High Risk Patients with Hematuria Are Not Evaluated According to Guideline Recommendations

doi:10.1002/cncr.25048

Cancer. Author manuscript; available in PMC 2011 June 15.

Published in final edited form as:

Cancer. 2010 June 15; 116(12): 2954–2959.

doi: 10.1002/cncr.25048

PMCID: PMC2940122

NIHMSID: NIHMS219541

High Risk Patients with Hematuria Are Not Evaluated According to Guideline Recommendations

Keren Elias,¹ Robert S. Svatek,¹ Samir Gupta,^2,³ Richard Ho,¹ and Yair Lotan¹^*

¹ Department of Urology, University of Texas Southwestern Medical Center at Dallas, TX, USA

² Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, TX, USA

³ Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, TX, USA

^* CORRESPONDENCE TO: Yair Lotan, M.D., Associate Professor of Urology, Department of Urology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9110, Ph: 214-648-0483, Fax: 214-648-8786, Email: Yair.Lotan/at/UTSouthwestern.edu

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Abstract

Purpose

To determine whether high risk patients with hematuria receive evaluation according to guideline recommendations.

Materials and Methods

We recently performed a screening study for bladder cancer using a urine-based tumor marker in 1502 subjects at high risk based on age over 50, ≥10-year smoking history, and/or a 15 year or more environmental exposure. We evaluated use of urinalysis (UA) within 3 years preceding the screening study. Chart review was performed to determine if this subset with microhematuria received any additional evaluation.

Results

Of 1502 study participants, routine urinalysis was performed in 73.2% and 164 (14.9%) subjects had documented hematuria (>3 RBCs/HPF) prior to inclusion. Of these, 42.1% had no further evaluation. Additional testing included repeat urinalysis (36%), urine culture (15.2%), cytology (10.4%), imaging (22.6% overall: 15.9% CT, 4.3% IVP; 2.4% MRI) and cystoscopy (12.8%).

Three subjects with microscopic hematuria (2%) were subsequently found to have bladder cancer during the screening study but were not referred for evaluation based on their hematuria. The source of hematuria was unknown in 65%, infection in 22%, benign prostatic enlargement in 10% and renal stone disease in 4% but these results are based on incomplete evaluation since only 12.8% underwent cystoscopy.

Conclusions

Subjects at high risk for bladder cancer based on ≥10 years of smoking or environmental exposure with microscopic hematuria are rarely evaluated thoroughly and only 12.8% were referred for urologic evaluation. Further studies are needed to evaluate both the utilization and effectiveness of guidelines for hematuria.

Keywords: Hematuria, Guidelines Recommendations, bladder cancer

Introduction

Bladder cancer is the 4^th most common cancer in men and 5^th most common overall with an estimated 68,800 new cases of bladder cancer and 14,100 deaths from the disease are expected in 2008 in the United States.(1) Most patients are diagnosed after presenting with hematuria. A urinalysis is a common test obtained by primary care physicians and the prevalence of microhematuria is between 9 and 18% in apparently normal individuals.(2–4) Approximately, 10% of patients with gross hematuria and 2 to 5% of patients with microscopic hematuria have bladder cancer.(2–5)

The American Urologic Association best practice policy states that patients at high-risk for bladder cancer (especially those with a history of smoking or chemical exposure) should be considered for a full urologic evaluation after one properly performed urinalysis documenting the presence of at least 3 red blood cells (RBCs) per high powered field (HPF).(2) An initial finding of microscopic hematuria on urinary dipstick should be confirmed by microscopic evaluation of the urinary sediment.(2) Patients in whom a carefully performed history suggests a “benign” cause of their microscopic hematuria should undergo a repeated urinalysis after 48 hours. The evaluation for high risk patients should include cystoscopy, cytology and upper tract imaging.(6) A separate review of clinical practice recommendations for microhematuria defined microscopic hematuria as two or more red cells per high-power field on microscopic examination.(5) This study in the New England Journal of Medicine recommended a repeat urinalysis for patients and no further evaluation if microscopic hematuria is absent on repeated testing in low risk patients. If patients have risk factors for bladder cancer such as cigarette smoking or exposure to toxins then further evaluation with upper tract imaging and cytology and cystoscopy are recommended especially for patients over the age of 50. There are few studies evaluating uptake of these recommendations by primary care physicians.

Two recent studies found sub-optimal referral patterns for microscopic hematuria or any hematuria.(7;8) A survey of 788 primary care physicians including internists, family practitioners, primary care physicians and gynaecologists found that only 36% of clinicians routinely refer patients to urologists.(7) Similarly, the observed rate of urologic referrals was 27% for women and 47% for men, when a health plan database of 926 patients with hematuria was queried.(8) These studies offer evidence for inconsistent referral but there may be differences between real life practice and response to a survey. Furthermore, the individual patient scenarios may be obscured during database searches. As such, we determined the evaluation for hematuria performed on a cohort of patients at high risk for bladder cancer enrolled in large screening study performed at our institution prior to inclusion in the screening study. Between March 2006 and November 2007 we screened 1502 subjects for bladder cancer using a urine-based tumor marker, Nuclear Matrix Protein 22 (NMP22).(9)

This previous screening study solicited subjects from well patient clinics 50 years of age or older, with a 10-year or greater smoking history (any number of cigarettes), and/or a significant (15 or more years) high risk occupation, such as working in the dye, petroleum or chemical industry.(9) The study excluded those with known cancer or hematuria. Therefore, participants were an asymptomatic cohort who would not otherwise require urologic evaluation and yet were at risk for bladder cancer based on age and smoking and/or environmental factors. We performed a chart review to determine the use of routine urinalysis by primary care physicians and assess what evaluation was performed if hematuria was identified.

Materials and Methods

All studies were performed with the approval and oversight of the Institutional Review Board for the Protection of Human Subjects. The study population included 1502 participants, including 925 from the Dallas Veterans Affairs Hospital (VA) and 577 from the University of Texas Southwestern (UTSW) recruited into our NMP-22 bladder cancer screening study between March 2006 and November 2007.(9) This previous screening study solicited subjects from well patient clinics 50 years of age or older, with a 10-year or greater smoking history (any number of cigarettes), and/or a significant (15 or more years) high risk occupation, such as working in the dye, petroleum or chemical industry. The study excluded subjects with a history of urologic malignancy, gross hematuria, active urinary tract infection or urolithiasis. The charts for each participant were reviewed for the 3 years prior to study entry to determine if there were any evaluations of the urine in the form of urine dipstick testing or urinalysis. Microscopic hematuria was defined as 3 or more RBCs/HPF. In those with evidence of hematuria, we checked transcripts, progress notes, imaging results, referrals and laboratory results for subsequent work up. All records at these institutions are electronic medical records. Based on the AUA guidelines for evaluation of high risk patients with hematuria, we defined patients who underwent cystoscopy and upper tract imaging as undergoing guidelines recommendations and patients who did not have complete evaluation as undergoing “guideline inappropriate” evaluation. The patient records at our institution are computerized allowing easy access to pertinent data.

Univariable and multivariable logistic regression analyses were performed to identify factors associated with further evaluation or referral for cystoscopy. Factors examined included age, gender, tobacco use, number of pack-years of tobacco smoked, exposure to occupational/environmental risks and location of evaluation. All statistical tests were performed with STATA/SE version 10.1(Stata Corp. LP, College Station, TX).

Results

There were 1502 participants in the original NMP-22 screening study, including 925 from the VA and 577 from UTSW. Of those, 73.2% had at least one urinalysis with or without microscopy during the three years prior to inclusion in the screening study. The proportion of subjects who had a urinalysis was 86.7% at VA hospital and 52.3% at UT Southwestern. Microhematuria was detected in 164 participants (46% UTSW, 54% VA) during the three years prior to inclusion.

Of the 164 participants found to have microhematuria, 69 (42.1%) had no further evaluation (48.3% VA and 34.7% UTSW). Of the remaining 95 participants who had additional testing, 36% had a repeat urinalysis, 15.2% a urine culture, 10.4% cytology, 22.6% received imaging (15.9% CT, 4.3% IVP; 2.4% MRI) and 12.8% received a cystoscopy. Table 1 and Figure 1 (flow chart) show the evaluation and description of subjects included in this study. Of subjects with repeat urinalysis, 28 (47.9%) of 59 were still positive for hematuria.

Table 1

Evaluation of Subjects with Microscopic Hematuria on Urinalysis (≥3 RBC/HPF)

Figure 1

Flow Chart of Subjects in Study

Table 2 shows findings from hematuria evaluations performed. Three participants with microscopic hematuria (2%) were subsequently found to have bladder cancer during the screening study but were not referred for evaluation based on on the hematuria that pre-dated study inclusion. The source of hematuria was unknown in 65%, infection in 22%, benign prostatic enlargement in 10% and renal stone disease in 4% but these results are based on incomplete evaluation since only 12.8% underwent cystoscopy.

Table 2

Final Diagnosis in Subjects with Microscopic Hematuria on Urinalysis (≥3 RBC/HPF)

Univariate and multivariate analyses were performed to identify factors associated with further evaluation or referral for cystoscopy. When evaluating factors including age, gender, tobacco use, number of pack years of tobacco, exposure to occupational/environmental risks and location of evaluation, only tobacco use was associated with a statistically significant decreased likelihood of evaluation. Of the 90 subjects who received some sort of evaluation, 29 (32%) were smokers, while 38 (51%) of subjects who did not get evaluated were smokers (n=74). Similarly, of the 21 subjects who underwent a cystoscopic evaluation, 6 (29%) were smokers, while 61 (74%) of 143 subjects who did not get a cystoscopy were smokers. On multivariate analysis, in a model including age, gender, occupational exposure, and pack years of tobacco, tobacco use was associated with a nearly 2.5-fold increased risk of no evaluation (OR 2.43 95% CI 1.12–5.26, p=0.025), and a nearly 4-fold increased risk of no cystoscopy (OR 3.84 (95% CI 1.06–14.3, p=0.04).

Discussion

Microscopic hematuria is a common condition with a prevalence of 9 to 18% of apparently normal individuals.(2–4) Mariani et al. evaluated 1000 consecutive patients with hematuria and 9.1% had life-threatening lesions but disease was localized in 92% of cases.(4) Khadra and colleagues evaluated 1,930 hematuria patients and found bladder cancer in 11.9% including 4.8% and 19.3% of patients with microscopic and gross hematuria, respectively.(10) Additional findings included urinary tract infections (13%), medical renal disease (9.8%), urolithiasis (3.6%), renal cancers (0.6%), and prostate cancer (0.4%). While significant diseases were less common in patients with microscopic hematuria (31.8%) as opposed to gross hematuria (47.5%), it still represented a considerable disease burden since the absolute number of patients with microscopic hematuria exceeds those with gross hematuria. Due to this risk, the AUA guidelines and clinical practice recommendations both state that patients at high risk for bladder cancer should undergo evaluation with cystoscopy, cytology and upper tract imaging.(5;6) It is concerning that 87% of subjects in our study did not undergo appropriate evaluation according to guidelines panels.

Our study identified subjects who were selected for bladder cancer screening based on age over 50 and ≥10 year history of smoking and/or ≥15 year environmental exposure. Similar to other studies, we found microscopic hematuria in 10.9% of our subjects with 73.2% having at least one urinalysis within 3 years prior to inclusion in our screening study. The etiology of most urothelial cancers has been associated with increasing age, tobacco exposure, occupational exposures to aromatic amines and exposures from the chemical and rubber industry.(11) Cigarette smoking accounts for a large proportion of the disease in men (50–75%) and women (14–35%), while the attributable risk for occupational exposures is only 10%.(12;13) Despite the fact that subjects in our population with microscopic hematuria clearly met the criteria for high risk of bladder cancer, only 12.8% were referred to see a urologist for cystoscopic evaluation. Furthermore, only 10.4% had urine cytologic evaluation and 22.6% had imaging. As such, the vast majority of the population with microscopic hematuria at high risk did not have a complete evaluation. Smokers, who are at particularly increased risk for bladder cancer were paradoxically less likely to be referred for guideline-appropriate evaluation than non-smokers. Furthermore, 3 subjects (2%) who were diagnosed with bladder cancer at time of screening study had hematuria that had not been previously evaluated.

Our study confirms prior reports which suggest that many patients with microscopic hematuria do not get referred for evaluation by urologists.(7;8) There are no available studies which explore the rationale for referring some patients in favour of others but our study suggests that at 2 separate hospitals, a similar pattern exists with regard to evaluation (or lack thereof) of microscopic hematuria. Future studies will be necessary to evaluate barriers to appropriate evaluation, and to test interventions to improve proper work-up of evaluation. Interventions might include education, or structured, reflexive protocols when hematuria is noted at laboratory testing. Problems with inconsistent referrals have been blamed for delays in diagnosis of bladder cancer.(14) At this time, 25% of bladder cancers are diagnosed with advanced stage and these patients have a significantly lower survival than patients with non-invasive disease. Of note, a greater proportion of women with bladder cancer die from their disease likely secondary to delay in diagnosis.(15)

One possibility for low referral rates is a perceived low yield of cancer in patients with microscopic hematuria. Since over 60% of patients who are evaluated have no explanation for the microscopic hematuria, some clinicians may feel that there is little benefit to referring patients and ordering expensive imaging.(10) Interestingly, there is significant pressure on clinicians to perform other tests of relatively low yield such as evaluation for colon cancer. As part of Prostate, Lung, Colorectal and Ovarian cancer screening trial, a total of 64,658 subjects underwent screening flexible sigmoidoscopy.(16) The yields for colorectal cancer per 1000 screened, depending on 5-year age group was 1.1–2.5 in women and 2.4–5.6 in men. This cancer yield is nearly 10 fold less than the likelihood of bladder cancer in patients with microscopic hematuria, yet screening for colorectal cancer is clearly accepted and promoted by primary physicians. Problems with appropriate evaluation of fecal occult blood are common and there are several studies that have attempted to improve physician management approaches, (17–19) including education and structured reflexive protocols; these may serve as a model for improvement of management of individuals with hematuria.

This study has several limitations. Data used for this study were originally collected for clinical, not research purposes, leading to the possibility of misclassification of the presence or absence of hematuria, or subsequent work-up. However, the central computerized medical records used for clinical care at both institutions in our study setting make the likelihood of misclassification unlikely. It is a retrospective chart review but performing a prospective study on compliance to guidelines would be self-defeating since clinicians would be biased to conform to guidelines if they knew they were being studied. Also, subjects with microhematuria, without subsequent work up, may have been aware of microhematuria, concerned about the finding, and perhaps more likely to participate in our screening study. This may have lead to an overestimation of the prevalence of subjects with inappropriate work up of hematuria.

Nonetheless, the raw frequency of inappropriate (n=143 of 164 subjects) work up was quite high, emphasizing that even if our prevalence estimates are high, that this is an important clinical problem that deserves further study. Finally, it is not clear why patients were not referred for evaluation and it is possible that some patients were referred but were noncompliant with recommendations to see a urologist.

Conclusions

Acknowledgments

Samir Gupta was supported by National Institutes of Health grant number 1 KL2 RR024983-01, titled, “North and Central Texas Clinical and Translational Science Initiative” (Milton Packer, M.D., PI) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research, and its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NCRR or NIH. Information on NCRR is available at http://www.ncrr.nih.gov/. Information on Re-engineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp.

Reference List

1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin. 2008 Mar-2008 Apr;58(2):71–96. [PubMed]

2. Grossfeld GD, Litwin MS, Wolf JS, Hricak H, Shuler CL, Agerter DC, Carroll PR. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy--part I: definition, detection, prevalence, and etiology. Urology. 2001 Apr;57(4):599–603. [PubMed]

3. Messing EM, Young TB, Hunt VB, Newton MA, Bram LL, Vaillancourt A, Hisgen WJ, Greenberg EB, Kuglitsch ME, Wegenke JD. Hematuria home screening: repeat testing results. J Urol. 1995 Jul;154(1):57–61. [PubMed]

4. Mariani AJ, Mariani MC, Macchioni C, Stams UK, Hariharan A, Moriera A. The significance of adult hematuria: 1,000 hematuria evaluations including a risk-benefit and cost-effectiveness analysis. J Urol. 1989 Feb;141(2):350–5. [PubMed]

5. Cohen RA, Brown RS. Clinical practice. Microscopic hematuria. N Engl J Med. 2003 Jun;May;348(23):2330–8. [PubMed]

6. Grossfeld GD, Litwin MS, Wolf JS, Jr, Hricak H, Shuler CL, Agerter DC, Carroll PR. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy--part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology. 2001 Apr;57(4):604–10. [PubMed]

7. Nieder AM, Lotan Y, Nuss GR, Langston JP, Vyas S, Manoharan M, Soloway MS. Are patients with hematuria appropriately referred to Urology? A multi-institutional questionnaire based survey. Urol Oncol. 2008 Dec 19; [PubMed]

8. Johnson EK, Daignault S, Zhang Y, Lee CT. Patterns of hematuria referral to urologists: does a gender disparity exist? Urology. 2008 Sep;72(3):498–502. discussion 502–3. [PubMed]

9. Lotan Y, Elias K, Svatek RS, Bagrodia A, Nuss G, Moran B, Sagalowsky AI. Bladder cancer screening in a high risk asymptomatic population using a point of care urine based protein tumor marker. J Urol. 2009 Jul;182(1):52–7. discussion 58. [PubMed]

10. Khadra MH, Pickard RS, Charlton M, Powell PH, Neal DE. A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice. J Urol. 2000 Feb;163(2):524–7. [PubMed]

11. Silverman DT, Hartge P, Morrison AS, Devesa SS. Epidemiology of bladder cancer. Hematol Oncol Clin North Am. 1992 Feb;6(1):1–30. [PubMed]

12. Zeegers MP, Tan FE, Dorant E, van Den Brandt PA. The impact of characteristics of cigarette smoking on urinary tract cancer risk: a meta-analysis of epidemiologic studies. Cancer. 2000 Aug 1;89(3):630–9. [PubMed]

13. Samanic C, Kogevinas M, Dosemeci M, Malats N, Real FX, Garcia-Closas M, Serra C, Carrato A, Garcia-Closas R, Sala M, et al. Smoking and bladder cancer in Spain: effects of tobacco type, timing, environmental tobacco smoke, and gender. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1348–54. [PubMed]

14. Wallace DM, Raghavan D, Kelly KA, Sandeman TF, Conn IG, Teriana N, Dunn J, Boulas J, Latief T. Neo-adjuvant (pre-emptive) cisplatin therapy in invasive transitional cell carcinoma of the bladder. Br J Urol. 1991 Jun;67(6):608–15. [PubMed]

15. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-2007 Feb;57(1):43–66. [PubMed]

16. Weissfeld JL, Schoen RE, Pinsky PF, Bresalier RS, Church T, Yurgalevitch S, Austin JH, Prorok PC, Gohagan JK. Flexible sigmoidoscopy in the PLCO cancer screening trial: results from the baseline screening examination of a randomized trial. J Natl Cancer Inst. 2005 Jul 6;97(13):989–97. Notes: CORPORATE NAME: PLCO Project Team. [PubMed]

17. Jimbo M, Myers RE, Meyer B, Hyslop T, Cocroft J, Turner BJ, Weinberg DS. Reasons patients with a positive fecal occult blood test result do not undergo complete diagnostic evaluation. Ann Fam Med. 2009 Jan-2009 Feb;7(1):11–6. [PubMed]

18. Singh H, Kadiyala H, Bhagwath G, Shethia A, El-Serag H, Walder A, Velez ME, Petersen LA. Using a multifaceted approach to improve the follow-up of positive fecal occult blood test results. Am J Gastroenterol. 2009 Apr;104(4):942–52. [PMC free article] [PubMed]

19. Rao SK, Schilling TF, Sequist TD. Challenges in the management of positive fecal occult blood tests. J Gen Intern Med. 2009 Mar;24(3):356–60. [PMC free article] [PubMed]