Bladder Biopsy of Normal-Appearing Mucosa is Not Helpful in Patients with Unexplained Positive Cytology after Nonmuscle Invasive Bladder Cancer John E. Musser,* Matthew J. O’Shaughnessy, Philip H. Kim and Harry W. Herr From the Urology Service, Department of Surgery, Memorial-Sloan Kettering Cancer Center, New York, New York

Abbreviations and Acronyms BCG ¼ bacillus Calmette-Guerin CIS ¼ carcinoma in situ CT ¼ computerized tomography PFS ¼ progression-free survival RFS ¼ recurrence-free survival TURBT ¼ transurethral resection of bladder tumor UTUC ¼ upper tract urothelial carcinoma Accepted for publication June 16, 2014. Study received institutional review board approval. Supported by the Sidney Kimmel Center for Prostate and Urologic Cancers. * Correspondence: Urology Service, Department of Surgery, Memorial-Sloan Kettering Cancer Center, 1275 York Ave., New York, New York 10065 (telephone: 646-422-4336; FAX: 212717-3169; e-mail: [email protected]).

Purpose: Malignant voided cytology with normal endoscopic evaluation represents a diagnostic and therapeutic challenge in many patients with a history of nonmuscle invasive bladder cancer. Bladder biopsy is often advised but its efficacy is unclear. We evaluated the usefulness of bladder biopsy in patients with unexplained positive cytology and describe recurrence patterns in this unique patient subset. Materials and Methods: From an institutional database we retrospectively identified patients with a history of nonmuscle invasive bladder cancer and surveillance cystoscopy from 2008 to 2012 who had malignant voided urine cytology but normal cystoscopy. Patients underwent systematic bladder biopsy or cystoscopic surveillance and were followed for recurrence and progression. Results: Of 444 patients 343 were followed with surveillance only and 101 underwent a total of 118 biopsies of normal-appearing bladder mucosa. Three biopsies (2.5%) showed carcinoma in situ and none revealed invasive carcinoma. During the median 32-month followup recurrence developed in the bladder in 194 patients (44%), in the upper tract in 24 (5%) and in the prostatic urethra in 5 (1%) while 219 (49%) had no recurrence. A previous diagnosis of upper tract urothelial carcinoma and a history of bacillus Calmette-Guerin treatment were associated with an increased recurrence risk on multivariate analysis. Recurrence rates and patterns were similar in the biopsy and surveillance groups. Conclusions: Patients with malignant cytology despite normal cystoscopy have a high recurrence rate. Biopsy of normal-appearing bladder mucosa in this setting is rarely positive and does not alter the recurrence pattern. Key Words: urinary bladder neoplasms; biopsy; neoplasm recurrence, local; cystoscopy; cytology

CYSTOSCOPY and voided urinary cytology are the foundation of surveillance for patients with a history of nonmuscle invasive bladder cancer.1,2 While limited in sensitivity, particularly for low grade tumors, voided cytology has a remarkably high specificity of greater than 90%.3 However, malignant cytology in the setting of a negative cystoscopy is a common

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clinical scenario that represents a diagnostic and therapeutic challenge. Perhaps because of the high specificity of urine cytology, an abnormal result may generate anxiety for patients and physicians. Although there is little evidence to support the benefits of various approaches in this setting, NCCN GuidelinesÒ1 and the EAU (European Association of

0022-5347/15/1931-0048/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.

http://dx.doi.org/10.1016/j.juro.2014.06.068 Vol. 193, 48-52, January 2015 Printed in U.S.A.

BLADDER BIOPSY FOR UNEXPLAINED POSITIVE CYTOLOGY

Urology)2 advise routine biopsy of the bladder along with upper tract evaluation. We evaluated the efficacy of bladder biopsy in the setting of unexplained positive urinary cytology. We also report recurrence patterns in these patients.

MATERIALS AND METHODS Patient Population After receiving institutional review board approval we retrospectively analyzed a prospectively maintained nonmuscle invasive bladder cancer (Ta, Tis and T1) database of patients followed with surveillance cystoscopy at our institution. We identified 444 patients with normal cystoscopy findings from January 2008 through December 2012 in whom a concurrent urine cytology result was also interpreted as positive or suspicious for urothelial carcinoma. At our institution a suspicious diagnosis is clinically regarded the same way as a positive diagnosis. Patients with a questionable lesion that was focally biopsied after the cytology result was known were excluded from study. Patients with unexplained positive cytology were evaluated by CT urogram unless contraindicated. Systematic bladder biopsies were performed in some patients depending on provider practice and patient preference. Patients were assessed at 3, 6 and 12 months by cystoscopy and repeat cytology testing. Followup cystoscopy and TURBT were performed using standard white light cystoscopy. All cystoscopies were done by experienced attending urologists at our institution. Data on demographics, bladder tumor histology, CIS history, BCG exposure, history of UTUC and imaging results were collected from the first diagnosis to the last known followup. Information on bladder biopsies was obtained from operative notes, including biopsy of normalappearing mucosa. Bladder biopsy and TURBT pathology results were reviewed for recurrence. Small papillary tumors were fulgurated at the clinic without biopsy and were considered recurrence. Patients were excluded from analysis if they had a history of muscle invasive bladder cancer or radical cystectomy, or if they were newly referred to our institution for UTUC or initial evaluation for restaging TURBT.

Statistical Analysis Descriptive statistics were used to report rates and findings of bladder biopsies and upper tract imaging. KaplanMeier curves were constructed to describe the probability of RFS and PFS in patients who underwent bladder biopsies and those who received surveillance only. Progression was defined as a diagnosis of muscle invasive disease or recurrent nonmuscle invasive disease that required radical cystectomy. Followup was calculated from the time of positive cytology concurrently with negative cystoscopy. Categorical variables were summarized using actual counts and percents, and continuous variables were summarized using the mean  SD or the median and IQR. The Fisher exact test was used to compare categorical variables and the Wilcoxon rank sum test was used for

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continuous variables with p 0.05 considered statistically significant for all statistical comparisons. Cox proportional hazards regression was used for univariate evaluation of characteristics that may predict disease recurrence, including CIS history, prior treatment with BCG instillation, tobacco use, gender and age. Variables significant at p 0.05 on univariate analysis were entered in a multivariate Cox regression model. Recurrence and progression were analyzed using the Kaplan-Meier method and comparisons were made using the log-rank test. Statistical analysis was done with StataÒ 12.0.

RESULTS Table 1 lists patient characteristics. Of the 444 patients 101 (23%) underwent biopsy of normalappearing bladder mucosa. A total of 118 bladder biopsy procedures were done since some patients underwent multiple biopsy procedures. The median number of biopsy specimens per procedure was

Table 1. Patient characteristics and first recurrence by bladder management strategy Bladder Biopsy

Surveillance Only

No. pts 101 343 Median age at diagnosis (IQR) 71 (64e78) 73 (66e79) No. male (%) 86 (85) 274 (80) No. female (%) 15 (15) 69 (20) No. race (%): White 95 (94) 324 (94) Black 1 (1) 6 (2) Asian 3 (3) 7 (2) Other/unknown 2 (2) 6 (2) No. any tobacco use (%) 67 (66) 251 (73) No. history (%): CIS 51 (50) 161 (47) UTUC 4 (4) 32 (9) BCG 64 (63) 201 (59) No. upper tract imaging (%): CT urogram 99 (98) 300 (87) Magnetic resonance 2 (2) 21 (6) urogram Other 0 3 (1) None 0 19 (6) No. cytology result (%): Pos 31 (30.7) 89 (25.9) Suspicious 70 (69.3) 254 (74.1) Median mos followup (IQR) 34.2 (15.9e51.1) 30.8 (12.8e48.3) No. recurrence (%): No 50 (49.5) 169 (49.3) Yes 51 (50.5) 174 (50.7) Median recurrence-free 30 24 survival (mos) No. 1st recurrence type/location (%): Upper tract urothelial Ca 6 (5.9) 18 (5.2) Bladder (total) 42 (41.6) 152 (44.3) Bladder Ta/Tis† 36 (35.6) 135 (39.4) Bladder T1 5 (5.0) 15 (4.4) Bladder T2 1 (1.0) 1 (0.3) Prostate/urethra 2 (2.0) 3 (0.9) Other 1 (1.0) 2 (0.6)

p Value* 0.17 0.25 0.88

0.13 0.57 0.10 0.42 0.014

0.373 0.27 1.0 0.27

0.80 0.63 0.56 0.79 0.40 0.32 0.54

* Wilcox rank sum test for continuous variables and Fisher exact test for categorical variables. † Includes pTx/fulgurated tumors.

0.75

0.75 0.50

Probability of PFS

0.25 0.00

0 Number at risk Cysto surveillance 343 Bladder biopsy 101

20

40 Months

60

80

208 66

115 36

33 12

0 0

Cysto surveillance

Bladder biopsy

Figure 2. Kaplan-Meier PFS probability curves by bladder management strategy. PFS differences were not statistically significant (log rank test p ¼ 0.70). Cysto, cystoscopy.

correlated with recurrence included previous CIS, BCG exposure and a history of UTUC. These factors were entered into a Cox multivariate logistic regression model. In that model CIS history was no longer associated but BCG exposure and UTUC history were still associated with an increased risk of recurrence. Multivariate modeling was not performed for the outcome of progression because of the limited number of events.

DISCUSSION In this study biopsy of normal-appearing bladder mucosa in patients with only cytology recurrence had limited efficacy in identifying recurrent carcinoma and it did not alter the natural history of the disease. Although these patients are at high risk for recurrence, these recurrences can be identified at a

Table 2. Recurrence predictors after positive cytology

0.25

0.50

Risk Factor

0.00

Probability of RFS

1.00

5 (IQR 4e8). Surveillance cystoscopy without routine bladder biopsy was used to observe 343 patients. Of the 444 patients 425 (96%) underwent some type of upper tract imaging at some point during evaluation, including CT urogram in 399, magnetic resonance urogram in 23, ultrasound in 2 and intravenous pyelogram in 1. Of these images 22 (5%) were positive for upper tract etiology. The 118 systematic bladder biopsies revealed no invasive carcinoma but CIS was identified in 3 cases (2.5%). Most biopsies demonstrated benign histology. Table 1 shows initial recurrence patterns in patients who underwent biopsy vs surveillance only. During followup recurrence was identified in approximately half of each group and almost all of these recurrences were in the bladder. Patterns of initial recurrence were similar in patients who underwent systematic biopsy and observation, and most recurrences were noninvasive. In only 5.0% of the biopsy group and 4.4% of the surveillance only group (p ¼ 0.79) the recurrence was a T1 lesion while it was T2 disease in only 1.0% and 0.3%, respectively (p ¼ 0.40). Figure 1 shows RFS stratified by bladder management strategy. Median RFS in patients treated with surveillance and systematic biopsy was 24 (95% CI 21.8e31.8) and 30 months (95% CI 21.4e41.1), respectively (p ¼ 0.27). Overall 31 patients (7%) experienced progression to muscle invasive disease or were treated with radical cystectomy for recurrent, high volume nonmuscle invasive disease. Figure 2 shows PFS stratified by bladder management strategy. There was no statistically significant difference between the groups in the RFS or PFS outcome. Table 2 shows univariate analysis of risk factors for recurrence. Factors that significantly

1.00

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0 Number at risk Cysto surveillance 343 Bladder biopsy 101

20

40 Months

60

80

130 49

58 19

15 6

0 0

Cysto surveillance

Bladder biopsy

Figure 1. Kaplan-Meier RFS probability curves by bladder management strategy. RFS differences were not statistically significant (log rank test p ¼ 0.34). Cysto, cystoscopy.

Age (by decade) Gender (female) Race: Black (vs white) Asian (vs white) Tobacco use Bladder biopsy History: CIS UTUC BCG History: CIS UTUC Bacillus Calmette-Guerin

HR (95% CI) Univariate 0.91 (0.80e1.04) 1.28 (0.93e1.77) 1.11 0.61 0.90 0.85

(0.46e2.7) (0.20e1.90) (0.67e1.22) (0.63e1.18)

p Value 0.17 0.14 0.82 0.35 0.51 0.34

1.44 (1.11e1.88) 1.86 (1.25e2.79) 1.89 (1.41e2.54) Multivariate

0.006 0.005