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Results of urine cytology testing and cystoscopy in women with irritative voiding symptoms
American Journal of Obstetrics and Gynecology (2005) 192, 1560–5
www.ajog.org
Results of urine cytology testing and cystoscopy in women with irritative voiding symptoms Eric R. Sokol, MD,a,* Sutchin R. Patel, BS,a Vivian W. Sung, MD,a Charles R. Rardin, MD,a Sherry Weitzen, PhD,a Jeffrey L. Clemons, MD,b Deborah L. Myers, MDa Department of Obstetrics and Gynecology, Division of Urogynecology and Pelvic Reconstructive Surgery, Women and Infants Hospital, Brown Medical School, Providence, RI,a Madigan Army Medical Center, Tacoma, Washb
KEY WORDS Urinary cytology testing Urothelial cancer Irritative voiding symptoms Cystoscopy
Objective: The purpose of this study was to assess rates of urinary cytologic abnormalities and cystoscopic outcomes in women with irritative voiding symptoms who were examined at a urogynecology clinic. Study design: All urinary cytology studies results that were sent between January 1, 2000, and July 31, 2003, for the evaluation of irritative voiding symptoms were reviewed. Data were then extracted from the charts of a subset of these patients to evaluate cystoscopic outcomes. Demographics, risk factors for urothelial cancer, laboratory results, and radiology imaging results were then analyzed and compared between patients with and without abnormal cytology and cystoscopic results. Results: Of the 1783 total urinary cytology that were reviewed, 1661 test results were read as normal (93.2%); 112 test results (6.3%) were read as atypical, and 3 test results (0.2%) were read as unsatisfactory. Seven cytologic test results were categorized as suspicious or malignant, which accounts for only 0.4% of all cytologic test results that were sent. Of the 564 consecutive women whose cases were chosen for subanalysis, cytology was normal in 91.5% and atypical in 8.5% of cases. No cytology were suspicious or malignant. Cystoscopic findings were normal in 548 patients (97.2%). Only 1 patient (0.2%) received a diagnosis of transitional cell carcinoma. Conclusion: Urinary cytology and cystoscopy are low yield tests and should not be used routinely in the initial evaluation of women with irritative voiding symptoms. Ó 2005 Elsevier Inc. All rights reserved.
Presented at the Joint Scientific Meeting of the American Urogynecologic Society and Society of Gynecologic Surgeons, San Diego, California, July 29-31, 2004. Supported by a grant from The Center for Women’s Surgery Endowment Fund. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. * Reprint requests: Eric R. Sokol, MD, The Center for Women’s Surgery, 695 Eddy St, Suite 12, Providence, RI 02903. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.10.629
Urinary cytology testing is used commonly in the evaluation of patients with irritative voiding symptoms to aid in the detection of urinary tract malignancies, but its role remains controversial, with some authors arguing for cytology testing only in high-risk patients.1 Clinicians often include cystoscopy in the diagnostic evaluation, which permits a complete visual inspection of the bladder and urethra and allows for the exclusion of benign or malignant mucosal lesions. There is general agreement among urogynecologists that cystoscopy is
Sokol et al indicated for women who complain of irritative voiding symptoms or hematuria,2 but algorithms that define the optimal approach for the evaluation of patients with these symptoms are lacking. Although urinary cytology combined with cystoscopy has become the standard diagnostic and monitoring tool for superficial bladder cancer,3 these tests may be low yield in an unscreened population of women with irritative voiding symptoms, and there are few studies on the subject to guide clinical practice. The purpose of this study was to assess the rates of urinary cytology abnormalities and cystoscopic outcomes in women with irritative voiding symptoms who were examined at a tertiary urogynecology clinic. Our hypothesis was that routine urinary cytology and cystoscopy are of limited value in the initial evaluation of irritative voiding symptoms because of the rarity of abnormal findings.
1561 categories: normal, atypical/indeterminate, suspicious, or malignant.5,6 Within our subset of patients, demographics, risk factors for urothelial cancer, symptoms, urinalysis and urine culture results, and upper urinary tract imaging results were analyzed and compared between patients with and without abnormal cytology and cystoscopic findings. Comparisons between groups were made with the Fisher’s exact test, the Student t test, and Pearson chi-squared test, where appropriate. Probability values !.05 were considered statistically significant. Unadjusted odds ratios (ORs) and 95% CIs for characteristics that were associated with abnormal cytology and cystoscopy were computed with the logistic regression analysis program on Stata software (version 8.0; Stata Corporation, College Station, Tex).
Results Material and methods As part of an ongoing institutional review board– approved study to evaluate the usefulness of urinary cytologic testing in women with irritative voiding symptoms who were examined at a tertiary urogynecology clinic, all urinary cytologic studies that were sent from the Division of Urogynecology at Women and Infants’ Hospital of Rhode Island between January 1, 2000, and July 31, 2003, were compiled and reviewed. To evaluate the value of cystoscopy efficiently, a more detailed analysis was performed with a convenience sample of consecutive patients over a 2-year period of the study (January 1, 2001, to January 1, 2003). Irritative voiding symptoms were defined as urinary urgency, pain or burning with urination, urinary frequency, and/or nocturia. Techniques and definitions conform to the standards that are recommended by the International Continence Society.4 Patients were included in the study if they had irritative voiding symptoms, had undergone urinary cytology and cystoscopic testing, and had no history of urinary tract malignancy. It has been our standard practice to perform urinalysis and cultures, urinary cytologic testing studies, and subsequent cystoscopies on all women with irritative voiding symptoms. Women with abnormal results are sent selectively for upper urinary tract imaging. All cystoscopies had been performed in the Division of Urogynecology with a 30-degree rigid endoscope with a 21-F sheath by or under the direct supervision of an attending urogynecologist. Urinary cytology specimens were evaluated by 1 of 2 board-certified attending cytopathologists at the same laboratory who used standard classification criteria. In accordance with accepted nomenclature, final urinary cytologic testing results were classified by the cytopathologist into 1 of 4
From January 1, 2000, to July 31, 2003, 1783 urinary cytology that were sent from the Division of Urogynecology were reviewed; of these, 1661 urinary cytology (93.2%) were classified as normal; 112 urinary cytology (6.3%) were classified as atypical/indeterminate, and 3 urinary cytology (0.2%) were classified as unsatisfactory. The remaining 7 urinary cytology were categorized as suspicious or malignant, which accounted for 0.4% of all urinary cytology that were sent. Five hundred sixty-four consecutive women whose condition met the inclusion criteria for subanalysis and who were evaluated for irritative voiding symptoms were identified. For this group, the mean age was 56.9 G 13.7 years, and the mean parity was 2.5 G 1.6. Three hundred thirteen women (55.7%) were postmenopausal; 189 women (33.6%) had a history of estrogen use, and 201 women (35.6%) were current or past tobacco users. Also, 154 women (27.3%) reported a history of urinary tract infections, and 11 women (1.9%) had a history of bladder stones. Two women (0.4%) reported previous treatment with pelvic radiation; 3 women (0.5%) had undergone previous chemotherapy, and none of the women had been exposed to aniline dyes or cyclophosphamide. Hematuria was diagnosed on dipstick urinalysis in 95 patients (16.8%); 85 patients (15.1%) had trace blood, and 10 patients (1.8%) had large blood. Microscopy confirmed microscopic hematuria (defined by our laboratory as R8 red blood cells per highpowered field) in 13 patients (2.3%). Urine culture confirmed urinary tract infections in 31 patients (5.5%). For the 564 women who were included in the subanalysis, 516 women (91.5%) had negative urinary cytology, and 48 women (8.5%) had atypical/indeterminate results. None of the women in this group had suspicious or malignant urinary cytology. Women with atypical cytologic testing results were demographically similar to women with normal urinary cytology with
1562 Table I
Sokol et al Risk factors for atypical urinary cytologic testing
Characteristic
Risk of atypical urinary cytology (n/N)*
Unadjusted OR (95% CI)y
Age Medical history Previous urinary tract infection Estrogen use Tobacco use Pelvic radiation Chemotherapy Bladder stones Familial urothelial cancer Symptom Urge incontinence Frequency Urgency Nocturia Hematuria Dysuria
N/A
1.01 (0.99-1.03)z
12/154 (8%) 12/189 (6%) 19/201 (9%) 0/2 0/3 2/11 (18%) 0/1
0.88 0.63 1.20 N/A N/A 2.44 N/A
(0.44-1.73) (0.32-1.24) (0.66-2.20)
17/275 (6%) 40/467 (9%) 31/368 (8%) 36/354 (10%) 6/47 (13%) 5/69 (7%)
0.55 1.16 0.96 1.85 1.64 0.82
(0.30-1.02) (0.50-2.68) (0.52-1.78) (0.94-3.64) (0.66-4.10) (0.31-2.14)
(0.51-11.65)
N/A, Not applicable. * N = 48 of 564. y Calculated with the logistic regression analysis program on Stata 8.0. z Odds of atypical urinary cytology per unit increase (eg, per year for age, 1% increase in risk of atypical cytologic result).
respect to mean age, mean parity, and mean weight. Women with and without atypical urinary cytology all had irritative voiding symptoms and had similar rates of urinary tract infections. Forty percent of women with an atypical urinary cytology were current or past tobacco users, compared with 35% of women with normal urinary cytology (P = .55). Five women with atypical cytologic testing results had abnormal findings on intravenous pyelogram, compared with 1 woman with normal urinary cytology (P = .02). Rates of abnormalities on computed tomography scan and renal ultrasonography were similarly uncommon, regardless of urinary cytology status. No upper urinary tract evaluations lead to the diagnosis of urothelial malignancies. The unadjusted ORs with 95% CIs for patient characteristics that are associated with atypical urinary cytology are listed in Table I. Past or current tobacco users were not significantly more likely than nonsmokers to have an atypical urinary cytology (OR, 1.2; 95% CI, 0.7, 2.2) and women with a history of bladder stones were also not more likely to have an atypical urinary cytology finding (OR, 2.4; 95% CI, 0.5, 11.7). Similarly, symptoms of neither nocturia (OR, 1.9; 95% CI, 0.9, 3.6) nor hematuria (OR, 1.6; 95% CI, 0.7, 4.1) increased the odds of having an atypical cytologic testing result. None of the patients who had been exposed to pelvic radiation or chemotherapy had an atypical urinary cytology reading. After a comparison of the women with and without abnormal cystoscopic findings, there were no significant differences in mean age, mean parity, or mean weight. Women with abnormal cystoscopic findings had similar rates of past or present tobacco use, compared with
those women with normal findings (44% vs 35%; P = .49). Exposure to other risk factors for urothelial cancer that include pelvic radiation, chemotherapy with cyclophosphamide, a history of bladder stones, and a history of recurrent urinary tract infections were similar between groups. Also, symptoms of urge incontinence, frequency, urgency, nocturia, and hematuria were not significantly different between groups. Women with abnormal cystoscopic findings did have significantly more dysuria than their counterparts with normal cystoscopic results (31% vs 12%; P = .02). Intravenous pyelogram and computed tomography scan abnormalities were rare, regardless of cystoscopic findings. Two women with abnormal findings on cystoscopy also had an abnormality on renal ultrasonography, compared with 4 women with normal cystoscopic results (P = .05), although none of the findings were malignancies. The only woman in the study who was diagnosed with transitional cell carcinoma of the bladder had a simple renal cyst that was found incidentally on renal ultrasound scanning. Risk factors for finding an abnormality on cystoscopy, with unadjusted ORs and 95% CIs, are listed in Table II. One of the 2 women who had been exposed to pelvic radiation had radiation cystitis seen on cystoscopy, and 1 of the 3 women with past exposure to chemotherapy had cystitis caused by a urinary tract infection. Increasing age, estrogen use, and history of urinary tract infections did not significantly alter the risk of finding a cystoscopic abnormality. No women with a history of bladder stones or a family history of urothelial cancer had an abnormal cystoscopic finding. The only symptom that was associated with an increased
Sokol et al Table II
1563 Risk factors for abnormal cystoscopy
Characteristic Age Postmenopausal status Medical history Previous urinary tract infection Estrogen use Tobacco use Symptom Urge incontinence Frequency Urgency Nocturia Hematuria Dysuria
Risk of abnormal cystoscopy result (n/N)*
Unadjusted OR (95% CI)y
N/A 9/313 (3%)
0.99 (0.96-1.03)z 1.08 (0.36-3.29)
3/154 (2%) 4/189 (2%) 7/201 (3%)
0.60 (0.17-2.04) 0.65 (0.21-2.04) 1.43 (0.52-3.89)
9/275 (3%) 13/467 (3%) 11/368 (3%) 11/354 (3%) 2/47 (4%) 5/69 (7%)
1.36 0.87 1.16 1.30 1.59 3.42
(0.50-3.71) (0.24-3.11) (0.40-3.40) (0.45-3.80) (0.35-7.20) (1.15-10.15)
N/A, Not applicable. * N = 16 of 564. y Calculated with the logistic regression analysis program on Stata 8.0. z Odds of abnormal cystoscopy per unit increase (eg, per year for age, 1% increase in risk of abnormal cystoscopic result).
risk of having an abnormal finding on cystoscopy was dysuria (OR, 3.4; 95% CI, 1.2, 10.2). Cystoscopic outcomes for the 564 women who underwent subanalysis are listed in Table III. Findings on cystoscopy were normal in 548 women (97.2%). The most common abnormal cystoscopic finding overall was cystitis in 10 women, of whom 4 women (0.7%) were found to have concurrent urinary tract infections at the time of evaluation, and 5 women (0.9%) were diagnosed subsequently with interstitial cystitis, using cystoscopy with anesthesia and hydrodistension. Three women (0.5%) had suspicious bladder lesions that were biopsied subsequently and found to be benign. One woman (0.2%) who was evaluated by cystoscopy for irritative voiding symptoms had a tumor that was seen at the time of examination and that was confirmed to be a transitional cell carcinoma of the bladder (grade 1, stage 1).
Comment Our study has shown that abnormal findings are rare when urinary cytologic testing and cystoscopic testing are performed routinely in the initial evaluation of women with irritative voiding symptoms. Of the 564 patients whose conditions were analyzed for our study, none of the women had suspicious or malignant urinary cytology results, and only 1 woman was found to have a low-grade bladder cancer. We therefore believe that these tests can be omitted safely from the initial evaluation in most women with these complaints. Although traditional teaching has implicitly advocated for the use of urinary cytology and cystoscopy, recommendations have been based mostly on studies that included men and patients with recognized hematuria,
not irritative voiding symptoms. Because it is welldocumented that men and patients with hematuria are at an increased risk for the development of urinary tract cancers,7 routine testing in these settings may make sense. However, in a population such as ours with an extremely low prevalence of urothelial cancer, routine testing may not be warranted. Recent studies that evaluated the use of urinary cytology have begun to argue for restricted use of the test. In a prospective study, Paez et al8 showed that no tumor could be diagnosed solely on the basis of urinary cytology and that negative urine cytologic testing could not exclude the presence of a urothelial tumor, which raises a serious question about its role in the evaluation of hematuria. Another study by Nabi et al9 reviewed 1400 urinary cytology specimens from 900 patients who had been referred to a single center and concluded that urinary cytology for malignant cells is, at best, a contributory investigation in the diagnosis of urologic malignancies and should be used only in the proper clinical context. This study included a large percentage of men and patients with recognized hematuria; even in this susceptible population, the test performance of cytology was poor. In addition, a disparity in positive cytologic testing findings between urologists and nonurologists was illustrated, which suggests that a higher risk population is referred to urologists for cytology. Because our practice does not include men and because gross hematuria is rare, our population of women has an a priori risk for urothelial cancer lower than a mixed referral population. Therefore, urinary cytology will yield even fewer positive results, which limits its usefulness. Indeed, none of the 564 women who were evaluated for irritative voiding symptoms in our study had a suspicious or malignant urinary cytology result.
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Sokol et al
Table III Cytologic and cystoscopic results from 564 women with irritative voiding symptoms Test result Cytology Negative Atypical Cystoscopy Normal Suspicious lesion Tumor Stones Cystitis Urethral diverticulum
With characteristic (n) 516 (91.5%) 48 (8.5%) 548 3 1 1 10 1
(97.2%) (0.5%)* (0.2%)y (0.2%) (1.8%)z (0.2%)
* All biopsy samples were negative for malignancy. y Cancer type, grade, stage (transitional-cell carcinoma, grade 1, stage 1). z Five patients received a diagnosis of interstitial cystitis; 4 patients received a diagnosis of urinary tract infections, and 1 patient received a diagnosis of radiation cystitis.
To our knowledge, only 1 other study to date specifically has explored the usefulness of urinary cytologic testing in women with irritative lower urinary tract symptoms. A study that reviewed 202 cytologic test specimens that were obtained from 128 women found that 5 patients with irritative symptoms and hematuria had transitional cell carcinoma.6 Urinary cytologic testing was positive in only 3 of these patients, and no positive cytologic testing results or carcinomas were noted in the absence of hematuria. Although this study was performed at a hospital-based urology referral service with a relatively high prevalence of urothelial cancer, the authors concluded that urinary cytology was not necessary in women with no history of urinary tract carcinoma who did not have hematuria, regardless of symptoms. We studied a similar population of women with predominantly irritative voiding symptoms, but our positivity rates for high-risk urinary cytology were far lower, as was our cancer detection rate (only 1 cancer was identified). If routine urinary cytology is difficult to justify in a population with a relatively high prevalence of urinary tract malignancy, it is even harder to justify in our population of women. Literature regarding the role of cystoscopy in the initial evaluation of irritative voiding symptoms is similarly scarce. One study that assessed the role of urethrocystoscopy in the evaluation of refractory idiopathic detrusor overactivity concluded that the test was warranted to facilitate timely diagnosis and treatment of these patients.10 This patient population was different from ours, however, because 6 months of conventional treatment with anticholinergic medications had failed in all of the patients. Even in this high-risk population of 100 women, only 1 low-grade bladder cancer was found. Other studies have tried to estimate the usefulness of cystoscopy in the routine evaluation of urinary incon-
tinence. Because many of the patients in these studies complained of mixed incontinence, inferences can be made regarding the role of cystoscopy in the routine evaluation of lower urinary tract symptoms. In studies that involve O600 incontinent patients who underwent selective cystoscopy, only 11 patients (!2%) were identified with metaplastic or neoplastic lesions.11-16 Even in elderly, incontinent populations, the yield of cystoscopy is !1%.14 Therefore, cystoscopy should not be performed routinely in incontinent patients to exclude neoplasm17; our study has shown this to be true for women with irritative voiding symptoms as well. Some studies have shown cystoscopy to be indicated in patients with recurrent urinary tract infections, hematuria, and voiding difficulties.18,19 However, the role of cystoscopy in the evaluation women with mixed urinary incontinence, which includes women with irritative voiding symptoms, lacks precise definition and has been ignored in most studies.11 In the present study, 564 patients underwent cystoscopic evaluation over a 2-year period, but only 1 patient (0.2%) was diagnosed with a transition cell carcinoma. Interestingly, this patient had normal urinary cytology. Our findings are in contrast to those of Cundiff and Bent,2 who found 2 cases of bladder cancer and 2 cases of cystitis glandularis of 84 cystoscopies that were performed in the evaluation of lower urinary tract dysfunction. However, as noted in the editorial comment that accompanies their study, most urogynecologists do not find 1 in 20 of their patients with cancer or precancer of the lower urinary tract. Our large-scale study reinforces this sentiment and shows a much lower rate of bladder cancer. The classification and subsequent treatment of patients with atypical or indeterminate urinary cytology is controversial and deserves comment.20,21 In the present study, we found no factors that increased the likelihood of finding an atypical result, and we found no atypical cytologic testing results that were associated with malignancies. We therefore feel that unscreened women with irritative voiding symptoms who have atypical cytologic testing results are at a low risk for the development of urothelial cancer and do not warrant further surveillance for urinary tract cancer. Our findings are in agreement with Novicki et al,21 who determined that patients with indeterminate urinary cytology who were not smokers and who had no history of hematuria or urothelial cancer were at low risk for malignancy and did not warrant complete urinary tract evaluations. However, as illustrated by the 5 women with atypical urinary cytology who had abnormal upper urinary tract imaging studies, other entities (such as bladder or kidney stones) possibly can cause atypical urinary cytology. Atypical findings may be more of a sign of an inflammatory process than a malignant one. The rarity of urothelial malignancies or other anatomic causes of irritative voiding symptoms that are
Sokol et al diagnosed by cytologic testing or cystoscopy testing limits our power to detect true differences between patients with and without abnormal findings. We were unable to estimate adjusted ORs because of the small number of abnormal findings on cytology and cystoscopic testing. The estimates of effect therefore do not take into account the influence of potential confounders. In our study, no factors were associated with an increased risk for atypical urinary cytology, and only the original complaint of dysuria increased the risk of finding an abnormality on cystoscopic evaluation. Traditional risk factors for bladder cancer (such as smoking, recurrent urinary tract infections, and bladder stones) did not increase the risk for abnormal testing results. Although definitive conclusions regarding risk factors cannot be made because only 1 of our patients was diagnosed with urothelial cancer, ours is the largest study to date to examine the use of urinary cytology and cystoscopy for the evaluation of women with irritative voiding symptoms. Further research is warranted in women with irritative voiding symptoms to select a high-risk population of patients who warrant full urinary tract evaluations to delineate specific risk factors. A cost-effectiveness analysis will be helpful in further elucidating the role of cytologic testing and cystoscopy and is currently underway at our institution. We have shown that, in our population of women with complaints of irritative voiding symptoms, high-risk abnormalities on urinary cytology and cystoscopic testing are rare. Urinary cytology and cystoscopy are low yield tests and should not be used routinely in the initial evaluation of women with irritative voiding symptoms.
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References 18. 1. Gamarra MC, Zein T. Cytologic spectrum of bladder cancer. Urology 1984;23:23-6. 2. Cundiff GW, Bent AE. The contribution of urethrocystoscopy to evaluation of lower urinary tract dysfunction in women. Int Urogynecol J Pelvic Floor Dysfunct 1996;7:307-11. 3. Raitanen MP, Aine R, Rintala E, Kallio J, Rajala P, Juusela H, et al. Differences between local and review urinary cytology in diagnosis of bladder cancer: an interobserver multicenter analysis. Eur Urol 2002;41:284-9. 4. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract
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function: report from the Standardisation Sub-committee of the International Continence Society. Am J Obstet Gynecol 2002;187:116-26. Murphy WM. Current status of urinary cytology in the evaluation of bladder neoplasms. Hum Pathol 1990;21:886-96. Duldulao KE, Diokno AC, Mitchell B. Value of urinary cytology in women presenting with urge incontinence and/or irritative voiding symptoms. J Urol 1997;157:113-6. Messing EM. Urothelial tumors of the urinary tract. In: Walsh PC, Retik AB, Vaughan ED, Wein AJ, editors. Campbell’s urology. Philadelphia: Saunders; 2002. p. 2732-84. Paez A, Coba JM, Murillo N, Fernandez P, de la Cal MA, Lujan M, et al. Reliability of the routine cytological diagnosis in bladder cancer. Eur Urol 1999;35:228-32. Nabi G, Greene DR, O’Donnell M. How important is urinary cytology in the diagnosis of urological malignancies? Eur Urol 2003;43:632-6. Groutz A, Samandarov A, Gold R, Pauzner D, Lessing JB, Gordon D. Role of urethrocystoscopy in the evaluation of refractory idiopathic detrusor instability. Urology 2001;58:544-6. Awad SA, Gajewski JB, Katz NO, Acker-Roy K. Final diagnosis and therapeutic implications of mixed symptoms of urinary incontinence in women. Urology 1992;39:352-7. Benson JT. Gynecologic and urodynamic evaluation of women with urinary incontinence. Obstet Gynecol 1985;66:691-4. Fischer-Rasmussen W, Hansen RI, Stage P. Predictive values of diagnostic tests in the evaluation of female urinary stress incontinence. Acta Obstet Gynecol Scand 1986;65:291-4. Ouslander JG, Hepps K, Raz S, Su HL. Genitourinary dysfunction in a geriatric outpatient population. J Am Geriatr Soc 1986;34:507-14. Ouslander JG, Leach GE, Staskin DR. Simplified tests of lower urinary tract function in the evaluation of geriatric urinary incontinence. J Am Geriatr Soc 1989;37:706-14. Vehkalahti I, Kivela SL, Seppanen J. Are cystometric and cystoscopic examinations of any value for disabled incontinent elderly? Scand J Prim Health Care 1986;4:243-7. AHCPR Urinary Incontinence in Adults Guideline Update Panel. Managing acute and chronic urinary incontinence. Am Fam Physician 1996;54:1661-72. Payne CK. Epidemiology, pathophysiology, and evaluation of urinary incontinence and overactive bladder. Urology 1998;51: 3-10. Ludviksson K. The value of clinical examination of the female incontinent patient. Acta Obstet Gynecol Scand Suppl 1997; 166:19-23. Schwalb DM, Herr HW, Fair WR. The management of clinically unconfirmed positive urinary cytology. J Urol 1993; 150:1751-6. Novicki DE, Stern JA, Nemec R, Lidner TK. Cost-effective evaluation of indeterminate urinary cytology. J Urol 1998; 160:734-6.
www.ajog.org
Results of urine cytology testing and cystoscopy in women with irritative voiding symptoms Eric R. Sokol, MD,a,* Sutchin R. Patel, BS,a Vivian W. Sung, MD,a Charles R. Rardin, MD,a Sherry Weitzen, PhD,a Jeffrey L. Clemons, MD,b Deborah L. Myers, MDa Department of Obstetrics and Gynecology, Division of Urogynecology and Pelvic Reconstructive Surgery, Women and Infants Hospital, Brown Medical School, Providence, RI,a Madigan Army Medical Center, Tacoma, Washb
KEY WORDS Urinary cytology testing Urothelial cancer Irritative voiding symptoms Cystoscopy
Objective: The purpose of this study was to assess rates of urinary cytologic abnormalities and cystoscopic outcomes in women with irritative voiding symptoms who were examined at a urogynecology clinic. Study design: All urinary cytology studies results that were sent between January 1, 2000, and July 31, 2003, for the evaluation of irritative voiding symptoms were reviewed. Data were then extracted from the charts of a subset of these patients to evaluate cystoscopic outcomes. Demographics, risk factors for urothelial cancer, laboratory results, and radiology imaging results were then analyzed and compared between patients with and without abnormal cytology and cystoscopic results. Results: Of the 1783 total urinary cytology that were reviewed, 1661 test results were read as normal (93.2%); 112 test results (6.3%) were read as atypical, and 3 test results (0.2%) were read as unsatisfactory. Seven cytologic test results were categorized as suspicious or malignant, which accounts for only 0.4% of all cytologic test results that were sent. Of the 564 consecutive women whose cases were chosen for subanalysis, cytology was normal in 91.5% and atypical in 8.5% of cases. No cytology were suspicious or malignant. Cystoscopic findings were normal in 548 patients (97.2%). Only 1 patient (0.2%) received a diagnosis of transitional cell carcinoma. Conclusion: Urinary cytology and cystoscopy are low yield tests and should not be used routinely in the initial evaluation of women with irritative voiding symptoms. Ó 2005 Elsevier Inc. All rights reserved.
Presented at the Joint Scientific Meeting of the American Urogynecologic Society and Society of Gynecologic Surgeons, San Diego, California, July 29-31, 2004. Supported by a grant from The Center for Women’s Surgery Endowment Fund. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. * Reprint requests: Eric R. Sokol, MD, The Center for Women’s Surgery, 695 Eddy St, Suite 12, Providence, RI 02903. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.10.629
Urinary cytology testing is used commonly in the evaluation of patients with irritative voiding symptoms to aid in the detection of urinary tract malignancies, but its role remains controversial, with some authors arguing for cytology testing only in high-risk patients.1 Clinicians often include cystoscopy in the diagnostic evaluation, which permits a complete visual inspection of the bladder and urethra and allows for the exclusion of benign or malignant mucosal lesions. There is general agreement among urogynecologists that cystoscopy is
Sokol et al indicated for women who complain of irritative voiding symptoms or hematuria,2 but algorithms that define the optimal approach for the evaluation of patients with these symptoms are lacking. Although urinary cytology combined with cystoscopy has become the standard diagnostic and monitoring tool for superficial bladder cancer,3 these tests may be low yield in an unscreened population of women with irritative voiding symptoms, and there are few studies on the subject to guide clinical practice. The purpose of this study was to assess the rates of urinary cytology abnormalities and cystoscopic outcomes in women with irritative voiding symptoms who were examined at a tertiary urogynecology clinic. Our hypothesis was that routine urinary cytology and cystoscopy are of limited value in the initial evaluation of irritative voiding symptoms because of the rarity of abnormal findings.
1561 categories: normal, atypical/indeterminate, suspicious, or malignant.5,6 Within our subset of patients, demographics, risk factors for urothelial cancer, symptoms, urinalysis and urine culture results, and upper urinary tract imaging results were analyzed and compared between patients with and without abnormal cytology and cystoscopic findings. Comparisons between groups were made with the Fisher’s exact test, the Student t test, and Pearson chi-squared test, where appropriate. Probability values !.05 were considered statistically significant. Unadjusted odds ratios (ORs) and 95% CIs for characteristics that were associated with abnormal cytology and cystoscopy were computed with the logistic regression analysis program on Stata software (version 8.0; Stata Corporation, College Station, Tex).
Results Material and methods As part of an ongoing institutional review board– approved study to evaluate the usefulness of urinary cytologic testing in women with irritative voiding symptoms who were examined at a tertiary urogynecology clinic, all urinary cytologic studies that were sent from the Division of Urogynecology at Women and Infants’ Hospital of Rhode Island between January 1, 2000, and July 31, 2003, were compiled and reviewed. To evaluate the value of cystoscopy efficiently, a more detailed analysis was performed with a convenience sample of consecutive patients over a 2-year period of the study (January 1, 2001, to January 1, 2003). Irritative voiding symptoms were defined as urinary urgency, pain or burning with urination, urinary frequency, and/or nocturia. Techniques and definitions conform to the standards that are recommended by the International Continence Society.4 Patients were included in the study if they had irritative voiding symptoms, had undergone urinary cytology and cystoscopic testing, and had no history of urinary tract malignancy. It has been our standard practice to perform urinalysis and cultures, urinary cytologic testing studies, and subsequent cystoscopies on all women with irritative voiding symptoms. Women with abnormal results are sent selectively for upper urinary tract imaging. All cystoscopies had been performed in the Division of Urogynecology with a 30-degree rigid endoscope with a 21-F sheath by or under the direct supervision of an attending urogynecologist. Urinary cytology specimens were evaluated by 1 of 2 board-certified attending cytopathologists at the same laboratory who used standard classification criteria. In accordance with accepted nomenclature, final urinary cytologic testing results were classified by the cytopathologist into 1 of 4
From January 1, 2000, to July 31, 2003, 1783 urinary cytology that were sent from the Division of Urogynecology were reviewed; of these, 1661 urinary cytology (93.2%) were classified as normal; 112 urinary cytology (6.3%) were classified as atypical/indeterminate, and 3 urinary cytology (0.2%) were classified as unsatisfactory. The remaining 7 urinary cytology were categorized as suspicious or malignant, which accounted for 0.4% of all urinary cytology that were sent. Five hundred sixty-four consecutive women whose condition met the inclusion criteria for subanalysis and who were evaluated for irritative voiding symptoms were identified. For this group, the mean age was 56.9 G 13.7 years, and the mean parity was 2.5 G 1.6. Three hundred thirteen women (55.7%) were postmenopausal; 189 women (33.6%) had a history of estrogen use, and 201 women (35.6%) were current or past tobacco users. Also, 154 women (27.3%) reported a history of urinary tract infections, and 11 women (1.9%) had a history of bladder stones. Two women (0.4%) reported previous treatment with pelvic radiation; 3 women (0.5%) had undergone previous chemotherapy, and none of the women had been exposed to aniline dyes or cyclophosphamide. Hematuria was diagnosed on dipstick urinalysis in 95 patients (16.8%); 85 patients (15.1%) had trace blood, and 10 patients (1.8%) had large blood. Microscopy confirmed microscopic hematuria (defined by our laboratory as R8 red blood cells per highpowered field) in 13 patients (2.3%). Urine culture confirmed urinary tract infections in 31 patients (5.5%). For the 564 women who were included in the subanalysis, 516 women (91.5%) had negative urinary cytology, and 48 women (8.5%) had atypical/indeterminate results. None of the women in this group had suspicious or malignant urinary cytology. Women with atypical cytologic testing results were demographically similar to women with normal urinary cytology with
1562 Table I
Sokol et al Risk factors for atypical urinary cytologic testing
Characteristic
Risk of atypical urinary cytology (n/N)*
Unadjusted OR (95% CI)y
Age Medical history Previous urinary tract infection Estrogen use Tobacco use Pelvic radiation Chemotherapy Bladder stones Familial urothelial cancer Symptom Urge incontinence Frequency Urgency Nocturia Hematuria Dysuria
N/A
1.01 (0.99-1.03)z
12/154 (8%) 12/189 (6%) 19/201 (9%) 0/2 0/3 2/11 (18%) 0/1
0.88 0.63 1.20 N/A N/A 2.44 N/A
(0.44-1.73) (0.32-1.24) (0.66-2.20)
17/275 (6%) 40/467 (9%) 31/368 (8%) 36/354 (10%) 6/47 (13%) 5/69 (7%)
0.55 1.16 0.96 1.85 1.64 0.82
(0.30-1.02) (0.50-2.68) (0.52-1.78) (0.94-3.64) (0.66-4.10) (0.31-2.14)
(0.51-11.65)
N/A, Not applicable. * N = 48 of 564. y Calculated with the logistic regression analysis program on Stata 8.0. z Odds of atypical urinary cytology per unit increase (eg, per year for age, 1% increase in risk of atypical cytologic result).
respect to mean age, mean parity, and mean weight. Women with and without atypical urinary cytology all had irritative voiding symptoms and had similar rates of urinary tract infections. Forty percent of women with an atypical urinary cytology were current or past tobacco users, compared with 35% of women with normal urinary cytology (P = .55). Five women with atypical cytologic testing results had abnormal findings on intravenous pyelogram, compared with 1 woman with normal urinary cytology (P = .02). Rates of abnormalities on computed tomography scan and renal ultrasonography were similarly uncommon, regardless of urinary cytology status. No upper urinary tract evaluations lead to the diagnosis of urothelial malignancies. The unadjusted ORs with 95% CIs for patient characteristics that are associated with atypical urinary cytology are listed in Table I. Past or current tobacco users were not significantly more likely than nonsmokers to have an atypical urinary cytology (OR, 1.2; 95% CI, 0.7, 2.2) and women with a history of bladder stones were also not more likely to have an atypical urinary cytology finding (OR, 2.4; 95% CI, 0.5, 11.7). Similarly, symptoms of neither nocturia (OR, 1.9; 95% CI, 0.9, 3.6) nor hematuria (OR, 1.6; 95% CI, 0.7, 4.1) increased the odds of having an atypical cytologic testing result. None of the patients who had been exposed to pelvic radiation or chemotherapy had an atypical urinary cytology reading. After a comparison of the women with and without abnormal cystoscopic findings, there were no significant differences in mean age, mean parity, or mean weight. Women with abnormal cystoscopic findings had similar rates of past or present tobacco use, compared with
those women with normal findings (44% vs 35%; P = .49). Exposure to other risk factors for urothelial cancer that include pelvic radiation, chemotherapy with cyclophosphamide, a history of bladder stones, and a history of recurrent urinary tract infections were similar between groups. Also, symptoms of urge incontinence, frequency, urgency, nocturia, and hematuria were not significantly different between groups. Women with abnormal cystoscopic findings did have significantly more dysuria than their counterparts with normal cystoscopic results (31% vs 12%; P = .02). Intravenous pyelogram and computed tomography scan abnormalities were rare, regardless of cystoscopic findings. Two women with abnormal findings on cystoscopy also had an abnormality on renal ultrasonography, compared with 4 women with normal cystoscopic results (P = .05), although none of the findings were malignancies. The only woman in the study who was diagnosed with transitional cell carcinoma of the bladder had a simple renal cyst that was found incidentally on renal ultrasound scanning. Risk factors for finding an abnormality on cystoscopy, with unadjusted ORs and 95% CIs, are listed in Table II. One of the 2 women who had been exposed to pelvic radiation had radiation cystitis seen on cystoscopy, and 1 of the 3 women with past exposure to chemotherapy had cystitis caused by a urinary tract infection. Increasing age, estrogen use, and history of urinary tract infections did not significantly alter the risk of finding a cystoscopic abnormality. No women with a history of bladder stones or a family history of urothelial cancer had an abnormal cystoscopic finding. The only symptom that was associated with an increased
Sokol et al Table II
1563 Risk factors for abnormal cystoscopy
Characteristic Age Postmenopausal status Medical history Previous urinary tract infection Estrogen use Tobacco use Symptom Urge incontinence Frequency Urgency Nocturia Hematuria Dysuria
Risk of abnormal cystoscopy result (n/N)*
Unadjusted OR (95% CI)y
N/A 9/313 (3%)
0.99 (0.96-1.03)z 1.08 (0.36-3.29)
3/154 (2%) 4/189 (2%) 7/201 (3%)
0.60 (0.17-2.04) 0.65 (0.21-2.04) 1.43 (0.52-3.89)
9/275 (3%) 13/467 (3%) 11/368 (3%) 11/354 (3%) 2/47 (4%) 5/69 (7%)
1.36 0.87 1.16 1.30 1.59 3.42
(0.50-3.71) (0.24-3.11) (0.40-3.40) (0.45-3.80) (0.35-7.20) (1.15-10.15)
N/A, Not applicable. * N = 16 of 564. y Calculated with the logistic regression analysis program on Stata 8.0. z Odds of abnormal cystoscopy per unit increase (eg, per year for age, 1% increase in risk of abnormal cystoscopic result).
risk of having an abnormal finding on cystoscopy was dysuria (OR, 3.4; 95% CI, 1.2, 10.2). Cystoscopic outcomes for the 564 women who underwent subanalysis are listed in Table III. Findings on cystoscopy were normal in 548 women (97.2%). The most common abnormal cystoscopic finding overall was cystitis in 10 women, of whom 4 women (0.7%) were found to have concurrent urinary tract infections at the time of evaluation, and 5 women (0.9%) were diagnosed subsequently with interstitial cystitis, using cystoscopy with anesthesia and hydrodistension. Three women (0.5%) had suspicious bladder lesions that were biopsied subsequently and found to be benign. One woman (0.2%) who was evaluated by cystoscopy for irritative voiding symptoms had a tumor that was seen at the time of examination and that was confirmed to be a transitional cell carcinoma of the bladder (grade 1, stage 1).
Comment Our study has shown that abnormal findings are rare when urinary cytologic testing and cystoscopic testing are performed routinely in the initial evaluation of women with irritative voiding symptoms. Of the 564 patients whose conditions were analyzed for our study, none of the women had suspicious or malignant urinary cytology results, and only 1 woman was found to have a low-grade bladder cancer. We therefore believe that these tests can be omitted safely from the initial evaluation in most women with these complaints. Although traditional teaching has implicitly advocated for the use of urinary cytology and cystoscopy, recommendations have been based mostly on studies that included men and patients with recognized hematuria,
not irritative voiding symptoms. Because it is welldocumented that men and patients with hematuria are at an increased risk for the development of urinary tract cancers,7 routine testing in these settings may make sense. However, in a population such as ours with an extremely low prevalence of urothelial cancer, routine testing may not be warranted. Recent studies that evaluated the use of urinary cytology have begun to argue for restricted use of the test. In a prospective study, Paez et al8 showed that no tumor could be diagnosed solely on the basis of urinary cytology and that negative urine cytologic testing could not exclude the presence of a urothelial tumor, which raises a serious question about its role in the evaluation of hematuria. Another study by Nabi et al9 reviewed 1400 urinary cytology specimens from 900 patients who had been referred to a single center and concluded that urinary cytology for malignant cells is, at best, a contributory investigation in the diagnosis of urologic malignancies and should be used only in the proper clinical context. This study included a large percentage of men and patients with recognized hematuria; even in this susceptible population, the test performance of cytology was poor. In addition, a disparity in positive cytologic testing findings between urologists and nonurologists was illustrated, which suggests that a higher risk population is referred to urologists for cytology. Because our practice does not include men and because gross hematuria is rare, our population of women has an a priori risk for urothelial cancer lower than a mixed referral population. Therefore, urinary cytology will yield even fewer positive results, which limits its usefulness. Indeed, none of the 564 women who were evaluated for irritative voiding symptoms in our study had a suspicious or malignant urinary cytology result.
1564
Sokol et al
Table III Cytologic and cystoscopic results from 564 women with irritative voiding symptoms Test result Cytology Negative Atypical Cystoscopy Normal Suspicious lesion Tumor Stones Cystitis Urethral diverticulum
With characteristic (n) 516 (91.5%) 48 (8.5%) 548 3 1 1 10 1
(97.2%) (0.5%)* (0.2%)y (0.2%) (1.8%)z (0.2%)
* All biopsy samples were negative for malignancy. y Cancer type, grade, stage (transitional-cell carcinoma, grade 1, stage 1). z Five patients received a diagnosis of interstitial cystitis; 4 patients received a diagnosis of urinary tract infections, and 1 patient received a diagnosis of radiation cystitis.
To our knowledge, only 1 other study to date specifically has explored the usefulness of urinary cytologic testing in women with irritative lower urinary tract symptoms. A study that reviewed 202 cytologic test specimens that were obtained from 128 women found that 5 patients with irritative symptoms and hematuria had transitional cell carcinoma.6 Urinary cytologic testing was positive in only 3 of these patients, and no positive cytologic testing results or carcinomas were noted in the absence of hematuria. Although this study was performed at a hospital-based urology referral service with a relatively high prevalence of urothelial cancer, the authors concluded that urinary cytology was not necessary in women with no history of urinary tract carcinoma who did not have hematuria, regardless of symptoms. We studied a similar population of women with predominantly irritative voiding symptoms, but our positivity rates for high-risk urinary cytology were far lower, as was our cancer detection rate (only 1 cancer was identified). If routine urinary cytology is difficult to justify in a population with a relatively high prevalence of urinary tract malignancy, it is even harder to justify in our population of women. Literature regarding the role of cystoscopy in the initial evaluation of irritative voiding symptoms is similarly scarce. One study that assessed the role of urethrocystoscopy in the evaluation of refractory idiopathic detrusor overactivity concluded that the test was warranted to facilitate timely diagnosis and treatment of these patients.10 This patient population was different from ours, however, because 6 months of conventional treatment with anticholinergic medications had failed in all of the patients. Even in this high-risk population of 100 women, only 1 low-grade bladder cancer was found. Other studies have tried to estimate the usefulness of cystoscopy in the routine evaluation of urinary incon-
tinence. Because many of the patients in these studies complained of mixed incontinence, inferences can be made regarding the role of cystoscopy in the routine evaluation of lower urinary tract symptoms. In studies that involve O600 incontinent patients who underwent selective cystoscopy, only 11 patients (!2%) were identified with metaplastic or neoplastic lesions.11-16 Even in elderly, incontinent populations, the yield of cystoscopy is !1%.14 Therefore, cystoscopy should not be performed routinely in incontinent patients to exclude neoplasm17; our study has shown this to be true for women with irritative voiding symptoms as well. Some studies have shown cystoscopy to be indicated in patients with recurrent urinary tract infections, hematuria, and voiding difficulties.18,19 However, the role of cystoscopy in the evaluation women with mixed urinary incontinence, which includes women with irritative voiding symptoms, lacks precise definition and has been ignored in most studies.11 In the present study, 564 patients underwent cystoscopic evaluation over a 2-year period, but only 1 patient (0.2%) was diagnosed with a transition cell carcinoma. Interestingly, this patient had normal urinary cytology. Our findings are in contrast to those of Cundiff and Bent,2 who found 2 cases of bladder cancer and 2 cases of cystitis glandularis of 84 cystoscopies that were performed in the evaluation of lower urinary tract dysfunction. However, as noted in the editorial comment that accompanies their study, most urogynecologists do not find 1 in 20 of their patients with cancer or precancer of the lower urinary tract. Our large-scale study reinforces this sentiment and shows a much lower rate of bladder cancer. The classification and subsequent treatment of patients with atypical or indeterminate urinary cytology is controversial and deserves comment.20,21 In the present study, we found no factors that increased the likelihood of finding an atypical result, and we found no atypical cytologic testing results that were associated with malignancies. We therefore feel that unscreened women with irritative voiding symptoms who have atypical cytologic testing results are at a low risk for the development of urothelial cancer and do not warrant further surveillance for urinary tract cancer. Our findings are in agreement with Novicki et al,21 who determined that patients with indeterminate urinary cytology who were not smokers and who had no history of hematuria or urothelial cancer were at low risk for malignancy and did not warrant complete urinary tract evaluations. However, as illustrated by the 5 women with atypical urinary cytology who had abnormal upper urinary tract imaging studies, other entities (such as bladder or kidney stones) possibly can cause atypical urinary cytology. Atypical findings may be more of a sign of an inflammatory process than a malignant one. The rarity of urothelial malignancies or other anatomic causes of irritative voiding symptoms that are
Sokol et al diagnosed by cytologic testing or cystoscopy testing limits our power to detect true differences between patients with and without abnormal findings. We were unable to estimate adjusted ORs because of the small number of abnormal findings on cytology and cystoscopic testing. The estimates of effect therefore do not take into account the influence of potential confounders. In our study, no factors were associated with an increased risk for atypical urinary cytology, and only the original complaint of dysuria increased the risk of finding an abnormality on cystoscopic evaluation. Traditional risk factors for bladder cancer (such as smoking, recurrent urinary tract infections, and bladder stones) did not increase the risk for abnormal testing results. Although definitive conclusions regarding risk factors cannot be made because only 1 of our patients was diagnosed with urothelial cancer, ours is the largest study to date to examine the use of urinary cytology and cystoscopy for the evaluation of women with irritative voiding symptoms. Further research is warranted in women with irritative voiding symptoms to select a high-risk population of patients who warrant full urinary tract evaluations to delineate specific risk factors. A cost-effectiveness analysis will be helpful in further elucidating the role of cytologic testing and cystoscopy and is currently underway at our institution. We have shown that, in our population of women with complaints of irritative voiding symptoms, high-risk abnormalities on urinary cytology and cystoscopic testing are rare. Urinary cytology and cystoscopy are low yield tests and should not be used routinely in the initial evaluation of women with irritative voiding symptoms.
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