In the present study, we found that preoperative VUC was associated with high tumor grade, which indicated biologically aggressive UTUC. In addition, preoperative positive VUC significantly increased the risk of intravesical recurrence. We confirmed that VUC before RNU was an independent prognostic factor for disease recurrence and cancer-specific mortality, but not overall mortality.
In agreement with several previous studies [5, 8, 9], we found that preoperative VUC was an independent predictor of bladder recurrence in UTUC patients (HR = 2.21, 95% CI 1.06–4.64; P = 0.035). Currently, two hypotheses have been proposed to explain bladder recurrence following RNU . One is field cancerization, in which exposure to carcinogens throughout the entire urothelium leads to independent multifocal tumor development . A more important view is intraluminal seeding and implantation of cancer cells from the upper urinary tract to the bladder . In favor of the intraluminal seeding theory, studies reported that the intravesical recurrence rate in patients undergoing surgery for UTUC was 22%–47% , while UTUC prevalence after cystectomy ranged from 0.75% to 6.4% . The occurrence of contralateral UTUC was much less than that of intravesical recurrence after RNU, ranging from 2% to 6% . Moreover, a meta-analysis proved that ureteroscopy before RNU did not improve RFS, CSS, and OS in UTUC patients, but increased the risk of intravesical recurrence. It may be that ureteroscopy promotes the implantation of tumor cells isolated from UTUC into the bladder . Therefore, it is reasonable that through seeding and planting of cancer cells, positive preoperative VUC significantly increased the risk of bladder recurrence after RNU. A multi-institutional study reported that positive preoperative urine cytology was a risk factor for intravesical recurrence after RNU, and early ligation of the ureter distal during surgery could not reduce the risk of intravesical recurrence after RNU . Thus, they hypothesized that cancer cells continuously detach from UTUC to bladder in the preoperative period leading to bladder recurrence . Akihiro et al. found that most sites of bladder recurrence were located in likely injured urothelium, which could serve as a site for tumor cell adhesion . Furthermore, the present study revealed that, compared with the renal pelvis, UTUC in the ureter was associated with bladder recurrence after RNU, indicating that the anatomic proximity to the bladder might largely promote intravesical implantation of tumor cells .
Intravenous chemotherapy after RNU for UTUC had no effect on intravesical RFS (P = 0.15) in this study but improved the outcome of CSS (P = 0.021) and OS (P = 0.017) (Table 2). Previous studies examined different chemotherapy drugs and bladder instillation regimens, yielding different results . Regardless of the intravesical chemotherapy protocol, we grouped all individuals who received intravesical chemotherapy after RNU into those with a positive history of bladder instillation, which might weaken the effect of intravesical chemotherapy on UTUC. Based on the intraluminal seeding hypothesis, we believe that it is rational to administer postoperative prophylactic intravesical chemotherapy to prevent tumor cell implantation. Two prospective randomized clinical trials confirmed that early single intravesical instillation of pirarubicin or mitomycin C could reduce bladder recurrence after RNU [22, 23]. Furthermore, Long et al. demonstrated that patients with positive VUC seemed to be more sensitive to intravesical chemotherapy . Therefore, we hypothesized that positive VUC could guide risk stratification to select suitable patients for intravesical chemotherapy and formulate the appropriate frequency of cystoscopies during follow-up.
Along with cystoscopy, preoperative VUC is advocated as the standard method for the diagnosis and surveillance of bladder cancer . Moreover, other studies showed that positive preoperative VUC is associated with disease recurrence and cancer-specific mortality after transurethral resection of bladder tumors [26-28]. The loss of intercellular adhesion is one of the critical biological processes for cancer cells acquiring invasive and metastatic potential, and thus positive VUC could indicate the fragility of intercellular adhesion and reflect the aggressiveness of bladder cancer . Similarly, Sakano et al. found that preoperative VUC increased cancer-specific mortality in UTUC patients , but 116 patients (22%) synchronously suffered bladder cancer, which made it difficult to identify the source of malignant cells in urine.
After excluding patients experiencing bladder cancer before and/or during RNU, the present study proved that preoperative VUC independently not only increased the risk of cancer-specific mortality (HR = 1.87, 95% CI 1.10–3.18; P = 0.020) but also the risk of disease recurrence (HR = 1.80, 95% CI 1.08–2.99; P = 0.023). The sensitivity of VUC for detecting high-grade and invasive bladder tumors was up to 84% but was only 16% for low-grade tumors . In a study to evaluate the predictive value of urine cytology for worse pathological outcomes of UTUC, Chen et al. reported positive urine cytology was associated with high-grade disease . In other studies, preoperative VUC also has been explored as a predictive tool for high-grade muscle-invasive (pT2–pT4) and/or non-organ-confined (pT3 or greater, or lymph node metastasis) UTUC [12, 13]. Sakano et al. did not further explore the relationship between positive VUC and the aggressive features of UTUC . Our data showed that preoperative VUC was significantly associated with high-grade UTUC (OR = 2.23, 95% CI 1.15–4.52), but had no interaction with tumor grade in survival analyses. Due to its ability to reflect the fragility of intercellular adhesion and its relationship with invasive disease, positive preoperative VUC might be an independent prognosticator in predicting disease recurrence and cancer-specific death in UTUC.
In accordance with previous studies, we found that pathologic stage and advanced age were independent predictors of disease recurrence and survival in UTUC. LVI poorly affected disease recurrence (OR = 2.66, 95% CI 1.32–5.34) and overall death (OR = 2.22, 95% CI 1.14–4.33) in pTa-4N0M0 patients. In a large multicenter study of >1400 patients, Kikuchi et al. found that LVI was an independent predictor of clinical outcomes in node-negative UTUC patients after RNU . LVI seemed to help identify a subgroup of patients with micro-metastases or false-negative lymph node status.
The present study has several limitations. First, this was a single-center retrospective design with a limited number of patients, which carried an intrinsic bias. Preoperative VUC was not a prognosticator for OS. The possible explanation was that the overall follow-up period was too restricted to observe the positive impact of VUC on OS. Second, patients who did not retain VUC were not included in the present analysis. Third, information of postoperative intravenous chemotherapy was not included in this study. Based on the National Cancer Database, Seisen et al. reported an OS benefit in pT3/T4 and/or pN+ UTUC patients who received adjuvant chemotherapy . However, there are insufficient data on which to base a recommendation of systemic chemotherapy for UTUC . Fourth, the EAU guideline considers neutrophil-to-lymphocyte ratio (NLR) as a prognostic factor for UTUC patients, which is an easily measurable and reproducible marker of the systemic immune response . Several biomarkers, such as C-reactive protein, platelet counts, and white blood cell counts, have also been found to represent prognostic factors in various human cancer types. However, the laboratory data were unavailable in the present study. Thus, we did not explore the prognostic impact of these biomarkers on UTUC.