UROLOGICAL ONCOLOGY Effects of Previous or Synchronous Non-Muscle Invasive Bladder Cancer on Clinical Results after Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Multi-Institutional Study Bup Wan Kim,1 Yun-Sok Ha,1 Jun Nyung Lee,1 Hyun Tae Kim,1 Tae-Hwan Kim,1 Jung Keun Lee,2 Seok-Soo Byun,2 Young Deuk Choi,3 Ho Won Kang,4 Seok-Joong Yun,4 Wun-Jae Kim,4 Young Suk Kwon,5 Tae Gyun Kwon1* Purpose: To evaluate the effects of the presence of previous or synchronous non-muscle invasive bladder cancer (NMIBC) on the oncologic outcomes of radical nephroureterectomy in patients with upper tract urothelial carci- noma (UTUC). Materials and Methods: In total, 505 patients with UTUC were enrolled from four different institutions. The clinicopathologic parameters of patients with and without previous or synchronous NMIBC were compared, and Kaplan-Meier estimates and multivariate Cox regression analyses were performed. Results: The median follow-up period was 38.4 months. In all, 408 patients had primary UTUC, 45 (8.9%) had a history of NMIBC, 59 (11.7%) had concomitant bladder cancer, and seven (1.4%) had experienced both. Tumors in patients with associated NMIBC were more commonly multifocal (P = .001) and associ- ated with surgical margin positivity (P = .001). Kaplan-Meier estimates revealed that previous or synchro- nous NMIBC was significantly associated with bladder recurrence (P < .001) and locoregional recurrence/ distant metastasis (P = .008). A multivariate Cox regression model identified previous or synchronous NMIBC as an independent predictor of bladder recurrence (P < .001). However, the presence of previ- ous or synchronous NMIBC was not a prognostic indicator of locoregional recurrence/distant metastasis. Conclusion: In patients with UTUC, previous or synchronous NMIBC was significantly associated with an increased risk of cancer recurrences in the bladder after radical nephroureterectomy. The present find- ings suggest that a close monitoring should be required for the patients with previous or concomitant NMIBC. Keywords: neoplasm recurrence; nephrectomy; urinary bladder neoplasms; treatment outcome; urologic surgical procedures; urothelium; pathology; urologic neoplasms. INTRODUCTION Both synchronous and metachronous multifocal de-velopment and frequent recurrences are common in bladder cancer (BC).(1,2) In fact, it is estimated that upper tract urothelial carcinomas (UTUCs) develop in 2-4% of patients with BC.(3-5) Conversely, the propor- tion of detected BC in patients with UTUC varies from 15 to 75%.(6-8) While experts attribute these phenom- ena to defect cancerization and clonal expansion,(9,10) no consensus has been reached in understanding the precise mechanisms underlying the proposed theories. (11-13) It has been reported that the chances of a recurrent urothelial carcinoma in normal-appearing urothelium with similar oncologic characteristics are about 50-80% after the initial resection of non-muscle-invasive BC (NMIBC) tumors.(1) Although several factors may play a role in this adverse prognosis in UTUC patients,(6,14,15) 1 Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea. 2 Department of Urology, Seoul National University, Bundang Hospital, Seongnam, Korea. 3 Department of Urology and Urological Science Institute, College of Medicine, Yonsei University, Seoul, Korea. 4 Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea. 5 Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, New Brun- swick, NJ, USA. *Correspondence: Department of Urology, Chilgok Kyungpook National University Hospital, 807 Hoguk-ro, Buk-gu, Daegu 702-210, Korea. Tel: +82 53 2003027 & Fax: +82 53 3213027. E-mail: tgkwon@knu.ac.kr. Received November 2014 & Accepted July 2015 few studies have reported the effect of previous NMIBC on cancer recurrence and overall survival.(16) Here, we investigated whether previous or synchronous NMIBC were associated with poor oncologic outcomes for UTUC patients following radical nephroureterectomy (RNU). MATERIALS AND METHODS In total 505 UTUC patients who underwent either open (n = 183) or laparoscopic RNU (n = 322) at four aca- demic institutions in Korea between March 2001 and December 2013 were included in our study and were retrospectively analyzed. Patients with previous or concurrent muscle-invasive BC (MIBC), those who received neoadjuvant chemotherapy, or those with the evidence of distant metastasis at the time of diagnosis were excluded in order to minimize the confounding er- rors in assessing survival estimates. After RNU, bladder Urological Oncology 2233 Figure 1. Effect of previous or concomitant non-muscle-invasive bladder cancer on blad- der recurrence (A) and locoregional recurrence/distant metastasis (B) after radical neph- roureterectomy. Abbreviations: UTUC, upper tract urothelial carcinoma; BC, bladder cancer. Figure 2. Effect of previous or concomitant non-muscle-invasive bladder cancer on can- cer-specific survival (A) and overall survival (B) after radical nephroureterectomy. Abbreviations: UTUC, upper tract urothelial carcinoma; BC, bladder cancer. Table 1. Clinicopathological characteristics of patients with previous or synchronous NMIBC and those without. Parameters UTUC without Previous UTUC with Previous or P Value Synchronous NMIBC (n = 408) Synchronous NMIBC (n = 97) Age, (mean ± SD), y 66.2 ± 10.5 66.6 ± 10.4 .719 BMI, kg/m² 23.7 ± 3.1 24.0 ± 2.9 .364 Gender, No. (%) .224 Male 276 (67.6) 72 (74.2) Female 132 (32.4) 25 (25.8) Smoking status, No. (%) .893 No 262 (64.3) 63 (65.3) Yes 146 (35.7) 34 (34.7) Laterality, No. (%) 1.000 Left 217 (53.2) 51 (52.6) Right 191 (46.8) 46 (47.4) Tumor size, (mean ± SD), mm 37.9 ± 22.7 41.8 ± 36.1 .316 Tumor location, No. (%) <.001 Renal pelvis 161 (39.5) 24 (24.7) Ureter 206 (50.5) 46 (47.4) Both 41 (10.0) 27 (27.8) Bladder cuff resection, No. (%) .485 No 46 (11.3) 14 (14.4) Yes 362 (88.7) 83 (85.6) Multifocality, No. (%) .001 No 298 (72.5) 53 (54.6) Yes 112 (27.5) 44 (45.4) Pathologic T stage, No. (%) .146 Ta, CIS, T1–2 232 (56.9) 63 (64.9) T3−4 176 (43.1) 34 (35.1) Pathologic N stage, No. (%) .748 Nx 177 (43.4) 41 (42.3) N0 207 (50.7) 52 (53.6) N+ 24 (5.9) 4 (4.1) Grade, No. (%) .374 Low 141 (34.6) 39 (40.2) High 267 (65.4) 58 (59.8) Concomitant CIS, No. (%) .148 No 383 (93.8) 86 (88.9) Yes 25 (6.2) 11 (11.1) Lymphovascular invasion, No. (%) .468 No 335 (82.1) 76 (78.4) Yes 73 (17.9) 21 (21.6) Margin status, No. (%) .001 Negative 394 (96.6) 85 (87.6) Positive 14 (3.4) 12 (12.4) Abbreviations: NMIBC, non-muscle-invasive bladder cancer; UTUC, upper tract urothelial carcinoma; CIS, carcinoma in situ; SD, standard deviation; BMI, body mass index. Vol 12 No 04 July-August 2015 2234 Upper Tract Urothelial Carcinoma after Non-Muscle Invasive Bladder Cancer-Kim et al. cuff resection was performed using standard procedures (i.e., an extravesical approach via a Gibson incision) stipulated by each center. Lymph node dissection was indicated if lymphadenopathy was suspected upon preoperative imaging or observed during surgery. A majority of patients with non-organ-confined disease received cisplatin-based adjuvant chemotherapy. Tum- ors were staged according to the American Joint Com- mittee on Cancer (6th edition) staging system.(17) Tu- mor grades were assessed according to the 1998 World Health Organization (WHO) classification system.(18) Tumor multifocality was defined as the synchronous presence of two or more pathologically confirmed tum- ors in any location (renal pelvis or ureter).(19) Follow-up regimen included cystoscopy, urine cytolo- gy, chest X-ray, and computed tomography (CT) of the chest. Cystoscopy and urine cytology were performed at 3, 6 and 12 months post-surgery, and yearly there- after. Imaging analyses (chest X-ray and CT of chest) were performed at 3, 6 and 12 months after RNU, and then at every 6 months from 1 to 5 years post-surgery. Scans were performed annually thereafter. Elective bone scans, chest CT, or positron emission tomography (PET) scans were performed when clinically indicated. The median follow-up period was 38.4 months (in- terquartile range, 15.6–56.5). One hundred and nine patients (21.6%) received adjuvant systemic chemo- therapy and 287 patients (56.8%) underwent lymph node dissection during RNU. Four hundred-and-eight patients had primary UTUC (no history of previous NMIBC or concomitant NMIBC), 45 (8.9%) had pre- vious NMIBC, 59 (11.7%) had concomitant NMIBC, and seven (1.4%) had experienced both. Thus, 97 pa- tients (19.2%) had previous or concomitant NMIBC. The demographic and clinical characteristics of the 505 patients are listed in Table 1. UTUC without NMIBC was more likely to be associated with pathologic stage T3 or greater; however, the difference was not statisti- cally significant. There were no significant differences between the two groups in terms of N stage, grade, lym- phovascular invasion, and concomitant carcinoma in situ (CIS). Tumors with associated NMIBC were more Figure 3. Bladder recurrence free survival between open and laparoscopic radi- cal nephroureterectomy. Abbreviations: OP, operative, RNU, radical nephroureterectomy. Parameters Univariate Analysis Multivariate Analysis HR (95%, CI) P Value HR (95%, CI) P Value Age 1.000 (0.986−1.014) .962 1.003 (0.984−1.023) .748 Gender (male vs. female) 1.043 (0.757−1.436) .797 1.199 (0.748−1.922) .451 Smoking (no vs. yes) 0.771 (0.534−1.113) .771 0.878 (0.547−1.407) .587 Tumor size 1.002 (0.996−1.008) .533 1.003 (0.996−1.011) .360 Tumor location Renal pelvis 1 ----- 1 ----- Ureter 1.599 (1.131−2.262) .008 1.088 (0.669−1.767) .735 Both 2.017 (1.272−3.201) .003 0.804 (0.354−1.830) .603 Bladder cuff resection (no vs. yes) 1.498 (0.867−2.588) .147 1.535 (0.722−3.264) .266 Multifocality (no vs. yes) 1.071 (0.779−1.472) .675 1.318 (0.657−2.646) .437 Pathologic T stage (Ta, CIS, T1–2 vs. T3–4) 1.035 (0.759−1.410) .830 1.350 (0.836−2.181) .219 Pathologic N stage (Nx, N0 vs. N+) 1.190 (0.607−2.332) .612 1.670 (0.714−3.906) .237 Grade (low vs. high) 1.274 (0.898−1.807) .175 0.736 (0.435−1.245) .253 Concomitant CIS (no vs. yes) 1.280 (0.709−2.312) .413 0.866 (0.441−1.701) .676 Lymphovascular invasion (no vs. yes) 1.027 (0.693−1.523) .895 0.901 (0.530−1.532) .700 Margin status (no vs. yes) 1.281 (0.676−2.428) .448 0.586 (0.228−1.506) .267 Previous or synchronous NMIBC (no vs. yes) 2.440 (1.768−3.367) <.001 2.845 (1.811−4.470) <.001 Table 2. Univariate and multivariate Cox regression analyses to identify predictors of bladder recurrence in patients with UTUC. Abbreviations: UTUC, upper tract urothelial carcinoma; HR, hazard ratio; CI, confidence interval; CIS, carcinoma in situ; NMIBBC, non-muscle-in- vasive bladder cancer. Urological Oncology 2235 Upper Tract Urothelial Carcinoma after Non-Muscle Invasive Bladder Cancer-Kim et al. often multifocal (P = .001), related to a positive surgical margin (P = .001), and localized to both the ureter and renal pelvis (P < .001). To evaluate the outcomes, the enrolled UTUC were allocated into two groups: those with previous or syn- chronous NMIBC, and those without. The Student’s t test and the Chi-square test were used to examine the association between variables between the two groups. Bladder recurrence-free survival, locoregional recur- rence/distant metastasis-free survival, cancer-specific survival, and overall survival after RNU were estimated using the Kaplan-Meier method and the log rank test. Multivariate Cox regression analyses were performed to identify independent predictors of bladder recurrence and locoregional recurrence/distant metastasis. All sta- tistical analyses were performed using Statistical Pack- age for the Social Science (SPSS Inc, Chicago, Illinois, USA) version 18.0. All reported P values were 2-sided and significance was set at P < .05. RESULTS In total, 173 patients (34.3%) experienced bladder re- currences after a median follow-up time of 17.0 months (interquartile range, 8.4-36.0). Bladder recurrence was significantly more common in patients with previous or concomitant NMIBC than in those with isolated UTUC (55.7% vs. 29.2%, respectively; P < .001). The Kaplan-Meier analysis revealed that bladder recur- rence-free survival was significantly higher in men with a history of NMIBC (Figure 1, panel A, P < .001; log rank test). During the follow-up period, locoregional recurrence/distant metastasis were observed in129 pa- tients (25.5%) after a median of 25.5 months (interquar- tile range, 12.0–51.4). Locoregional recurrence/distant metastasis was also more commonly seen in patients with previous or concomitant NMIBC than in those without (38.1% vs. 22.5%, respectively; P = .002). Lo- coregional recurrence/distant metastasis-free survival was significantly lower in patients with previous or concomitant NMIBC than in those without (Figure 1, panel B, P = .008; log rank test). There were no sig- nificant differences in cancer-specific survival (Figure 2, panel A, P = .634; log rank test) or overall survival (Figure 2, panel B; P = .658; log rank test) between pa- tients with previous or concomitant NMIBC and those without. Univariate Cox analyses identified tumor localization in areas other than the renal pelvis [ureter, hazard ratio (HR): 1.599, P = .008; both ureter and renal pelvis, HR: 2.017, P = .003] and previous or synchronous NMIBC (HR: 2.440; P < .001) as factors associated with blad- der recurrence (Table 2). Multivariate Cox regression analysis identified previous or synchronous NMIBC as an independent predictor of bladder recurrence (HR: 2.845; P < .001; Table 2). Univariate analysis identi- fied older age, larger tumor size, tumors located in both the ureter and renal pelvis, bladder cuff resection, worse pathologic T stage, pathologic N stage, grade, lympho- vascular invasion, positive margin status, and previous or synchronous NMIBC as factors significantly asso- ciated with locoregional recurrence/distant metastasis (Table 3). Multivariate analysis identified bladder cuff resection, worse pathologic T stage, pathologic N stage, lymphovascular invasion, higher grade, and positive margin status as independent predictors of locoregional recurrence/distant metastasis. Previous or concurrent Table 3. Univariate and multivariate Cox regression analyses to identify predictors of locoregional recurrence/distant metastasis in patients with UTUC. Parameters Univariate Analysis Multivariate Analysis HR (95%, CI) P Value HR (95%, CI) P Value Age 1.020 (1.002−1.038) .025 1.009 (0.983−1.036) .506 Gender (male vs. female) 0.951 (0.653−1.385) .795 0.791 (0.440−1.421) .432 Smoking (no vs. yes) 0.952 (0.618−1.466) .823 0.677 (0.385−1.192) .177 Tumor size 1.007 (1.001−1.012) .018 1.002 (0.995−1.009) .64 Tumor location Renal pelvis 1 ----- 1 ----- Ureter 1.176 (0.793−1.743) .42 0.874 (0.488−1.567) .652 Both 1.847 (1.123−3.038) .016 0.840 (0.302−2.336) .738 Bladder cuff resection (no vs. yes) 0.274 (0.195−0.917) .019 0.475 (0.236−0.956) .037 Multifocality (no vs. yes) 1.180 (0.821−1.695) .371 1.284 (0.544−3.032) .568 Pathologic T stage (Ta, CIS, T1–2 vs. T3–4) 3.274 (2.051−5.226) <.001 2.221 (1.630−2.367) .005 Pathologic N stage (Nx, N0 vs. N+) 5.845 (3.616−9.448) <.001 3.908 (1.919−7.959) <.001 Grade (low vs. high) 4.992 (2.686−9.278) <.001 3.547 (1.305−9.639) .013 Concomitant CIS (no vs. yes) 0.999 (0.481−2.031) .975 1.135 (0.530−2.429) .745 Lymphovascular invasion (no vs. yes) 4.069 (2.863−5.783) <.001 1.877 (1.087−6.750) .024 Margin status (no vs. yes) 4.979 (3.054−8.116) <.001 3.045 (1.373−6.750) .006 Previous or synchronous NMIBC (no vs. yes) 1.664 (1.136−2.483) .009 1.571 (0.922−2.677) .097 Abbreviations: UTUC, upper tract urothelial carcinoma; HR, hazard ratio; CI, confidence interval; CIS, carcinoma in situ; NMIBC, non-muscle-inva- sive bladder cancer. Vol 12 No 04 July-August 2015 2236 Upper Tract Urothelial Carcinoma after Non-Muscle Invasive Bladder Cancer-Kim et al. NMIBC showed a marginal association with locore- gional recurrence/distant metastasis (HR: 1.571; P = .097; Table 3). DISCUSSION To the best of our knowledge, the cohort of 505 patients with UTUC recruited from four academic centers in Korea represents the largest of its kind in East Asia to date. Our results revealed that previous or synchronous NMIBC was an independent predictor of bladder recur- rence in patients with UTUC, but this was not associ- ated with locoregional recurrence/distant metastasis, cancer-specific survival, or overall survival. These re- sults were consistent with previously published reports. (16,20) A study performed in Serbia reported that a history of NMIBC was significantly associated with bladder recurrence, but not with non-bladder recurrence and cancer-specific survival.(16) A recent multi-institutional study performed in France(20) found that patients with previous or synchronous BC were more likely to expe- rience bladder recurrence; this study also excluded the patients with previous or concomitant MIBC that was treated by cystectomy. The study also found that me- tastasis-free survival and cancer-specific survival rates were not significantly affected by the presence of asso- ciated BC. Hence, the more frequent incidence of blad- der recurrence in patients with previous or synchronous NMIBC is likely attributed to the natural propensity of NMIBC to recur, but this association does not adversely affect the prognosis of patents with UTUC. In this current study, patients with previous or synchro- nous NMIBC were more likely to show multifocality, and the tumors were localized in both the ureter and renal pelvis. Thus, our results were consistent with the earlier studies on tumor location and multifocality as predictors of bladder recurrence.(19,21,22) In addition, patients with NMIBC were also more likely to have a positive surgical margin than those with primary UTUC (12.4% vs. 3.4%, respectively; P = .001). Because pos- itive margin status after RNU is associated with a poor prognosis and has a higher chance of developing me- tastasis,(23,24) it was likely that previous or synchronous NMIBC was also associated with locoregional recur- rence/distant metastasis based on univariate analysis. The effect of operative methods between laparoscopic versus open RNU on bladder recurrence was controver- sial.(25) In this study, there were no significant differenc- es in bladder recurrence-free survival between open and laparoscopic procedures (P = .428) (Figure 3). In contrast to previous studies, our current study, which was performed exclusively in East Asia, displays sev- eral distinctive characteristics. In particular, the rela- tively low incidence of those with a history of NMIBC should be noted. For example, the incidence of previous NIMBC in the present study was 8.9%, compared to 12.5-28% reported in other prior studies.(16,20,26) Similar- ly, with the inclusion of concomitant NMIBC, we found that the rate of previous or synchronous NMIBC was 19.2% when Pignot and colleagues reported that 220 out of 662 patients (33.2%) had previous or synchro- nous NMIBC.(20) These findings collectively indicate that ethnicity may play a role concerning the discrep- ancies as our study population is uniformly composed of Koreans, as opposed to the earlier studies comprised of predominantly Caucasian study participants. Among the reported ethnic patterns in UTUC, it was shown that the incidence of UTUC was unusually high in Taiwan- ese patients. Also, the relative proportion of ureter tu- mors was higher among Korean patients with UTUC when compared to other ethnicities.(24,27) Indeed, our current study supported that ureter tumors were more commonly observed than tumors in the renal pelvis. As Matsumoto and colleagues highlighted some major differences in clinicopathological characteristics (gen- der distribution, pathologic stage, and grade) between Caucasian and Japanese patients,(28) race and ethnicity may account for the difference in the incidence rate of NMIBC between our current study and the previous re- ports. Even though this is the largest cohort of UTUC patients in Asia, the present study is not without its limitations. First and foremost were the limitations inherent in ret- rospective analyses, which inevitably resulted in selec- tion bias. Second, we were unable to obtain detailed clinicopathologic information on previous or concom- itant NMIBC, including T stage, grade, and tumor size and number. Our data also lacked information on the clinical courses (e.g. number of recurrence and tumor progression) and types of treatments (e.g. intravesical therapy and radical cystectomy) in patients with blad- der recurrence. Because the data were gathered from four different institutions, we were unable to combine a multiple set of complex information into a uniform database. Third, as we excluded patients with MIBC, we were not able to examine the potentially different oncologic patterns between MIBC and NMIBC. For example, several studies that included MIBC patients demonstrated that a history of BC has an adverse ef- fect on the prognosis of UTUC patients.(26,29) However, the inclusion would go beyond the scope of our current study. Nonetheless, this may be an important investiga- tion into which future prospective studies could possi- bly delve deeper. The prevention of bladder recurrence after RNU is an important task for clinicians. As recent prospective randomized II study showed that a single intravesical instillation of anthracycline could reduce bladder re- currence after RNU,(30) our current study findings could provide useful information for clinicians to stratify pa- tients and select patients who would most likely benefit from intravesical chemotherapy. CONCLUSIONS Our study findings demonstrated that the presence of a previous or synchronous NMIBC is associated with increased risk of developing bladder recurrence after RNU. These findings may assist physicians to estimate the risk of bladder recurrences in individual and estab- lish, a risk-stratified surveillance strategy. ACKNOWLEDGEMENT This research was supported by the Kyungpook Nation- al University Research Fund, 2012. CONFLICT OF INTEREST None declared. REFERENCES 1. Kakizoe T. Development and progression of urothelial carcinoma. Cancer Sci. 2006;97:821-8. Urological Oncology 2237 Upper Tract Urothelial Carcinoma after Non-Muscle Invasive Bladder Cancer-Kim et al. 2. Jeong P, Min BD, Ha YS, et al. RUNX3 methylation in normal surrounding urothelium of patients with non-muscle-invasive bladder cancer: potential role in the prediction of tumor progression. Eur J Surg Oncol. 2012;38:1095- 100. 3. Rabbani F, Perrotti M, Russo P, Herr HW. Upper-tract tumors after an initial diagnosis of bladder cancer: argument for long-term surveillance. J Clin Oncol. 2001;19:94-100. 4. Solsona E, Iborra I, Ricos JV, Dumont R, Casanova JL, Calabuig C. Upper urinary tract involvement in patients with bladder carcinoma in situ (Tis): its impact on management. Urology. 1997;49:347-52. 5. Latz S, Hauser S, Muller SC, Fechner G. Kidney sparing surgery for urothelial carcinoma of the pyelocalyceal system: is there a role for open techniques? Results from a small series. Urol J. 2014;11:1442-6. 6. Hisataki T, Miyao N, Masumori N, et al. Risk factors for the development of bladder cancer after upper tract urothelial cancer. Urology. 2000;55:663-7. 7. Miyake H, Hara I, Arakawa S, Kamidono S. A clinicopathological study of bladder cancer associated with upper urinary tract cancer. BJU Int. 2000;85:37-41. 8. Kang CH, Yu TJ, Hsieh HH, et al. The development of bladder tumors and contralateral upper urinary tract tumors after primary transitional cell carcinoma of the upper urinary tract. Cancer. 2003;98:1620-6. 9. Garcia SB, Park HS, Novelli M, Wright NA. Field cancerization, clonality, and epithelial stem cells: the spread of mutated clones in epithelial sheets. J Pathol. 1999;187:61-81. 10. Harris AL, Neal DE. Bladder cancer-- field versus clonal origin. N Engl J Med. 1992;326:759-61. 11. Miyake H, Hara I, Kamidono S, Eto H. Multifocal transitional cell carcinoma of the bladder and upper urinary tract: molecular screening of clonal origin by characterizing CD44 alternative splicing patterns. J Urol. 2004;172:1127-9. 12. Hafner C, Knuechel R, Zanardo L, et al. Evidence for oligoclonality and tumor spread by intraluminal seeding in multifocal urothelial carcinomas of the upper and lower urinary tract. Oncogene. 2001;20:4910-5. 13. Goyal S, Singh UR, Sharma S, Kaur N. Correlation of mitotic indices, AgNor count, Ki-67 and Bcl-2 with grade and stage in papillary urothelial bladder cancer. Urol J. 2014;11:1238-47. 14. Hall MC, Womack S, Sagalowsky AI, Carmody T, Erickstad MD, Roehrborn CG. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology. 1998;52:594-601. 15. Ehdaie B, Shariat SF, Savage C, Coleman J, Dalbagni G. Postoperative nomogram for disease recurrence and cancer-specific death for upper tract urothelial carcinoma: comparison to American Joint Committee on Cancer staging classification. Urol J. 2014;11:1435-41. 16. Milojevic B, Djokic M, Sipetic-Grujicic S, et al. Prognostic significance of non-muscle- invasive bladder tumor history in patients with upper urinary tract urothelial carcinoma. Urol Oncol. 2013;31:1615-20. 17. Greene FL. The American Joint Committee on Cancer: updating the strategies in cancer staging. Bull Am Coll Surg. 2002;87:13-5. 18. Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol. 1998;22:1435-48. 19. Chromecki TF, Cha EK, Fajkovic H, et al. The impact of tumor multifocality on outcomes in patients treated with radical nephroureterectomy. Eur Urol. 2012;61:245- 53. 20. Pignot G, Colin P, Zerbib M, et al. Influence of previous or synchronous bladder cancer on oncologic outcomes after radical nephroureterectomy for upper urinary tract urothelial carcinoma. Urol Oncol. 2014;32:23. e1-8. 21. Zigeuner RE, Hutterer G, Chromecki T, Rehak P, Langner C. Bladder tumour development after urothelial carcinoma of the upper urinary tract is related to primary tumour location. BJU Int. 2006;98:1181-6. 22. Elalouf V, Xylinas E, Klap J, et al. Bladder recurrence after radical nephroureterectomy: predictors and impact on oncological outcomes. Int J Urol. 2013;20:1078-83. 23. Colin P, Ouzzane A, Yates DR, et al. Influence of positive surgical margin status after radical nephroureterectomy on upper urinary tract urothelial carcinoma survival. Ann Surg Oncol. 2012;19:3613-20. 24. Lee JN, Kwon SY, Choi GS, et al. Impact of surgical wait time on oncologic outcomes in upper urinary tract urothelial carcinoma. J Surg Oncol. 2014;110:468-75. 25. Ni S, Tao W, Chen Q, et al. Laparoscopic versus open nephroureterectomy for the treatment of upper urinary tract urothelial carcinoma: a systematic review and cumulative analysis of comparative studies. Eur Urol. 2012;61:1142- 53. 26. Nuhn P, Novara G, Seitz C, et al. Prognostic value of prior history of urothelial carcinoma of the bladder in patients with upper urinary Vol 12 No 04 July-August 2015 2238 Upper Tract Urothelial Carcinoma after Non-Muscle Invasive Bladder Cancer-Kim et al. tract urothelial carcinoma: results from a retrospective multicenter study. World J Urol. 2015;33:1005-13. 27. Yang MH, Chen KK, Yen CC, et al. Unusually high incidence of upper urinary tract urothelial carcinoma in Taiwan. Urology. 2002;59:681- 7. 28. Matsumoto K, Novara G, Gupta A, et al. Racial differences in the outcome of patients with urothelial carcinoma of the upper urinary tract: an international study. BJU Int. 2011;108:E304-9. 29. Mullerad M, Russo P, Golijanin D, et al. Bladder cancer as a prognostic factor for upper tract transitional cell carcinoma. J Urol. 2004;172:2177-81. 30. Ito A, Shintaku I, Satoh M, et al. Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol. 2013;31:1422- 7. Urological Oncology 2239 Upper Tract Urothelial Carcinoma after Non-Muscle Invasive Bladder Cancer-Kim et al.