Clinical significance of immediate urine cytology after transurethral resection of bladder tumor in patients with non-muscle invasive bladder cancer

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1 International Journal of Urology (2011) 18, doi: /j x Original Article: Clinical Investigationiju_ Clinical significance of immediate urine cytology after transurethral resection of bladder tumor in patients with non-muscle invasive bladder cancer Yu Seob Shin, 1 Sang Deuk Kim, 1 Jai Seong Cha, 1 Myung Ki Kim, 1,2,3 Young Beom Jeong 1,2,3 and Hyung Jin Kim 1,2,3 1 Department of Urology, Chonbuk National University Hospital, 2 Chonbuk National University Medical School, and 3 Institute for Medical Sciences, Jeonju, Korea Objectives: To assess the clinical significance of immediate urine cytology (IUC) after transurethral resection of bladder tumor (TURBT) for non-muscle invasive bladder cancer (NMIBC). Methods: We reviewed the records of 174 patients who underwent IUC after TURBT for NMIBC. IUC was obtained just before Foley catheter removal after TURBT. The relationship between IUC and tumor stage, grade, size and multiplicity, as well as preoperative urine cytology and immediate intravesical epirubicin therapy, were assessed. The relationship between a positive IUC and cancer recurrence was also assessed. Multivariate Cox proportional hazards regression analysis was carried out, including IUC, tumor stage, tumor grade, tumor size, tumor multiplicity, preoperative urine cytology and immediate intravesical epirubicin therapy. Results: IUC was positive in 76 patients (43.7%) and negative in 98 patients (56.3%). In the positive IUC group, tumor stage and grade were higher (P = 0.001, <0.001), tumor size was larger (P = 0.001), tumor multiplicity was higher (P = 0.002) and positive preoperative cytology was more likely (P = 0.006) than in the negative IUC group. In the positive IUC group, the cancer recurrence rate was 72.3% and that of the negative IUC group was 30.6% (P < 0.001). In a multivariate Cox proportional hazards regression analysis, positive IUC (HR 1.83, P = 0.019), tumor size (HR 1.72, P = 0.045), tumor multiplicity (HR 3.63, P = 0.015), preoperative urine cytology (HR 1.23, P = 0.043) and immediate intravesical epirubicin therapy (HR 0.171, P = 0.001) were independent prognostic factors for cancer recurrence. Conclusion: These data suggest that IUC after TURBT for NMIBC can be an independent prognostic factor to predict cancer recurrence. Key words: bladder cancer, cytology, recurrence. Introduction Urothelial cancer of the bladder is the most common urinary tract tumor with approximately new cases in the USA each year. 1 Bladder cancer, the incidence and mortality of which increases directly with age, is the second most common urological malignancy in Korea and is approximately fivefold more common in men as it is in women. 2 Complete transurethral resection of the visible tumor burden is the current standard of care in patients with non-muscle invasive bladder cancer (NMIBC). 3 Generally, a newly diagnosed tumor is first removed by transurethral resection of bladder tumor (TURBT), showing NMIBC (stage Ta, carcinoma in situ [CIS], T1) in 75 85% of cases. 4 However, Correspondence: Hyung Jin Kim M.D., Ph.D., Department of Urology, Chonbuk National University Hospital, Keumamdong, Dukjingu, Jeonju , Republic of Korea. hjkim@ jbnu.ac.kr Received 14 December 2010; accepted 17 March Online publication 11 April 2011 except in patients with low grade Ta tumors, treatment with transurethral resection alone is associated with a 60 80% chance of bladder tumor recurrence within 5 years. 5 These patients might also receive intravesical therapy, such as mitomycin or bacillus Calmette Guérin (BCG), and then surveillance. 4 Despite aggressive treatment with surgery and adjuvant therapy, tumors recur in approximately 50% of patients and the rate might be as high as 78% in the high-risk group. 6 There is no proven cause of tumor recurrence after TURBT. However, tumor implantation after TURBT, invisible tumor during TURBT and incomplete TURBT can be a cancer recurrence factor for NMIBC. Factors that are known to be prognostic factors in NMIBC are number of tumors, tumor size, prior recurrence rate, T category and the presence of carcinoma in situ according to the European Organization for Research and Treatment of Cancer (EORTC) scoring system. 6 Urine cytology is an easy and non-invasive examination method to detect tumors of the upper and/or lower urinary tract, including the urethra. Urinary cytology is still the most 2011 The Japanese Urological Association 439

2 YS SHIN ET AL. common tool for screening urothelial cell carcinoma. 7 There are no reports that have evaluated the significance of urine cytology just before Foley catheter removal after TURBT. Therefore, we assessed the clinical significance of immediate urine cytology (IUC) after TURBT for NMIBC. Methods We reviewed the records of 174 patients who underwent IUC after TURBT for NMIBC between October 1999 and November 2009, excluding patients who had muscle invasive bladder cancer, metastatic bladder cancer, combined urinary upper tract tumor and where permanent biopsy showed the presence of CIS. After TURBT, patients received bladder irrigation twice a day. The Foley catheter was removed when the gross hematuria has resolved, after TURBT. IUC was carried out just before Foley catheter removal, because we wanted to study the relationship between early urine cytology that is obtained a few days after TURBT and bladder cancer recurrence. Through a Foley catheter, washed urine for urine cytology was obtained by bladder irrigation with 0.9% normal saline solution. Bladder irrigation with saline washing provides a better cell yield and improves cytological results secondary to the release by hydroscopic forces of loosely adherent cells from the urothelium. IUC was evaluated by a pathologist in accordance with the 1999 World Health Organization classification. The cytology was categorized as positive if cancer cells or cells with atypical changes suggesting malignancy were found, and it was regarded as negative in cases with mild to moderate atypical changes. We recently started using intravesical epirubicin treatment according to EAU guidelines on NMIBC. In the present study, patients who had recently undergone TURBT for NMIBC were routinely treated with intravesical epirubicin. We analyzed 32 patients who were treated with intravesical epirubicin compared with patients who were not treated with intravesical epirubicin. Patients received 50 mg of epirubicin in 50 ml of saline solution, which was instilled within 6 h after TURBT. The catheter was clamped for 1 h. In patients with positive or negative urine cytology, no additional investigations were carried out, and according to EAU guidelines on NMIBC, intravesical chemotherapy or BCG or routine surveillance was continued. Patients who were free of disease 3 months after treatment were assessed every 3 months for the first 2 years and every 6 months for the second 2 years and annually thereafter. Patients with solitary low-grade Ta were assessed at 3 months and 1 year and annually thereafter. The BCG therapy was carried out in high-grade Ta, and low- and high-grade T1 disease. A total of 120 patients underwent intravesical BCG instillation. Intravesical BCG instillation was carried out once every week for the first 6 weeks after bladder transitional cell cancers were identified in pathological tissue examinations after transurethral resections and Table 1 then maintenance therapy was carried out for 12 months. Repeat resection was not carried out in the present study. Tumors were staged according to the 2002 American Joint Committee on Cancer (AJCC) staging system. Tumors were graded according to the 2004 World Health Organization/ International Society of Urologic Pathology (WHO/ISUP) classification of urothelial neoplasia. Tumor size was classified into less than 3 cm of tumor diameter and 3 cm or larger of tumor diameter. Tumor multiplicity was classified into one and two to three lesions, and more than three lesions. To measure the association between positive IUC with six variables, including tumor stage, tumor grade, tumor size, tumor multiplicity, preoperative urine cytology and immediate intravesical epirubicin therapy, univariate analysis were carried out. Student s t-test was applied to assess the association between positive IUC with six variables. The comparison of the cancer recurrence rate of the positive IUC group and the negative IUC group was carried out. Prognostic value of the positive IUC in NMIBC was studied by use of multivariate Cox proportional hazards regression models. Statistical analysis was carried out by using SPSS 16.0 software, and P-values of <0.05 were considered statistically significant. Results Patients baseline characteristics Stage Ta 86 T1 88 Grade Low 118 High 56 Size <3 cm cm 52 Multiplicity IIET 32 PUC Positive 86 Negative 63 No. patients IIET, immediate intravesical epirubicin therapy; PUC, preoperative urine cytology. The median age was 65 years (range 39 85). The median follow-up period was 24 months (range 3 77). Table The Japanese Urological Association

3 Significance of IUC after TURBT in NMIBC Table 2 Comparison of the cancer characteristics between the two groups Negative IUC group (n = 98) Positive IUC group (n = 76) P-value Stage (Ta/T1) 59/39 27/ Grade (low/high) 78/20 40/36 <0.001 Size (<3 cm/ 3 cm) 77/21 45/ Multiplicity (1/2 3/ 4) 47/34/17 21/29/ IIET PUC (+/ ) 46/41 40/ IIET, immediate intravesical epirubicin therapy; IUC, immediate urine cytology; PUC, preoperative urine cytology. shows tumor stage, tumor grade, tumor size, tumor multiplicity, preoperative urine cytology and immediate intravesical epirubicin therapy of study patients who underwent IUC after TURBT for NMIBC. Positive IUC was found in 76 patients (43.7%) and negative IUC was found in 98 patients (56.3%). The relationship between positive urine cytology with six variables was in the univariate analysis (Table 2). In the positive IUC group, tumor stage was higher than the negative IUC group (P = 0.001). Also, tumor grade was higher (P < 0.001), and there were more tumor lesions in the positive IUC group (P = 0.002). Tumor size was larger in the positive IUC group and there was a significant difference between the two groups (P = 0.006). In the positive IUC group, positive preoperative urine cytology was more than the negative IUC group, which is significantly different in the two groups (P = 0.006). The number of patients who received immediate intravesical epirubicin therapy showed no significant difference between the two groups. The median duration of recurrence since the first diagnosis of bladder cancer was months. In the positive IUC group, the recurrence rate for cancer was 72.3% and that for the negative IUC group was 30.6% (P < 0.001). In the positive IUC group, the cancer recurrence rate was higher at each factor including tumor stage, tumor grade, tumor size, tumor multiplicity, preoperative urine cytology and immediate intravesical epirubicin therapy (Table 3). However, the cancer recurrence rate was higher in patients who underwent intravesical BCG instillation than in patients who did not undergo intravesical BCG instillation (58.3% vs 27.7%). Multivariate Cox proportional hazards regression analysis showed that positive IUC was significantly associated with cancer recurrence in the patients with NMIBC (HR 1.83, P = 0.019). Also, tumor size (HR 1.72, P = 0.045), tumor multiplicity (HR 3.63, P = 0.015) and preoperative urine cytology (HR 1.23, P = 0.043) were significantly associated with cancer recurrence in the patients with NMIBC (Table 4). In patients who received immediate intravesical epirubicin therapy, the recurrence rate was lower than those who did not receive immediate intravesical epirubicin therapy (34.4% vs 52.1%, Table 3 Comparison of the cancer recurrence rate between the two groups P = 0.026). In the multivariate Cox proportional hazards regression analysis, immediate intravesical epirubicin therapy was significantly associated with cancer recurrence in the patients with NMIBC (HR 0.171, P < 0.001; Table 4). Discussion No. patients with recurrence/total (%) Negative IUC Positive IUC 30/98 (30.6) 55/76 (72.3) Stage Ta (n = 86) 16/59 (27.1) 17/27 (63.0) T1 (n = 88) 14/39 (35.9) 38/49 (77.6) Grade Low (n = 118) 21/78 (26.9) 23/40 (57.5) High (n = 56) 9/20 (45.0) 32/36 (88.9) Size <3cm (n = 122) 22/77 (28.6) 30/45 (66.7) 3cm (n = 52) 8/21 (38.1) 25/31 (80.6) Multiplicity 1(n = 68) 11/47 (23.4) 14/21 (66.7) 2 3 (n = 63) 11/34 (32.4) 21/29 (72.4) 4(n = 43) 8/17 (47.0) 20/26 (76.9) IIET (n = 32) 6/21 (28.6) 5/11 (54.5) PUC Positive (n = 86) 23/46 (50.0) 31/40 (77.5) Negative (n = 63) 6/41 (14.6) 15/22 (68.2) IIET, immediate intravesical epirubicin therapy; IUC, immediate urine cytology; PUC, preoperative urine cytology. The initial diagnosis and follow up of previous bladder cancer are commonly based on urine cytology and cystoscopy. The sensitivity value of urinary cytology for detecting bladder cancer reported in various series ranges from 16% to 2011 The Japanese Urological Association 441

4 YS SHIN ET AL. Table 4 Multivariate analysis of prognostic factor for cancer recurrence Hazard ratio P-value 95% CI IUC (+/ ) Stage (Ta/T1) Grade (low/high) Size (<3 cm/ 3 cm) Multiplicity PUC (+/ ) IIET < IIET, immediate intravesical epirubicin therapy; IUC, immediate urine cytology; PUC, preoperative urine cytology. 60%. 8 These variations in sensitivity can be explained by various factors, including inherent limitations of cytological and morphological criteria to distinguish low-grade cancer cells from normal cells, technical heterogeneity, observer subjectivity, and variations in grade and stage distribution of study populations. 9 Budman et al. reported that urine cytology has % sensitivity and % specificity. 10 Its very high specificity is the most important feature of cytology, because a positive reading regardless of cystoscopic or radiographic findings suggests the existence of malignancy in the vast majority of patients. 10 IUC has the same pathological property as usual follow-up urine cytology, but IUC can predict cancer recurrence immediately. Also, urine cytology is an easy and non-invasive examination method to detect the recurrence of NMIBC. Some studies have suggested that positive preoperative urine cytology was related to bladder cancer recurrence. 11,12 However, there is no research that has studied IUC. TURBT is one of the most common urological procedures. Complete tumor resection is mandatory for adequate staging and it serves as definitive therapy, at least for NMIBC. However, there is growing evidence that TURBT is incomplete in a significant number of cases. 13 It might contribute to the high number of recurrences observed in up to 50 80% of patients, of which most occur during the first year after TURBT. 14 The majority of patients diagnosed with new or recurrent bladder tumors after a first transurethral resection have a significant tumor load based on the findings of a contemporary second resection. 13 Most urologists would agree in general that initial transurethral resection of bladder tumors should be thorough and complete, but there are many factors that confound the adequacy of resection, including multiplicity of disease, capability and perseverance of the resectionist, quality of specimens provided, and pathological analysis. Tumor burden can be left in the bladder after TURBT for NMIBC. We assume that it can be detected by IUC. Several studies have suggested risk tables for the recurrence and progression of NMIBC, such as the number of tumors, tumor size, prior recurrence rate, T category and presence of CIS. 5,15 However, they cannot calculate the probability of recurrence sufficiently, and situations such as tumor implantation after TURBT, invisible tumor during TURBT and incomplete TURBT can be a cause of cancer recurrence. To our knowledge, the natural history in patients with positive IUC after TURBT for NMIBC is not known. We can expect that positive IUC after TURBT for NMIBC is useful for identifying cancer recurrence. In the present study, the recurrence rate of the positive IUC group was significantly higher than in the negative IUC group. And known prognostic factors of NMIBC were included in the present study. Tumor stage, tumor grade, tumor size, tumor multiplicity and preoperative urine cytology have a significant relationship with positive IUC. In multivariate Cox proportional hazards regression analysis, positive IUC was significantly associated with cancer recurrence. A recent meta-analysis has shown that a single immediate postoperative instillation of chemotherapy after TURBT decreases the risk of recurrence by approximately 40% in patients with NMIBC. 16 BCG allowed a significantly longer recurrence-free survival time for patients with NMIBC compared with those who had undergone TURBT plus intravesical chemotherapy. 17 A number of randomized studies have been carried out showing that a single instillation of a cytotoxic drug, mainly epirubicin or mitomycin, decreases the number of subsequent recurrences. 18,19 Also, in the present study, among the patients who received immediate intravesical epirubicin therapy, the recurrence rate was lower than in those who did not receive immediate intravesical epirubicin therapy. Furthermore, immediate intravesical epirubicin therapy reduces the hazard ratio of cancer recurrence. However, in the positive IUC group, the cancer recurrence rate was higher than in the negative IUC group, regardless of immediate intravesical epirubicin therapy, and the cancer recurrence rate was higher in patients who underwent intravesical BCG instillation than in patients who did not undergo intravesical BCG instillation. This result means that stage and grade are the significant prognostic factors for cancer recurrence. The relationship between intravesical BCG therapy with cancer recurrence can be measured by comparison of patients who were treated with intravesical BCG versus patients who were not treated with intravesical BCG in the same grade and stage of bladder cancer. However, in the present study, all patients with high-grade Ta, and low- and high-grade T1 disease underwent intravesical BCG therapy. Therefore, the present study cannot measure the relationship between BCG therapy versus recurrence. Our analysis is limited by the number of IUC findings available for evaluation in each patient. A prospectively The Japanese Urological Association

5 Significance of IUC after TURBT in NMIBC designed study with standardized protocols to evaluate IUC after TURBT for NMIBC is needed to verify our findings. However, we can expect that IUC shows benefits for patients through the better prediction of cancer recurrence. In the positive IUC group, intravesical immunotherapy, repeated TURBT, upper tract imaging and close surveillance are more needed for prevention of cancer recurrence. IUC might be added as a prognostic factor for cancer recurrence for NMIBC. In the present study, positive IUC was significantly associated with cancer recurrence in patients with NMIBC. The present study suggests that IUC for NMIBC can be an independent prognostic factor for cancer recurrence. References 1 Jemal A, Siegel R, Ward E et al. Cancer statistics, CA Cancer J. Clin. 2009; 59: Won YJ, Sung J, Jung KW et al. Nationwide cancer incidence in Korea, Cancer Res. Treat. 2009; 41: Hall MC, Chang SS, Dalbagni G et al. Guideline for the management of nonmuscle invasive bladder cancer (stage Ta, T1, and Tis) update. J. Urol. 2007; 178: Babjuk M, Oosterlinck W, Sylvester R et al. EAU Guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur. Urol. 2008; 54: Millan-Rodriguez F, Chechil-Toniolo G, Salvador-Bayarri J et al. Primary superficial bladder cancer risk groups according to progression, mortality and recurrence. J. Urol. 2000; 164: Sylvester RJ, van der Meijden AP, Oosterlinck W et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur. Urol. 2006; 49: van Rhijin BW, van der Poel HG, van der Kwast TH. Urine markers for bladder cancer surveillance: a systematic review. Eur. Urol. 2005; 47: Lokeshwar VB, Soloway MS. Current bladder tumor tests: does their projected utility fulfill clinical necessity? J. Urol. 2001; 165: Pfister C, Chautard D, Devonec M et al. Immunocyt test improves the diagnostic accuracy of urinary cytology: results of a French multicenter study. J. Urol. 2003; 169: Budman LI, Kassouf W, Steinberg JR. Biomarkers for detection and surveillance of bladder cancer. Can. Urol. Assoc. J. 2008; 2: Smith NW, Strutton GM, Walsh MD et al. Transferrin receptor expression in primary superficial human bladder tumors identifies patients who develop recurrences. Br. J. Urol. 1990; 65: Giella JG, Ring K, Olsson CA et al. The predictive value of flow cytometry and urinary cytology in the followup of patients with transitional cell carcinoma of the bladder. J. Urol. 1992; 148: Harry WH. The Value of a second transurethral resection in evaluation patients with bladder tumors. J. Urol. 1999; 162: Kurth KH, Bouffioux C, Sylvester R et al. Treatment of superficial bladder tumors: achievements and needs. The EORTC Genitourinary Group. Eur. Urol. 2000; 37: Kiemeney LA, Witjes JA, Heijbrom RP et al. Predictability of recurrent and progressive disease in individual patients with primary superficial bladder cancer. J. Urol. 1993; 150: Sylvester RJ, Oosterlinck W, van der Meijden A. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials. J. Urol. 2004; 171: van der Meijden AP, Brausi M, Zambon V et al. Intravesical instillation of epirubicin, bacillus Calmette-Guerin and bacillus Calmette-Guerin plus isoniazid for intermediate and high risk Ta, T1 papillary carcinoma of the bladder: a European Organization for Research and Treatment of Cancer Genito-Urinary Group randomized phase III trial. J. Urol. 2001; 166: Burnand KG, Boyd PJR, Mayo ME et al. Single dose intravesical thiotepa as an adjuvant to cystodiathermy in the treatment of transitional cell bladder carcinoma. Br. J. Urol. 1976; 48: Okamura K, Ono Y, Kinukawa T et al. Randomized study of single early instillation of (2==R)-4=-0-Tetrahydropyranyl-doxorubicin for a single superficial bladder carcinoma. Cancer 2002; 94: The Japanese Urological Association 443

GUIDELINES ON NON-MUSCLE- INVASIVE BLADDER CANCER

GUIDELINES ON NON-MUSCLE- INVASIVE BLADDER CANCER (Limited text update December 21) M. Babjuk, W. Oosterlinck, R. Sylvester, E. Kaasinen, A. Böhle, J. Palou, M. Rouprêt Eur Urol 211 Apr;59(4):584-94 Introduction