The Influence of Preoperative Hydronephrosis on the Prognosis after Radical Cystectomy among Patients with Different Pathological Stages of Bladder Cancer Open Access

Radical cystectomy (RC) with pelvic lymph node dissection remains the mainstay of treatment for patients with muscle-invasive and high‐risk nonmuscle-invasive bladder urothelial carcinoma [1‒4]. The factors influencing postoperative survival are important to estimate prognosis, develop follow-up protocols, and select adjuvant treatment for patients after radical surgery. The TNM pathological staging (pTNM) system proposed by the American Joint Committee on Cancer/Union for International Cancer Control (UICC) is the main prognostic indicator for bladder cancer patients [5]. Besides the pTNM stage, many studies have found that preoperative hydronephrosis had a significant influence on the survival of patients after RC for bladder cancer [6‒17]. For example, Georg C. Bartsch et al. reported in 2007 [18] that preoperative hydronephrosis is an independent prognostic factor for recurrence-free survival of bladder cancer patients after radical surgery. Berkan Resorlu et al. reported in 2009 [19] that the presence of hydronephrosis before RC is a significant prognostic parameter associated with poor cancer-specific survival (CSS) and advanced disease stage. Manuel S. Eisenberg et al. [11] also found that preoperative hydronephrosis was significantly associated with the risk of bladder cancer death.

It is the consensus that preoperative hydronephrosis is a risk factor for the survival of patients after RC [6‒19], but to our knowledge, whether preoperative hydronephrosis can affect the postoperative survival of patients with different pathological stages of bladder cancer is still rarely reported, and little attention has been paid to the value of this problem. Therefore, in this study, with the help of Cox proportional hazards regression models, Kaplan-Meier plots, and the log-rank test, we explored the relationship between preoperative hydronephrosis and the overall survival (OS) after RC of patients with different pathological stages of bladder urothelial carcinoma within our institutional dataset.

Our research enrolled patients with bladder urothelial carcinoma who underwent radical surgical treatment between January 2013 and December 2017 at the Department of Urology, the Second Affiliated Hospital of Kunming Medical University (Kunming, China). Eligible cases met the following criteria: (1) had accepted RC and pelvic lymphadenectomy for bladder cancer at our institution; (2) the postoperative pathological diagnosis was urothelial carcinoma; (3) there were imaging data (ultrasound, intravenous urography, CT, MRI, etc.) within 2 weeks before the surgery to suggest the presence of hydronephrosis; (4) preoperative comorbid hydronephrosis was due to bladder neoplasm and had excluded nonneoplastic pathogenic reasons such as urinary calculi, inflammatory stricture, congenital malformations, benign prostatic hyperplasia, and ureteral injury; (5) postoperative survival was at least 3 months. Also excluded were patients who were lost in follow-up, refused to cooperate with the investigation, had a history of tumors coming from other visceral organs, or combined with upper urinary tract tumors.

Follow-up visits included outpatient reviews, phone calls, and short messages. Patients were offered reviews every 3 months for the first 1–2 years after surgery, every 6 months for years 2–3, and yearly after that if no recurrence occurred. The follow-up continued until the cutoff time of the study or patient death, whichever occurred first. We calculated the OS as the time from operation to the point of death or the last time of follow-up. Patients still alive at the end point of follow-up were treated as censored data. The factors employed for research included age, gender, Eastern Cooperative Oncology Group (ECOG) score, history of TURBT, body mass index, comorbid disease, preoperative hydronephrosis, pathological grade and T stage of the tumor, lymph node metastasis, history of adjuvant chemotherapy, surgical approach (open surgery or laparoscopic surgery), urinary diversion (cutaneous ureterostomy or orthotopic neobladder), and estimated glomerular filtration rate (eGFR). We diagnosed the pathological staging according to the 8th edition of the TNM staging method issued by the UICC in 2017 and diagnosed the pathological grading according to the 2004/2016 grading system of the World Health Organization. If the patient had distant metastases within a short time (<3 months) after radical surgery, we considered the metastasis had occurred before the surgery. The end of the study was January 2021.

IBM SPSS statistical software version 21.0 (IBM Corp.) and GraphPad Prism 9 (GraphPad Software) were employed for data analysis and statistical mapping. The survival curves were exhibited with the help of Kaplan-Meier curves. The differences in OS were calculated using the log-rank test. Independent influencing factors on OS after radical surgery were identified using the Cox proportional hazards regression analysis. The hazard ratio (HR) and 95% confidence interval (CI) were calculated finally. The p value for multiple testing was corrected using the Bonferroni correction.

A total of 231 patients with bladder urothelial carcinoma were included in the study, namely, 202 males and 29 females (detailed data for each patient have been submitted to the journal as an online suppl. material; for all online suppl. material, see https://doi.org/10.1159/000531080). There were 96 patients (41.6%) who had preoperative hydronephrosis. The clinical characteristics of all patients are shown in Table 1. The median follow-up time was 47 months (interquartile range 25–68 months). The 3-year OS of patients with and without preoperative hydronephrosis were 62.5% ± 4.9% and 74.8% ± 3.7% (p < 0.001), respectively. The 5-year OS of patients with and without preoperative hydronephrosis were 38.5% ± 5% and 66.8% ± 4.1% (p < 0.001), respectively (shown in Fig. 1).

The univariate analysis found that patient age, surgical approach, urinary diversion, preoperative hydronephrosis, adjuvant chemotherapy, ECOG score, pathological grade, T stage of the tumor, and lymph node metastasis were significantly associated with OS of patients after RC (shown in Table 2). The multivariate analysis showed that preoperative hydronephrosis (HR = 2.059, 95% CI: 1.401–3.025, p < 0.001), tumor T stage (HR = 3.479, 95% CI: 2.237–5.411, p < 0.001), and lymph node metastasis (HR = 2.978, 95% CI: 1.704–5.203, p < 0.001) were independent prognostic factors of OS after RC (shown in Table 2).

Of the 231 patients, 96 were classified into the hydronephrosis group and 135 were classified into the no hydronephrosis group. Subsequently, the patients were divided into eight subgroups according to the TNM stage for subgroup analysis (shown in Fig. 2). As shown in Figure 3, in pT₁N₀M₀ patients (n = 64), no statistical difference (p = 0. 980) in OS was found between the hydronephrosis group and the no hydronephrosis group. In pT₂N₀M₀ patients (n = 76), the difference in OS between the hydronephrosis group and the no hydronephrosis group was significant (p = 0.050) (shown in Fig. 4). In pT_3–4N₀M₀ patients (n = 71), the 3- and 5-year OS of the no hydronephrosis group was 63.3% ± 8.8% and 40.2% ± 9.5%, respectively. The 3- and 5-year OS of the hydronephrosis group was 12.2% ± 5.1% and 7.3% ± 4.1%, respectively. The difference in OS between the hydronephrosis group and the no hydronephrosis group was significant (p < 0.001) (shown in Fig. 5). In pT_xN₊M_x patients (n = 20), the difference in OS between the hydronephrosis group and no hydronephrosis group was insignificant (p = 0.518) (shown in Fig. 6). The corrected p values using the Bonferroni correction showed that there was a significant difference in OS between the hydronephrosis group and no hydronephrosis group of pT_3–4N₀M₀ patients.

It is well known that preoperative hydronephrosis affects the prognosis of bladder cancer patients undergoing radical surgery. A meta-analysis reported by Zhaowei Zhu et al. [9] found that preoperative hydronephrosis significantly affected OS and CSS in patients after RC, and the CSS was worse in patients with bilateral hydronephrosis. Another systematic review by Jong Jin Oh et al. [10] reached similar conclusions. However, the conclusions of different studies on the question of whether preoperative hydronephrosis can affect the postoperative prognosis of patients with different pathological stages of bladder cancer remain confusing and even contradictory. For example, in the research by Huan-yi Lin et al.[20], 3-year recurrence-free survival rates of the subgroups of stage pT_3aN₀M₀ were 75.0% ± 21.7% for patients without hydronephrosis and 22.2% ± 12.6% for patients with hydronephrosis, which differed significantly, but no significant difference was found in patients with other pTNM stages. In another study, Thomas Hofner et al. [13] reported that there was no significant difference in CSS rates between patients with and without preoperative hydronephrosis across pTNM stages.

In this study, we found that preoperative hydronephrosis had a significant impact on postoperative OS in bladder cancer patients with tumor stage pT_3–4N₀M₀. To our knowledge, this is the first study to examine the effect of preoperative hydronephrosis on postoperative OS in patients with different pathological stages of bladder cancer. According to our study, preoperative hydronephrosis could divide pT_3–4N₀M₀ bladder cancer patients into two risk groups, those with preoperative hydronephrosis being the high-risk group and those without preoperative hydronephrosis being the opposite, with patients in the high-risk group having significantly lower postoperative survival rates than those in the low-risk group. Therefore, preoperative hydronephrosis is an influencing factor for risk stratification of patients after radical surgery for pT_3–4N₀M₀ bladder cancer.

Studies have found that the causes of hydronephrosis due to bladder cancer include bladder tumors growing near the ureteral orifice, combined ureteral tumors, and advanced bladder tumors that compress or invade the ureter [18‒23]. In patients with early pathological stages (pT₁N₀M₀ and pT₂N₀M₀) of bladder cancer, the presence of hydronephrosis is due to bladder tumor growth near the ureteral orifice rather than advanced tumor compression or invasion of the ureter, so preoperative hydronephrosis has no impact on patient survival postoperatively [6, 24, 25]. In patients with pT_xN₊M_x bladder cancer, poor prognosis due to advanced tumor stage may override the impact of preoperative hydronephrosis on survival after radical surgery. Therefore, preoperative hydronephrosis has no significant impact on postoperative survival in patients with pT_xN₊M_x bladder cancer.

Preoperative renal insufficiency is also an important factor influencing the long-term survival of patients after radical bladder cancer surgery. Itsuto Hamano et al. [26] reported that preoperative chronic kidney disease predicts poor oncological outcomes after RC in patients with muscle-invasive bladder cancer, and preoperative chronic kidney disease was significantly associated with poor PFS, CSS, and OS after RC. Dai Koguchi et al. [27] also found that severely reduced preoperative eGFR was an independent risk factor for worse PFS and worse CSS in patients after RC. Because hydronephrosis is one of the mechanisms for the development of renal insufficiency, we observed the preoperative eGFR of patients included in the study. It was found that the percentage of patients with preoperative hydronephrosis whose preoperative eGFR was no more than 60 mL/min/1.73 m² reached 11.8%, which was significantly higher than that of patients without preoperative hydronephrosis (Table 1); there was an obvious correlation between preoperative hydronephrosis and renal insufficiency. Therefore, we believe that renal insufficiency is a mediator between preoperative hydronephrosis and the survival outcomes of patients after radical surgery. To avoid the occurrence of multicollinearity, we did not look at preoperative eGFR as an influencing factor in the present study. In addition, it has been found that renal insufficiency is also associated with various factors such as age, diabetes mellitus, and hypertension [28‒30], so that preoperative renal insufficiency in patients undergoing RC may have complex mechanisms of occurrence. Further studies are necessary to investigate the relationship between preoperative hydronephrosis, renal insufficiency, and survival prognosis after radical surgery for bladder cancer.

Our study has several limitations: data in this study were collected retrospectively, patients were from a single institution, and the effects of grade of hydronephrosis, unilateral, and bilateral hydronephrosis were not included in the study. These shortcomings would have affected the statistical testing power of this study.

Preoperative hydronephrosis mainly affects postoperative OS in bladder cancer patients with a pathological stage of pT_3–4N₀M₀. Because patients with pT_3–4N₀M₀ bladder cancer complicated by preoperative hydronephrosis have a poorer prognosis, a more aggressive treatment strategy may be beneficial for them. However, further studies are needed to validate the results of this study.

We thank Medjaden Inc. for scientific editing of this manuscript.

This study protocol was in accordance with the 1964 Helsinki Declaration and its later amendments and was reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Kunming Medical University, approval number SPJK-2022-18. Written informed consent was obtained from all of the participants.

The authors have no conflicts of interest to declare.

The work was not supported by any funding.

Conceptualization, study design, and project administration were provided by Hui Zhan and Jian Chen. Material and data collection was performed by Jingwei Du, Mingxia Ding, and Hairong Wei. Data analysis and interpretation were provided by Jiansong Wang, Chengcai Yang, and Ting Luan. The first draft of the manuscript was written by Jingwei Du, Hui Zhan, and Shi Fu. All authors read and approved the final manuscript.

All data generated or analyzed during this study are included in this article and its supplementary material files. Further inquiries can be directed to the corresponding author.