-Stat and hematuria detection.The sensitivity of the HA-HAase test (75%) and cytology

(66.7%) to detect superficial bladder tumors was significantlyhigher than that of BTA-Stat, hematuria detection and UBC-Rapid (table 2). It should be noted that cytology results wereavailable only on 18 of 28 patients with stage Ta disease. All13 T1 and 9 T2 bladder cancer cases were detected by theHA-HAase test (100% sensitivity). The sensitivity of BTA-Stat, hematuria detection and UBC-Rapid to detect T1 blad-der tumors was comparable to one another and that of theHA-HAase test was the highest at 100%. However, UBC-Rapid had poor sensitivity to detect T2 tumors compared toBTA-Stat, hematuria detection and the HA-HAase test. Cy-tology had 87.5% sensitivity to detect T1 tumors and 33.3%sensitivity to detect T2 tumors. The poor sensitivity of cytol-ogy for detecting T2 tumors may be attributable to the lownumber of T2 cases (3 of 9) on which cytology results wereavailable. The sensitivity of the HA-HAase test to detect CIS,Ta � CIS, T1 � CIS and T2 � CIS was also higher than thatof other biomarkers, although the number of patients in eachcategory was small. In the 2 undetermined stage cases de-tected by cytology the HA-HAase test was positive for each,UBC-Rapid was positive for 1, and BTA-Stat and hematuriadetection were negative for each one.

DISCUSSION

Voided urine cytology is the standard noninvasive markerfor detecting bladder cancer.2–4 Several noninvasive testsshow higher sensitivity than cytology for detecting bladdercancer, in particular low grade bladder cancer.2–4 However,these tests often have lower specificity than cytology. Threeof the 4 biomarkers that we examined in this study hadsignificantly lower sensitivity than cytology. BTA-Stat andhematuria detection had sensitivity in the 50% range,whereas UBC-Rapid had even lower sensitivity (ie approxi-mately 35%). On the contrary, cytology had overall 70.6%sensitivity. However, it should be noted that of the 59 spec-imens from patients with active disease cytology results were

available only on 34. Of all 4 biomarkers and cytology theHA-HAase test had the highest sensitivity at 88.1%. Thehigh sensitivity of the HA-HAase test observed in this studyis consistent with that in previous studies showing about91% sensitivity for detecting bladder cancer and monitoringits recurrence in patients from a different institution thanthe one providing patients for this study.18, 19

When comparing the sensitivity of various biomarkers, itappears that the HA-HAase test consistently has higher sen-sitivity (25% to 40% higher) to detect different grades andstages of bladder cancer compared to other 3 biomarkers andcytology. However, BTA-Stat has lower sensitivity (ie 25%) todetect G1 tumors compared to approximately 74% sensitivityfor detecting G3 tumors. Since the presence of hematuria isnot related to tumor grade,5, 6 in this study we found thathematuria detection had 50% to 56% sensitivity for detectingG1 to G3 bladder tumors. It has been previously reportedthat UBC-Rapid has 21.3% sensitivity for detecting Ta tu-mors.10 Consistent with these findings, we found that UBC-Rapid has 12.5% and 25% sensitivity for detecting G1 and Tatumors, respectively. As expected, cytology has higher sensi-tivity for detecting high grade (73% to 75%) than low grade(50%) tumors.In this study there were 2 patients in whom cystoscopy

revealed dysplasia, whereas cytology was positive for malig-nant cells. An explanation for this discrepancy would be thatbiopsy missed the tumor area. Nevertheless, the HA-HAasetest was positive in these 2 cases and UBC-Rapid detected 1.The specificity of all 4 biomarkers was comparable to one

another and to that of cytology. It should be noted that allpatients in this study were being assessed for microhematu-ria and/or were under surveillance for bladder cancer. It hasbeen previously shown that the specificity of BTA-Stat andUBC-Rapid is low in patients with benign urological dis-eases, in particular inflammatory diseases. Hematuria is notbladder cancer specific and several benign urological condi-tions can cause hematuria.5, 6, 20, 21 Notably in this study thenumber of patients with other benign genitourinary condi-tions was small. In fact, the majority of study individualswith no evidence of bladder cancer had a history of bladdercancer but no other benign urological condition. These rea-sons could have resulted in higher specificity for differentbiomarkers than previously reported. For example, we havereported that BTA-Stat has 74% specificity in patients with abladder cancer history but no disease at testing. Consistentwith that observation in this study BTA-Stat had 76.7%specificity. The HA-HAase test has been shown to have 84%specificity for detecting bladder cancer.19 Consistent withthat study in this study the HA-HAase test had 81% speci-ficity.To our knowledge this is the first report in which HA-

HAase test performance was compared with that of 3 other

TABLE 2. Sensitivity of biomarkers and cytology by tumor grade and stage

Category% (No./total No.)

HA-HAase BTA-Stat Hemastix UBC-Rapid Cytology

Grade:G1 75 (6/8) 25 (2/8) 50 (4/8) 12.5 (1/8) 50 (3/3)G2 84.6 (22/26) 46.1 (12/26) 50 (13/26) 42.3 (11/26) 75 (12/16)G3 95.7 (22/23) 73.9 (17/23) 56.5 (13/23) 34.8 (8/23) 72.7 (8/11)Not determined* 100 (2/2) 0 (0/2) 0 (0/2) 50 (1/2) 100 (2/2)

Stage:Ta 75 (21/28) 35.7 (10/28) 35.7 (10/28) 25 (7/28) 66.7 (12/18)T1 100 (13/13) 69.2 (9/13) 76.9 (10/13) 69.2 (9/13) 87.5 (7/8)T2 100 (9/9) 88.9 (8/9) 66.7 (6/9) 22.2 (2/9) 33.3 (1/3)CIS 100 (2/2) 0 (0/2) 50 (1/2) 0 (0/2) 0 (0/1)Ta � CIS 100 (2/2) 50 (1/2) 0 (0/2) 0 (0/2) 100 (1/1)T1 � CIS 100 (1/1) 100 (1/1) 0 (0/1) 0 (0/1) NoneT2 � CIS 100 (2/2) 100 (2/2) 100 (2/2) 100 (2/2) 100 (1/1)Undetermined 100 (2/2) 0 (0/2) 0 (0/2) 50 (1/2) 100 (2/2)

* Cytology positive for malignant cells but dysplasia observed on biopsy.

COMPARISON OF CYTOLOGY AND BLADDER TUMOR MARKERS 1125

biomarkers and cytology. In this study there were 59 bladdercancer cases and 79 bladder cancer negative cases, and theHA-HAase test had the highest sensitivity, specificity, accu-racy, PPV and NPV of the 4 biomarkers tested and cytology.Notably the center at which the biomarker study was done(University of Miami) was different from the center whereurine specimens were obtained and cytology inferences weredrawn, and the study was done in a blinded fashion. Theseresults demonstrate that biomarkers with specificity compa-rable to that of cytology and sensitivity higher than that ofcytology could serve as accurate diagnostic tests for detectingbladder cancer and surveillance.

BTA-Stat kits were purchased from Polymedco, Inc., NewYork, New York and Hemastix was purchased from BayorCorp.

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