Robert A. Hiatt2 and Juan D. Ordo#{241}ez

Division of Research, Kaiser Permanente Medical Care Program IR. A. HI,

and the Department of Medicine Ii. D. 0.1, Kaiser Permanente MedicalCenter, Oakland, California

Received 1 1/1 5/93; revised 4/1 5/94; accepted 4/1 5/94.

1 Presented at Bladder Cancer Hematuria Screening Workshop, Madison,

WI, October 1 8-1 9, 1 991 . The research was supported in part by theNorthern California Kaiser Foundation Hospitals, Inc., Community Service

Program; the Medical Editing department of Kaiser Foundation ResearchInstitute provided editorial assistance.

2 To whom requests for reprints should be addressed, at Division of Re-

search, Kaiser Permanente Medical Care Program, 3505 Broadway, 1 3thfloor, Oakland, CA 9461 1.

Vol. 3, 439-443, July/August 1994 Cancer Epidemiology, Biomarkers & Prevention 439

tuna.

Review

Dipstick Urinalysis Screening, Asymptomatic Microhematuria, andSubsequent Urological Cancers in a Population-based Sample”

Abstract

Screening urine for microhematuria as an indicator ofserious disease is controversial because of the lowpositive predictive value of such screening and the costsand risks of the associated evaluation. To furtherevaluate test properties, we retrospectively examined theoutcomes of 20,571 men aged �35 years and womenaged �55 years who voluntarily had a Personal HealthAppraisal in 1 980 as members of a large prepaid healthplan. Hematuria was deteded by dipstick in 876 cases(4.3%); 278 were excluded because of evidence ofprevious urological disease which could causehematuria. Review of the medical records of 598patients with asymptomatic microhematuria as shown bya positive dipstick result indicated that 99% had afollow-up evaluation within 3 months of positive testresults for hematuria and had various levels of urologicalevaluation thereafter. However, urological cancers (2prostate, i bladder) developed in only 3 patients withinthe next 3 years. On the basis of San Francisco-OaklandSurveillance, Epidemiology, and End Results programdata, rates of urological cancer were evaluated amongpatients whose test results were negative for hematuria,and these cancer rates were found to be almost thesame as the rate among patients with asymptomaticmicrohematuria. Sensitivity of a single dipstick urinalysisresult using microhematuria to indicate urologicalcancer within 3 years was 2.9%; specificity was 96.7%;and positive predictive value was 0.5%. Multivariateanalysis which adjusted for age, gender, and raceshowed that the relative risk of 2.i (95% confidenceinterval, 0.7-6.6) for urological cancer was notsignificantly elevated among patients with asymptomaticmicrohematuria compared with patients who hadnegative test results. These findings based on a singletest are consistent with the current lack ofrecommendations for screening for microhematuriaamong asymptomatic adults.

IntrodudionDipstick urinalysis is a simple, quick, and inexpensivemethod of detecting microhematunia and other urinary ab-normalities (1 ). However, the value of dipstick urinalysis inscreening for urological malignancies and other seriousdiseases of the urinary tract has not been supported byseveral population-based studies (2, 3), except perhaps inpopulations aged >60 years (4, 5). Clinicians are concernedabout whether an evaluation for microhematunia is justifiedconsidering the associated risks: morbidity generated byirradiation (1); potential allergic reactions from iv. pyelo-grams (6); and complications from renal biopsy (7). Further-more, the cost of screening and a complete urinalysis eval-uation for hematunia can be substantial. An estimated $150million is spent on dipstick urinalysis testing annually in theUnited States (1 ). However, although about 52,300 cases ofbladder cancer and 27,200 cases of kidney and other un-nary cancers were estimated for 1 993 (8), no effectivescreening measures for these cancers have been found. Tofind these cases, we would currently test many people to

benefit a few (9). Is this approach justified?To date, studies that evaluated dipstick urinalysis for

microhematunia reported only the positive predictive valueof the test, and no randomized trials or case-control studiesof screening have been conducted. Further, only 2 studies,in which a group of patients had negative test results formicrohematunia from dipstick screening, followed patientsto determine “false-negatives” (1 0, 1 1 ), and selection fac-tons may have played a role in one of these studies (1 1).

We have used a continuing program of screening andhealth appraisal within a large prepaid health plan to eval-uate the outcomes associated with dipstick screening formicrohematunia, including outcomes of patients whose dip-stick tests showed no evidence of microhematuria. Wesought to confirm the results of other population-basedcohort studies concerning the positive predictive value ofthe test and to reassess sensitivity and specificity of screen-ing dipstick analysis in this setting.

MethodsPopulation. The KPMCP3 is a large prepaid health planwhich serves about 30% of the population in the majorurban areas of northern California. The age and sex distri-bution of the membership parallels that of the U.S. Censuspopulation (i 2), and, on the basis of census block groupcharacteristics analysis, the racial and socioeconomic statusof the membership is closely comparable with that of theU.S. Census population except for extremes of income (1 3).

3 The abbreviations used are: KPMCP, Kaiser Permanente Medical CareProgram; PHA, Personal Health Appraisal; AMH, asymptomatic microhema-

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440 Review: Urological Cancer Screening

Study Population. Patients selected for study were 20,891members who had a PHA in i 980 at the Oakland on SanFrancisco Kaiser Permanente Medical Centers. Only men

age �35 years and women age �55 years were eligible foranalysis. Women aged

Cancer Epidemiology, Biomarkers & Prevention 441

Table 1 Prevalence of asymptomatic hematuria among patients having aPHA in 1980, by age and sex

Hematuria

Age(yr)

No. No. negative No. No.studied (%) excluded asymptomatic

(%) (%)

Men

35-54 7,059 6,901 (97.8) 32 (.5) 126 (1 .8)

55-74 5,428 5,279 (97.3) 53 (1 .0) 96 (1.8)

75+ 543 526 (96.9) 12 (2.2) 5 (1.0)

Women55-74 6,861 6,362 (92.7) 157 (2.3) 342 (5.0)

75+ 860 807 (93.8) 24 (2.8) 29 (3.4)

Total 20,751 19,875 (95.8) 278 (1.3) 598 (2.9)

Table 2 Outcomes in 598 patients with asymptomatic microhematuria

within 3 years after detection, by seriousness of disease

Age(yr)

Urological disease

No. with , No. No.microhematunia No. minor moderate serious

( o) � (0/,,)

Men

35-54 126 12(10) 16(13) 0(0)

55-74 96 16(17) 14(15) 3(3)

75+ 5 2 (40) 1 (2) 0 (0)

Women55-74 342 8 (2) 45 (1 3) 0 (0)

75+ 29 4(14) 3(10) 0(0)

Total 598 42(7) 79(13) 3(55 years, most of the associated cancers were in theprostate. Among patients with no hematunia, i 02 urinarytract cancers (68 prostate) were diagnosed in the 3 yearsafter hematunia was detected. Thus, after exclusions, sensi-tivity of AMH in indicating urological cancers was 2.9%(3/105), and specificity was 96.7% (19,703/20,368). Thepredictive value of a single specimen with microhematuniawas O.S% (3/598). If only bladder and renal cancers wereselected as cancer outcomes likely to be detected by

Table 3 Distribution of asymptomatic urobogical find

in 598 patients with microhematuriaings (outcomes)

No. of menOutcome (0/)

No. of women

(0/)

Serious

Uroepithelial cancer (bladder) 1 (0.2) 0 (0)

Prostate cancer 2 (0.4) 0 (0)

Moderately serious

Renal and ureteral calculi 4 (0.7) 3 (0.5)

Urinary tract infection 24 (4.0) 42 (7.0)

Nephnitis or renal insufficiency 2 (0.4) 1 (0.2)

Other 4(0.7) 7(1.2)

Minor

BPH� 27)4.5) 0(0)

Renal cyst 4 (0.7) 2 (0.4)

Cystocele 0 )0) 3 0.5)

Persistent microhematunia 18 (3.0) 14 (2.3)

Other 1 (0.2) 1 (0.2)

a BPH, benign prostatic hypertrophy.

Table 4 Urological cancer’ outcomes in 20,571 patients having a PHAwithin 3 years of test, by age and sex

Hematuria

Age (yr) No. negative(n = 19,875)

(%)

No. excluded(n = 278)

(%)

No.asymptomatic(n = 598) (%)

Men

35-54 4(0.06) 1 (3.1) 0(0)

55-74 72(1.4) 0(0) 3(3.1)

75+ 15(2.9) 1 (8.3) 0(0)

Women55-74 6(0.09) 2(1.3) 0(0)

75+ 5(0.06) 0(0) 0(0)

Total 102(0.5) 4(1.4) 3(0.5)

a Urobogical cancer: renal; bladder; and prostate cancer.

screening for AMH, then only i (a bladder cancer) wasdetected among patients with AMH, 4 among those in theexcluded group, and 34 among those who had negative testresults. Sensitivity was 2.9% (1/35), specificity was 97%(19,841/20,438), and positive predictive value was 0.2%(1/598).

Crude rates for any of these 3 cancers together did notsignificantly differ between patients with AMH and patientswith negative test results after 3 years offollow-up (Table 5).Patients excluded because they had known on suspectedcauses of hematunia had rates 3 times greater than those notso excluded, but the difference was not statistically signif-icant. The actual number of cancers was small, and confi-dence intervals around the point estimates for relative riskwere wide. When only bladder and renal cancerswere included in these rates, the relative pattern wassimilar.

Finally, we evaluated the outcome of any urinary tractcancer, adjusting for age, gender, and race, by using theCox proportional hazards model. Risks for urological can-cer were twice as high overall and 2.6 times higher for menwith AMH compared with those with no hematuria, al-though these differences were not statistically significant(Table 6). As expected, patients with hematunia who had

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442 Review: Urological Cancer Screening

Table 5 Urobogical cancer rates among patients having a PHA during

3 years of follow-up

Crude rate/i 000 person-years (95% Cl�)

. AsymptomaticNegative Excluded

hematunia

Men 2.2 (1 .8-2.7) 6.2 (0.7-22.5) 4.0 (0.8-1 1.7)

Women 0.5 (0.2-0.8) 3.3 (0.4-1 i .8) 0 (0-0)

Total 1 .5 (1 .3-1 .9) 4.3 (1 .2-i 1 .0) 1 .5 (0.3-4.4)

.,dl, confidence interval.

Table 6 Relative risk of urological cancer in 3 years after

microhematunia�’

Relative risk (95% Cl)

Asymptomatic. . Exclusion vs.

microhematunia vs.. negative

negative

Men 2.6 0.8-8.3) 1 .9 (0.5-7.7)

Women 9.6(2.0-46.5)Total 2.1 (0.7-6.6) 3.1 (1.1-8.5)

.,Adjusted for age, race, and (for total) sex. CI, confidence interval.

exclusions had a significantly greater chance of unologicalcancer developing in the next 3 years (relative risk, 3.1,95% confidence interval, 1.1-8.5).

Discussion

These results suggest that the probability of detecting seni-ous urinary tract disease with a single screening dipstickurinalysis is small. Specifically, AMH occurred in 2.9% ofthis population of men aged �35 years and women aged�55 years, and urinary tract cancers of the kidney, bladder,and prostate occurred in 0.5% of persons with AMH duringa 3-year period. The proportion of persons with seriousurinary tract disease found among persons with AMH wasnot statistically significantly different than that found amongthe remainder of the cohort in whom no hematunia wasdetected.

A comparable large population-based study of AMHalso found a low rate of serious disease (1.8%) (2). In arecent case-control comparison in the same population,serious disease was found in i .2% of persons with AMHand 0.2% of persons who had negative test results, a smallbut significant difference (P = 0.04) (10). However, otherstudies of selected or referred populations have yieldedhigher rates of both hematunia and associated malignancy(1 , 4, 1 1 , 1 4-1 7). Data on the benefits of screening fromsuch studies must be evaluated with an appreciation of theeffect of selection and referral bias.

Are the current results aberrant, or do they representthe prevalence of urinary tract cancer in a general popula-tion more accurately than has been reflected by the bio-medical literature in English to date? First, the study popu-lation consisted of adult members of a prepaid health planand may have been healthier than the general populationalthough demographically comparable (12, 13). However,other studies have found that KPMCP members who have aPHA have rates of cancers (i8) and inflammatory bowel(i9) and renal disease (12) similar to rates in the generalpopulation, and substantial difference between their healthand the health of the general population is unlikely.

Second, the rate of AMH was 2.9%. Although substan-tially less than the 21 % reported among volunteer men aged�50 years in Wisconsin (20) or the 20% reported from

Leeds, England (21 ), both after multiple screenings, our rateis comparable with other population-based studies (22-24).However, in the population-based study most comparablewith ours, the rate was 1 3% (2) as determined from micro-scopic examination of a spun urine sediment and when �1erythrocyte/high-powered field was defined as hematunia.The younger age of our subjects relative to that in otherstudies could partially explain the lower prevalence ofAMH in our study. However, in this population we did notobserve the expected increase in the prevalence of AMHwith age. Mohr et a!. (2) also noted no age-related increasein the prevalence of AMH. Within the KPMCP PHA popu-lation, we examined the overall frequency of hematuniawithout any exclusion from 1 978 through 1 985 and foundthat the percentage ranged between 3.2 and 9.0%; themean of 4.9% suggested that 4.3% (in 1980) was not anextreme value in this population.

A third factor for comparison was the proportion ofpatients with AMH who had serious disease. We found 3patients (0.5%) (all men) in whom cancer developed duringthe 3-year follow-up period. None of our patients had poly-cystic kidney disease, hydronephrosis, or renal cancer, al-though 7 had renal or ureteral calculi, a serious findingaccording to other schemata used (2). We were uncertainwhether detection of hematunia had led to diagnosis in 2 ofthe 3 patients. Our finding is comparable with the Roches-ten, Ml, study (2) finding of 1 4 patients (1 .8%) with neopla-sia associated with hematunia but is less than the 3 to 6%derived from studies of male volunteers for urine screening(1 , 1 1 , 20, 21 ) which included complete unological evalu-ation of most subjects. If we restrict our evaluation to the101 men �55 years old in our study, 3% had seriousoutcomes (i.e., cancers), or a level of cancer comparable tothat found in the more intensively investigated subjects instudies restricted to olden men (1 1 , 20, 21). Thus, we be-lieve the incidence of unological cancer in our cohort isreasonably comparable with that found in other popula-tions, especially when restricted to men over age 55. Be-cause we assume that cancers of the urinary tract whichcause hematunia would become apparent within 3 yearsand that our detection of cancers in the KPMCP populationis nearly complete, the thoroughness of the evaluation isless relevant in this retrospective analysis of cancer out-comes. Even when we extended our analysis to includedata from a 5-year follow-up, our findings did not changesubstantially.

In summary, we believe that our data are compatiblewith those of the available population-based studies andthat differences with other investigations exist principallybecause of the selected on referred nature of their popula-tions.

The level of sensitivity of AMH for indicating urinarytract neoplasia depends on outcome data from a compara-ble population of patients who had negative test results forhematunia (1, 10). Our data show low sensitivity at 2.9%;i.e., after excluding patients with known reasons for hema-tuna, 1 05 cancers of the urinary tract developed during the3-year follow-up screening, but only 3 cancers occurred inpatients who had AMH as detected by dipstick. Prostatecancer is less prone to bleed than renal or bladder cancer,but the sensitivity of dipstick urinalysis in detecting the 35renal and bladder cancers which developed during the next

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Cancer Epidemiology, Biomarkers & Prevention 443

3 years was the same as that in detecting prostate cancer-2.9% (1/35). Ofcourse, because urological cancer-inducedhematuria is intermittent (4), sensitivity could be increasedby doing repeated dipstick or microscopic unmnalyses (1 1,20, 21 ), although repeating the procedure would producemore false-positive results and lower specificity. We couldnot evaluate this approach in our retrospective study. How-ever, 595 of our 20,368 (2.9%) patients with no cancer hadhematunia which resulted from a source which was notlife-threatening, according to our definition and that ofMohr et a!. (2). These patients may be unnecessarily sub-jected to full-scale urological evaluations and their resultantadverse effects and costs. Recommendations to instituterepeated testing are likely to produce small gains in sensi-tivity of cancer detection but would increase the size of thisfalse-positive population substantially and should, there-fore, be considered carefully.

Our results suggest that no change should be made inthe current recommendation against screening asymptom-atic adults for microhematunia (1 ). Perhaps screening can bemade sufficiently more sensitive and specific by requiringrepeated positive results in a given period, but our data donot help to answer this question. Technical advances arenecessary to produce a more accurate screening test whichwould reduce the morbidity and the cost of urological

evaluation for hematunia. Nonionic contrast media, al-though more costly, lower the risk of fatal reactions (25).Using bladder cytology with hematunia screening has beensuggested (2i). In some populations at especially high risk,such as chemical workers and other occupational groups,more intensive screening may be justified (26).

More complete studies that quantitatively assess risksand benefits of urological evaluation are needed (9). Ourstudy provides insufficient data to make an informed nec-ommendation on the appropriate indications for full-scaleurological evaluation. However, we believe that the lowprobability offmnding patients with treatable life-threatening

lesions must be weighed against the risk of diagnostic eval-uation (1). Our limited conclusion supports those (1, 27)who believe that full urological evaluation should not berecommended for persons with a single positive dipstickscreening test for microhematunia.

AcknowledgmentsWe appreciate the useful comments of Dr. Edward Messing.

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1994;3:439-443. Cancer Epidemiol Biomarkers Prev R A Hiatt and J D Ordoñez sample.and subsequent urological cancers in a population-based Dipstick urinalysis screening, asymptomatic microhematuria,

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