Abstract
Objective
Clinical features of upper tract urothelial carcinoma (UTUC) vary widely across countries. We aimed to provide clinical observations and compare oncological outcomes among regions in East Asia and Europe.
Methods
This retrospective study (March 2000 to July 2020) included 664 UTUC patients undergoing radical nephroureterectomy in China, Japan, the Republic of Korea, and Germany. Cohorts from China comprised patients from the Hong Kong Special Administrative Region and the Taiwan region, respectively. Demographic and clinicopathological parameters were analyzed. Continuous variables were analyzed using the Student's t-test, and categorical variables were assessed using the Pearson's chi-square test. The Cox proportional hazards model was employed to evaluate overall survival (OS), cancer-specific survival (CSS), and bladder recurrence-free survival across regions and various parameters.
Results
Females had a higher proportion of patients than males only in Taiwan, China. Few patients received preoperative ureteroscopic biopsy prior to radical surgery in Seoul, the Republic of Korea. In the multivariate analysis, patients' regional origin was not associated with worse OS and CSS. Older age, multifocal tumors, high pT stage (pT4), positive lymphovascular invasion, and distant metastasis were associated with worse OS. High pT stage (pT4) and distant metastasis were independent factors leading to worse CSS. Patients' regional origin (Seoul, the Republic of Korea; Schleswig-Holstein, Germany; and Chiba, Japan) was associated with worse bladder recurrence-free survival. The preoperative ureteroscopic biopsy did not increase the intravesical recurrence.
Conclusion
This international observational study revealed variations in the epidemiological distributions and practice patterns among UTUC patients in China, Japan, the Republic of Korea, and Germany. Cohorts from China comprised patients from the Hong Kong Special Administrative Region and the Taiwan region, respectively. However, ethnic and regional differences did not affect OS and CSS after radical nephroureterectomy.
Keywords: Upper tract urothelial cancer, Survival, Prognostic factors, Ethnicity, Ureteroscopy, Nephroureterectomy, Epidemiology
1. Introduction
Upper tract urothelial carcinoma (UTUC) is an uncommon and aggressive urological malignancy, accounting for only 5%–10% of all urothelial carcinomas (UCs) [1]. In Western countries, males generally exhibit higher UTUC incidence rates than females. In the Taiwan region of China, however, UTUC shows relatively high prevalence with a female predominance [2]. Moreover, in contrast to the low proportion of UTUC among UCs in most regions, the proportion of UTUC in the Taiwan region of China is up to 40% of all UCs, with a male-to-female age-standardized incidence rate ratio of UTUC of 0.95:1 [2]. Additionally, the pattern of cancer presentation differs from that reported in Western countries. For example, in the Taiwan region of China, a greater proportion of ureteric UTUC has been reported [3]. Previous studies have attributed these unusual epidemiological features to specific carcinogenic exposures, including arsenic and aristolochic acid (AA) [4,5]. The consumption of arsenic-contaminated artesian well water and the use of Chinese medicine potentially containing AA may have been associated with this phenomenon in the past few decades [4,5]. However, the Taiwan region of China still had a higher incidence of UTUC after the installation of a municipal water supply and forbidding the usage of AA in Chinese medicine [2]. The latency period of carcinogen-related etiologies may contribute to the current high incidence of UTUC in the Taiwan region of China, but underlying mechanisms remain unclear. Whether other sex-specific, geographic, and ethnic characteristics are associated with different epidemiological presentations is still to be elucidated.
Previous literature has compared clinical characteristics and oncologic outcomes of UTUC between China and the United States (U.S.) [6], among different regions in Asia [2], and among different Asian ethnic groups in North America [7]. However, the data comparing clinical and oncological features among multiple Asian populations are still limited. In the present study, we aimed to provide a further clinical observational review and comparison of oncological outcomes in populations from East Asia, including China (with data from the Taiwan region and Hong Kong Special Administrative Region), Japan, and the Republic of Korea. We also aimed to compare these features with those of Western European populations.
2. Patients and methods
This retrospective study included 664 patients with UTUC from five hospitals (Kaohsiung Medical University Hospital; Taipei Veterans General Hospital; The Jikei University School of Medicine, Kashiwa Hospital; Seoul National University Hospital; and University Hospital Schleswig-Holstein) in four countries (China, Japan, the Republic of Korea, and Germany) who underwent radical nephroureterectomy (RNU) with bladder cuff excision from March 2000 to July 2020. Cohorts from China comprised patients from the Hong Kong Special Administrative Region and the Taiwan region, respectively. Demographic and clinicopathological parameters, including sex, age, body mass index (BMI), smoking status, tumor location, simultaneous bladder cancer (BCa), BCa history, preoperative hydronephrosis, tumor multifocality, preoperative diagnostic ureteroscopic (URS) biopsy, preoperative urine cytology, the American Society of Anesthesiologists score, pT stage, tumor grade, lymphovascular invasion (LVI), lymph node dissection, tumor margin, adjuvant systemic chemotherapy, contralateral recurrence, and distant metastasis, were recorded. All tumor specimens were graded according to the 2004 World Health Organization/International Society of Urologic Pathology consensus classification [8] and staging was performed according to the 2017 Tumor, Node, Metastasis classification [9]. The oncological outcomes after RNU observed in the present study were overall survival (OS), cancer-specific survival (CSS), defined as the duration from the date of diagnosis until death due to UTUC, and bladder recurrence-free survival (BRFS), defined as survival without UC recurrence in the bladder, within 5 years. This study was approved by the institutional review board of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20180214). The need for consent was waived by the review board due to the retrospective nature of the study.
Demographic and clinicopathological parameters were compared using Student's t-test for continuous variables, which were reported as mean±standard deviation. For categorical variables, which were presented as percentages, Pearson's chi-square test was used. Using the Cox proportional hazards model, we evaluated OS, CSS, and BRFS between regions and various parameters. The log-rank test was used to compare survival curves. A p-value less than 0.05 was considered statistically significant in all statistical assessments. Statistical analyses were performed using SPSS version 22.0 for Windows (IBM Corp, Armonk, NY, USA).
3. Results
In total, we identified 664 patients with UTUC, including 219 from Taiwan, China and 127 from Hong Kong, China; 145 from Chiba, Japan; 108 from Seoul, the Republic of Korea; and 65 from Schleswig-Holstein, Germany. Table 1 shows the comparison of clinicopathological characteristics of the patients in five cohorts. For sex distribution, females had a higher proportion than males only in the Taiwan region of China (52% vs. 48%, p<0.001). Patients in Chiba, Japan had the lowest mean BMI (22.18 kg/m2, p<0.001). Patients in the Taiwan region of China had the lowest smoking history rate (11%, p<0.001), but the highest preoperative hydronephrosis rate (71%, p<0.001). The patients from Schleswig-Holstein, Germany were the youngest (with a mean age of 57.42 years old, p<0.001), with the lowest proportion of patients presenting preoperative hydronephrosis (25%, p<0.001), the highest proportion of patients with a history of bladder UC (25%, p=0.016), and the highest proportion of patients with contralateral recurrence (11%, p<0.001). Few patients underwent preoperative URS biopsy before radical surgery in Seoul, the Republic of Korea (1.9%, p<0.001). In addition, the highest proportion of patients in Seoul, the Republic of Korea had simultaneous bladder tumors (23%, p=0.008) and postoperative adjuvant chemotherapy (14%, p=0.001) among the five cohorts.
Table 1.
Demographics and clinicopathological characteristics.
| Characteristic | Total (n=664) | Taiwan, China (n=219) | Hong Kong, China (n=127) | Chiba, Japan (n=145) | Seoul, the Republic of Korea (n=108) | Schleswig-Holstein, Germany (n=65) | p-Value |
|---|---|---|---|---|---|---|---|
| Sex | <0.001 | ||||||
| Female | 251 | 113 (52) | 42 (33) | 42 (29) | 36 (33) | 18 (28) | |
| Male | 413 | 106 (48) | 85 (67) | 103 (71) | 72 (67) | 47 (72) | |
| Age, year | 664 | 68.85±9.78 | 68.61±8.95 | 72.83±9.57 | 67.17±8.95 | 57.42±1.83 | <0.001 |
| BMI, kg/m2 | 664 | 24.68±3.78 | 24.57±5.47 | 22.18±3.88 | 24.70±2.95 | 26.53±4.47 | <0.001 |
| Follow-up, year | 664 | 2.66±2.50 | 5.01±4.45 | 2.20±1.60 | 2.75±1.03 | 0.76±1.18 | <0.001 |
| Smoking | <0.001 | ||||||
| No | 403 | 195 (89) | 53 (48) | 60 (41) | 51 (47) | 44 (68) | |
| Yes | 244 | 24 (11) | 57 (52) | 85 (59) | 57 (53) | 21 (32) | |
| Tumor location | 0.12 | ||||||
| Renal pelvis | 364 | 127 (58) | 65 (51) | 82 (57) | 49 (45) | 41 (63) | |
| Ureter | 300 | 92 (42) | 62 (49) | 63 (43) | 59 (55) | 24 (37) | |
| Tumor side | 0.5 | ||||||
| Left | 343 | 115 (54) | 64 (50) | 67 (46) | 60 (56) | 37 (57) | |
| Right | 316 | 99 (46) | 63 (50) | 78 (54) | 48 (44) | 28 (43) | |
| History of bladder UC | 0.016 | ||||||
| No | 574 | 192 (88) | 117 (92) | 127 (88) | 89 (82) | 49 (75) | |
| Yes | 90 | 27 (12) | 10 (7.9) | 18 (12) | 19 (18) | 16 (25) | |
| Simultaneous bladder tumor | 0.008 | ||||||
| No | 574 | 194 (89) | 116 (91) | 128 (88) | 83 (77) | 53 (82) | |
| Yes | 90 | 25 (11) | 11 (8.7) | 17 (12) | 25 (23) | 12 (18) | |
| Hydronephrosis | <0.001 | ||||||
| No | 304 | 61 (29) | 72 (57) | 74 (51) | 48 (44) | 49 (75) | |
| Yes | 354 | 153 (71) | 54 (43) | 71 (49) | 60 (56) | 16 (25) | |
| Multifocal | 0.15 | ||||||
| No | 557 | 187 (85) | 103 (81) | 128 (88) | 90 (83) | 49 (75) | |
| Yes | 107 | 32 (15) | 24 (19) | 17 (12) | 18 (17) | 16 (25) | |
| URS biopsy | <0.001 | ||||||
| No | 277 | 56 (26) | 20 (16) | 75 (52) | 106 (98) | 20 (31) | |
| Yes | 387 | 163 (74) | 107 (84) | 70 (48) | 2 (1.9) | 45 (69) | |
| Preoperative urine cytology | <0.001 | ||||||
| Negative | 132 | 32 (15) | 23 (18) | 6 (4.1) | 58 (54) | 13 (20) | |
| Dysplasia | 165 | 35 (16) | 71 (56) | 51 (35) | 0 (0) | 8 (12) | |
| Suspicious | 130 | 30 (14) | 19 (15) | 34 (23) | 43 (40) | 4 (6.2) | |
| Highly suspicious | 56 | 37 (17) | 0 (0) | 17 (12) | 0 (0) | 2 (3.1) | |
| Positive | 88 | 46 (21) | 2 (1.6) | 30 (21) | 7 (6.5) | 3 (4.6) | |
| Nota | 93 | 39 (18) | 12 (9.4) | 7 (4.8) | 0 (0) | 35 (54) | |
| ASA score | <0.001 | ||||||
| 1 | 84 | 0 (0) | 25 (20) | 36 (25) | 22 (20) | 1 (1.6) | |
| 2 | 309 | 60 (28) | 59 (46) | 91 (63) | 79 (73) | 20 (33) | |
| ≥3 | 261 | 153 (72) | 43 (34) | 18 (12) | 7 (6.5) | 40 (66) | |
| pT | <0.001 | ||||||
| Ta | 142 | 39 (18) | 21 (17) | 38 (27) | 30 (28) | 14 (22) | |
| T1 | 152 | 55 (25) | 22 (18) | 31 (22) | 31 (29) | 13 (20) | |
| T2 | 160 | 43 (20) | 79 (65) | 13 (9.2) | 19 (18) | 6 (9.2) | |
| T3 | 169 | 68 (31) | 0 (0) | 49 (35) | 28 (26) | 24 (37) | |
| T4 | 33 | 14 (6.4) | 0 (0) | 11 (7.7) | 0 (0) | 8 (12) | |
| Tumor grade | <0.001 | ||||||
| 1 | 93 | 37 (17) | 17 (15) | 14 (9.9) | 20 (19) | 5 (7.7) | |
| 2 | 115 | 0 (0) | 37 (33) | 50 (35) | 0 (0) | 28 (43) | |
| 3 | 436 | 180 (83) | 58 (52) | 78 (55) | 88 (81) | 32 (49) | |
| LVI | 0.6 | ||||||
| No | 550 | 181 (83) | 105 (83) | 116 (80) | 95 (88) | 53 (82) | |
| Yes | 114 | 38 (17) | 22 (17) | 29 (20) | 13 (12) | 12 (18) | |
| LN dissection | <0.001 | ||||||
| No | 481 | 158 (72) | 120 (94) | 78 (54) | 84 (78) | 41 (63) | |
| Yes | 183 | 61 (28) | 7 (5.5) | 67 (46) | 24 (22) | 24 (34) | |
| Margin | 0.001 | ||||||
| Free | 628 | 208 (95) | 125 (98) | 136 (94) | 105 (97) | 54 (83) | |
| Positive | 36 | 11 (5.0) | 2 (1.6) | 9 (6.2) | 3 (2.8) | 11 (17) | |
| Adjuvant systemic chemotherapy | 0.001 | ||||||
| No | 628 | 215 (98) | 123 (97) | 138 (95) | 93 (86) | 59 (91) | |
| Yes | 36 | 4 (1.8) | 4 (3.1) | 7 (4.8) | 15 (14) | 6 (9.2) | |
| Contralateral recurrence | <0.001 | ||||||
| No | 648 | 212 (97) | 126 (99) | 145 (100) | 107 (99) | 58 (89) | |
| Yes | 16 | 7 (3.2) | 1 (0.8) | 0 (0) | 1 (0.9) | 7 (11) | |
| Distant metastasis | 0.5 | ||||||
| No | 522 | 178 (81) | 97 (76) | 108 (74) | 86 (80) | 53 (82) | |
| Yes | 142 | 41 (19) | 30 (24) | 37 (26) | 22 (20) | 12 (18) | |
ASA, American Society of Anesthesiologists; BMI, body mass index; LN, lymph node; LVI, lymphovascular invasion; UC, urothelial carcinoma; URS, ureteroscopic.
Note: the data are presented as n, n (%), or mean±standard deviation; the percentages may not add up to 100% due to rounding; discrepancies between the total and the sum of individual variables are attributable to missing data.
“Not” indicates that cytology was not obtained and therefore the data were missing.
3.1. OS
In the univariate analysis (Supplementary Table 1), worse OS was associated with older age, multifocal tumors, higher pT stage (pT2–4), higher tumor grade, positive LVI, lymph node dissection, positive surgical margin, and distant metastasis. Patients from Seoul, the Republic of Korea had better OS. In the multivariate stepwise analysis (Table 2), patients' regional origin was not associated with worse OS. Older age, multifocal tumors, higher pT stage (pT4), positive LVI, and distant metastasis were identified as independent prognostic factors for worse OS (adjusted hazard ratio [AHR]: 1.04, p=0.005; AHR: 2.35, p<0.001; AHR: 3.57, p=0.018; AHR: 1.93, p=0.007; AHR: 6.52, p<0.001, respectively). Upon comparison of the Kaplan–Meier curves using the log-rank test, a significant difference in OS was observed among regions (p<0.001, Fig. 1A). Among the regions analyzed, the 5-year OS rate was the highest in Seoul, the Republic of Korea at 92.6%, while the Hong Kong Special Administrative Region of China exhibited the lowest OS rate at 70.1%. In addition, the 5-year OS rates in Taiwan, China, Chiba, Japan, and Schleswig-Holstein, Germany were 83.6%, 84.1%, and 92.3%, respectively.
Table 2.
Comparative multivariable survival analysis.
| Variable | OS |
CSS |
BRFS |
|||
|---|---|---|---|---|---|---|
| AHR (95% CI) | p-Value | AHR (95% CI) | p-Value | AHR (95% CI) | p-Value | |
| Region/province and country (Ref: Taiwan, China) | ||||||
| Chiba, Japan | 0.72 (0.39–1.32) | 0.3 | 1.78 (0.85–3.76) | 0.13 | 2.29 (1.48–3.53) | <0.001 |
| Seoul, the Republic of Korea | 0.42 (0.17–1.03) | 0.057 | 0.90 (0.29–2.80) | 0.9 | 1.98 (1.27–3.10) | 0.003 |
| Hong Kong, China | 1.04 (0.49–2.18) | 0.9 | 1.93 (0.70–5.35) | 0.2 | 1.37 (0.84–2.25) | 0.2 |
| Schleswig-Holstein, Germany | 1.26 (0.42–3.80) | 0.7 | 2.28 (0.61–8.46) | 0.2 | 3.83 (1.97–7.48) | <0.001 |
| Age, year | 1.04 (1.01–1.06) | 0.005 | 1.02 (0.99–1.05) | 0.3 | 1.02 (1.00–1.03) | 0.058 |
| Sex (Ref: female), male | 1.00 (0.64–1.57) | 1 | 0.62 (0.35–1.09) | 0.097 | 1.22 (0.88–1.70) | 0.2 |
| Tumor side (Ref: left), right | 1.12 (0.84–1.50) | 0.4 | ||||
| URS biopsy (Ref: no), yes | 0.76 (0.43–1.34) | 0.3 | ||||
| History of bladder UC (Ref: no), yes | 0.86 (0.44–1.67) | 0.7 | ||||
| Simultaneous bladder tumor (Ref: no), yes | 2.28 (1.60–3.25) | <0.001 | ||||
| Multifocal (Ref: single), yes | 2.35 (1.47–3.75) | <0.001 | 1.05 (0.70–1.56) | 0.8 | ||
| Preoperative urine cytology (Ref: negative) | ||||||
| Dysplasia | 1.29 (0.63–2.65) | 0.5 | 1.47 (0.62–3.53) | 0.4 | ||
| Suspicious | 0.78 (0.36–1.70) | 0.5 | 0.64 (0.24–1.73) | 0.4 | ||
| Highly suspicious | 0.46 (0.18–1.20) | 0.11 | 0.51 (0.14–1.86) | 0.3 | ||
| Positive | 0.81 (0.37–1.77) | 0.6 | 1.19 (0.50–2.84) | 0.7 | ||
| Nota | 0.98 (0.40–2.40) | 1 | 1.48 (0.51–4.28) | 0.5 | ||
| pT (Ref: Ta) | ||||||
| T1 | 0.47 (0.17–1.30) | 0.14 | 1.95 (0.37–10.19) | 0.4 | ||
| T2 | 1.51 (0.71–3.18) | 0.3 | 2.31 (0.50–10.78) | 0.3 | ||
| T3 | 1.93 (0.88–4.25) | 0.10 | 3.34 (0.73–15.15) | 0.12 | ||
| T4 | 3.57 (1.24–10.23) | 0.018 | 11.08 (1.99–61.85) | 0.006 | ||
| LVI (Ref: no), yes | 1.93 (1.20–3.11) | 0.007 | 1.61 (0.89–2.93) | 0.12 | ||
| Distant metastasis (Ref: no), yes | 6.52 (4.06–10.45) | <0.001 | 25.21 (12.10–52.53) | <0.001 | 1.23 (0.87–1.75) | 0.2 |
AHR, adjusted hazard ratio; BRFS, bladder recurrence-free survival; CI, confidence interval; CSS, cancer-specific survival; Ref, reference; LVI, lymphovascular invasion; OS, overall survival; UC, urothelial carcinoma; URS, ureteroscopic.
“Not” indicates that cytology was not obtained and therefore the data were missing.
Figure 1.
Kaplan–Meier plots among patients from Taiwan, China; Hong Kong, China; Chiba, Japan; Seoul, the Republic of Korea; and Schleswig-Holstein, Germany. (A) Overall survival; (B) Cancer-specific survival; (C) Bladder recurrence-free survival.
3.2. CSS
In the univariate analysis (Supplementary Table 1), worse CSS was associated with the region of origin (Chiba, Japan), positive preoperative urine cytology, higher pT stage (pT2–4), higher tumor grade, positive LVI, performance of lymph node dissection, positive surgical margin, receipt of adjuvant systemic therapy, contralateral recurrence, and distant metastasis. Lower BMI was associated with better CSS. In the multivariate stepwise analysis (Table 2), patients' regional origin was not associated with worse CSS. High pT stage (pT4) stage and distant metastasis were identified as independent factors leading to worse CSS (AHR: 11.08, p=0.006; AHR: 25.21, p<0.001, respectively). Upon comparison of the Kaplan–Meier curves using the log-rank test, a significant differences in CSS was observed among regions (p<0.001) (Fig. 1B). Taiwan, China had the best 5-year CSS rate at 94.1%, whereas Hong Kong Special Administrative Region of China showed the lowest CSS rate at 81.9%. The 5-year CSS rates in Chiba, Japan, Seoul, the Republic of Korea, and Schleswig-Holstein, Germany were 83.4%, 93.5%, and 93.8%, respectively.
3.3. BRFS
In the univariate analysis (Supplementary Table 1), worse BRFS was associated with the patients' regional origin (Chiba, Japan; Seoul, the Republic of Korea; and Schleswig-Holstein, Germany), male sex, a history of bladder UC, tumor grade 2, and simultaneous bladder tumor. In the multivariate stepwise analysis (Table 2), patients in Chiba, Japan, Seoul, the Republic of Korea, and Schleswig-Holstein, Germany had a higher risk of intravesical recurrence (IVR) compared to patients in the Taiwan region of China (AHR: 2.29, p<0.001; AHR: 1.98, p=0.003; AHR: 3.83, p<0.001, respectively). Except for patients' regional origin, simultaneous bladder tumor was the only prognostic factor for worse BRFS (p<0.001). The preoperative URS biopsy did not increase the incidence of IVR. Upon comparison of the Kaplan–Meier curves using the log-rank test, a significant difference in BRFS was observed among regions (p<0.001) (Fig. 1C). Taiwan, China had the highest 5-year BRFS rate at 83.1%, while Seoul, the Republic of Korea recorded the lowest BRFS rate at 57.4 %. In addition, the 5-year BRFS rates in Chiba, Japan, the Hong Kong Special Administrative Region of China, and Schleswig-Holstein, Germany were 60.0%, 70.9%, and 76.9%, respectively.
4. Discussion
A few studies have compared epidemiological observations and oncological outcomes between patients in endemic areas for UTUC cases, such as China, and other Asian or Western countries [2,6]. Singla et al. [6] evaluated the differences between patients with UTUC in China and the U.S. Patients in the U.S. were more frequently male, had more prior history of BCa, and worse OS, while patients in China had relatively better baseline health status but unfavorable pathological features. In this international multi-institutional study, we compared the clinical and pathological patterns and oncological outcomes between patients with UTUC treated in Taiwan, China, Hong Kong, China, and Seoul, the Republic of Korea. Additionally, we included patients in Schleswig-Holstein, Germany (a Western population) in our analysis.
In terms of sex distribution, females had a higher proportion than males only among the patients from the Taiwan region of China in the present study. In addition, significantly fewer patients had a smoking habit in the Taiwan region of China cohort compared to the other four regions. This could be partially explained by female predominance of UTUC in the Taiwan region of China. Furthermore, a previous study in the Taiwan region of China disclosed a higher prevalence of smoking in the male UTUC population, suggesting that factors other than smoking may contribute to the development of UTUC and the distinctive sex distribution [10]. The higher prevalence of UTUC in the female patients from the Taiwan region of China has been attributed to exposure to particular carcinogens, including arsenic and AA [4,5]. AA is a well-established risk factor for UTUC in endemic areas, including China, and some Balkan countries [[11], [12], [13]]. Aristolactam-DNA adducts and specific mutations (A>T) in TP53 have been found in patients with UTUC, supporting the underlying carcinogenic mechanism of AA [14]. The higher prevalence of Chinese herbal medicine usage among women, which may contain AA, was suggested to be a cause of female predominance in the UTUC patients from the Taiwan region of China [4]. The use of traditional remedies containing AA has been prohibited for decades, but a higher incidence of UTUC can still be observed in the women of the Taiwan region of China. The underlying causes remain to be elucidated. A previous study also proposed the possibilities of contamination of soil organic matter by AA, especially where Aristolochia plants and seeds could be found, suggesting possible carcinogen exposure even after the ban on AA medical usage [14].
The data on the sex effect on the oncological outcomes of UTUC were mixed [7]. Male sex was associated with worse BRFS in a previous study of patients from the Taiwan region of China [15], while female patients had higher OS and CSS in a large hospital-based cancer registry study conducted in an endemic area [16]. However, no significant sex-based differences in OS, CSS, or BRFS were observed in the cohort of the present study. Nevertheless, sex effects on pathogenesis and oncological outcomes of UTUC are still to be elucidated and warrant further studies in different ethnic populations.
Another interesting observation in our study regarding pre-RNU diagnostic management is that few patients had received URS biopsy before RNU in Seoul, the Republic of Korea. Compared to 74% of their counterparts in the Taiwan region of China, only fewer than 1.9% of the patients in Seoul, the Republic of Korea had undergone URS biopsy before radical operation. A previous retrospective study of patients in the Republic of Korea with UTUC also revealed relatively fewer patients had received URS before RNU [17]. The diagnostic modalities of UTUC, such as URS, URS with biopsy, and percutaneous biopsy, vary widely in different institutes [18]. Whether preoperative URS biopsy and even URS alone could increase the risk of IVR after RNU remains a controversial topic. Several studies and meta-analyses have found that diagnostic URS was associated with worse IVR-free survival, and tumor seeding during URS manipulation or biopsy was considered to be the major underlying mechanism [17,19,20]. However, some authors have also proposed conflicting data. Jiang et al. [21] disclosed that tumor diameter and tumor stage were independent risk factors for IVR instead of URS biopsy in a propensity score-matched case–control study. In addition, Lee et al. [22] also found that diagnostic URS did not increase IVR rate. Interestingly, they performed a subgroup analysis in patients with and without a history of BCa, an important risk factor for IVR, and no increase in the risk of IVR was noted regardless of undergoing URS or not before RNU. In the present study, simultaneous bladder tumor was associated with a higher risk of worse BRFS, which is similar to a previous study by Liu et al. [23], claiming that concurrent bladder UC was the dominant risk factor for bladder recurrence. On the other hand, we found that URS biopsy showed no significant influence on BRFS. Furthermore, although patients in Seoul, the Republic of Korea had fewer URS biopsies before RNU, patients in Seoul, the Republic of Korea, Chiba, Japan, and Schleswig-Holstein, Germany had a higher risk of IVR in our analysis. This finding is in accordance with previous studies that preoperative URS was not associated with worse BRFS [21,22]. The pathogenesis of IVR after RNU is complex and multifactorial, and the definite causative relationship between diagnostic URS and subsequent IVR is yet to be clarified. As for the association between URS biopsy and other survival outcomes, in a recent large study of 1912 high-risk UTUC patients from the ROBUUST (RObotic surgery for Upper tract Urothelial cancer STudy) dataset, Ditonno et al. [24] explored the prognostic role and impact on outcomes of diagnostic URS before curative surgery. Interestingly, they found no difference in recurrence-free survival or metastasis-free survival between URS and non-URS groups, but a significantly higher CSS and OS were noted in the URS group. Nevertheless, according to current guidelines [12], diagnostic URS is still a valuable diagnostic tool before radical surgery, especially in patients with equivocal cross-sectional imaging findings of suspicious UTUC.
It has been well established that tumor stage is one of the main prognostic factors for patients with UTUC in the current guidelines and numerous pieces of literature [12,13]. Likewise, pT stage was found to be an important predictive factor for both OS and CSS in the present study. In another study of patients in China and the U.S., Singla et al. [6] reported that patients in the U.S. had worse OS, while the region of origin did not influence local recurrence and CSS. The relatively poorer baseline health status of American patients in the study could be the reason for the difference in OS between these two populations. In a study of different Asian ethnic groups (including Chinese, Japanese, Koreans, Filipinos, and Vietnamese) in North America, Colla Ruvolo et al. [7] disclosed that Chinese and Vietnamese patients had more advanced tumor stage at UTUC diagnosis. In addition, Vietnamese ethnicity was associated with higher CSS, while other Asian ethnic populations showed similar CSS. In another large multicenter retrospective analysis using the ROBUUST registry, including 1446 patients stratified by races (White, Black, Hispanic, and Asian), Zappia et al. [25] found that Asian patients had significantly higher OS when compared with White patients, but their study failed to demonstrate a statistically significant difference in recurrence-free survival or metastasis-free survival between races. No survival disadvantage among specific racial groups with UTUC who underwent RNU was found in their study [25]. In this international study, the multivariate analysis showed that regional origin did not predict OS and CSS in patients from the five areas. Further studies to explore the influence of environmental exposure on UTUC incidence and prognosis are still warranted to clarify the divergent UTUC epidemiological distribution and oncological outcomes in different countries and regions.
While the present study showed no significant association between adjuvant chemotherapy and survival benefit, previous research, such as the POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial, demonstrated a high level of evidence for the efficacy of adjuvant chemotherapy in UTUC when platinum-based chemotherapy was initiated within the first 3 months after RNU [26]. Additionally, a recent study from the ROBUUST 2.0 registry revealed that neoadjuvant chemotherapy was independently associated with improved CSS in patients with cT3 or higher disease and enhanced both CSS and OS in patients with clinically positive lymph nodes [26]. Further studies and clinical trials are warranted to elucidate the additional roles of neoadjuvant chemotherapy in UTUC.
There are some limitations to the present study. First, the retrospective nature of this study limited the acquisition of certain variables of interest, such as the use of intravesical chemotherapy, the use of AA-containing herbal medicine, and exposure to other potential carcinogens. Second, as a multi-institutional study, we could not standardize screening and management protocols and surgical approaches. Third, genetic susceptibility is important in transracial comparisons, but genomic data were not included in our analyses. Nevertheless, we presented the real-world data that compare epidemiological characteristics, management patterns, and oncological outcomes of UTUC patients in East Asia and Europe, reflecting current UTUC presentations and management in different countries and regions across these two continents.
5. Conclusion
This international observational study revealed different epidemiological distributions and practice patterns among UTUC patients in China, Japan, the Republic of Korea, and Germany. Cohorts from China comprised patients from the Hong Kong Special Administrative Region and the Taiwan region, respectively. However, ethnic and regional differences did not affect overall and cancer-specific survival after RNU. The impact of environmental factors on UTUC incidence needs to be further elucidated.
Author contributions
Study concept and design: Hsiang-Ying Lee, Tzu-Chun Wei, Jeremy Yuen-Chun Teoh.
Data acquisition: Hsiang-Ying Lee, Tzu-Chun Wei, Jun Miki, Jeremy Yuen-Chun Teoh, Chi Hang Yee, Hyeong Dong Yuk, Sung Yong Cho, Mario Wolfgang Kramer.
Data analysis: Hsiang-Ying Lee, Pei-Shan Ho, Yu-Ting Huang.
Drafting of the manuscript: Tai-Hua Chiu, Hsiang-Ying Lee.
Critical revision of the manuscript: Hsiang-Ying Lee, Tzu-Chun Wei, Jeremy Yuen-Chun Teoh.
Conflicts of interest
The authors declare no conflict of interest.
Acknowledgments
The authors thank the Division of Medical Statistics and Bioinformatics, Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, China for statistical analysis support in this study.
Footnotes
Peer review under responsibility of Tongji University.
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ajur.2025.03.015.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
References
- 1.Siegel R.L., Miller K.D., Fuchs H.E., Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71:7–33. doi: 10.3322/caac.21654. [DOI] [PubMed] [Google Scholar]
- 2.Nally E., Young M., Chauhan V., Wells C., Szabados B., Powles T., et al. Upper tract urothelial carcinoma (UTUC): prevalence, impact and management challenge. Cancer Manag Res. 2024;16:467–475. doi: 10.2147/CMAR.S445529. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Chen T.S., Chen Y.T., Wang H.J., Chiang P.H., Yang W.C., Lee W.C. The prognostic impact of tumor location in pT3N0M0 upper urinary tract urothelial carcinoma: a retrospective cohort study. Front Oncol. 2022;12:850874. doi: 10.3389/fonc.2022.850874. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Das S., Thakur S., Korenjak M., Sidorenko V.S., Chung F.F., Zavadil J. Aristolochic acid-associated cancers: a public health risk in need of global action. Nat Rev Cancer. 2022;22:576–591. doi: 10.1038/s41568-022-00494-x. [DOI] [PubMed] [Google Scholar]
- 5.Lopez J.F., Fernandez M.I., Coz L.F. Arsenic exposure is associated with significant upper tract urothelial carcinoma health care needs and elevated mortality rates. Urol Oncol. 2020;38:638. doi: 10.1016/j.urolonc.2020.01.014. e7–13. [DOI] [PubMed] [Google Scholar]
- 6.Singla N., Fang D., Su X., Bao Z., Cao Z., Jafri S.M., et al. A multi-institutional comparison of clinicopathological characteristics and oncologic outcomes of upper tract urothelial carcinoma in China and the United States. J Urol. 2017;197:1208–1213. doi: 10.1016/j.juro.2016.11.094. [DOI] [PubMed] [Google Scholar]
- 7.Colla Ruvolo C., Wurnschimmel C., Nocera L., Wenzel M., Tian Z., Shariat S.F., et al. Stage and cancer-specific mortality differ within specific Asian ethnic groups for upper tract urothelial carcinoma: North American population-based study. Int J Urol. 2021;28:1247–1252. doi: 10.1111/iju.14682. [DOI] [PubMed] [Google Scholar]
- 8.Lopez-Beltran A., Sauter G., Gasser T., Hartmann A., Schmitz-Dräger B.J., Helpap B., et al. In: World Health Organization classification of tumours: pathology and genetics of tumours of the urinary system and male genital organs. Eble J.N., Sauter G., Epstein J.I., Sesterhenn I.A., editors. IARC Press; Lyon, France: 2004. Chapter: Infiltrating urothelial carcinoma; Sauter G, Algaba F, Amin MB, Busch C, Cheville J, Gasser T, et al. Chapter: Non-invasive urothelial tumours; pp. 90–123. [Google Scholar]
- 9.Brierley J., Gospodarowicz M.K., Wittekind C. 8th edition. John Wiley & Sons, Inc.; Chichester, West Sussex, UK; Hoboken, NJ, USA: 2017. TNM classification of malignant tumours; pp. 202–203. [Google Scholar]
- 10.Chou Y.H., Chang W.C., Wu W.J., Li C.C., Yeh H.C., Hou M.F., et al. The association between gender and outcome of patients with upper tract urothelial cancer. Kaohsiung J Med Sci. 2013;29:37–42. doi: 10.1016/j.kjms.2012.08.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Grollman A.P., Shibutani S., Moriya M., Miller F., Wu L., Moll U., et al. Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci U S A. 2007;104:12129–12134. doi: 10.1073/pnas.0701248104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Roupret M., Seisen T., Birtle A.J., Capoun O., Comperat E.M., Dominguez-Escrig J.L., et al. European Association of Urology guidelines on upper urinary tract urothelial carcinoma: 2023 update. Eur Urol. 2023;84:49–64. doi: 10.1016/j.eururo.2023.03.013. [DOI] [PubMed] [Google Scholar]
- 13.Wang Q., Zhang T., Wu J., Wen J., Tao D., Wan T., et al. Prognosis and risk factors of patients with upper urinary tract urothelial carcinoma and postoperative recurrence of bladder cancer in central China. BMC Urol. 2019;19:24. doi: 10.1186/s12894-019-0457-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Gruia A.T., Oprean C., Ivan A., Cean A., Cristea M., Draghia L., et al. Balkan endemic nephropathy and aristolochic acid I: an investigation into the role of soil and soil organic matter contamination, as a potential natural exposure pathway. Environ Geochem Health. 2018;40:1437–1448. doi: 10.1007/s10653-017-0065-9. [DOI] [PubMed] [Google Scholar]
- 15.Hu X., Xue Y., Zhu G. Clinical characteristics and current status of treatment for recurrent bladder cancer after surgeries on upper tract urothelial carcinoma. Diagnostics (Basel) 2023;13:1004. doi: 10.3390/diagnostics13051004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Huang C.C., Su Y.L., Luo H.L., Chen Y.T., Sio T.T., Hsu H.C., et al. Gender is a significant prognostic factor for upper tract urothelial carcinoma: a large hospital-based cancer registry study in an endemic area. Front Oncol. 2019;9:157. doi: 10.3389/fonc.2019.00157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Yoo S., You D., Song C., Hong B., Hong J.H., Kim C.S., et al. Risk of intravesical recurrence after ureteroscopic biopsy for upper tract urothelial carcinoma: does the location matter? J Endourol. 2017;31:259–265. doi: 10.1089/end.2016.0611. [DOI] [PubMed] [Google Scholar]
- 18.Sharma V., Miest T.S., Juvet T.S., Toussi A., Packiam V., Chamie K., et al. The impact of upper tract urothelial carcinoma diagnostic modality on intravesical recurrence after radical nephroureterectomy: a single institution series and updated meta-analysis. J Urol. 2021;206:558–567. doi: 10.1097/JU.0000000000001834. [DOI] [PubMed] [Google Scholar]
- 19.Katims A.B., Say R., Derweesh I., Uzzo R., Minervini A., Wu Z., et al. Risk factors for intravesical recurrence after minimally invasive nephroureterectomy for upper tract urothelial cancer (ROBUUST collaboration) J Urol. 2021;206:568–576. doi: 10.1097/JU.0000000000001786. [DOI] [PubMed] [Google Scholar]
- 20.Nowak L., Krajewski W., Chorbinska J., Kielb P., Sut M., Moschini M., et al. The impact of diagnostic ureteroscopy prior to radical nephroureterectomy on oncological outcomes in patients with upper tract urothelial carcinoma: a comprehensive systematic review and meta-analysis. J Clin Med. 2021;10:4197. doi: 10.3390/jcm10184197. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Jiang Y., Yao Z., Zhu X., Wu B., Bai S. Risk factors and oncological outcome for intravesical recurrence in organ-confined upper urinary tract urothelial carcinoma patients after radical nephroureterectomy: a propensity score-matched case control study. Int J Surg. 2020;76:28–34. doi: 10.1016/j.ijsu.2020.02.015. [DOI] [PubMed] [Google Scholar]
- 22.Lee H.Y., Yeh H.C., Wu W.J., He J.S., Huang C.N., Ke H.L., et al. The diagnostic ureteroscopy before radical nephroureterectomy in upper urinary tract urothelial carcinoma is not associated with higher intravesical recurrence. World J Surg Oncol. 2018;16:135. doi: 10.1186/s12957-018-1411-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Liu K., Zhao H., Alvarez-Maestro M., Gravas S., Van Renterghem K., Zeng G., et al. Concomitant bladder tumor is a risk factor for bladder recurrence but not upper tract. Curr Oncol. 2022;29:9284–9293. doi: 10.3390/curroncol29120727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Ditonno F., Franco A., Veccia A., Bertolo R., Wu Z., Wang L., et al. Decisional and prognostic impact of diagnostic ureteroscopy in high-risk upper tract urothelial carcinoma: a multi-institutional collaborative analysis (ROBUUST collaborative group) Urol Oncol. 2024;42:290.e1–290.e9. doi: 10.1016/j.urolonc.2024.04.021. [DOI] [PubMed] [Google Scholar]
- 25.Zappia J., Yong C., Slaven J., Wu Z., Wang L., Djaladat H., et al. Survival outcomes by race following surgical treatment for upper tract urothelial carcinoma. Clin Genitourin Cancer. 2024;22 doi: 10.1016/j.clgc.2024.102220. [DOI] [PubMed] [Google Scholar]
- 26.Birtle A., Johnson M., Chester J., Jones R., Dolling D., Bryan R.T., et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet. 2020;395:1268–1277. doi: 10.1016/S0140-6736(20)30415-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
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