Influence of Biopsy Gleason Score on the Risk of Lymph Node Invasion in Patients With Intermediate-Risk Prostate Cancer Undergoing Radical Prostatectomy

Objective: To analyze the influence of biopsy Gleason score on the risk for lymph node invasion (LNI) during pelvic lymph node dissection (PLND) in patients undergoing radical prostatectomy (RP) for intermediate-risk prostate cancer (PCa). Materials and Methods: We retrospectively analyzed 684 patients, who underwent RP between 2014 and June 2020 due to PCa. Univariable and multivariable logistic regression, as well as binary regression tree models were used to assess the risk of positive LNI and evaluate the need of PLND in men with intermediate-risk PCa. Results: Of the 672 eligible patients with RP, 80 (11.9%) men harbored low-risk, 32 (4.8%) intermediate-risk with international society of urologic pathologists grade (ISUP) 1 (IR-ISUP1), 215 (32.0%) intermediate-risk with ISUP 2 (IR-ISUP2), 99 (14.7%) intermediate-risk with ISUP 3 (IR-ISUP3), and 246 (36.6%) high-risk PCa. Proportions of LNI were 0, 3.1, 3.7, 5.1, and 24.0% for low-risk, IR-ISUP1, IR-ISUP 2, IR-ISUP-3, and high-risk PCa, respectively (p < 0.001). In multivariable analyses, after adjustment for patient and surgical characteristics, IR-ISUP1 [hazard ratio (HR) 0.10, p = 0.03], IR-ISUP2 (HR 0.09, p < 0.001), and IR-ISUP3 (HR 0.18, p < 0.001) were independent predictors for lower risk of LNI, compared with men with high-risk PCa disease. Conclusions: The international society of urologic pathologists grade significantly influence the risk of LNI in patients with intermediate- risk PCa. The risk of LNI only exceeds 5% in men with IR-ISUP3 PCa. In consequence, the need for PLND in selected patients with IR-ISUP 1 or IR-ISUP2 PCa should be critically discussed.


INTRODUCTION
Prostate cancer (PCa) is the most common malignancy in men and still results in high amounts of cancer-specific deaths (1)(2)(3)(4)(5) worldwide. There is an ongoing debate, which patients undergoing radical prostatectomy (RP) in a curative intent, benefit most from pelvic lymph node dissection (PLND) (6,7). Due to the morbidity caused by PLND (8,9), European guidelines recommend PLND in selected patients with a risk for lymph node invasion (LNI) of >5%, using specific nomograms (10)(11)(12)(13)(14). Temporal trends have shown higher rates of PLND in patients with D'Amico intermediate and high risk in recent years (15). Nonetheless, since patients with D'Amico intermediaterisk group PCa have a high heterogeneity according to tumor characteristics (16)(17)(18), it still remains unclear, if PLND can be avoided in selected patients with intermediate-risk PCa (19).
We tried to address this relevant question by analyzing patients, who underwent RP with PLND for intermediaterisk PCa. In the present study, we stratified patients with intermediate-risk PCa by their international society of urologic pathologists (ISUP) grade, to identify patients with PCa with higher risk of LNI and the need of undergoing PLND.

Study Population
After approval of the ethic committee, 684 consecutive patients who underwent RP (either robotic or open) at the Department of Urology at Frankfurt University Hospital between January 2014 to June 2020 were identified from the institutional database and evaluated retrospectively. Indications for RP was biopsy (either systematic or targeted biopsy) confirmed PCa. Patients with unknown PSA at PCa diagnosis, unknown clinical T stage and unknown ISUP grade at biopsy were excluded (n = 12). This selection criteria yielded in 672 eligible patients, of whom 366 patients harbored intermediate-risk PCa.

Statistical Analysis
Descriptive statistics included frequencies and proportions for categorical variables. The means, medians and interquartile ranges (IQR) were reported for continuously coded variables. The Chi-square test was used for statistical significance in proportions' differences. The t-test and Kruskal-Wallistest examined the statistical significance of means' and distributions' differences. To
Those observations reflect the heterogeneity of patients with intermediate-risk PCa and make it crucial to distinguish several risk groups within those patients with intermediate-risk PCa (16,20), since each of our subgroups differ in patient and tumor characteristics. For example, National Comprehensive Cancer Network (NCCN) guidelines recommend distinguishing and stratify between favorable and unfavorable intermediate-risk PCa, taking into account, that IR-ISUP3 accounts for an unfavorable status in any case (21). The distinction into three groups according to ISUP grade in the present study leads automatically to higher proportions of PSA > 10 ng/ml and/or cT2b stages in patients with IR-ISUP1, since otherwise those patients would have been classified into low-risk D'Amico group and thus reflect a relatively rare cohort of patients with intermediate-risk PCa. However, in IR-ISUP1 patients, the higher proportions of more unfavorable tumor characteristics did not translate into higher proportions of unfavorable pathological characteristics. Conversely, unfavorable pathological characteristics, for example, ≥pT3 stage were the highest in patients with IR-ISUP3 and IR-ISUP2 PCa, in that order. This observation may confirm that ISUP grade/Gleason score is the best predictor for worse pathological outcome of those tumor characteristics used within the D'Amico classification (22)(23)(24)(25).
Second, we showed important findings concerning the influence of ISUP grade at biopsy and risk of LNI after PLND. According to intermediate-risk stratified analyses, IR-ISUP3 exhibited highest rates of LNI (5%), followed by IR-ISUP2 (4%) and IR-ISUP1 (3%), in that order. Moreover, significantly higher rates of LNI were observed in patients with high-risk PCa (24%), where the stratification according to ISUP grades also yielded to different probabilities of LNI (Figure 1) (10,11). Nonetheless, it is noteworthy to consider that a contemporary investigation demonstrated that PLND in patients with >5% risk of LNI did not yield to better oncological survival outcome in patients with intermediate-and high-risk PCa, relative to non-performance of PLND (24). However, our results suggest that stratification according to ISUP grade in patients with intermediate-risk PCa predicts LNI for clinical considerations, as previous publications have also shown ISUP grade/Gleason score at biopsy in general to be an independent risk factor for LNI (26). In consequence, PLND should be performed in patients with higher ISUP/Gleason score at biopsy and might be omitted in selected patients with intermediate risk with ISUP grade 1.
Third, the median numbers of removed lymph nodes were 10, 12, and 12 for IR-ISUP1, IR-ISUP2, and IR-ISUP3 subgroups, respectively. In univariable logistic regression, the number of removed lymph nodes was a predictor of LNI but failed statistical significance in multivariable analyses (p = 0.058). Since guidelines recommend an extended PLND, due to improved staging information, our median number of removed lymph nodes in intermediate-risk subgroups may suggest that extended PLND was not performed in all patients especially with IR-ISUP1. Nevertheless, a conclusive assessment cannot be made solely looking at the numbers of removed lymph nodes, instead of anatomical regions (6,10,27). However, it should be emphasized that some studies question the need for extended PLND in intermediate-risk PCa and 90% of all lymph node metastases in cT2 tumors can be detected with the removal of six to eight lymph nodes (28,29). In consequence, our median number of removed lymph nodes might discover the majority of lymph node metastases in our intermediate-risk PCa patient subgroups.
Our study has several limitations. First, our study is based on retrospective analyses. Second, LNI is affected by the extension of PLND and number of removed lymph nodes. Unfortunately, information regarding the field and template of the LND were not available for the current study and may also be influenced by the surgical approach. Third, information on patients' comorbidities are missing. Fourth, no information regarding the use of modern staging modalities such as PSMA PET/CT was available. Furthermore, no information of the Gleason scores and numbers of different PCa foci were available. Finally, our results consist of no data according to biochemical recurrence or survival. However, this study did not aim to investigate those outcomes.
Taken together, important differences according to LNI in different intermediate-risk subgroups exist. Intermediate-risk PCa is heterogeneous according to patient and tumor characteristics and can be stratified according to ISUP grade. The risk of LNI increases with higher ISUP grade at biopsy in intermediate-risk PCa and reaches >5% only in the IR-ISUP3 subgroup. Therefore, PLND might be omitted in selected patients with intermediaterisk PCa.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by Ethics Committee, Goethe University Hospital Frankfurt, SUG-1-2018. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

AUTHOR CONTRIBUTIONS
MW: manuscript writing/editing, protocol/project development, and data analysis. BH, CWi, CWü, AB, and PM: manuscript writing/editing. MW and FP: data analysis. CH: data collection or management. PK: data analysis and manuscript writing/editing. FC: protocol/project development. LK: protocol/project development and manuscript writing/editing. All authors contributed to the article and approved the submitted version.