Upper urinary tract urothelial carcinoma is a relatively rare tumor, but the incidence rate and mortality rate gradually increase [16]. Raman JD found that slowly increasing incidence of UTUC with an increasing ureteral disease and decreasing renal pelvis/local diseases have been recorded over the past 30 years in U.S.A. In addition, the incidence rate of UTUC involving renal pelvis and ureter remained low in Western countries, around 2.06 cases per 100,000 person-years, which accounts for 5% of all urothelial carcinoma [17, 18]. However, the percentage of renal pelvis and ureter urothelial carcinoma accounts for 20% of all urothelial carcinoma in southern Taiwan [19], suggesting high prevalence of UTUC in Taiwan.
At diagnosis, tumor in renal pelvis is two to three times more common than in the ureter [17, 20]. Nevertheless, the incidence rate of ureteral tumor was greater in Taiwan. In our study, renal pelvis tumor and ureteral tumor account for 70% and 30% in BFD non-endemic area. While in BFD endemic area, 55% of UTUC were located in renal pelvis and 45% were located in ureter. It is consistent with the previous studies [11, 19], where the ratio of renal pelvic and ureteric tumor is around 1:1.
It is reported that the male predilection of UTUC could be seen in other countries with the male to female ratio being approximately 2:1 and the median age being 66 to 70 [21, 22]. However, in Taiwan, female predominance, with male to female ratio of 1:2, has been reported in previous studies [11, 19].
In this study, female predominance could be also seen in both BFD non-endemic and endemic areas. The male to female ratio is 1:1.2–1.4 and the median age is 66 to 69. Tan [11] proposed that women in BFD-endemic areas tended to be exposed to arsenic well water due to farming, fishery, salt production and daily laundry. Yet, compared to the past figures, the number of female patients with UTUC decreased. The public awareness of arsenic intoxication has been aroused, which might lead to reduction in the usage of arsenic well water. It could possibly explain the female predilection declines in the present study.
Besides, there were no statistical difference in proportion of smoking among two groups. Although there were only half of the medical records including these data, we assumed that the variation is neglectable among non-endemic and endemic groups. The clinicopathological differences between BFD non-endemic and endemic group in UTUC revealed higher grade and higher pathologic stages in BFD-endemic group. It contradicts the results of previous studies where no remarkable differences in UTUC associated with arsenic exposure. Nevertheless, higher histologic grade was observed in urinary bladder urothelial carcinomas [11]. Higher prevalence of previous bladder tumor and ureteral tumor in endemic BFD group suggesting urinary bladder and ureter are more sensitive to inorganic arsenic than the renal pelvis. Greater proportion of end-stage renal diseases in BFD non-endemic group could be another risk factor for developing UTUC so that the high incidence of UTUC was found in end-stage renal disease population in Taiwan [23].
Variables of age, end stage renal diseases and tumor location were used in adjustment of all Kaplan-Meier curves. Compared to non-endemic patients, the poor prognosis of UTUC patients in BFD endemic area was observed in terms of overall survival, disease-free survival and cancer specific survival curves. Poorer survival curves were found in higher pathological stages. It is compatible to previous study that the pathological stage is a predictive factor of prognosis in UTUC patients.[24] Though poor prognosis of BFD endemic UTUC patients, the average follow-up time was 26 months and average time from operation to death was 23.5 months, compared to non-endemic group, 20 months and 17 months, respectively. Both following time and time from operation to death were longer than that in endemic group. Such differences could attribute to arsenic intoxication; however, other confounding factors such as rural-urban disparity and latency of initial diagnosis should not be neglected. Further investigation excluding confounding factors is required to explore the prognostic indicators in UTUC patients.
Arsenic intoxication has been identified as a risk factor for lung cancer and bladder cancer in a dose-response relationship [25]. Several carcinogenesis of arsenic have been proposed including generation of oxidative stress, perturbation of DNA methylation patterns, inhibition of DNA repair, and modulation of signal transduction pathways [26]. The inorganic arsenic was detoxicated with methylation process and transformed into monomethylarsonic acid (MMAV), monomethylarsonous acid (MMAIII), and dimethylarsinic acid (DMAV) [27]. Animal studies suggested that Dimethylarsinic acid DMA(V) could induce bladder carcinogenesis in the rat with the generation of a reactive metabolite (DMA(II I)) [28]. Monomethylarsonous acid [MMA(III)] also induced bladder cell transformation into immortal cells [29]. The relationship between arsenate metabolites and UTUC carcinogenesis in human remains to be assessed.
There are some limitations to the present study. It is a retrospective observational study analyzing different clinicopathological features between UTUC patients in BFD non-endemic and endemic area. Another limitation is that some possible risk factors such as smoking were not completed. Nevertheless, it is currently the largest UTUC collaborative group in Taiwan. The patients in this study outnumber than those in any previous studies.
In conclusion, there is a slightly female predominance in UTUC patients in Taiwan, which is different from other countries. Clinicopathological profiles of the BFD endemic UTUC patients feature younger age, previous bladder tumor history, higher pathological grade and stage, more ureteral tumor, less lymphovascular invasion and unfavorable prognosis, compared to BFD non-endemic UTUC patients. Despite the fact that arsenic intoxication appears to be responsible for poor prognosis of BFD endemic UTUC patients according to our current data, more explicit features should be taken into account in the analyses.