Urologic Oncology: Seminars and Original Investigations ] (2014) ∎∎∎–∎∎∎
Original article
Incidence, characteristics, treatment strategies, and oncologic outcomes of synchronous bilateral upper tract urothelial carcinoma in the Chinese population Dong Fang, M.D.a,1, Gengyan Xiong, M.D.a,1, Xuesong Li, M.D., Ph.D.a,*, Yongming Kang, M.D.a,b, Lei Zhang, M.D.a, Guangzhi Zhao, M.D.a, Xiaopeng Chen, M.D.a,c, Lin Yao, M.D.a, Xiaoyu Zhang, M.D.a, Wei Yu, M.D., Ph.D.a, Kan Gong, M.D., Ph.D.a, Yi Song, M.D., Ph.D.a, Qun He, M.D., Ph.D.a, Zhisong He, M.D., Ph.D.a, Liqun Zhou, M.D., Ph.D.a,*, Yinglu Guo, M.D., Ph.D.a a
Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Centre, Beijing, China b Department of Urology, Suining Central Hospital, Suining, Sichuan, China c Department of Urology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China Received 22 March 2014; received in revised form 3 July 2014; accepted 3 July 2014
Abstract Objectives: To investigate the incidence and treatment strategies for bilateral upper tract urothelial carcinoma (UTUC) and to compare the characteristic and oncologic outcomes of bilateral UTUC with those of unilateral tumors. Methods and materials: The study included 892 consecutive patients with UTUC. Bilateral UTUC was defined as synchronous bilateral carcinoma on preoperative imaging before confirmation by pathology or positive urine cytology result plus direct visualization. Radical nephroureterectomy (RNU) or nephron-sparing surgery (NSS) or both were carried out. Results: A total of 39 patients (4.37%) suffered from bilateral disease. Discordant histological grade of bilateral tumor was found in 39.3% cases. Bilateral tumors were associated with female sex (P o 0.001), preoperative renal insufficiency (P o 0.001), previous or concomitant bladder tumors (P ¼ 0.013), lower tumor stages (P ¼ 0.020), papillary architecture (P ¼ 0.001), and smaller-sized tumors (P ¼ 0.020). Patients with worse renal function (P o 0.001) or large-sized tumors (P ¼ 0.039) tended to be treated with bilateral RNU. Most patients (67.6%) were treated with unilateral RNU plus unilateral NSS, with NSS being performed on tumors that only extended to the ureter (P ¼ 0.003) and had a smaller size (P ¼ 0.005). The median follow-up duration was 56 months. The 5-year cancer-specific survival and bladder recurrence-free survival rates were 81.2% and 64.5%, respectively, similar to those of unilateral tumors. Male sex (hazard ratio ¼ 11.535) and higher tumor stage (hazard ratio ¼ 3.386) were independent worse prognostic factors. Conclusions: The prevalence of bilateral UTUC is rare. Female patients, patients with renal insufficiency, and those with bladder tumor tended to suffer from bilateral disease and were less likely to present with worse pathological outcomes in the Chinese population. The tumor characteristics and renal function were informative in treatment selection. The oncologic outcomes were similar to those in unilateral UTUC, and male sex and a higher tumor stage were poor prognostic factors for these patients. r 2014 Elsevier Inc. All rights reserved.
Keywords: Bilateral; Chronic kidney disease (CKD); Sex; Nephron-sparing surgery (NSS); Radical nephroureterectomy (RNU); Upper tract urothelial carcinoma (UTUC)
1. Introduction 1
These authors contribute equally.
Corresponding authors. Tel.: þ86-10-8357-5101; fax: þ86-10-66551726. E-mail addresses: [email protected], pineneedlelixuesong@gmail. com (X. Li), [email protected] (L. Zhou). *
http://dx.doi.org/10.1016/j.urolonc.2014.07.001 1078-1439/r 2014 Elsevier Inc. All rights reserved.
Upper tract urothelial carcinomas (UTUC) are uncommon and account for only 5% to 10% of urothelial carcinomas [1,2]. Synchronous bilateral UTUC is even rarer. A large Swedish study reported that only 1.6% of
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Table 1 Clinical and pathological characteristics of bilateral UTUC compared with unilateral tumors All
Patients, no. (%) Preoperative characteristics Sex, no. (%) Male Female Age, no. (%), y o70 Z70 Age, mean ⫾ SD, y Gross hematuria, no. (%) Absent Present Previous or concomitant BT, no. (%) Absent Present Preoperative renal function, no. (%) No CKD (eGFR Z 60) Moderate CKD (60 4 eGFR Z 15) End-stage CKD (eGFR o 15) History of smoking, no. (%) Absent Present Urinary cytology, no. (%) Negative Missing data Positive Postoperative characteristics Architecture, no. (%) Papillary Sessile Tumor stage, no. (%)a Ta–T1 T2 T3–T4 Lymph node status, no. (%) N0 Nx Nþ Tumor grade, no. (%)a G1 G2 G3 Tumor size, mean ⫾ SDa
Presence of UTUC
Univariate analysis
Unilateral
χ2 or Z
Bilateral
892 (100) 853 (95.6)
39 (4.4)
400 (44.8) 393 (46.1) 492 (55.2) 460 (53.9)
7 (17.9) 32 (82.1)
Multivariate analysis
P value HR
95% CI
P value
3.534 (female vs. male)
1.466–8.523
0.005*
0.842 (Z70 vs. o70)
0.427–1.659
0.618
0.991 (present vs. absent)
0.451–2.178
0.982
2.393 (present vs. absent)
1.139–5.026
0.021*
5.192 (end-stage vs. no CKD) 2.477 (end-stage vs. moderate CKD)
1.909–14.120 0.001* 1.039–5.904 0.041*
0.721 (present vs. absent)
0.204–2.547
0.612
1.277 (positive vs. negative) 1.070 (positive vs. missing)
0.511–3.195 0.511–2.243
0.601 0.857
11.926 o0.001*
0.175 497 (55.7) 474 (55.6) 23 (59.0) 395 (44.3) 379 (44.4) 16 (41.0) 66.59 ⫾ 10.57 67.35 ⫾ 7.34 0.047 0.121 227 (25.4) 218 (25.6) 9 (23.1) 665 (74.6) 635 (74.4) 30 (76.9) 6.860 751 (84.2) 724 (84.9) 141 (15.8) 129 (15.1)
0.402
0.962 0.448
0.013*
27 (69.2) 12 (30.8) 18.879 o0.001*
388 (43.5) 379 (44.4) 441 (49.4) 420 (49.2) 63 (7.1)
54 (6.3)
9 (23.1) 21 (53.8) 9 (23.1) 3.108
728 (81.6) 692 (81.1) 164 (18.4) 161 (18.9)
36 (92.3) 3 (7.7)
201 (22.5) 194 (22.7) 316 (35.4) 301 (35.3) 375 (42.0) 358 (42.0)
7 (17.9) 15 (38.5) 17 (43.6)
685 (76.8) 649 (76.1) 192 (21.5) 191 (22.4)
36 (92.3) 1 (2.6)
314 (35.2) 292 (34.2) 297 (33.3) 288 (33.8) 273 (30.6) 265 (31.1)
22 (56.4) 9 (23.1) 8 (20.5)
96 (10.8) 90 (10.6) 760 (85.2) 728 (85.3) 36 (4.0) 35 (4.1)
6 (15.4) 32 (82.1) 1 (2.6)
27 (3.0) 25 (2.9) 505 (56.6) 484 (56.7) 358 (40.1) 342 (40.1) 3.41 ⫾ 2.22
2 (5.1) 21 (53.8) 16 (41.0) 2.54 ⫾ 1.46
0.510
0.051
0.775
8.319
0.001*
7.777
0.020*
1.076
0.584
0.666
0.717
2.323
0.020*
eGFR ¼ estimated glomerular filtration rate; HR ¼ hazard ratio; SD ¼ standard deviation. * Statistically significant. a The higher stage/grade and larger size of bilateral tumors were used for analysis.
UTUC were bilateral [3]. The only commonly accepted shared characteristic of these patients is their renal insufficiency [3–5], and proper treatment measures for bilateral UTUC remain to be elucidated. Radical nephroureterectomy (RNU) with the resection of bladder cuff is the gold standard treatment for UTUC [6];
however, for patients with bilateral UTUC, the resection of both kidneys would lead to the total loss of renal function and inevitable permanent dialysis. Nephron-sparing surgery (NSS), such as segmental ureterectomy or endoscopic management, has been shown to provide a cancer-specific and overall survival (CSS and OS) equivalent to that of
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Table 2 Clinical and pathological characteristics between different treatment groups All
Treatment group Bilateral RNU
RNU plus NSS
Bilateral NSS
Patients, no. (%)
34 (100)
5 (14.7)
23 (67.6)
6 (17.6)
Sex, no. (%) Male Female
4 (11.8) 30 (88.2)
0 (0) 5 (100)
3 (13.0) 20 (87.0)
1 (16.7) 5 (83.3)
Age, no. (%), y o70 Z70
21 (61.8) 13 (38.2)
3 (60) 2 (40)
13 (56.5) 10 (43.5)
5 (83.3) 1 (16.7)
Required dialysis before surgeries, no. (%) No Yes
29 (85.3) 5 (14.7)
0 (0) 5 (100)
23 (100) 0 (0)
6 (100) 0 (0)
Required dialysis after surgeries, no. (%) No Yes
25 (73.5) 9 (26.5)
0 (0) 5 (100)
19 (82.6) 4 (17.4)
6 (100) 0 (0)
Required dialysis in follow-up, no. (%) No Yes
22 (64.7) 12 (35.3)
0 (0) 5 (100)
16 (69.6) 7 (30.4)
6 (100) 0 (0)
Preoperative renal function, no. (%) No CKD (eGFR Z 60) Moderate CKD (60 4 eGFR Z 15) End-stage CKD (eGFR o 15)
7 (20.6) 19 (55.9) 8 (23.5)
0 (0) 0 (0) 5 (100)
3 (13.0) 17 (73.9) 3 (13.0)
4 (66.7) 2 (33.3) 0 (0)
Previous or concomitant BT, no. (%) Absent Present
25 (73.5) 9 (26.5)
2 (40) 3 (60)
18 (78.3) 5 (21.7)
5 (83.3) 1 (16.7)
Urinary cytology, no. (%) Negative Positive Missing data
8 (23.5) 17 (50.0) 9 (26.5)
0 (0) 1 (20) 4 (80)
6 (26.1) 13 (56.5) 4 (17.4)
2 (33.3) 3 (50.0) 1 (16.7)
Unilateral multifocality, no. (%) Absent Unilateral present Bilateral present
17 (50.0) 11 (32.4) 6 (17.6)
1 (20) 4 (80) 0 (0)
13 (56.5) 6 (26.1) 4 (17.4)
3 (50.0) 1 (16.7) 2 (33.3)
Ureter involvement, no. (%) Absent Unilateral present Bilateral present
10 (29.4) 16 (47.1) 8 (23.5)
2 (40) 2 (40) 1 (20)
7 (30.4) 12 (52.2) 4 (17.4)
1 (16.7) 2 (33.3) 3 (50.0)
Presence of hydronephrosis, no. (%) Absent Unilateral present Bilateral present
13 (38.2) 12 (35.3) 9 (26.5)
1 (20) 2 (40) 2 (40)
9 (39.1) 7 (30.4) 7 (30.4)
3 (50.0) 3 (50.0) 0 (0)
Stage, no. (%)a Ta T1 T2 T3
3 15 9 7
0 1 3 1
Grade, no. (%)a G2 G3
19 (55.9) 15 (44.1)
1 (20) 4 (80)
16 (69.6) 7 (30.4)
2 (33.3) 4 (66.7)
Tumor size, no. (%)a r2 cm 42 cm
13 (38.2) 21 (61.8)
1 (20) 4 (80)
7 (30.4) 16 (69.6)
5 (83.3) 1 (16.7)
(8.8) (44.1) (26.5) (20.6)
(0) (20) (60) (20)
eGFR ¼ estimated glomerular filtration rate. significant. a The higher stage/grade and larger size of bilateral tumors were used for analysis. * Statistically
2 10 6 5
(8.7) (43.5) (26.1) (21.7)
1 4 0 1
χ2 or Z
P value
0.842
0.656
1.456
0.483
34.000
o0.001*
17.023
o0.001*
12.677
0.002*
27.444
o0.001*
3.449
0.178
8.928
0.063
7.059
0.133
3.133
0.536
3.280
0.512
5.986
0.425
5.595
0.061
6.464
0.039*
(16.7) (66.7) (0) (16.7)
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Table 3 Clinical and pathological characteristics between each lateral group in patients treated with unilateral RNU plus unilateral NSS All
χ2 or Z
Treatment group RNU
NSS
Surgeries, no. (%)
46 (100)
23 (50)
23 (50)
Multifocality, no. (%) No Yes
32 (69.6) 14 (30.4)
14 (60.9) 9 (39.1)
18 (78.3) 5 (21.7)
Side, no. (%) Left Right
23 (50.0) 23 (50.0)
11 (47.8) 12 (52.2)
12 (52.2) 11 (47.8)
Location, no. (%) Ureter Pelvis Pelvis þ ureter
15 (32.6) 25 (54.3) 6 (13.0)
2 (8.7) 17 (73.9) 4 (17.4)
13 (56.5) 8 (34.8) 2 (8.7)
Hydronephrosis, no. (%) No Yes
25 (54.3) 21 (45.7)
12 (52.2) 9 (39.1)
11 (47.8) 10 (43.5)
Stage, no. (%) Ta T1 T2 T3
8 21 9 5
(17.4) (45.7) (19.6) (10.9)
2 (8.7) 12 (52.2) 4 (17.4) 5 (21.7)
6 9 5 0
Grade, no. (%) G1 G2 G3
3 (6.5) 31 (67.4) 9 (19.6)
0 (0) 17 (73.9) 6 (26.1)
3 (13.9) 14 (60.9) 3 (13.9)
2.40 ⫾ 1.32
1.48 ⫾ 0.96
Tumor size, mean ⫾ SD
P value
a
1.643
0.168
0.087
0.500
11.973
0.003*
0.096
0.757
7.366
0.061
4.101
0.129
(26.1) (39.1) (21.7) (0)
2.809
0.005*
SD ¼ standard deviation. * Statistically significant. a Information on the tumor stages and grades of 3 patients was unavailable.
RNU in patients with lower grade or lower stage diseases [7–9] but worse oncologic outcomes in patients with highgrade tumor [10]. Thus, how to determine the proper candidates for NSS remains controversial. Furthermore, there is currently very little knowledge on the potential role of NSS in bilateral UTUC [3,4]. Therefore, in this large single-center cohort of patients, we sought to validate the incidence and any clinical features that might help practitioners to discover the presence of bilateral tumors. We also investigated the pathological characteristics that might assist in the research of mechanisms for multiple urothelial tumors, in the treatment selection for these patients, and in survival outcomes that might help to improve risk stratification.
2. Methods 2.1. Patient selection Following institutional review board approval, we initially collected the clinicopathological data of 912 consecutive patients with UTUC who received treatment in the
Department of Urology, Peking University First Hospital from 2000 to 2012. For all patients, bilateral upper urinary tract was evaluated before surgery. We defined synchronous bilateral UTUC as bilateral urothelial carcinoma on preoperative imaging and confirmed the finding using pathology or positive urine cytology finding plus the direct visualization of the tumors by endoscopy or conclusive image studies. We excluded 20 patients who had undergone previous surgeries for UTUC or solitary kidneys, leaving 892 patients for the final analysis. We also excluded 56 patients who were lost to follow-up in survival analysis. 2.2. Treatment All patients underwent surgery within 3 months after their symptoms began to occur. The surgery measures considered in both unilateral and bilateral UTUCs consisted of RNU (open or laparoscopic) and NSS (segmental ureterectomy, endoscopic ablation, and open renal pelvis tumor resection). For bilateral UTUC, the treatment measures were judged by the patient's surgeon and performed after obtaining the patient's consent, and bilateral surgeries were carried out simultaneously or separately within
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Fig. 1. Estimated Kaplan-Meier cancer-specific survival curves stratified by sex (A) (P o 0.001) and tumor stage (B) (P ¼ 0.006). (Color version of figure is available online.)
6 months. None of these patients received neoadjuvant chemotherapy or prophylactic postoperative intravesical instillation chemotherapy. 2.3. Patients evaluation The estimated glomerular filtration rate was calculated using the modified glomerular filtration rate–estimating equation for the Chinese patients: estimated glomerular filtration rate (ml/min/1.73 m2) = 175 Scr1.234 age0.179 ( 0.79 if female) [11]. The tumor stage was assessed according to the 2002 Union for International Cancer Control TNM classification. Tumor grading was performed according to the World Health Organization's classification of 1973. The tumor's architecture was defined as papillary or sessile after examining the final specimen. 2.4. Follow-up schedule For the patients who were followed at our institute, the follow-up regimen of the affected patients included cystoscopy every 3 months for the first 2 years. The cystoscopy intervals were extended to 1 year thereafter. Chest x-rays, serum creatine level, and abdominal ultrasound or computed tomography/magnetic resonance imaging were assessed at the same time. We defined recurrence as discovering urothelial cancer in the remnant urinary tract (e.g., bladder, contralateral ureter
or pelvis, or remnant ureter) or operative site, and bladder recurrence as finding a subsequent bladder tumor (BT) during cystoscopy and confirmed by pathology. The cause of death was determined by the patients' treating physicians or by death certificates. Follow-ups were censored until their last visit or death. 2.5. Statistical analysis All statistical tests were performed with SPSS 20.0 (IBM Corp, Armonk, NY), and statistical significance was set at P o 0.05. The Pearson test and chi-square test were used to examine the distribution of categorical variables, and the Mann-Whitney U test was used for continuous variables. Multivariate logistic regression was used to calculated the predictive factors. Univariable analysis using the log-rank test and multivariable analysis using the Cox proportional hazards regression model were used. 3. Results 3.1. Incidence and clinical characteristics Of the 892 patients with UTUC, 39 suffered from bilateral disease (4.37%). The median age was 68 years (range: 48–82), with 7 male and 32 female patients. Of the 39 patients, 7 (17.9%) had previous BT, including 1 patient with a previous total cystectomy; 7 exhibited concomitant
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Table 4 Univariable and multivariable analyses of predictive factors for worse overall survival and cancer-specific survival Variables
Overall mortality Pts (events), no. (no.)
Univariable analysis P value o0.001*
Sex Female Male Age, y o70 Z70 Preoperative renal function No CKD (eGFR Z 60) Moderate CKD (60 4 eGFR Z 15) End-stage CKD (eGFR o 15) Previous or concomitant BT Absent Present Presence of hydronephrosis Absent Unilateral present Bilateral present Surgical approach Bilateral RNU Unilateral RNU Bilateral NSS Only unilateral surgery Adjuvant therapy No Yes Ureter involvement Absent Unilateral present Bilateral present Unilateral multifocality Absent Unilateral present Bilateral present Tumor stagea Ta T1 T2 T3 Lymph node status N0 Nx Nþ Tumor gradea G1–2 G3 Tumor sizea r2 cm 42 cm
Cancer-specific mortality Multivariable analysis HR
95% CI
Pts (events), no. (no.)
P value
35.389 3.850– 0.002* 325.272
31 (6) 7 (4) 0.332
HR
o0.001*
11.535 1.058–125.768 0.045*
95% CI
P value
0.095 22 (6) 16 (2)
0.021*
0.073
0.046*
9 (2) 20 (3)
9 (2) 20 (2)
9 (5)
9 (4) 0.082
0.107
0.093
26 (4) 12 (6)
26 (3) 12 (5) 0.259
0.374
15 (1) 14 (6) 9 (3)
15 (1) 14 (4) 9 (3) 0.474
0.554
(2) (6) (0) (2)
5 22 6 5
(2) (5) (0) (1)
0.741
0.608
35 (9) 3 (1)
35 (7) 3 (1) 0.754
0.958
11 (2) 17 (6) 10 (2)
11 (2) 17 (4) 10 (2) 0.219
0.148
19 (7) 13 (2) 6 (1)
19 (6) 13 (1) 6 (1) 0.026*
4 18 9 7
Multivariable analysis
31 (5) 7 (3)
22 (6) 16 (4)
5 22 6 5
Univariable analysis P value
0.127
(0) (4) (3) (3)
0.006* 4 18 9 7
0.771 5 (2) 32 (8) 1 (0)
3.386 1.073–10.684
0.038*
(0) (2) (3) (3) 0.580
5 (2) 32 (6) 1 (0) 0.687
22 (6) 16 (4)
0.862 22 (4) 16 (4)
0.195 16 (3) 22 (7)
eGFR ¼ estimated glomerular filtration rate; HR ¼ hazard ratio; Pts ¼ patients. * Statistically significant. a The higher stage/grade and larger size of the bilateral tumors were used for analysis.
0.030* 16 (1) 22 (7)
0.236
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BT; and 2 (5.1%) had both previous and current BT. A total of 15 patients had taken Chinese herbs containing aristolochic acid (AA) for at least 6 months; 5 patients denied of the consumption of herbs, and the remainder could not provide information about what kind or how much of the herb(s) they had taken. Overall, 30 patients (76.9%) initially presented with gross hematuria, 8 patients complained of flank or abdominal pain, and 1 patient was diagnosed during a routine ultrasound examination. All of these patients were diagnosed using CT and ultrasound. Some patients underwent other relevant examinations: ureteroscopy (altogether 21 patients underwent ureteroscopy), intravenous urography (18 patients), retrograde pyelogram (17 patients), nuclear renal scan (to get split renal function, 16 patients), magnetic resonance imaging (9 patients), and selected ureter washing urinary cytology (8 patients). Bilateral renal pelvic tumors were found in 12 patients (30.8%), and bilateral ureter tumors in 6 (15.4%). Moreover, 11 had renal pelvic and contralateral ureteral tumors, and the remaining 10 patients had both ureter and pelvic tumors in the unilateral upper urinary tract. For 28 patients with complete information on bilateral tumor histological grade, discordant grade was found in 11 patients (39.3%). The clinical and pathological characteristics, according to bilateral UTUC vs. unilateral UTUC, are shown in Table 1. Patients with bilateral UTUC tended to be female (P o 0.001), to have worse preoperative renal function (P o 0.001), and to have had previous or concomitant BT (P ¼ 0.013). Additionally, their pathological outcomes tended to involve a lower tumor stage (P ¼ 0.020), papillary architecture (P ¼ 0.001), and a smaller tumor size (P ¼ 0.020). Patients with bilateral tumors had a higher proportion of end-stage renal disease (ESRD) (23.1% vs. 6.3%). In multivariate logistic regression, after controlling for clinical factors, female sex, previous or concomitant BT, and renal insufficiency were each significantly related to bilateral UTUC.
3.2. Treatment strategies There were 5 patients who only received unilateral treatment (1 case of RNU, 1 case of pelvis tumor resection, and 3 cases of endoscopic ablation) because they refused any further surgery on the contralateral tumor (the primary algorithms were contralateral RNU). These cases were excluded from analysis for the treatment strategies. Bilateral RNU was performed in 5 patients. Overall, 23 patients underwent unilateral RNU plus unilateral NSS, including 8 cases of segmental ureterectomy, 11 cases of endoscopic ablation, and 4 cases of open pelvis tumor resection. Moreover, 6 patients underwent bilateral NSS, including the 3 types of aforementioned operations. For the concomitant BT, 6 patients were treated with transurethral resection and 1 with total cystectomy.
7
Comparing the clinical and pathological features of each treatment group, patients with ESRD (P o 0.001) and large-sized tumors (P ¼ 0.039) tended to be treated with bilateral RNU (Table 2). In 23 patients (67.6%), we performed unilateral RNU plus unilateral NSS, although in 3 patients we tried to perform bilateral RNU but the patients refused. Comparing the characteristics of RNU specimens and NSS specimens, we found that the tumors that only involved the ureter (P ¼ 0.003) and were smaller (P ¼ 0.005) tended to be treated with NSS, whereas unilateral radical surgery was suitable for both the renal pelvis and ureter-involved tumors (Table 3). Besides, in 3 patients, diagnostic ureteroscopy biopsy results were considered (data not shown). 3.3. Oncologic outcomes The median follow-up duration of this cohort of patients was 56 (15–155) months. Among the patients followed, 1 was lost to follow-up. Overall, 10 patients (26.3%) died, 8 of whom (21.1%) died of urothelial cancer. The 2- and 5year OS rates were 94.6% and 78.1%, respectively, with CSS rates of 94.6% and 81.2%, respectively. By multivariable analysis, male sex was the only risk factor for worse OS, whereas male sex (hazard ratio ¼ 11.535) and higher tumor stage (hazard ratio ¼ 3.386) independently predicted worse CSS (Fig. 1 and Table 4). Rerunning the data set by excluding those patients with only unilateral treatment had no effect on the result. Disease recurrence occurred in 14 patients (36.8%). Among them, 1 patient treated with unilateral RNU and contralateral segmental ureterectomy experienced a ureter recurrence after 23 months, and 1 patient treated with unilateral RNU and contralateral endoscopic pelvis tumor ablation experienced a local recurrence after 5 months. We performed salvage RNU on these patients. The remaining 12 recurrences were all found in the bladder (31.6%) and were treated with transurethral resection or cystectomy. The 5year probabilities of being free from recurrence and of bladder recurrence were 61.3% and 64.5%, respectively. No parameter had a statistically significant effect on any recurrence-free or bladder recurrence-free survival (Table 5). The oncologic outcomes for patients with unilateral UTUC are shown in Table 6. No difference between unilateral and bilateral UTUCs in OS, CSS, any recurrence or bladder recurrence (Fig. 2) was found using the log-rank test or after adjusting for tumor stage. 4. Discussion In our cohort of patients with UTUC, the incidence of synchronous bilateral disease was 4.37%, slightly higher than the values of previous reports [3]. Holmang and Johansson [3] found that, owing to the prohibition of phenacetin-containing analgesics, the incidence of bilateral
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Table 5 Univariable and multivariable analyses of predictive factors for any recurrence and bladder recurrence Variables
Pts (events), no. (no.) Sex Female Male Age, y o70 Z70 Preoperative renal function No CKD (eGFR Z 60) Moderate CKD (60 4 eGFR Z 15) End-stage CKD (eGFR o 15) Previous or concomitant BT Absent Present Presence of hydronephrosis Absent Unilateral present Bilateral present Surgical approach Bilateral RNU Unilateral RNU Bilateral NSS Only unilateral surgery Adjuvant therapy No Yes Ureter involvement Absent Unilateral present Bilateral present Unilateral multifocality Absent Unilateral present Bilateral present Tumor stageb Ta T1 T2 T3 Lymph node status N0 Nx Nþ Tumor gradeb G1–2 G3 Tumor sizeb r2 cm 42 cm
Bladder recurrencea
Any recurrence P value
Pts (events), no. (no.)
0.384 31 (11) 7 (3)
0.291 29 (9) 7 (3)
0.455 22 (9) 15 (5)
0.851 21 (7) 15 (5)
0.819 9 (3) 20 (7) 9 (4)
0.987 9 (3) 20 (7) 7 (2)
0.987 26 (10) 12 (4)
0.416 26 (8) 10 (4)
0.629 15 (7) 14 (4) 9 (3)
0.276 14 (7) 14 (3) 8 (2)
0.398 5 22 6 5
(1) (11) (1) (1)
0.742 3 22 6 5
(1) (9) (1) (1)
0.906 35 (13) 3 (1)
0.995 33 (11) 3 (1)
0.890 11 (5) 17 (6) 10 (3)
0.996 11 (4) 15 (5) 10 (3)
0.138 19 (9) 13 (2) 6 (3)
0.272 19 (7) 11 (2) 6 (3)
0.071 4 18 9 7
P value
(3) (4) (3) (4)
0.078 4 18 7 7
(3) (3) (3) (3)
0.806 5 (2) 32 (12) 1 (0)
0.593 4 (2) 31 (10) 1 (0)
0.485 22 (9) 16 (5)
0.670 21 (7) 15 (5)
0.527 16 (5) 22 (9)
0.957 15 (5) 21 (7)
eGFR ¼ estimated glomerular filtration rate; Pts ¼ patients. A patient with previous cystectomy and 1 patient with synchronous cystectomy were excluded. b The higher stage/grade and larger size of the bilateral tumors were used for analysis. a
tumors has gradually decreased in the past several decades. Considering that the most commonly reported risk factor for Chinese patients with UTUC is the consumption of AAcontaining herbs [12–14]; this prevalence might be different from that in Western countries. The present patients with bilateral UTUC were characterized by the presence of previous concomitant BT, similar to Holmang's research
[3], and a recent article found that a previous history of non–muscle-invasive BT was significantly associated with tumor multifocality and recurrence [15]. Contrary to the Swedish study [3], female patients tended to suffer from bilateral UTUC. Female sex was regarded as a risk factor for contralateral recurrence in a Taiwanese report [16]; this sex difference among Chinese
D. Fang et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–11
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Table 6 Comparison of the follow-up results for patients with unilateral UTUC and bilateral UTUCa Pts (events), no. (no.)
Overall mortality Unilateral Bilateral Cancer-specific mortality Unilateral Bilateral Any recurrence Unilateral Bilateral Bladder recurrenceb Unilateral Bilateral
Univariable analysis
Adjusted for tumor stage
P value
HR
95% CI
P value
0.108
0.889
0.469–1.685
0.718
0.089
0.843
0.413–1.720
0.638
0.805
1.026
0.593–1.773
0.927
0.776
1.036
0.575–1.867
0.907
798 (255) 38 (10) 798 (223) 38 (8) 798 (242) 38 (14) 792 (219) 36 (12)
HR ¼ hazard ratio; Pts ¼ patients. Patients without follow-up data were excluded. b Patients with previous cystectomy or synchronous cystectomy were excluded. a
patients with UTUC might be unique. Moreover, although not to a major extent, male patients encountered a worse prognosis after treatment. The predictive role of sex on the pathological outcomes or prognosis remains controversial. Studies in the Surveillance Epidemiology and End Results database found that females tended to have higher tumor stage and grade [17], whereas male sex was predictive for muscle-invasive and non–organ-confined UTUC in our previous research [18,19]. It is difficult to explain this discord. The use of AA-containing Chinese herbs in China is common, especially among females. We believe that the
distribution and prognostic differences in the sexes may be attributable to the mechanisms behind AA-induced carcinoma. Chronic kidney disease (CKD) was prevalent in patients with bilateral UTUC and was most likely related to the mechanisms of tumor multifocality. The field cancerization hypothesis [20,21] might play a more important role in the development of bilateral UTUC. Chinese herbal nephropathy might introduce nephrotoxic and carcinogenic toxins into the system, inducing neoplasms within the entire urothelial field [12,22]. Our previous research found that
Fig. 2. Estimated Kaplan-Meier cancer-specific survival curves (A) (P ¼ 0.089) and bladder recurrence-free survival curves (B) (P ¼ 0.776) stratified by unilateral vs. bilateral UTUC. (Color version of figure is available online.)
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D. Fang et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–11
the rate of renal insufficiency was higher in patients with multifocality [19], and other previous reports found that CKD was related to an increased risk of urothelial cancer [23] and bladder recurrence after RNU [16,24]. On the contrary, CKD also affected treatment options. For patients with ESRD or patients already requiring dialysis, NSS did not help to preserve their renal function. Rather, bilateral radical surgery and renal replacement therapy afterward are preferred [4,5]. Moreover, our previous research has demonstrated that even for patients with unilateral UTUC, renal insufficiency is a risk factor for contralateral recurrence after RNU; therefore, prophylactic contralateral RNU is a reasonable choice [25]. NSS has gained popularity in the treatment of UTUC over the years. The present limited ability to predict tumor stage and grade accurately before surgery makes it difficult to select proper surgeries for bilateral UTUC. For instance, a casual bilateral NSS might not thoroughly resect a potentially advanced tumor. In our practice, we performed unilateral RNU of the dominant side plus contralateral NSS on most patients. The following factors are informative in evaluating which is the dominant side: (1) tumor size, as it is related to the CSS and recurrence-free survival [26–28] and was easy to evaluate using preoperative CT films; (2) the multifocality and location of tumors, as it is technically easy to cure a solitary ureteral tumor by NSS, especially in partial ureterectomy; and (3) in several cases, the ureteroscopy results, which could first be performed simultaneously on both sides to ensure that the biopsy result is more informative. The recurrence and death rates of the patients undergoing NSS were similar to those of the bilateral RNU group, and most patients benefitted from NSS by avoiding dialysis, indicating that NSS was associated with superior postoperative renal function [29]. Most likely owing to the limited sample size, several well-established risk factors had no effect on survival or bladder recurrence. Moreover, we found no significant difference between unilateral and bilateral UTUCs in survival or recurrence rates, especially after adjusting for the tumor stage. Because all patients with bilateral UTUC suffered from “multiple” tumors, this cohort of patients should have experienced a high rate of bladder recurrence [30]. Our result might be biased by the limited sample size and short follow-up interval, but we are unsure whether a greater tumor burden would have affected the cancer control result. The limitations of this study include its retrospective design and data collection, which did not allow us to evaluate some of the potentially useful variables, especially the consumption of Chinese herbs, and our study cohort might have been subject to selection and recall bias. Lack of percutaneous management was another limitation. Additionally, indications for the surgical approach were not standardized and were based on the clinical judgment of the treating physician, after discussing possible treatment options and expectations with the patient. Some patients'
refusal for RNU and dialysis affected the treatment strategies. Despite these limitations, our research provides the highest known prevalence of bilateral UTUC and also constitutes the first Asian report. Ours is the first study to analyze the clinical features and treatment measures of this cohort of patients, and we have provided the first results on the oncologic outcomes of this cohort of patients and described their worst predictive factors. Future studies on molecular research would be required to elucidate the mechanisms for the development of bilateral tumors and their relationship with AA.
5. Conclusions The prevalence of bilateral UTUC is rare. Female patients, patients with renal insufficiency, and those with BT tended to suffer from bilateral disease and were less likely to present with worse pathological outcomes in the Chinese population. The tumor characteristics and renal function are informative for decisions concerning treatment strategies. Oncologic outcomes were similar to those of unilateral UTUC, and male sex and higher tumor stage are poor prognostic factors for these patients. Prospective multiinstitutional studies and molecular research are required in the future. Acknowledgment The authors thank the entire staff of the Department of Urology, Peking University First Hospital. References [1] Munoz JJ, Ellison LM. Upper tract urothelial neoplasms: incidence and survival during the last 2 decades. J Urol 2000;164:1523–5. [2] Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin 1998;48:6–29. [3] Holmang S, Johansson SL. Synchronous bilateral ureteral and renal pelvic carcinomas: incidence, etiology, treatment and outcome. Cancer 2004;101:741–7. [4] Kang CH, Yu TJ, Hsieh HH, Yang JW, Shu K, Shiue YL. Synchronous bilateral primary transitional cell carcinoma of the upper urinary tracts: ten patients with more than five years of follow-up. Urology 2004;63:380–2. [5] Tai HC, Lai MK, Chung SD, Huang KH, Chueh SC, Yu HJ. Intermediate-term oncological outcomes of hand-assisted laparoscopic versus open bilateral nephroureterectomy for dialysis and kidney transplant patients with upper urinary tract urothelial carcinoma. J Endourol 2009;23:1139–44. [6] Cummings KB. Nephroureterectomy: rationale in the management of transitional cell carcinoma of the upper urinary tract. Urol Clin North Am 1980;7:569–78. [7] Colin P, Ouzzane A, Pignot G, et al. Comparison of oncological outcomes after segmental ureterectomy or radical nephroureterectomy in urothelial carcinomas of the upper urinary tract: results from a large French multicentre study. BJU Int 2012;110:1134–41.
D. Fang et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–11 [8] Gadzinski AJ, Roberts WW, Faerber GJ, Wolf JS Jr. Long-term outcomes of nephroureterectomy versus endoscopic management for upper tract urothelial carcinoma. J Urol 2010;183:2148–53. [9] Lughezzani G, Jeldres C, Isbarn H, et al. Nephroureterectomy and segmental ureterectomy in the treatment of invasive upper tract urothelial carcinoma: a population-based study of 2299 patients. Eur J Cancer 2009;45:3291–7. [10] Fajkovic H, Klatte T, Nagele U, et al. Results and outcomes after endoscopic treatment of upper urinary tract carcinoma: the Austrian experience. World J Urol 2013;31:37–44. [11] Ma YC, Zuo L, Chen JH, et al. Modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease. J Am Soc Nephrol 2006;17:2937–44. [12] 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;342:1686–92. [13] Chen CH, Dickman KG, Huang CY, et al. Aristolochic acid-induced upper tract urothelial carcinoma in Taiwan: clinical characteristics and outcomes. Int J Cancer 2013;133:14–20. [14] Li XB, Xing NZ, Wang Y, Hu XP, Yin H, Zhang XD. Transitional cell carcinoma in renal transplant recipients: a single center experience. Int J Urol 2008;15:53–7. [15] 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. [16] Li CC, Chang TH, Wu WJ, et al. Significant predictive factors for prognosis of primary upper urinary tract cancer after radical nephroureterectomy in Taiwanese patients. Eur Urol 2008;54:1127–34. [17] Lughezzani G, Sun M, Perrotte P, et al. Gender-related differences in patients with stage I to III upper tract urothelial carcinoma: results from the Surveillance, Epidemiology, and End Results database. Urology 2010;75:321–7. [18] Yu W, Zhao YY, Shen Q, et al. Gender-related differences in pathological characteristics of upper urinary tract urothelial carcinoma: analysis of 597 cases. Beijing Da Xue Xue Bao 2011;43:522–4. [19] Chen XP, Xiong GY, Li XS, et al. Predictive factors for worse pathological outcomes of upper tract urothelial carcinoma: experience from a nationwide high-volume centre in China. BJU Int 2013;112: 917–24.
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[20] 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. [21] Millan-Rodriguez F, Chechile-Toniolo G, Salvador-Bayarri J, Huguet-Perez J, Vicente-Rodriguez J. Upper urinary tract tumors after primary superficial bladder tumors: prognostic factors and risk groups. J Urol 2000;164:1183–7. [22] Cosyns JP, Jadoul M, Squifflet JP, Wese FX, van Ypersele de Strihou C. Urothelial lesions in Chinese-herb nephropathy. Am J Kidney Dis 1999;33:1011–7. [23] Wang SM, Lai MN, Chen PC, Wang JD. Increased risk of urothelial cancer in young and middle aged patients with end-stage renal disease. J Formos Med Assoc 2013. [24] Chung SD, Huang KH, Lai MK, et al. CKD as a risk factor for bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma. Am J Kidney Dis 2007;50:743–53. [25] Fang D, Zhang L, Li X, et al. Risk factors and treatment outcomes of new contralateral upper urinary urothelial carcinoma after nephroureterectomy: the experiences of a large Chinese center. J Cancer Res Clin Oncol 2014;140:477–85. [26] Milenkovic-Petronic D, Milojevic B, Djokic M, et al. The impact of tumor size on outcomes in patients with upper urinary tract urothelial carcinoma. Int Urol Nephrol 2014;46:563–9. [27] Espiritu PN, Sverrisson EF, Sexton WJ, et al. Effect of tumor size on recurrence-free survival of upper tract urothelial carcinoma following surgical resection. Urol Oncol 2014;32:619–24. [28] Pieras E, Frontera G, Ruiz X, Vicens A, Ozonas M, Piza P. Concomitant carcinoma in situ and tumour size are prognostic factors for bladder recurrence after nephroureterectomy for upper tract transitional cell carcinoma. BJU Int 2010;106:1319–23. [29] Silberstein JL, Power NE, Savage C, et al. Renal function and oncologic outcomes of parenchymal sparing ureteral resection versus radical nephroureterectomy for upper tract urothelial carcinoma. J Urol 2012;187:429–34. [30] Azemar MD, Comperat E, Richard F, Cussenot O, Roupret M. Bladder recurrence after surgery for upper urinary tract urothelial cell carcinoma: frequency, risk factors, and surveillance. Urol Oncol 2009;29:130–6.
Original article
Incidence, characteristics, treatment strategies, and oncologic outcomes of synchronous bilateral upper tract urothelial carcinoma in the Chinese population Dong Fang, M.D.a,1, Gengyan Xiong, M.D.a,1, Xuesong Li, M.D., Ph.D.a,*, Yongming Kang, M.D.a,b, Lei Zhang, M.D.a, Guangzhi Zhao, M.D.a, Xiaopeng Chen, M.D.a,c, Lin Yao, M.D.a, Xiaoyu Zhang, M.D.a, Wei Yu, M.D., Ph.D.a, Kan Gong, M.D., Ph.D.a, Yi Song, M.D., Ph.D.a, Qun He, M.D., Ph.D.a, Zhisong He, M.D., Ph.D.a, Liqun Zhou, M.D., Ph.D.a,*, Yinglu Guo, M.D., Ph.D.a a
Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Centre, Beijing, China b Department of Urology, Suining Central Hospital, Suining, Sichuan, China c Department of Urology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China Received 22 March 2014; received in revised form 3 July 2014; accepted 3 July 2014
Abstract Objectives: To investigate the incidence and treatment strategies for bilateral upper tract urothelial carcinoma (UTUC) and to compare the characteristic and oncologic outcomes of bilateral UTUC with those of unilateral tumors. Methods and materials: The study included 892 consecutive patients with UTUC. Bilateral UTUC was defined as synchronous bilateral carcinoma on preoperative imaging before confirmation by pathology or positive urine cytology result plus direct visualization. Radical nephroureterectomy (RNU) or nephron-sparing surgery (NSS) or both were carried out. Results: A total of 39 patients (4.37%) suffered from bilateral disease. Discordant histological grade of bilateral tumor was found in 39.3% cases. Bilateral tumors were associated with female sex (P o 0.001), preoperative renal insufficiency (P o 0.001), previous or concomitant bladder tumors (P ¼ 0.013), lower tumor stages (P ¼ 0.020), papillary architecture (P ¼ 0.001), and smaller-sized tumors (P ¼ 0.020). Patients with worse renal function (P o 0.001) or large-sized tumors (P ¼ 0.039) tended to be treated with bilateral RNU. Most patients (67.6%) were treated with unilateral RNU plus unilateral NSS, with NSS being performed on tumors that only extended to the ureter (P ¼ 0.003) and had a smaller size (P ¼ 0.005). The median follow-up duration was 56 months. The 5-year cancer-specific survival and bladder recurrence-free survival rates were 81.2% and 64.5%, respectively, similar to those of unilateral tumors. Male sex (hazard ratio ¼ 11.535) and higher tumor stage (hazard ratio ¼ 3.386) were independent worse prognostic factors. Conclusions: The prevalence of bilateral UTUC is rare. Female patients, patients with renal insufficiency, and those with bladder tumor tended to suffer from bilateral disease and were less likely to present with worse pathological outcomes in the Chinese population. The tumor characteristics and renal function were informative in treatment selection. The oncologic outcomes were similar to those in unilateral UTUC, and male sex and a higher tumor stage were poor prognostic factors for these patients. r 2014 Elsevier Inc. All rights reserved.
Keywords: Bilateral; Chronic kidney disease (CKD); Sex; Nephron-sparing surgery (NSS); Radical nephroureterectomy (RNU); Upper tract urothelial carcinoma (UTUC)
1. Introduction 1
These authors contribute equally.
Corresponding authors. Tel.: þ86-10-8357-5101; fax: þ86-10-66551726. E-mail addresses: [email protected], pineneedlelixuesong@gmail. com (X. Li), [email protected] (L. Zhou). *
http://dx.doi.org/10.1016/j.urolonc.2014.07.001 1078-1439/r 2014 Elsevier Inc. All rights reserved.
Upper tract urothelial carcinomas (UTUC) are uncommon and account for only 5% to 10% of urothelial carcinomas [1,2]. Synchronous bilateral UTUC is even rarer. A large Swedish study reported that only 1.6% of
D. Fang et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–11
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Table 1 Clinical and pathological characteristics of bilateral UTUC compared with unilateral tumors All
Patients, no. (%) Preoperative characteristics Sex, no. (%) Male Female Age, no. (%), y o70 Z70 Age, mean ⫾ SD, y Gross hematuria, no. (%) Absent Present Previous or concomitant BT, no. (%) Absent Present Preoperative renal function, no. (%) No CKD (eGFR Z 60) Moderate CKD (60 4 eGFR Z 15) End-stage CKD (eGFR o 15) History of smoking, no. (%) Absent Present Urinary cytology, no. (%) Negative Missing data Positive Postoperative characteristics Architecture, no. (%) Papillary Sessile Tumor stage, no. (%)a Ta–T1 T2 T3–T4 Lymph node status, no. (%) N0 Nx Nþ Tumor grade, no. (%)a G1 G2 G3 Tumor size, mean ⫾ SDa
Presence of UTUC
Univariate analysis
Unilateral
χ2 or Z
Bilateral
892 (100) 853 (95.6)
39 (4.4)
400 (44.8) 393 (46.1) 492 (55.2) 460 (53.9)
7 (17.9) 32 (82.1)
Multivariate analysis
P value HR
95% CI
P value
3.534 (female vs. male)
1.466–8.523
0.005*
0.842 (Z70 vs. o70)
0.427–1.659
0.618
0.991 (present vs. absent)
0.451–2.178
0.982
2.393 (present vs. absent)
1.139–5.026
0.021*
5.192 (end-stage vs. no CKD) 2.477 (end-stage vs. moderate CKD)
1.909–14.120 0.001* 1.039–5.904 0.041*
0.721 (present vs. absent)
0.204–2.547
0.612
1.277 (positive vs. negative) 1.070 (positive vs. missing)
0.511–3.195 0.511–2.243
0.601 0.857
11.926 o0.001*
0.175 497 (55.7) 474 (55.6) 23 (59.0) 395 (44.3) 379 (44.4) 16 (41.0) 66.59 ⫾ 10.57 67.35 ⫾ 7.34 0.047 0.121 227 (25.4) 218 (25.6) 9 (23.1) 665 (74.6) 635 (74.4) 30 (76.9) 6.860 751 (84.2) 724 (84.9) 141 (15.8) 129 (15.1)
0.402
0.962 0.448
0.013*
27 (69.2) 12 (30.8) 18.879 o0.001*
388 (43.5) 379 (44.4) 441 (49.4) 420 (49.2) 63 (7.1)
54 (6.3)
9 (23.1) 21 (53.8) 9 (23.1) 3.108
728 (81.6) 692 (81.1) 164 (18.4) 161 (18.9)
36 (92.3) 3 (7.7)
201 (22.5) 194 (22.7) 316 (35.4) 301 (35.3) 375 (42.0) 358 (42.0)
7 (17.9) 15 (38.5) 17 (43.6)
685 (76.8) 649 (76.1) 192 (21.5) 191 (22.4)
36 (92.3) 1 (2.6)
314 (35.2) 292 (34.2) 297 (33.3) 288 (33.8) 273 (30.6) 265 (31.1)
22 (56.4) 9 (23.1) 8 (20.5)
96 (10.8) 90 (10.6) 760 (85.2) 728 (85.3) 36 (4.0) 35 (4.1)
6 (15.4) 32 (82.1) 1 (2.6)
27 (3.0) 25 (2.9) 505 (56.6) 484 (56.7) 358 (40.1) 342 (40.1) 3.41 ⫾ 2.22
2 (5.1) 21 (53.8) 16 (41.0) 2.54 ⫾ 1.46
0.510
0.051
0.775
8.319
0.001*
7.777
0.020*
1.076
0.584
0.666
0.717
2.323
0.020*
eGFR ¼ estimated glomerular filtration rate; HR ¼ hazard ratio; SD ¼ standard deviation. * Statistically significant. a The higher stage/grade and larger size of bilateral tumors were used for analysis.
UTUC were bilateral [3]. The only commonly accepted shared characteristic of these patients is their renal insufficiency [3–5], and proper treatment measures for bilateral UTUC remain to be elucidated. Radical nephroureterectomy (RNU) with the resection of bladder cuff is the gold standard treatment for UTUC [6];
however, for patients with bilateral UTUC, the resection of both kidneys would lead to the total loss of renal function and inevitable permanent dialysis. Nephron-sparing surgery (NSS), such as segmental ureterectomy or endoscopic management, has been shown to provide a cancer-specific and overall survival (CSS and OS) equivalent to that of
D. Fang et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–11
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Table 2 Clinical and pathological characteristics between different treatment groups All
Treatment group Bilateral RNU
RNU plus NSS
Bilateral NSS
Patients, no. (%)
34 (100)
5 (14.7)
23 (67.6)
6 (17.6)
Sex, no. (%) Male Female
4 (11.8) 30 (88.2)
0 (0) 5 (100)
3 (13.0) 20 (87.0)
1 (16.7) 5 (83.3)
Age, no. (%), y o70 Z70
21 (61.8) 13 (38.2)
3 (60) 2 (40)
13 (56.5) 10 (43.5)
5 (83.3) 1 (16.7)
Required dialysis before surgeries, no. (%) No Yes
29 (85.3) 5 (14.7)
0 (0) 5 (100)
23 (100) 0 (0)
6 (100) 0 (0)
Required dialysis after surgeries, no. (%) No Yes
25 (73.5) 9 (26.5)
0 (0) 5 (100)
19 (82.6) 4 (17.4)
6 (100) 0 (0)
Required dialysis in follow-up, no. (%) No Yes
22 (64.7) 12 (35.3)
0 (0) 5 (100)
16 (69.6) 7 (30.4)
6 (100) 0 (0)
Preoperative renal function, no. (%) No CKD (eGFR Z 60) Moderate CKD (60 4 eGFR Z 15) End-stage CKD (eGFR o 15)
7 (20.6) 19 (55.9) 8 (23.5)
0 (0) 0 (0) 5 (100)
3 (13.0) 17 (73.9) 3 (13.0)
4 (66.7) 2 (33.3) 0 (0)
Previous or concomitant BT, no. (%) Absent Present
25 (73.5) 9 (26.5)
2 (40) 3 (60)
18 (78.3) 5 (21.7)
5 (83.3) 1 (16.7)
Urinary cytology, no. (%) Negative Positive Missing data
8 (23.5) 17 (50.0) 9 (26.5)
0 (0) 1 (20) 4 (80)
6 (26.1) 13 (56.5) 4 (17.4)
2 (33.3) 3 (50.0) 1 (16.7)
Unilateral multifocality, no. (%) Absent Unilateral present Bilateral present
17 (50.0) 11 (32.4) 6 (17.6)
1 (20) 4 (80) 0 (0)
13 (56.5) 6 (26.1) 4 (17.4)
3 (50.0) 1 (16.7) 2 (33.3)
Ureter involvement, no. (%) Absent Unilateral present Bilateral present
10 (29.4) 16 (47.1) 8 (23.5)
2 (40) 2 (40) 1 (20)
7 (30.4) 12 (52.2) 4 (17.4)
1 (16.7) 2 (33.3) 3 (50.0)
Presence of hydronephrosis, no. (%) Absent Unilateral present Bilateral present
13 (38.2) 12 (35.3) 9 (26.5)
1 (20) 2 (40) 2 (40)
9 (39.1) 7 (30.4) 7 (30.4)
3 (50.0) 3 (50.0) 0 (0)
Stage, no. (%)a Ta T1 T2 T3
3 15 9 7
0 1 3 1
Grade, no. (%)a G2 G3
19 (55.9) 15 (44.1)
1 (20) 4 (80)
16 (69.6) 7 (30.4)
2 (33.3) 4 (66.7)
Tumor size, no. (%)a r2 cm 42 cm
13 (38.2) 21 (61.8)
1 (20) 4 (80)
7 (30.4) 16 (69.6)
5 (83.3) 1 (16.7)
(8.8) (44.1) (26.5) (20.6)
(0) (20) (60) (20)
eGFR ¼ estimated glomerular filtration rate. significant. a The higher stage/grade and larger size of bilateral tumors were used for analysis. * Statistically
2 10 6 5
(8.7) (43.5) (26.1) (21.7)
1 4 0 1
χ2 or Z
P value
0.842
0.656
1.456
0.483
34.000
o0.001*
17.023
o0.001*
12.677
0.002*
27.444
o0.001*
3.449
0.178
8.928
0.063
7.059
0.133
3.133
0.536
3.280
0.512
5.986
0.425
5.595
0.061
6.464
0.039*
(16.7) (66.7) (0) (16.7)
D. Fang et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–11
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Table 3 Clinical and pathological characteristics between each lateral group in patients treated with unilateral RNU plus unilateral NSS All
χ2 or Z
Treatment group RNU
NSS
Surgeries, no. (%)
46 (100)
23 (50)
23 (50)
Multifocality, no. (%) No Yes
32 (69.6) 14 (30.4)
14 (60.9) 9 (39.1)
18 (78.3) 5 (21.7)
Side, no. (%) Left Right
23 (50.0) 23 (50.0)
11 (47.8) 12 (52.2)
12 (52.2) 11 (47.8)
Location, no. (%) Ureter Pelvis Pelvis þ ureter
15 (32.6) 25 (54.3) 6 (13.0)
2 (8.7) 17 (73.9) 4 (17.4)
13 (56.5) 8 (34.8) 2 (8.7)
Hydronephrosis, no. (%) No Yes
25 (54.3) 21 (45.7)
12 (52.2) 9 (39.1)
11 (47.8) 10 (43.5)
Stage, no. (%) Ta T1 T2 T3
8 21 9 5
(17.4) (45.7) (19.6) (10.9)
2 (8.7) 12 (52.2) 4 (17.4) 5 (21.7)
6 9 5 0
Grade, no. (%) G1 G2 G3
3 (6.5) 31 (67.4) 9 (19.6)
0 (0) 17 (73.9) 6 (26.1)
3 (13.9) 14 (60.9) 3 (13.9)
2.40 ⫾ 1.32
1.48 ⫾ 0.96
Tumor size, mean ⫾ SD
P value
a
1.643
0.168
0.087
0.500
11.973
0.003*
0.096
0.757
7.366
0.061
4.101
0.129
(26.1) (39.1) (21.7) (0)
2.809
0.005*
SD ¼ standard deviation. * Statistically significant. a Information on the tumor stages and grades of 3 patients was unavailable.
RNU in patients with lower grade or lower stage diseases [7–9] but worse oncologic outcomes in patients with highgrade tumor [10]. Thus, how to determine the proper candidates for NSS remains controversial. Furthermore, there is currently very little knowledge on the potential role of NSS in bilateral UTUC [3,4]. Therefore, in this large single-center cohort of patients, we sought to validate the incidence and any clinical features that might help practitioners to discover the presence of bilateral tumors. We also investigated the pathological characteristics that might assist in the research of mechanisms for multiple urothelial tumors, in the treatment selection for these patients, and in survival outcomes that might help to improve risk stratification.
2. Methods 2.1. Patient selection Following institutional review board approval, we initially collected the clinicopathological data of 912 consecutive patients with UTUC who received treatment in the
Department of Urology, Peking University First Hospital from 2000 to 2012. For all patients, bilateral upper urinary tract was evaluated before surgery. We defined synchronous bilateral UTUC as bilateral urothelial carcinoma on preoperative imaging and confirmed the finding using pathology or positive urine cytology finding plus the direct visualization of the tumors by endoscopy or conclusive image studies. We excluded 20 patients who had undergone previous surgeries for UTUC or solitary kidneys, leaving 892 patients for the final analysis. We also excluded 56 patients who were lost to follow-up in survival analysis. 2.2. Treatment All patients underwent surgery within 3 months after their symptoms began to occur. The surgery measures considered in both unilateral and bilateral UTUCs consisted of RNU (open or laparoscopic) and NSS (segmental ureterectomy, endoscopic ablation, and open renal pelvis tumor resection). For bilateral UTUC, the treatment measures were judged by the patient's surgeon and performed after obtaining the patient's consent, and bilateral surgeries were carried out simultaneously or separately within
D. Fang et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–11
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Fig. 1. Estimated Kaplan-Meier cancer-specific survival curves stratified by sex (A) (P o 0.001) and tumor stage (B) (P ¼ 0.006). (Color version of figure is available online.)
6 months. None of these patients received neoadjuvant chemotherapy or prophylactic postoperative intravesical instillation chemotherapy. 2.3. Patients evaluation The estimated glomerular filtration rate was calculated using the modified glomerular filtration rate–estimating equation for the Chinese patients: estimated glomerular filtration rate (ml/min/1.73 m2) = 175 Scr1.234 age0.179 ( 0.79 if female) [11]. The tumor stage was assessed according to the 2002 Union for International Cancer Control TNM classification. Tumor grading was performed according to the World Health Organization's classification of 1973. The tumor's architecture was defined as papillary or sessile after examining the final specimen. 2.4. Follow-up schedule For the patients who were followed at our institute, the follow-up regimen of the affected patients included cystoscopy every 3 months for the first 2 years. The cystoscopy intervals were extended to 1 year thereafter. Chest x-rays, serum creatine level, and abdominal ultrasound or computed tomography/magnetic resonance imaging were assessed at the same time. We defined recurrence as discovering urothelial cancer in the remnant urinary tract (e.g., bladder, contralateral ureter
or pelvis, or remnant ureter) or operative site, and bladder recurrence as finding a subsequent bladder tumor (BT) during cystoscopy and confirmed by pathology. The cause of death was determined by the patients' treating physicians or by death certificates. Follow-ups were censored until their last visit or death. 2.5. Statistical analysis All statistical tests were performed with SPSS 20.0 (IBM Corp, Armonk, NY), and statistical significance was set at P o 0.05. The Pearson test and chi-square test were used to examine the distribution of categorical variables, and the Mann-Whitney U test was used for continuous variables. Multivariate logistic regression was used to calculated the predictive factors. Univariable analysis using the log-rank test and multivariable analysis using the Cox proportional hazards regression model were used. 3. Results 3.1. Incidence and clinical characteristics Of the 892 patients with UTUC, 39 suffered from bilateral disease (4.37%). The median age was 68 years (range: 48–82), with 7 male and 32 female patients. Of the 39 patients, 7 (17.9%) had previous BT, including 1 patient with a previous total cystectomy; 7 exhibited concomitant
D. Fang et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–11
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Table 4 Univariable and multivariable analyses of predictive factors for worse overall survival and cancer-specific survival Variables
Overall mortality Pts (events), no. (no.)
Univariable analysis P value o0.001*
Sex Female Male Age, y o70 Z70 Preoperative renal function No CKD (eGFR Z 60) Moderate CKD (60 4 eGFR Z 15) End-stage CKD (eGFR o 15) Previous or concomitant BT Absent Present Presence of hydronephrosis Absent Unilateral present Bilateral present Surgical approach Bilateral RNU Unilateral RNU Bilateral NSS Only unilateral surgery Adjuvant therapy No Yes Ureter involvement Absent Unilateral present Bilateral present Unilateral multifocality Absent Unilateral present Bilateral present Tumor stagea Ta T1 T2 T3 Lymph node status N0 Nx Nþ Tumor gradea G1–2 G3 Tumor sizea r2 cm 42 cm
Cancer-specific mortality Multivariable analysis HR
95% CI
Pts (events), no. (no.)
P value
35.389 3.850– 0.002* 325.272
31 (6) 7 (4) 0.332
HR
o0.001*
11.535 1.058–125.768 0.045*
95% CI
P value
0.095 22 (6) 16 (2)
0.021*
0.073
0.046*
9 (2) 20 (3)
9 (2) 20 (2)
9 (5)
9 (4) 0.082
0.107
0.093
26 (4) 12 (6)
26 (3) 12 (5) 0.259
0.374
15 (1) 14 (6) 9 (3)
15 (1) 14 (4) 9 (3) 0.474
0.554
(2) (6) (0) (2)
5 22 6 5
(2) (5) (0) (1)
0.741
0.608
35 (9) 3 (1)
35 (7) 3 (1) 0.754
0.958
11 (2) 17 (6) 10 (2)
11 (2) 17 (4) 10 (2) 0.219
0.148
19 (7) 13 (2) 6 (1)
19 (6) 13 (1) 6 (1) 0.026*
4 18 9 7
Multivariable analysis
31 (5) 7 (3)
22 (6) 16 (4)
5 22 6 5
Univariable analysis P value
0.127
(0) (4) (3) (3)
0.006* 4 18 9 7
0.771 5 (2) 32 (8) 1 (0)
3.386 1.073–10.684
0.038*
(0) (2) (3) (3) 0.580
5 (2) 32 (6) 1 (0) 0.687
22 (6) 16 (4)
0.862 22 (4) 16 (4)
0.195 16 (3) 22 (7)
eGFR ¼ estimated glomerular filtration rate; HR ¼ hazard ratio; Pts ¼ patients. * Statistically significant. a The higher stage/grade and larger size of the bilateral tumors were used for analysis.
0.030* 16 (1) 22 (7)
0.236
D. Fang et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–11
BT; and 2 (5.1%) had both previous and current BT. A total of 15 patients had taken Chinese herbs containing aristolochic acid (AA) for at least 6 months; 5 patients denied of the consumption of herbs, and the remainder could not provide information about what kind or how much of the herb(s) they had taken. Overall, 30 patients (76.9%) initially presented with gross hematuria, 8 patients complained of flank or abdominal pain, and 1 patient was diagnosed during a routine ultrasound examination. All of these patients were diagnosed using CT and ultrasound. Some patients underwent other relevant examinations: ureteroscopy (altogether 21 patients underwent ureteroscopy), intravenous urography (18 patients), retrograde pyelogram (17 patients), nuclear renal scan (to get split renal function, 16 patients), magnetic resonance imaging (9 patients), and selected ureter washing urinary cytology (8 patients). Bilateral renal pelvic tumors were found in 12 patients (30.8%), and bilateral ureter tumors in 6 (15.4%). Moreover, 11 had renal pelvic and contralateral ureteral tumors, and the remaining 10 patients had both ureter and pelvic tumors in the unilateral upper urinary tract. For 28 patients with complete information on bilateral tumor histological grade, discordant grade was found in 11 patients (39.3%). The clinical and pathological characteristics, according to bilateral UTUC vs. unilateral UTUC, are shown in Table 1. Patients with bilateral UTUC tended to be female (P o 0.001), to have worse preoperative renal function (P o 0.001), and to have had previous or concomitant BT (P ¼ 0.013). Additionally, their pathological outcomes tended to involve a lower tumor stage (P ¼ 0.020), papillary architecture (P ¼ 0.001), and a smaller tumor size (P ¼ 0.020). Patients with bilateral tumors had a higher proportion of end-stage renal disease (ESRD) (23.1% vs. 6.3%). In multivariate logistic regression, after controlling for clinical factors, female sex, previous or concomitant BT, and renal insufficiency were each significantly related to bilateral UTUC.
3.2. Treatment strategies There were 5 patients who only received unilateral treatment (1 case of RNU, 1 case of pelvis tumor resection, and 3 cases of endoscopic ablation) because they refused any further surgery on the contralateral tumor (the primary algorithms were contralateral RNU). These cases were excluded from analysis for the treatment strategies. Bilateral RNU was performed in 5 patients. Overall, 23 patients underwent unilateral RNU plus unilateral NSS, including 8 cases of segmental ureterectomy, 11 cases of endoscopic ablation, and 4 cases of open pelvis tumor resection. Moreover, 6 patients underwent bilateral NSS, including the 3 types of aforementioned operations. For the concomitant BT, 6 patients were treated with transurethral resection and 1 with total cystectomy.
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Comparing the clinical and pathological features of each treatment group, patients with ESRD (P o 0.001) and large-sized tumors (P ¼ 0.039) tended to be treated with bilateral RNU (Table 2). In 23 patients (67.6%), we performed unilateral RNU plus unilateral NSS, although in 3 patients we tried to perform bilateral RNU but the patients refused. Comparing the characteristics of RNU specimens and NSS specimens, we found that the tumors that only involved the ureter (P ¼ 0.003) and were smaller (P ¼ 0.005) tended to be treated with NSS, whereas unilateral radical surgery was suitable for both the renal pelvis and ureter-involved tumors (Table 3). Besides, in 3 patients, diagnostic ureteroscopy biopsy results were considered (data not shown). 3.3. Oncologic outcomes The median follow-up duration of this cohort of patients was 56 (15–155) months. Among the patients followed, 1 was lost to follow-up. Overall, 10 patients (26.3%) died, 8 of whom (21.1%) died of urothelial cancer. The 2- and 5year OS rates were 94.6% and 78.1%, respectively, with CSS rates of 94.6% and 81.2%, respectively. By multivariable analysis, male sex was the only risk factor for worse OS, whereas male sex (hazard ratio ¼ 11.535) and higher tumor stage (hazard ratio ¼ 3.386) independently predicted worse CSS (Fig. 1 and Table 4). Rerunning the data set by excluding those patients with only unilateral treatment had no effect on the result. Disease recurrence occurred in 14 patients (36.8%). Among them, 1 patient treated with unilateral RNU and contralateral segmental ureterectomy experienced a ureter recurrence after 23 months, and 1 patient treated with unilateral RNU and contralateral endoscopic pelvis tumor ablation experienced a local recurrence after 5 months. We performed salvage RNU on these patients. The remaining 12 recurrences were all found in the bladder (31.6%) and were treated with transurethral resection or cystectomy. The 5year probabilities of being free from recurrence and of bladder recurrence were 61.3% and 64.5%, respectively. No parameter had a statistically significant effect on any recurrence-free or bladder recurrence-free survival (Table 5). The oncologic outcomes for patients with unilateral UTUC are shown in Table 6. No difference between unilateral and bilateral UTUCs in OS, CSS, any recurrence or bladder recurrence (Fig. 2) was found using the log-rank test or after adjusting for tumor stage. 4. Discussion In our cohort of patients with UTUC, the incidence of synchronous bilateral disease was 4.37%, slightly higher than the values of previous reports [3]. Holmang and Johansson [3] found that, owing to the prohibition of phenacetin-containing analgesics, the incidence of bilateral
D. Fang et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–11
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Table 5 Univariable and multivariable analyses of predictive factors for any recurrence and bladder recurrence Variables
Pts (events), no. (no.) Sex Female Male Age, y o70 Z70 Preoperative renal function No CKD (eGFR Z 60) Moderate CKD (60 4 eGFR Z 15) End-stage CKD (eGFR o 15) Previous or concomitant BT Absent Present Presence of hydronephrosis Absent Unilateral present Bilateral present Surgical approach Bilateral RNU Unilateral RNU Bilateral NSS Only unilateral surgery Adjuvant therapy No Yes Ureter involvement Absent Unilateral present Bilateral present Unilateral multifocality Absent Unilateral present Bilateral present Tumor stageb Ta T1 T2 T3 Lymph node status N0 Nx Nþ Tumor gradeb G1–2 G3 Tumor sizeb r2 cm 42 cm
Bladder recurrencea
Any recurrence P value
Pts (events), no. (no.)
0.384 31 (11) 7 (3)
0.291 29 (9) 7 (3)
0.455 22 (9) 15 (5)
0.851 21 (7) 15 (5)
0.819 9 (3) 20 (7) 9 (4)
0.987 9 (3) 20 (7) 7 (2)
0.987 26 (10) 12 (4)
0.416 26 (8) 10 (4)
0.629 15 (7) 14 (4) 9 (3)
0.276 14 (7) 14 (3) 8 (2)
0.398 5 22 6 5
(1) (11) (1) (1)
0.742 3 22 6 5
(1) (9) (1) (1)
0.906 35 (13) 3 (1)
0.995 33 (11) 3 (1)
0.890 11 (5) 17 (6) 10 (3)
0.996 11 (4) 15 (5) 10 (3)
0.138 19 (9) 13 (2) 6 (3)
0.272 19 (7) 11 (2) 6 (3)
0.071 4 18 9 7
P value
(3) (4) (3) (4)
0.078 4 18 7 7
(3) (3) (3) (3)
0.806 5 (2) 32 (12) 1 (0)
0.593 4 (2) 31 (10) 1 (0)
0.485 22 (9) 16 (5)
0.670 21 (7) 15 (5)
0.527 16 (5) 22 (9)
0.957 15 (5) 21 (7)
eGFR ¼ estimated glomerular filtration rate; Pts ¼ patients. A patient with previous cystectomy and 1 patient with synchronous cystectomy were excluded. b The higher stage/grade and larger size of the bilateral tumors were used for analysis. a
tumors has gradually decreased in the past several decades. Considering that the most commonly reported risk factor for Chinese patients with UTUC is the consumption of AAcontaining herbs [12–14]; this prevalence might be different from that in Western countries. The present patients with bilateral UTUC were characterized by the presence of previous concomitant BT, similar to Holmang's research
[3], and a recent article found that a previous history of non–muscle-invasive BT was significantly associated with tumor multifocality and recurrence [15]. Contrary to the Swedish study [3], female patients tended to suffer from bilateral UTUC. Female sex was regarded as a risk factor for contralateral recurrence in a Taiwanese report [16]; this sex difference among Chinese
D. Fang et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–11
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Table 6 Comparison of the follow-up results for patients with unilateral UTUC and bilateral UTUCa Pts (events), no. (no.)
Overall mortality Unilateral Bilateral Cancer-specific mortality Unilateral Bilateral Any recurrence Unilateral Bilateral Bladder recurrenceb Unilateral Bilateral
Univariable analysis
Adjusted for tumor stage
P value
HR
95% CI
P value
0.108
0.889
0.469–1.685
0.718
0.089
0.843
0.413–1.720
0.638
0.805
1.026
0.593–1.773
0.927
0.776
1.036
0.575–1.867
0.907
798 (255) 38 (10) 798 (223) 38 (8) 798 (242) 38 (14) 792 (219) 36 (12)
HR ¼ hazard ratio; Pts ¼ patients. Patients without follow-up data were excluded. b Patients with previous cystectomy or synchronous cystectomy were excluded. a
patients with UTUC might be unique. Moreover, although not to a major extent, male patients encountered a worse prognosis after treatment. The predictive role of sex on the pathological outcomes or prognosis remains controversial. Studies in the Surveillance Epidemiology and End Results database found that females tended to have higher tumor stage and grade [17], whereas male sex was predictive for muscle-invasive and non–organ-confined UTUC in our previous research [18,19]. It is difficult to explain this discord. The use of AA-containing Chinese herbs in China is common, especially among females. We believe that the
distribution and prognostic differences in the sexes may be attributable to the mechanisms behind AA-induced carcinoma. Chronic kidney disease (CKD) was prevalent in patients with bilateral UTUC and was most likely related to the mechanisms of tumor multifocality. The field cancerization hypothesis [20,21] might play a more important role in the development of bilateral UTUC. Chinese herbal nephropathy might introduce nephrotoxic and carcinogenic toxins into the system, inducing neoplasms within the entire urothelial field [12,22]. Our previous research found that
Fig. 2. Estimated Kaplan-Meier cancer-specific survival curves (A) (P ¼ 0.089) and bladder recurrence-free survival curves (B) (P ¼ 0.776) stratified by unilateral vs. bilateral UTUC. (Color version of figure is available online.)
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D. Fang et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–11
the rate of renal insufficiency was higher in patients with multifocality [19], and other previous reports found that CKD was related to an increased risk of urothelial cancer [23] and bladder recurrence after RNU [16,24]. On the contrary, CKD also affected treatment options. For patients with ESRD or patients already requiring dialysis, NSS did not help to preserve their renal function. Rather, bilateral radical surgery and renal replacement therapy afterward are preferred [4,5]. Moreover, our previous research has demonstrated that even for patients with unilateral UTUC, renal insufficiency is a risk factor for contralateral recurrence after RNU; therefore, prophylactic contralateral RNU is a reasonable choice [25]. NSS has gained popularity in the treatment of UTUC over the years. The present limited ability to predict tumor stage and grade accurately before surgery makes it difficult to select proper surgeries for bilateral UTUC. For instance, a casual bilateral NSS might not thoroughly resect a potentially advanced tumor. In our practice, we performed unilateral RNU of the dominant side plus contralateral NSS on most patients. The following factors are informative in evaluating which is the dominant side: (1) tumor size, as it is related to the CSS and recurrence-free survival [26–28] and was easy to evaluate using preoperative CT films; (2) the multifocality and location of tumors, as it is technically easy to cure a solitary ureteral tumor by NSS, especially in partial ureterectomy; and (3) in several cases, the ureteroscopy results, which could first be performed simultaneously on both sides to ensure that the biopsy result is more informative. The recurrence and death rates of the patients undergoing NSS were similar to those of the bilateral RNU group, and most patients benefitted from NSS by avoiding dialysis, indicating that NSS was associated with superior postoperative renal function [29]. Most likely owing to the limited sample size, several well-established risk factors had no effect on survival or bladder recurrence. Moreover, we found no significant difference between unilateral and bilateral UTUCs in survival or recurrence rates, especially after adjusting for the tumor stage. Because all patients with bilateral UTUC suffered from “multiple” tumors, this cohort of patients should have experienced a high rate of bladder recurrence [30]. Our result might be biased by the limited sample size and short follow-up interval, but we are unsure whether a greater tumor burden would have affected the cancer control result. The limitations of this study include its retrospective design and data collection, which did not allow us to evaluate some of the potentially useful variables, especially the consumption of Chinese herbs, and our study cohort might have been subject to selection and recall bias. Lack of percutaneous management was another limitation. Additionally, indications for the surgical approach were not standardized and were based on the clinical judgment of the treating physician, after discussing possible treatment options and expectations with the patient. Some patients'
refusal for RNU and dialysis affected the treatment strategies. Despite these limitations, our research provides the highest known prevalence of bilateral UTUC and also constitutes the first Asian report. Ours is the first study to analyze the clinical features and treatment measures of this cohort of patients, and we have provided the first results on the oncologic outcomes of this cohort of patients and described their worst predictive factors. Future studies on molecular research would be required to elucidate the mechanisms for the development of bilateral tumors and their relationship with AA.
5. Conclusions The prevalence of bilateral UTUC is rare. Female patients, patients with renal insufficiency, and those with BT tended to suffer from bilateral disease and were less likely to present with worse pathological outcomes in the Chinese population. The tumor characteristics and renal function are informative for decisions concerning treatment strategies. Oncologic outcomes were similar to those of unilateral UTUC, and male sex and higher tumor stage are poor prognostic factors for these patients. Prospective multiinstitutional studies and molecular research are required in the future. Acknowledgment The authors thank the entire staff of the Department of Urology, Peking University First Hospital. References [1] Munoz JJ, Ellison LM. Upper tract urothelial neoplasms: incidence and survival during the last 2 decades. J Urol 2000;164:1523–5. [2] Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin 1998;48:6–29. [3] Holmang S, Johansson SL. Synchronous bilateral ureteral and renal pelvic carcinomas: incidence, etiology, treatment and outcome. Cancer 2004;101:741–7. [4] Kang CH, Yu TJ, Hsieh HH, Yang JW, Shu K, Shiue YL. Synchronous bilateral primary transitional cell carcinoma of the upper urinary tracts: ten patients with more than five years of follow-up. Urology 2004;63:380–2. [5] Tai HC, Lai MK, Chung SD, Huang KH, Chueh SC, Yu HJ. Intermediate-term oncological outcomes of hand-assisted laparoscopic versus open bilateral nephroureterectomy for dialysis and kidney transplant patients with upper urinary tract urothelial carcinoma. J Endourol 2009;23:1139–44. [6] Cummings KB. Nephroureterectomy: rationale in the management of transitional cell carcinoma of the upper urinary tract. Urol Clin North Am 1980;7:569–78. [7] Colin P, Ouzzane A, Pignot G, et al. Comparison of oncological outcomes after segmental ureterectomy or radical nephroureterectomy in urothelial carcinomas of the upper urinary tract: results from a large French multicentre study. BJU Int 2012;110:1134–41.
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