Abstract
Introduction:
This study aimed to evaluate whether lymphovascular invasion (LVI) can replace lymph node (LN) involvement as a prognostic marker in patients who do not undergo lymph node dissection (LND) during surgery in patients with upper tract urothelial carcinoma (UTUC).
Methods:
A total of 505 patients who underwent radical nephroureterectomy (RNU) were recruited from four academic centres and divided into four groups: node negative (N0, Group 1); node positive (N+, Group 2); no LND without LVI (NxLVI−, Group 3); and no LND with LVI (NxLVI+, Group 4).
Results:
Patients in Group 2 had larger tumours, a higher incidence of left-sided involvement, more aggressive T stage and grade, and a higher positive surgical margin rate than patients in other groups. Pathological features (T stage and grade) were poorer in Group 4 than in Groups 1 and 3. Compared to other groups, Group 2 had the worst prognostic outcomes regarding locoregional/distant metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). LVI and LN status in Group 4 was not associated with MFS in multivariate analysis. Among Nx diseases, LVI was not an independent predictor of MFS or CCS. The small number of cases in Groups 2 and 4 is a major limitation of this study.
Conclusions:
Clinical outcomes according to LVI did not correlate with those outcomes predicted by LN involvement in patients with UTUC. Therefore, LVI may not be used as a substitute for nodal status in patients who do not undergo LND at the time of surgery.
Introduction
The prevalence of upper tract urothelial carcinoma (UTUC) is approximately 5–10%.1–5 Approximately 20–40% of patients initially present with locally advanced disease and lymph node (LN) metastases at the time of diagnosis.6–9 Recently, Margulis et al identified age, high tumour grade, high pathological T stage, LN metastasis, sessile architecture, an infiltrative growth pattern, and lymphovascular invasion (LVI) as independent prognostic indicators of disease recurrence and cancer-specific survival (CSS).8 Tumour stage, grade, and LVI are independent predictors of clinical outcome in patients with UTUC;10,11 however, knowledge of assessable prognostic factors in UTUC is still limited.
Radical nephroureterectomy (RNU) with excision of the ipsilateral bladder cuff is the treatment of choice for localized UTUC.12 In most retrospective studies on UTUC treated by RNU, LVI is detected in approximately 20% of cases.13 LVI is a critical step in the systemic dissemination of cancer cells.14 LVI is also associated with high stage and grade, and has a negative impact on UTUC prognosis.15–18 Metastasis of UTUC to regional LNs occurs frequently and is a significant predictor of oncologic outcomes. LN dissection (LND) is highly recommended in muscle-invasive UTUC;10,19 however, LND for UTUC is not universally performed. A recent study presented at the American Urological Association (AUA) annual meeting suggested that LVI is associated with LN involvement in patients with UTUC and may be used as a surrogate marker in patients who do not undergo LND at the time of surgery.20 In that study, no differences in oncologic outcomes were observed between node positive (N+) and LVI positive patients who did not undergo LND (NxLVI+); however, limitations of the study, such as the small study population (n=131), prevent definitive conclusions.
To address this issue, a large multicentre cohort of patients with UTUC who underwent RNU was analyzed for the first time. The aim of the present study was to evaluate whether LVI can be used as a prognostic substitute for LN involvement in patients who do not undergo LND during surgery in a large cohort.
Methods
Study population
Data obtained from 505 patients who underwent RNU (open, 183 [36.2%], or laparoscopic, 322 [63.8%]) for UTUC at four institutions in Korea between March 2001 and December 2013 were analyzed. All of the patients had com plete followup data available and were considered for the anal yses. To avoid the introduction of bias in the survival estimates, patients with previous or concurrent muscle-invasive bladder cancer, those who received neoadjuvant chemotherapy, or those with evidence of distant metastasis at the time of diagnosis were excluded. Patients had undergone preoperative cystoscopy, urine cytology, and chest and abdominal-pelvic computed tomography (CT) scans.
Surgery was performed according to the standard criteria for RNU. After RNU, bladder cuff resection was performed using standard procedures (i.e., an extravesical approach via a Gibson incision) as stipulated by each centre. LND was performed if lymphadenopathy was suspected upon preoperative imaging or observed during surgery. The majority of patients with non-organ-confined disease received cisplatin-based adjuvant chemotherapy. Tumours were staged according to the American Joint Committee on Cancer (6th edition) staging system.21 Tumour grades were assessed according to the 1998 World Health Organization classification system.22 All specimens were histologically confirmed to be urothelial carcinoma. LVI was defined as the presence of tumour cells in an endothelium-lined space without underlying muscular walls.13 Tumour multifocality was defined as the synchronous presence of two or more pathologically confirmed tumours in any location (renal pelvis or ureter).23
Followup regimen
Followup examinations included cystoscopy, urine cytology, chest X-ray, and CT scanning. Cystoscopy and urine cytology were performed at three, six, and 12 months post-surgery, and yearly thereafter. Image analyses were performed at three, six, and 12 months after RNU, and then every six months from 1–5 years post-surgery. Scans were performed annually thereafter. In this study, locoregional/distant metastasis was defined as a locoregion al recurrence or a new distant metastasis based on clinical and radiographic findings. Metastasis-free survival (MFS) was defined as the period between surgery and the detection of locoregional recurrence, distant metastasis, or the study’s endpoint. Time to CSS was calculated as the time from surgery to the date of cancer-attributable mortality.
Statistical analysis
To evaluate patient outcomes, subjects were divided into node negative (N0, Group 1); node positive (N+, Group 2); no LND without LVI (NxLVI−, Group 3); and no LND with LVI present (NxLVI+, Group 4). For comparison of variables, differences in variables with continuous distributions across dichoto mous categories were assessed using ANOVA. The Fisher’s ex act and Pearson chi-square tests were used to evaluate the association between categorical variables. The Kaplan-Meier method was used to draw survival curves. The log-rank test was used to assess significance, with p≤0.05 considered statistically significant. Potential prognostic factors were established by univariate analyses and only factors considered significant were entered into multivariate Cox proportional hazards regression models. All statistical analyses were performed using the SPSS v.18.0 (IBM Corp., Armonk, NY, U.S.).
Results
The mean age was 66.26 years. Of 505 patients included in the study, 94 (18.6%) had LVI. Regional LND was performed in 287 (56.8%) patients, of which 28 (9.8%) were N+. The number of patients in each group was: 259 (51.3%) in Group 1, 28 (5.5%) in Group 2, 181(35.8%) in Group 3, and 37 (7.3%) in Group 4.
Differences in pre- and postoperative characteristics among the groups stratified by the presence of LNs and LVI are summarized in Table 1. Regarding clinical N stage, most patients (78.6%) in Group 2 had positive LNs in the preoperative CT images. Patients in Group 2 also had larger tumours than those in the other groups. Considering the pathologic characteristics of the tumour specimens, statistically significant differences were found for pathologic T stage (p<0.001), surgical margin status (p=0.015), multifocality (p=0.008), and tumour grade (p=0.009).
Table 1.
Differences in clinicopathological results among the four groups stratified by the presence of lymph nodes and lymphovascular invasion
| Group 1 (n=259) | Group 2 (n=28) | Group 3 (n=181) | Group 4 (n=37) | |
|---|---|---|---|---|
| Age (years, mean ± SD) | 66.05 ± 10.67 | 66.07 ± 9.40 | 65.69 ± 10.56 | 70.68 ± 9.09 |
| BMI (kg/m2) | 23.6 ± 3.2 | 23.4 ± 2.4 | 23.9 ± 3.0 | 24.3 ± 2.9 |
| Gender (%) | ||||
| Male | 174 (67.2) | 22 (78.6) | 125 (69.1) | 27 (73.0) |
| Female | 85 (32.8) | 6 (21.4) | 56 (30.9) | 10 (27.0) |
| Smoking status (%) | ||||
| No | 166 (64.2) | 17 (60.7) | 116 (64.1) | 25 (67.6) |
| Yes | 93 (35.8) | 11 (39.3) | 65 (35.9) | 12 (32.4) |
| Laterality (%) | ||||
| Left | 147 (56.8) | 17 (60.7) | 88 (48.6) | 16 (43.2) |
| Right | 112 (43.2) | 11 (39.3) | 93 (51.4) | 21 (56.8) |
| Clinical N stage | ||||
| N0 | 240 (92.7) | 6 (21.4) | 180 (99.4) | 34 (91.9) |
| N+ | 19 (7.3) | 22 (78.6) | 1 (0.6) | 3 (8.1) |
| Tumour size (mm, mean ± SD) | 38.1 ± 24.7 | 52.9 ± 30.7 | 36.7 ± 26.5 | 40.8 ± 22.8 |
| Tumour location (%) | ||||
| Renal pelvis | 94 (36.3) | 11 (39.3) | 64 (35.4) | 16 (43.2) |
| Ureter | 136 (52.5) | 13 (46.4) | 90 (49.7) | 13 (35.1) |
| Both | 29 (11.2) | 4 (14.3) | 27 (14.9) | 8 (21.7) |
| Previous or concomitant BC (%) | ||||
| No | 207 (79.9) | 24 (85.7) | 147 (81.2) | 30 (81.1) |
| Yes | 52 (20.1) | 4 (14.3) | 34 (18.8) | 7 (18.9) |
| Bladder cuff resection (%) | ||||
| No | 29 (11.2) | 4 (14.3) | 21 (11.6) | 6 (16.2) |
| Yes | 230 (88.8) | 24 (85.7) | 160 (88.4) | 31 (83.8) |
| Multifocality (%) | ||||
| No | 164 (63.3) | 17 (60.7) | 141 (77.9) | 27 (73.0) |
| Yes | 95 (36.7) | 11 (39.3) | 40 (22.1) | 10 (27.0) |
| Pathologic T stage, (%) | ||||
| Ta, T1, CIS, T2 | 141 (54.4) | 5 (17.9) | 137 (75.7) | 12 (32.4) |
| T3–T4 | 118 (45.6) | 23 (82.1) | 44 (24.3) | 25 (67.6) |
| Grade (%) | ||||
| Low | 81 (31.3) | 3 (10.7) | 45 (24.9) | 4 (10.8) |
| High | 178 (68.7) | 25 (89.3) | 136 (75.1) | 33 (89.2) |
| Margin status, (%) | ||||
| Negative | 245 (94.6) | 24 (85.7) | 177 (97.8) | 33 (89.2) |
| Positive | 14 (5.4) | 4 (14.3) | 4 (2.2) | 4 (10.8) |
BC: bladder cancer; BMI: body mass index; SD: standard deviation.
The median followup period was 38.4 months (interquartile range [IQR] 15.6–56.5). One hundred and nine (109) patients (21.6%) received adjuvant systemic chemotherapy. During the followup period, 173 patients (34.3%) had bladder recurrence after a median followup time of 17.0 months (IQR 8.4–36.0). Overall, locoregional recurrence/distant metastasis occurred in 129 patients (25.5%) after a median period of 25.5 months (IQR 12.0–51.4). One hundred and eleven (111) patients (22.0%) died; 88 deaths (17.4%) were directly related to cancer. Kaplan-Meier curves were used to assess bladder recurrence, MFS, CCS, and overall survival (OS) according to LN and LVI status. No statistically significant differences in bladder recurrence were observed among the four groups (Fig. 1A). Group 2 had the worst prognostic outcomes regarding MFS and Group 4 patients had significantly worse MFS than Groups 1 and 3 (Fig. 1B). LN and LVI status (Groups 2 and 4) was helpful in predicting MFS compared to Group 1 in univariate Cox analysis; however, Group 4 did not appear as an independent predictor of MFS (Table 2). Considering CCS and OS, the poorest oncologic outcomes were found in Group 2 (Figs. 2A and 2B), and no differences in CCS and OS were detected between Groups 1 and 4 (Figs. 2A and B).
Fig 1.
Effect of lymph node (LN) and lymphovasclular invasion (LVI) status on (A) bladder recurrence; and (B) locoregional recurrence/distant metastasis after radical nephroureterctomy. Patients were divided into node negative (N0, Group 1); node positive (N+, Group 2); no lymph node dissection (LND) without LVI (NxLVI−, Group 3); and no LND with LVI present (NxLVI+, Group 4).
Table 2.
Univariate and multivariate Cox regression analyses to identify predictors of locoregional recurrence/distant metastasis in patients with UTUC
| Parameters | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
|
| ||||
| HR (95% CI) | p value | HR (95% CI) | p value | |
| Age | 1.020 (1.002−1.038) | 0.025 | 1.017 (0.997−1.036) | 0.096 |
| Gender (male vs. female) | 0.951 (0.653−1.385) | 0.795 | − | − |
| Smoking (no vs. yes) | 0.952 (0.618−1.466) | 0.823 | − | − |
| Tumour size | 1.007 (1.001−1.012) | 0.018 | 1.000 (0.994−1.006) | 0.997 |
| Tumour location | ||||
| Renal pelvis | 1 | − | 1 | − |
| Ureter | 1.176 (0.793−1.743) | 0.42 | 0.971 (0.637−1.480) | 0.892 |
| Both | 1.847 (1.123−3.038) | 0.016 | 1.613 (0.942−2.761) | 0.081 |
| Bladder cuff resection (no vs. yes) | 0.274 (0.195−0.917) | 0.019 | 0.629 (0.370−1.069) | 0.087 |
| Multifocality (no vs. yes) | 1.180 (0.821−1.695) | 0.371 | − | − |
| Pathologic T stage (Ta, CIS, T1–2 vs. T3–4) | 3.274 (2.051−5.226) | <0.001 | 1.786 (1.065−2.996) | 0.028 |
| Grade (low vs. high) | 4.992 (2.686−9.278) | <0.001 | 4.251 (2.146−8.421) | <0.001 |
| Concomitant CIS (no vs. yes) | 0.999 (0.481−2.031) | 0.975 | − | − |
| Margin status (no vs. yes) | 4.979 (3.054−8.116) | <0.001 | 3.741 (2.195−6.375) | <0.001 |
| LVI and LN status | ||||
| Group 1 (N0) | 1 | − | 1 | − |
| Group 2 (N+) | 6.834 (4.061−11.500) | <0.001 | 5.896 (3.428−10.141) | <0.001 |
| Group 3 (NxLVI−) | 1.203 (0.802−1.805) | 0.372 | 1.187 (0.778−1.811) | 0.425 |
| Group 4 (NxLVI+) | 2.281 (1.283−4.058) | 0.005 | 1.549 (0.861−2.786) | 0.144 |
CI: confidence interval; CIS: carcinoma in situ; HR: hazard ratio; LVI: lymphovascular invasion; LN: lymph node; UTUC: upper tract urothelial carcinoma.
Fig 2.
Effect of lymph node (LN) and lymphovasclular invasion (LVI) status on (A) cancer-specific survival; and (B) overall survival after radical nephroureterctomy. Patients were divided into node negative (N0, Group 1); node positive (N+, Group 2); no lymph node dissection (LND) without LVI (NxLVI−, Group 3); and no LND with LVI present (NxLVI+, Group 4).
In the subgroup of patients with Nx disease (Group 3 vs. Group 4), LVI status had a negative impact on MFS and CSS (p=0.032 and p=0.035, respectively; Figs. 1B and 2A); however, LVI was not an independent prognostic factor for MFS and CSS in multivariate analysis (supplementary Tables 1 and 2). Among the patients who underwent LND (only including Groups 1 and 2), LVI was a significant prognostic marker predicting the MFS, CCS, and OS (supplementary Fig. 1).
Discussion
In the present study, we showed that N+ patients (Group 2) had worse prognostic outcomes regarding MFS, CSS, and OS than those in the other groups. According to the European guidelines on UTUC, LND should be performed in association with RNU for better tumour staging and to improve prognosis;10 however, LND is not routinely performed during RNU and many patients will experience regional LN relapse during followup.24 Therefore, knowledge of LN status is important because it influences patient counselling and, more importantly, clinical decision-making regarding followup scheduling and adjuvant chemotherapy.25,26
A recent meta-analysis identified LVI as a strong predictor of poor prognosis among patients with UTUC.27 Consistent with previous studies, our results showed that Group 4 (NxLVI+) patients had worse pathological features than Groups 1 (N0) and 3 (NxLVI−) patients in terms of T stage and grade; however, despite the fact that Group 4 patients had worse MFS than those in Groups 1 and 3 in the univariate analysis, Group 4 (NxLVI+) was not an independent predictor of MFS compared to the patients in Group 1 (N0) based on multivariate Cox regression analysis. Furthermore, patients in Group 4 (NxLVI+) showed no additional prognostic advantages regarding OS and CSS compared to those in Group 1 (N0). Therefore, whether LVI is a universal prognostic marker for UTUC and a surrogate for LN involvement remains unclear. Previous studies supporting our results showed that LVI is not an independent predictor of MFS28–31 and CCS.28,29,32,33 A recent study among Korean UTUC patients showed that LVI was not a significant predictor for OS.9 In a Taiwanese study by Lee et al, LVI represented a significant prognosticator for both CSS and MFS in multivariate analysis only in patients with ureteral tumours, but not in those with pyelocaliceal tumours.34 In other words, LVI failed to be independently associated with CSS and MFS in pyelocaliceal tumours. They concluded that the prognostic value of LVI is further highlighted with respect to ureteral tumours specifically.
In the present study, subgroup analysis of patients with Nx disease showed that LVI status had a negative impact on MFS and CSS on univariate analysis; however, we failed to find a negative impact of LVI on RFS and CSS on multivariate analysis. These results were in accordance with the report from Colin et al,35 who assessed the risk factors of metastasis in UTUC patients undergoing RNU without LND. LVI status was not significantly associated with worse MFS on multivariate analysis.35 In the present study, the independent prognostic factors for RFS and CSS among the patients with Nx disease were pathologic T stage and positive surgical margin. These factors were also identified as independent prognostic indicators in the subgroup of patients with pN0/x disease in a recent study;36 however, this study showed that LVI was a significant prognostic factor on multivariate analysis. In our subgroup analysis including N0 and N1 patients, LVI remained a useful predictor for MFS, CSS, and OS, in agreement with previous results,36 which suggests that LVI is an important factor in patients who undergo LND, but not in those who do not undergo LND. Therefore, LND, which lacks standardization in UTUC, should be performed to improve the prediction of prognosis and the establishment of an adjuvant therapy schedule. A recent study showed that LVI was a significant predictor for CSS in the Nx group and might be used as a surrogate marker in patients who do not undergo LDN at the time of surgery;20 however, this study had a limited population size (n=131), and other well-known independent predictors, such as pathologic T stage, were not included as significant variables in multivariate analysis. Therefore, the establishment of standardized guidelines for the management of UTUC patients requires further investigation.
Our study had several limitations associated with its retrospective nature. Although we could control for numerous potential confounders, we were unable to control for surgeon and pathologist experience, treatment decisions (such as patient and surgeon preferences), or the anatomical template of the preferred LND. Relatively short periods of followup warranted consideration. Moreover, we did not report the information of the LN yield from surgeries at the centre. The other limitation of our study is the small number of cases in Groups 2 and 4.
Conclusions
Although LVI was a predictor of poor outcome in patients with UTUC, it could not replace LN positivity as a prognostic marker. In particular, LVI did not provide important prognostic information in patients with Nx. Therefore, LVI may not be used as a substitute for nodal status in patients who do not undergo LND at the time of surgery.
Figure and Tables
Prognostic values of lymphovascular invasion (LVI) in patients with lymph node dissection (LND) (N0 and N1).
Subgroup analyses of the patients with Nx: Univariate and multivariate Cox regression analyses to identify predictors of locoregional recurrence/distant metastasis
| Parameters | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
|
| ||||
| HR (95% CI) | p value | HR (95% CI) | p value | |
| Age | 1.013 (0.987−1.039) | 0.34 | − | − |
| Gender (male vs. female) | 0.660 (0.356−1.223) | 0.186 | − | − |
| Smoking (no vs. yes) | 1.045 (0.588−1.857) | 0.88 | − | − |
| Tumour size | 1.000 (0.991−1.009) | 0.959 | − | − |
| Tumour location | ||||
| Renal pelvis | 1 | − | − | − |
| Ureter | 1.489 (0.805−2.755) | 0.205 | − | − |
| Both | 1.966 (0.959−4.030) | 0.065 | − | − |
| Bladder cuff resection (no vs. yes) | 0.598 (0.302−1.181) | 0.139 | − | − |
| Multifocality (no vs. yes) | 1.224 (0.694−2.156) | 0.485 | − | − |
| Pathologic T stage (Ta, CIS, T1–2 vs. T3–4) | 2.898 (1.729−4.859) | <0.001 | 2.355 (1.340−4.256) | 0.005 |
| Grade (low vs. high) | 2.802 (1.267−6.201) | 0.011 | 1.771 (0.760−4.123) | 0.185 |
| Concomitant CIS (no vs. yes) | 1.497 (0.678−3.306) | 0.318 | − | − |
| Margin status (no vs. yes) | 5.665 (2.561−12.530) | <0.001 | 4.556 (1.983−10.465) | <0.001 |
| LVI (no vs. yes) | 1.886 (1.047−3.395) | 0.035 | 1.063 (0.547−2.066) | 0.185 |
CI: confidence interval; CIS: carcinoma in situ; HR: hazard ratio; LVI: lymphovascular invasion; UTUC: upper tract urothelial carcinoma.
Subgroup analyses of the patients with Nx: Univariate and multivariate Cox regression analyses to identify predictors of cancer specific survival
| Parameters | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
|
| ||||
| HR (95% CI) | p value | HR (95% CI) | p value | |
| Age | 1.034 (0.991−1.078) | 0.126 | − | − |
| Gender (male vs. female) | 1.095 (0.472−2.538) | 0.833 | − | − |
| Smoking (no vs. yes) | 0.621 (0.227−1.697) | 0.353 | − | − |
| Tumour size | 1.003 (0.991−1.015) | 0.639 | − | − |
| Tumour location | ||||
| Renal pelvis | 1 | − | − | − |
| Ureter | 0.813 (0.305−2.169) | 0.679 | − | − |
| Both | 2.280 (0.878−5.922) | 0.091 | − | − |
| Bladder cuff resection (no vs. yes) | 0.408 (0.163−1.024) | 0.056 | − | − |
| Multifocality (no vs. yes) | 1.507 (0.663−3.423) | 0.328 | − | − |
| Pathologic T stage (Ta, CIS, T1–2 vs. T3–4) | 4.903 (2.161−11.126) | <0.001 | 4.432 (1.823−10.771) | 0.001 |
| Grade (low vs. high) | 4.244 (0.998−18.050) | 0.05 | − | − |
| Concomitant CIS (no vs. yes) | 0.960 (0.226−4.077) | 0.956 | − | − |
| Margin status (no vs. yes) | 5.654 (1.928−16.582) | <0.002 | 4.238 (1.382−13.002) | 0.012 |
| LVI (no vs. yes) | 2.406 (1.037−5.581) | 0.041 | 1.073(0.419−2.749) | 0.185 |
CI: confidence interval; CIS: carcinoma in situ; HR: hazard ratio; LVI: lymphovascular invasion; UTUC: upper tract urothelial carcinoma.
Acknowledgments
This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT& Future Planning (NRF-2014M3A9D3033887) and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. NRF-2014R1A2A1A09006983).
Footnotes
Competing interests: The authors declare no competing personal or financial interests.
This paper has been peer-reviewed.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Prognostic values of lymphovascular invasion (LVI) in patients with lymph node dissection (LND) (N0 and N1).
Subgroup analyses of the patients with Nx: Univariate and multivariate Cox regression analyses to identify predictors of locoregional recurrence/distant metastasis
| Parameters | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
|
| ||||
| HR (95% CI) | p value | HR (95% CI) | p value | |
| Age | 1.013 (0.987−1.039) | 0.34 | − | − |
| Gender (male vs. female) | 0.660 (0.356−1.223) | 0.186 | − | − |
| Smoking (no vs. yes) | 1.045 (0.588−1.857) | 0.88 | − | − |
| Tumour size | 1.000 (0.991−1.009) | 0.959 | − | − |
| Tumour location | ||||
| Renal pelvis | 1 | − | − | − |
| Ureter | 1.489 (0.805−2.755) | 0.205 | − | − |
| Both | 1.966 (0.959−4.030) | 0.065 | − | − |
| Bladder cuff resection (no vs. yes) | 0.598 (0.302−1.181) | 0.139 | − | − |
| Multifocality (no vs. yes) | 1.224 (0.694−2.156) | 0.485 | − | − |
| Pathologic T stage (Ta, CIS, T1–2 vs. T3–4) | 2.898 (1.729−4.859) | <0.001 | 2.355 (1.340−4.256) | 0.005 |
| Grade (low vs. high) | 2.802 (1.267−6.201) | 0.011 | 1.771 (0.760−4.123) | 0.185 |
| Concomitant CIS (no vs. yes) | 1.497 (0.678−3.306) | 0.318 | − | − |
| Margin status (no vs. yes) | 5.665 (2.561−12.530) | <0.001 | 4.556 (1.983−10.465) | <0.001 |
| LVI (no vs. yes) | 1.886 (1.047−3.395) | 0.035 | 1.063 (0.547−2.066) | 0.185 |
CI: confidence interval; CIS: carcinoma in situ; HR: hazard ratio; LVI: lymphovascular invasion; UTUC: upper tract urothelial carcinoma.
Subgroup analyses of the patients with Nx: Univariate and multivariate Cox regression analyses to identify predictors of cancer specific survival
| Parameters | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
|
| ||||
| HR (95% CI) | p value | HR (95% CI) | p value | |
| Age | 1.034 (0.991−1.078) | 0.126 | − | − |
| Gender (male vs. female) | 1.095 (0.472−2.538) | 0.833 | − | − |
| Smoking (no vs. yes) | 0.621 (0.227−1.697) | 0.353 | − | − |
| Tumour size | 1.003 (0.991−1.015) | 0.639 | − | − |
| Tumour location | ||||
| Renal pelvis | 1 | − | − | − |
| Ureter | 0.813 (0.305−2.169) | 0.679 | − | − |
| Both | 2.280 (0.878−5.922) | 0.091 | − | − |
| Bladder cuff resection (no vs. yes) | 0.408 (0.163−1.024) | 0.056 | − | − |
| Multifocality (no vs. yes) | 1.507 (0.663−3.423) | 0.328 | − | − |
| Pathologic T stage (Ta, CIS, T1–2 vs. T3–4) | 4.903 (2.161−11.126) | <0.001 | 4.432 (1.823−10.771) | 0.001 |
| Grade (low vs. high) | 4.244 (0.998−18.050) | 0.05 | − | − |
| Concomitant CIS (no vs. yes) | 0.960 (0.226−4.077) | 0.956 | − | − |
| Margin status (no vs. yes) | 5.654 (1.928−16.582) | <0.002 | 4.238 (1.382−13.002) | 0.012 |
| LVI (no vs. yes) | 2.406 (1.037−5.581) | 0.041 | 1.073(0.419−2.749) | 0.185 |
CI: confidence interval; CIS: carcinoma in situ; HR: hazard ratio; LVI: lymphovascular invasion; UTUC: upper tract urothelial carcinoma.