The significance of pelvic lymph node dissection in radical prostatectomy and its influence on the prognosis of patients with prostate cancer

Introduction

Prostate cancer (PCa), with the second highest mortality rate, has become the most common malignant tumor among men in the United States (1). Also, this illness has recently become the most common malignancy in the male genitourinary system in China (2).

The gold standard for determining the lymph node metastasis (LNM) is pelvic lymph node dissection (PLND) (3). After estimating the likelihood of LNM via the Briganti nomogram, extended PLND (ePLND) was then conducted in patients with a metastatic risk of more than 5%, according to European Association of Urology (EAU) guidelines (4). PLND was commonly believed to enhance pathological staging precision; nevertheless, it can increase the risk of intraoperative anesthetic and perioperative complications (5). For lack of high-quality and large-sample cohort studies in China, the benefits of PLND in PCa treatment remain uncertified.

The aim of the study is to inspect the risk factors for LNM and the impact of PLND on patient’s oncology outcomes. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-200/rc).

Methods

Patient population

Data was retrospectively collected from 1,502 patients who underwent radical prostatectomy (RP) by a single surgeon at our institution between February 2009 and April 2021. Twenty-eight patients were excluded due to incomplete clinical data. There were 1,474 patients with intact clinical details with regard to PLND included, amongst which 956 cases (64.9%) went through PLND while 518 cases (35.1%) did not. In general, the extent of PLND consists of obturator node resection and ePLND; the obturator node resection includes the removal of the obturator region alone, and ePLND includes the removal of the obturator, external iliac, and internal iliac lymph nodes. The data of all patients included in this study were obtained from the PCa clinical medical data platform designated by the China Prostate Cancer Consortium.

Oncological outcomes

Considering the survival analysis, patients who received neoadjuvant hormonal therapy and adjuvant therapy were excluded. A total of 1,038 individuals were enrolled, including 137 node-positive patients. Evaluation indexes of oncological outcomes consist of biochemical recurrence and disease progression. Biochemical recurrence was defined as two consecutive prostate-specific antigen (PSA) values ≥0.2 ng/mL; radiographic progression was defined as positive imaging performed during follow-up following radical prostatectomies, such as bone scans, pelvic computed tomography (CT)/magnetic resonance imaging (MRI), prostate-specific membrane antigen (PSMA)-positron emission tomography (PET)/CT or chest CT. Any of the above conditions were referred to as disease progression.

Statistical analyses

Descriptive statistical methods were used to compare the clinical characteristics of the patients. For continuous variables, median values were calculated via interquartile ranges (IQRs) and compared with the Mann-Whitney test. Categorical variables were presented as counts and proportions (%) and compared using the Chi-squared test. Multivariable logistic regression analysis (MVA) was used to assess the relationships between variables and PLND as well as the associations between variables and LNM. Variables consisted of age, body mass index (BMI), PSA, International Society of Urological Pathology (ISUP) grades, clinical T stage and risk stratification. Risk stratification was based on the EAU guidelines. Survival estimates were generated and compared using the Kaplan-Meier method and log-rank test, respectively. Propensity score matching (PSM) was used minimize selection bias with a caliper distance of 0.001 based on baseline characteristics. Age, BMI, PSA, ISUP grades, clinical T stage and risk stratification were used in PSM. All tests were two-sided with a statistical significance set at P<0.05. Analyses were performed with the IBM SPSS Statistics 25 program.

Ethics statement

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethics committee of Shanghai Changhai Hospital (No. CHEC2023-310). The requirement for informed consent was waived because clinical data, including patient information and laboratory test results, were retrospectively obtained and analyzed.

Results

Patients characteristics

Clinical and pathological characteristics of 1,474 patients with PCa are presented in Table 1. PLND was performed in 956 (64.9%) patients during RP, of which 368 (38.49%) patients underwent obturator node resection, 583 (60.98%) patients ePLND, and 5 (0.52%) patients with unknown extent of lymph node resection.

MVA analysis identifying predictors of PLND implied that patients with lower age [odds ratio (OR) =0.975; 95% confidence interval (CI): 0.958–0.992; P=0.004], higher PSA values (OR =1.034; 95% CI: 1.024–1.045; P<0.001), higher ISUP grade (OR =1.621; 95% CI: 1.439–1.825; P<0.001), lower clinical T stage (OR =0.712; 95% CI: 0.571–0.890; P=0.003) and higher risk stratification (OR =1.438; 95% CI: 1.102–1.877; P=0.008) were at higher risk for undergoing PLND during RP (Table 2).

Extent of PLND

Patients’ characteristics are shown in Table 3. The positive rates of obturator resection and ePLND were 10.05% and 20.58%, respectively, and the difference was statistically significant (P<0.001). In the clinical T1/T2, ISUP ≤3, PSA <20 ng/mL and PSA ≥20 ng/mL subgroup analysis, a statistically significant difference was noted in the positive rate of lymph nodes between the two methods (P<0.05); in the clinical T3/T4, ISUP >3 subgroup, there was no statistical difference (P>0.05; Table 4).

Predictors of LNM

Among 956 patients who underwent PLND, 159 lymph node invasion (LNI) patients (16.63%) were confirmed LNM by postoperative pathology. MVA analysis identified independent predictors of LNM were correlated with higher ISUP grade (OR =1.506; 95% CI: 1.259–1.802; P<0.001), higher clinical T stage (OR =1.737; 95% CI: 1.340–2.253; P<0.001) and higher risk stratification (OR =9.138; 95% CI: 2.187–38.176; P=0.002; Table 5).

Prognostic effect of PLND

The median follow-up time in this study was 25 (95% CI: 23.13–26.87) months. In the entire cohort, compared with the RP + PLND group (n=629), the RP group (n=409) had better biochemical recurrence-free survival (P<0.001; Figure 1A). After PSM of patients with and without PLND, 190 patients were identified in each group (Table S1), no significant difference of survival outcomes was found in patients with and without PLND (P=0.80; Figure 1B). Considering of the extent of PLND, as shown in Figure 1C, patients with obturator PLND (n=264) had better biochemical recurrence-free survival compared to those with ePLND (n=362, P=0.007). In the PSM cohort, 118 patients were identified in each group, and there was no significant difference in survival outcomes between the two groups (P=0.16; Figure 1D).

Figure 1 Biochemical recurrence-free survival for patients receiving RP + PLND and RP in the entire cohort: (A) before PSM, (B) after PSM; biochemical recurrence-free survival for patients receiving obturator resection and ePLND: (C) before PSM, (D) after PSM. PLND, pelvic lymph node dissection; ePLND, extended pelvic lymph node dissection; RP, radical prostatectomy; PSM, propensity score matching.

Among the 137 patients with positive lymph nodes, 61 patients received adjuvant therapy, and 76 patients did not receive adjuvant therapy. The disease progression-free survival of the two groups was compared, and the results showed that the adjuvant therapy group was better than the non-adjuvant therapy group, with statistical significance (P<0.001; Figure 2A). Compared with patients without PLND, the results indicated that the adjuvant therapy group had better disease progression-free survival than the non-PLND group, with prominent statistical significance (P=0.02; Figure 2B).

Figure 2 Prognostic analysis of positive lymph nodes in patients with prostate cancer: (A) disease progression-free survival for patients with adjuvant and without adjuvant in the positive lymph nodes cohort; (B) disease progression-free survival for patients with adjuvant and RP alone. PLND, pelvic lymph node dissection; LNI, lymph node invasion; RP, radical prostatectomy.

Discussion

It is generally believed that the prognosis after RP would probably be less than satisfactory when there are adverse pathological features, such as extraprostatic extension, seminal vesicle invasion or LNM. Although abundant advanced imaging techniques can be used to assess nodal invasion, the accuracy remains controversial, for example, CT and MRI sensitivity is only about 40% (6). PLND not only provides accurate pathological staging, but also provides solid evidence for adjuvant treatment. On the other hand, as the scope of PLND expands, it will extend operation time and increase the chance of perioperative complications as well (5). Thus, there are differing views regarding the role and scope of PLND in patients with PCa. According to the EAU and National Comprehensive Cancer Network (NCCN) guidelines, PLND and the extent of resection benefit limited patients, yet previous studies have shown that surgeons’ compliance with the recommendations of the guidelines is only 67% to 70% and the rate of pelvic lymphadenectomy is approximately 63.5% amongst multiple centers (7,8). In our study, the overall PLND rate was 64.9%, conducted after a thorough evaluation of PSA, Gleason score of biopsy and distribution of suspicious lesions.

The incidence of LNM ranges from 1.1% to 26% (9). In this study, the rate of LNM was 16.63%. Studies have shown that in patients with PSA <10 ng/mL and GS ≤6, the probability of LNM is about 1–2% (10,11). Heidenreich et al. found that among patients with PSA <10.5 ng/mL and GS ≤6, only 2.4% of them developed LNM, while LNM occurred to 95% of high-risk patients (PSA >10.5 ng/mL and GS >7) (12). According to our research, as for patients with PSA <10 ng/mL, only 6 (2.8%) of them had LNM; while in T3/4 and ISUP 4/5 patients, the LNM rates were 33.8% and 25.8%, respectively. The study by Briganti et al. showed that the detection rate of LNM amplified with the amount of removed lymph nodes (13). In our research, the detection rate of positive-lymph nodes in ePLND was positively higher than that of obturator lymph node resection. Differences in the clinical characteristics of patients between the two groups may explain this phenomenon. Similarly, in the subgroup analysis of clinical T1/T2 group, ISUP ≤3 group and PSA <20 ng/mL group, the difference still existed. We believe that this may be correlated with disease characteristics that require more extensive resection to detect more node-positive patients in the early stages of the disease.

Studies have shown that there is no statistically significant difference in the effect of PLND on the postoperative biochemical recurrence of patients, and this conclusion might still be drawn in each subgroup analysis (14,15). Conversely, Boehm et al. found in 11,127 PCa patients that compared with the PLND group, the risk of biochemical recurrence was reduced in the non-PLND group [hazard ratio (HR) =0.81; 95% CI: 0.72–0.9; P<0.05] (16). Similar conclusions were reached by Liss et al. in a cohort study of 492 patients (17). Akin results were achieved in this research. Differences in baseline data between the two groups may, to some extent, explain the higher risk of recurrence in the PLND group. A retrospective study suggests that resection of more lymph node regions may provide a better survival benefit (18). A single-center randomized prospective phase III study, containing 300 patients with intermediate/high-risk localized PCa, showed no significant difference in biochemical recurrence-free survival and metastasis-free survival between ePLND and standard PLND (19). In this study, comparing the biochemical recurrence-free survival of patients with obturator node resection and ePLND, statistical significance of obturator node resection was observed in improving the survival outcomes. After PSM, baseline characteristics were well balanced and no significant difference in survival was found between men with and without PLND, as well as those underwent obturator node resection and ePLND.

LNM often predicts poor disease outcomes and is associated with an increased risk of mortality from disease (20,21). Currently, treatment of positive lymph nodes includes observation (until disease progression), androgen deprivation therapy (ADT), and adjuvant radiotherapy (aRT). A previous study was implemented on the prognostic effects of observation and ADT in 98 PCa patients with positive lymph nodes. The 7-year overall survival rate and disease-specific survival rate of the ADT group were advantageous over those of the observation group (85.1% vs. 64.7%, P=0.02; 93.6% vs. 68%, P=0.001) (22). Similar conclusions were observed in this study. In addition, we compared the prognosis of patients with positive-lymph nodes who received adjuvant therapy after surgery with those who did not undergo PLND. The results showed that the prognosis of patients in the adjuvant therapy group preceded the non-PLND group, which sufficiently depicted the necessity of PLND in some patients. Therefore, we hypothesized that for some patients, it would be beneficial to carry out an evaluation of LNM and timely adjuvant therapy.

It should be pointed out that this study is a retrospective study, and the time span of surgery was from 2009 to 2021. During this period, changes in the pathological assessment of disease (Gleason Grade), patient selection for PLND, and surgical technique were unavoidable sources of bias. In addition, the median follow-up time of this cohort was merely 25 months. A more comprehensive evaluation of the patient’s oncological prognosis would require a relatively long-time follow-up.

Conclusions

The direct effect of PLND on the oncological prognosis of PCa patients has not yet been entirely determined, yet ePLND can significantly improve the detection rate of positive lymph nodes, offer subsequent treatment guidance for patients, and somehow affect the oncological prognosis of patients.

Acknowledgments

Funding: This work was supported by Program of Shanghai Subject Chief Scientist (No. 22XD1405000), Promote Clinical Skills and Innovation Ability of Municipal Hospitals Project (No. SHDC22021215).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-24-200/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-200/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-200/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-200/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethics committee of Shanghai Changhai Hospital (No. CHEC2023-310). The requirement for informed consent was waived because clinical data, including patient information and laboratory test results, were retrospectively obtained and analyzed.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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