BJUI RESULTS. Study Type Prognosis (inception cohort study) Level of Evidence 1b

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1 . JOURNAL COMPILATION 2008 BJU INTERNATIONAL Urological Oncology TCC OF THE RENAL PELVIS AND THE URETER IN TAIWAN TAN et al. BJUI BJU INTERNATIONAL Transitional cell carcinomas of the renal pelvis and the ureter: comparative demographic characteristics, pathological grade and stage and 5-year survival in a Taiwanese population Lia-Beng Tan, Lin-Li Chang*, Kuang-I. Cheng, Chun-Hsiung Huang and Aij-Lie Kwan Department of Urology, St. Joesh s Hospital, Yunlinsien, and Department of Environmental and Occupational Health, Cheng Kung University, and Departments of *Microbiology Anaesthesiology, Neurosurgery and Urology, and Graduate Institute of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Accepted for publication 17 June 2008 Study Type Prognosis (inception cohort study) Level of Evidence 1b OBJECTIVE To compare the predictive value for 5-year survival of demographic characteristics, pathological grade and stage between upper tract urothelial carcinoma (UTUC) of the renal pelvis () and ureter (UUC) in a Taiwanese population. PATIENTS AND METHODS In this study ( ) we analysed 141 patients with UTUC, including 71 with and 70 with UUC (median age 59 years; median follow-up 54 months, SD 2.5). Prognostic indicators were examined by univariate and multivariate logistic regression analyses. RESULTS A significant percentage of patients had tumour on the right side and a high proportion of those with UUC were women. Gross haematuria and hypertension were the most common symptoms of. The sensitivity of intravenous pyelography in diagnosing and UUC was 49% (34/69) and 36% (25/70), respectively. However, in patients assessed by retrograde pyelography the diagnostic sensitivity was 85% (60/71) for and 89% (55/62) for UUC. The incidence of tumour recurrence after nephroureterectomy with bladder cuff excision was significantly higher in those with UUC (13%) than (3.6%). Distant metastasis was detected in 37 of 141 (26%) patients, the most common sites being bone (46%), lung (22%), liver (14%) and colon (8%). Univariate logistic regression analysis showed significant differences in the prognosis for high-grade and high-stage tumours. The prognosis was particularly poor in patients aged >60 years. According to the multivariate logistic regression analysis, tumour stage and grade were the best outcome predictors for, but stage and age were the best outcome predictors for UUC. CONCLUSION UUC is more common in women and has a more aggressive clinical outcome than after nephroureterectomy with bladder cuff incision. Tumour stage and grade are the best predictors of survival in patients with. Also, in patients with UUC the prognosis is poor in older patients and those with advanced stages of cancer. KEYWORDS upper tract urothelial carcinoma, renal pelvis tumour, ureter tumour, Taiwan INTRODUCTION A recent review [1] indicated that the incidence of upper urinary tract TCC of the renal pelvis (RP) and ureter is relatively rare. RP TCC accounts for only 5 6% of all urothelial tumours and 10% of all renal tumours. However, TCC of the RP comprises 23% of all urothelial TCC () and % of all RCCs in Taiwan, particularly in area of endemic Blackfoot disease (BFD) [2,3]. The rates of both kidney and bladder cancers are reportedly higher in areas where BFD is highly prevalent [4 6]. and ureteric TCC (UC) differ in their clinical features and prognosis, gross anatomy, lymphatic drainage and blood supply. However, few studies have characterized how TCC differs between these groups. In the present study we prospectively recruited patients with pathologically confirmed TCC of the upper urinary tract from three Taiwanese hospitals to compare the clinical features, 5-year survival rates and factors affecting survival between patients with and those with UUC. PATIENTS AND METHODS In all, 608 patients with TCC (including 141 with upper urinary tract TCC and 467 with TCC of the urinary bladder) were treated at three teaching hospitals in southern Taiwan from July 1986 to July Of these, the 141 with upper tract UC, including 71 with and 70 with UUC, were selected for analysis. Patients with TCC involving both RP and ureter were excluded if the primary origin of the TCC could not be determined by clinical or pathological data. 312 JOURNAL COMPILATION 2008 BJU INTERNATIONAL 103, doi: /j x x

2 T CC OF THE RENAL PELVIS AND THE URETER IN TAIWAN TABLE 1 The demographic and clinical characteristics, tumour grade and stage, and 5-year survival rates n (%) Characteristic UUC Odds ratio (95% CI) (15.5) 12 (17.1) 0.9 ( ) (32.4) 18 (25.7) 1.4 ( ) (38.0) 33 (47.1) 0.9 ( ) >69 10 (14.1) 7 (10.0) 0.6 ( ) Gender Male 43 (60.6) 28 (40.0) Female 28 (39.4) 42 (60.0) 2.3 ( )* Arsenic exposure Non-endemic 48 (67.6) 39 (55.7) Endemic 23 (32.4) 31 (44.3) 1.7 ( ) Tumour grade I 9 (12.7) 9 (12.9) 1.0 ( ) II 38 (53.5) 37 (52.9) 1.0 ( ) III 24 (33.8) 24 (34.3) 1.0 ( ) Stage pta, pt1 30 (42.3) 42 (60.0) 0.5 ( )* pt2 22 (31.0) 12 (17.1) 2.6 ( )* pt3 8 (11.3) 9 (12.9) 1.2 ( ) pt4 11 (15.5) 7 (10.0) 0.5 ( ) Tumour location Right 30 (42.3) 42 (60.0) Left 41 (57.7) 28 (40.0) 0.5 ( )* 5-year survival Died 39 (54.9) 35 (50.0) Survived 32 (45.1) 35 (50.0) 1.2 ( ) Symptoms and signs Gross haematuria 71 (100.0) 61 (87.0) 0.1 ( ) Flank pain 29 (41.0) 30 (43.0) 1.1 ( ) Azotaemia 6 (8.4) 13 (18.6) 2.5 ( ) Fever and chills 6 (8.4) 6 (8.6) 1.0 ( ) Abdominal pain 1 (1.4) 6 (8.6) 6.6 ( ) Weight loss 6 (8.4) 5 (7.1) 0.8 ( ) Abdominal mass 4 (5.6) 1 (1.4) 0.2 ( ) Hypertension 9 (13.0) 0 (0.0) 0.1 ( )* Complications UTI 3 (4.3) 7 (10.0) 2.5 ( ) Wound infection 2 (0.8) 5 (7.2) 2.7 ( ) Acute renal failure 6 (8.5) 1 (1.4) 0.2 ( ) Cardiovascular accident 1 (1.4) 1 (1.4) 1.0 ( ) Urine leakage 1 (1.4) 1 (1.4) 1.0 ( ) Heart failure 0 3 (4.3) 7.4 ( ) Epidydimitis 0 2 (3.0) 5.2 ( ) Upper gastro-intestinal bleeding 0 2 (3.0) 5.2 ( ) Thrombosis 0 1 (1.4) 3.1 ( ) to locate the lesion. Tumour stage was classified according to the TNM system [7] and tumours were graded according to the WHO/International Society of Urological Pathology grading system, 1998 [8]. The surgical treatment, recurrence and follow-up were reviewed for each patient. Differences in frequencies were evaluated using the chi-square or Fisher s exact test, and continuous variables were compared by twosample t-tests. Univariate logistic regression and multivariate logistic regression analyses were used identify independent factors affecting the 5-year survival. RESULTS Upper tract UC comprised 23% (141/608) of all urothelial cancers, and comprised 63% of all renal tumours. The mean age of patients with and UUC was 59.4 and 59.2 years, respectively (P = 0.91; Table 1). The overall male-to-female ratio was 1:1 but this ratio for UUC was 1:1.5 and for was 1.5:1. The incidence of UUC was significantly higher in women (odds ratio 2.3; 95% CI ). Patients with in the infundibulocalyceal area was 58% (41/71) and 42% (30/71) were in the pelvis proper. In those with UUC, 54% (38/70) had tumours in the lower third, 23% (16/70) in the upper and 23% (16/70) in the middle third of the ureter. There was a high incidence of pta-pt1 stage tumours and right-sided ureteric tumours (Table 1). The overall 5-year survival rate was 48%; there were no gender differences between patients with (45%) and UUC (50%). had significantly more related symptoms of gross haematuria and hypertension (odds ratio 0.1, 95% CI for both). However, the incidence of azotaemia was higher in those with UUC than (2.5, ) (Table 1). The most common complications in the and UUC groups were acute renal failure and UTI, respectively (Table 1). *P < All patients had comprehensive evaluations, including a medical history review, genitourinary tract evaluation, physical examination and laboratory tests. The genitourinary tract evaluation included urine analysis, urine culture, haematology, basic metabolic profiling, chest X-ray, intravenous pyelography (IVP) and ultrasonography. Retrograde pyelography, antegrade pyelography and CT were also use if IVP failed All patients had IVP except for two with who had poor renal function. Tumour lesions were detected or suspected in 34 (49%) patients with and in 25 (36%) with UUC, but the difference was not statistically significant (P = 0.143). All patients with and 62 with UUC had retrograde pyelography; tumours were identified in 85% (60/71) and 89% (55/62) of those with and UUC, JOURNAL COMPILATION 2008 BJU INTERNATIONAL 313

3 T AN ET AL. respectively. These results showed the superior diagnostic accuracy of retrograde pyelography. The other eight patients with UUC had antegrade pyelography after failure to pass a ureteric catheter beyond the tumour; all eight had lower ureteric cancers and had a filling defect with ureteric obstruction during antegrade pyelography. We also examined the survival, treatment efficacy and predictive factors for recurrence and progression in the patients; 69 with UUC had open surgery by total nephroureterectomy (NU) with bladder cuff excision (BCE), and one had palliative procedures. The bladder cancer recurred in 13% of patients. Of 28 patients with who had open surgery by total NU and BCE, and one who had palliative procedures, one (3.6%) subsequently developed bladder tumours. However, in the other 42 patients with who had open surgery by NU with no BCE, five had a recurrence, including two (5%) in the urinary tract and three (7%) in the bladder (P = 0.39). The 5-year survival rate for patients with was 57% (16/28) in those treated with NU and BCE, and 38% (16/42) in those treated with NU with no BCE (P = 0.117). Distant metastases were detected in 37 of the 141 (26%) patients, including 19 (27%) with and 18 (26%) with UUC. The most common sites of distant metastasis were bone (46%), lung (22%), liver (14%) and colon (8%). TABLE 2 Comparison of crude odds ratio for 5-year survival with gender, age and pathological grade and stage in patients with or UUC UUC Variable Survival, n (%) OR (95% CI) Survival, n (%) OR (95% CI) Gender Male 20 (46.5) 1.2 ( ) 14 (50.0) 1.0 ( ) Female 12 (42.9) (50.0) (52.9) 1.8 ( ) 21 (70.0) 4.3 ( ) >60 14 (37.8) (35.0) 1.0 Stage pta, pt1 20 (66.7) 4.8 ( ) 27 (64.3) 4.5 ( ) pt2 12 (29.3) (28.6) 1.0 Grade I, II 29 (61.7) 11.3 ( ) 28 (60.9) 3.8 ( )* III 3 (12.5) (29.2) 1.0 *P < 0.05; P < Adjusted odds ratio (95% CI) Variable UUC ( ) 5.4 ( ) > Tumour stage pta, pt1 4.3 ( )* 5.0 ( ) pt Tumour grade I, II 8.6 ( ) 2.7 ( ) TABLE 3 Multivariate logistic regression analysis of adjusted odds ratio of 5- year survival in patients with or UUC III *P < 0.05; P < Table 2 shows the 5-year survival rates by gender, age, pathological grade and stage. High stage and high grade were significantly associated with survival; furthermore, survival in patients with UUC was significantly lower in those aged >60 years. Multivariate logistic regression analysis indicated that patients with high stages and high-grade tumours had lower survival rates, and that tumour grade and stage were the most important factors in prognosis for. Age >60 years and a high tumour stage were significant predictors of death in patients with UUC (Table 3). DISCUSSION TCC of the ureter and RP is relatively rare outside Taiwan; in the present study, the upper tract comprised 23% of all urothelial TCCs, and accounted for 63% of the kidney tumours, which is 4 and 6 10 times, respectively, higher than rates reported in other countries [2,3,9 11]. The higher incidence of upper tract TCC might be associated with arsenic exposure, smoking, analgesic abuse, occupational carcinogens, hypertension, long-standing urinary obstructions, infection and Balkan nephropathy [12 17]. However, the incidence of upper tract TCC did not significantly differ between patients who had lived in endemic areas of BFD and those who had lived outside these areas. This finding suggests that inorganic arsenic is not the only causative factor influencing the incidence of upper tract TCC. Cosyns et al. [18] and Nortier et al. [19] reported a high prevalence of upper tract TCC in patients treated for Chinese herb nephropathy, which is associated with the use of carcinogenic remedies containing aristolochic acid. Exposure to these carcinogens might increase the life-long risk of UC [18,19]. However, the carcinogenic effects of arsenic or exposure to herbal remedies require further study. The significantly high prevalence of hypertension in patients with renal pelvic cancer still lacks a causative explanation. The risk of hypertension is times higher in patients with RP cancer exposed to arsenic, diuretics or antihypertension drugs [15,17]. Furthermore, Tseng [20] suggested that the atherogenicity of arsenic could be associated with its effects on hypercoagulability, endothelial injury, smooth muscle cell proliferation, somatic mutation, oxidative stress and apoptosis. Further investigation is needed of the underlying aetiologies of our clinical findings. Because of the significantly high recurrence rate of urothelial tumours, some researchers have recommended a more sensitive diagnostic tool and aggressive treatment for patients with these tumours [21 23]. Because it is not invasive, IVP is often used to screen for upper tract TCC, but IVP lacks the required 314 JOURNAL COMPILATION 2008 BJU INTERNATIONAL

4 T CC OF THE RENAL PELVIS AND THE URETER IN TAIWAN sensitivity to diagnose and UUC. In accordance with previously published data [24,25], the present study showed that retrograde pyelography, which has a sensitivity of >85%, is a more accurate diagnostic tool. In this study, the recurrence rate after total NU with BCE was 13%, which is lower than the reported 20 45% rate of recurrence after incomplete ureterectomy [26 28]. Tumour stage, grade, vessel invasion and age are important factors in prognosis and survival [21,22,28 32]. Recent studies evaluated minimally invasive treatments for upper tract TCC, e.g. adjuvant topical therapy [32 34]. Ureteroscopic management remains the preferred procedure for initial diagnosis and therapeutic treatment of low-grade upper tract TCC. However, percutaneous management, e.g. complete NU with BCE is still recommended for patients with high grade disease [25,33]. Recently, laparoscopic NU has proven to be a minimally invasive, safe and effective alternative approach [35]. In summary, this study showed differences between UUC and in terms of gender distribution, affected side and prognosis. Taken together, tumour stage and grade are highly predictive of prognosis and survival in patients with. Also, advanced stage and patient age are associated with a poor prognosis in UUC. These findings highlight the need for more accurate diagnostic tools for the follow-up and appropriate treatment of high-risk patients. ACKNOWLEDGEMENTS We gratefully thank professor Shun-Jen Chang, Department of public health, Kaohsiung Medical University for statistical assistance. CONFLICT OF INTEREST None declared. REFERENCES 1 Nocks BN, Heney NM, Daly JJ, Perrone TA, Griffin PP, Prout GR Jr. Transitional cell carcinoma of renal pelvis. Urology 1982; 19: Hsieh YF, Ling GC, Lu YB, Yeh MT, Chiang CP. Incidence of tumor of the renal pelvis in Taiwan. Taiwan Yi Xue Hui Za Zhi 1979; 78: Chou YH, Huang CH. Unusual clinical presentation of upper urothelial carcinoma in Taiwan. Cancer 1999; 85: Chen CJ, Chuang YC, Lin TM, Wu HY. Malignant neoplasms among residents of a blackfoot disease-endemic area in Taiwan: high-arsenic artesian well water and cancers. Cancer Res 1985; 45: Guo HR, Chiang HS, Hu H, Lipsitz SR, Monson RR. Arsenic in drinking water and incidence of urinary cancers. Epidemiology 1997; 8: Lamm SH, Byrd DM, Kruse MB, Feinleib M, Lai SH. Bladder cancer and arsenic exposure: differences in the two populations enrolled in a study in southwest Taiwan. Biomed Environ Sci 2003; 16: Sobin LH, Fleming ID. TNM Classification of Malignant Tumors, 5th edn. (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer 1997; 80: 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: Murphy DM, Zincke H, Furlow WL. Primary grade 1 transitional cell carcinoma of the renal pelvis and ureter. J Urol 1980; 123: Munoz JJ, Ellison LM. Upper tract urothelial neoplasms: incidence and survival during the last 2 decades. J Urol 2000; 164: Yang MH, Chen KK, Yen CC et al. Unusually high incidence of upper urinary tract urothelial carcinoma in Taiwan. Urology 2002; 59: Mahony JF, Storey BG, Ibanez RC, Stewart JH. Analgesic abuse, renal parenchymal disease and carcinoma of the kidney or ureter. Aust NZ J Med 1977; 7: McLaughlin JK, Silverman DT, Hsing AW et al. Cigarette smoking and cancers of the renal pelvis and ureter. Cancer Res 1992; 52: Mellemgaard A, Carstensen B, Norgaard N, Knudsen JB, Olsen JH. Trends in the incidence of cancer of the kidney, pelvis, ureter and bladder in Denmark Scand J Urol Nephrol 1993; 27: Chen CJ, Hsueh YM, Lai MS et al. Increased prevalence of hypertension and long-term arsenic exposure. Hypertension 1995; 25: Linet MS, Chow WH, McLaughlin JK et al. Analgesics and cancers of the renal pelvis and ureter. Int J Cancer 1995; 62: Liaw KL, Linet MS, McLaughlin JK et al. Possible relation between hypertension and cancers of the renal pelvis and ureter. Int J Cancer 1997; 70: Cosyns JP, Jadoul M, Squifflet JP, Wese FX, van Ypersele de Strihou C. Urothelial lesions in Chinese-herb nephropathy. Am J Kidney Dis 1999; 33: Nortier JL, Martinez MC, Schmeiser HH et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 2000; 342: Tseng CH. Blackfoot disease and arsenic: a never-ending story. J Environ Sci Health 2005; 23: Mills C, Vaughan ED Jr. Carcinoma of the ureter: natural history, management and 5-year survival. J Urol 1983; 129: 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: Krambeck AE, Thompson RH, Lohse CM et al. Endoscopic management of upper tract urothelial carcinoma in patients with a history of bladder urothelial carcinoma. J Urol 2007; 177: McCarron JP, Mills C, Vaughn ED Jr. Tumors of the renal pelvis and ureter: current concepts and management. Semin Urol 1983; 1: Landman J, Lev RY, Bhayani S et al. Comparison of hand assisted and standard laparoscopic radical nephroureterectomy for the management of localized transitional cell carcinoma. J Urol 2002; 167: Reitelman C, Sawczuk IS, Olsson CA, Puchner PJ, Benson MC. Prognostic variables in patients with transitional cell carcinoma of the renal pelvis and proximal ureter. J Urol 1987; 138: JOURNAL COMPILATION 2008 BJU INTERNATIONAL 315

5 T AN ET AL. 27 Ozsahin M, Zouhair A, Villa S et al. Prognostic factors in urothelial renal pelvis and ureter tumours: a multicentre Rare Cancer Network study. Eur J Cancer 1999; 35: Holmang S, Johansson SL. Impact of diagnostic and treatment delay on survival in patients with renal pelvic and ureteral cancer. Scand J Urol Nephrol 2006; 40: Heney NM, Nocks BN, Daly JJ, Blitzer PH, Parkhurst EC. Prognostic factors in carcinoma of the ureter. J Urol 1981; 125: Wallace DM, Wallace DM, Whitfield HN, Hendry WF, Wickham JE. The late results of conservative surgery for upper tract urothelial carcinomas. Br J Urol 1981; 53: Huang PC, Huang CY, Huang SW et al. High incidence of and risk factors for metachronous bilateral upper tract urothelial carcinoma in Taiwan. Int J Urol 2006; 13: Joudi FN, Crane CN, O Donnell MA. Minimally invasive management of upper tract urothelial carcinoma. Curr Urol Rep 2006; 7: Chew BH, Pautler SE, Denstedt JD. Percutaneous management of uppertract transitional cell carcinoma. J Endourol/Endourol Soc 2005; 19: Park S, Meng MV. Endoscopic and minimally invasive approaches to upper tract urothelial carcinoma. Curr Opin Urol 2005; 15: Shiong Lee L, Yip SK, Hong Tan Y, Cheng CW. Laparoscopic nephroureterectomy for upper urinary tract transitional cell carcinoma. Scand J Urol Nephrol 2006; 40: Correspondence: Aij-Lie Kwan, Department of Neurosurgery, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan. med725006@yahoo.com.tw, or a_lkwan@yahoo.com Abbreviations: (RP)(U)UC, (renal pelvis) (ureteric) urothelial carcinoma; BFD, blackfoot disease; NU, nephroureterectomy; BCE, bladder cuff excision; IVP, intravenous pyelography. 316 JOURNAL COMPILATION 2008 BJU INTERNATIONAL