Predictive Value of Platelet-to-Lymphocyte Ratio and Systemic Immune ‐ Inammation Index in Adverse Pathology at Radical Prostatectomy in Patients with Low-Grade Prostate Cancer

Purpose: To determine the potential role of several biochemical and clinical markers in predicting adverse pathology (AP) and ISUP GG upgrading at radical prostatectomy (RP) with low-grade (ISUP Gleason Group (ISUP GG) 1 and 2) prostate cancer (PCa). Methods: We retrospectively reviewed the patients who underwent radical prostatectomy following criteria: clinical stage T2a or less,and were identied low-grade PCa (ISUP GG 1−2, prostate-specic antigen (PSA) <20 ng/ml) through prostate biopsy, univariate and multivariate analyses were performed to evaluate the association of patient and tumor characteristics with reclassication, dened as dened as stage ≥ T3 and/or ISUP GG ≥ 3. Results: A total of 155 patients were eligible for this study. AP at RP occurred in 20 of 97 (20.62%) patients with ISUP GG 1, and 28 of 58 (48.28%) with ISUP GG 2. At univariate analysis, bioptic ISUP GG emerged as signicant risk factors of AP(p (cid:0) 0.001). platelets to lymphocyte ratio(PLR) might be the risk factor of AP(p=0.059). At multivariate analysis, we found PLR and bioptic ISUP GG kept statistical signicance. The area under the curve for PLR was 0.592. Multivariate analyses showed that systemic immune inammation index(SII), and bioptic ISUP GG were signicantly associated with ISUP GG upgrading (ORs ranging from 0.453 to 0.999) showing a protective effect. Conclusions: We found that SII could not be a signicant risk factor of AP at low-grade prostate cancer (PCa) after RP. PLR might be used as an independent predictor which was inversely correlated with presence of AP in low-grade PCa after RP. While SII might be a predict factor for ISUP GG upgrading in low-grade PCa.


Background
In ammation plays a key role in the occurrence and development of many tumors. In ammatory oxidative stress stimulation may cause normal cells to produce relatively abnormal protein expression and DNA damage, which is associated with the occurrence of cancer [1]. In fact, tumor-related in ammation is considered to be a key factor for tumor invasion, migration and metastasis in many cancer [2,3]. The immune system can also recognize and eliminate transformed tumor cells that express modi ed antigens, a phenomenon known as immune surveillance [4]. At present, many clinical studies commonly use some in ammation indicators to predict the in ammation level.
The ratio of neutrophil to lymphocyte ratio (NLR) has been proposed as an indicator of cancer-related in ammation and poor prognosis of several types of cancer [5,6]. Jang et al reported that preoperative NLR could be used as an independent factor to predict cancer-speci c survival [7]. Gokce et al proposed that higher NLR was related with higher Gleason Score of prostate cancer(PCa) in their study [8]. The prognostic nutritional index(PNI) and systemic immune in ammation index(SII) could demonstrated the nutritional status and in ammation level of the human body. The previous studies also showed the predictive value of PNI and SII in various tumors [9,10]. However, few studies have shown the predictive role of PNI and SII in the prognosis of PCa. Therefore, in this present study, we invested the relationship between PNI, SII, NLR, platelets to lymphocyte ratio(PLR) and pathology results(adverse pathology, ISUP GG upgrading) in patients with low-grade PCa having undergone RP.

Study End Points
The primary end points of the study were to determine the accuracy of PNI, SII, NLR, PLR in predicting AP and ISUP GG upgrading after RP. The de nitions of PNI, SII, NLR, and PLR were shown as follows: PNI = albumin (g/L) + 5 × total lymphocyte counts (10 9 /L); SII = platelet × neutrophil/lymphocyte counts; NLR = neutrophil/lymphocyte counts; and PLR = platelet/lymphocyte counts. Adverse pathology(AP) at RP de ned as ISUP GG ≥ 3 and/or extraprostatic disease (≥ T3).

Statistical Analysis
The entire statistical process was performed with SPSS 22.0 software. Non-normal and continuous variables are expressed as mean ± SD. The Pearson's chi-square test was used to compare dichotomous variables. Univariate and multivariate logistic regression analysis were used to screen out the independent risk factors for adverse pathology of all biopsy patients. All analyses are bilateral analysis, p < 0.05 has statistical signi cance.

Results
Between April 2010 to May 2020, a total of 155 patients underwent PBx and RP at our Institution. Among them, 155 patients, namely 99 (63.8%) with ISUP GG ≤ 1 PCa and 56 (36.2%) with ISUP GG 2 PCa were eligible for this study. The mean age (± SD) of the study subjects was 65.9 (± 6.86) years, and the mean PSA was 9.64 (± 4.32; Table 1). At multivariate analysis, we found PLR, bioptic ISUP GG kept predictive value in the incidence risk of AP (Table 3). The AUC of the model was 0.592 of PLR (Fig. 1). Univariate analysis showed that ISUP GG upgrading ( Table 2), but not AP (Table 2), was signi cantly associated with Biopsy ISUP GG, with p values = 0.043. Multivariate analysis con rmed the association of ISUP GG upgrading with SII, Biopsy ISUP GG with ORs ranging from 0.453 to 0.999.

Discussion
Previous studies [11,12]had shown in their studies that most patients with low-grade PCa through biopsy might have pathological upgrade/upstage after RP. Although many recent studies have found some valuable clinical markers or parameters that can predict postoperative pathological upgrade in patients with low-risk PCa [13,14].There were no clinically recognized biomarkers or other indicators that could determine whether low-grade PCa would upgraded after surgery.
At different stages of tumor development, the in ammatory response plays a decisive role, including initiation, promotion, malignant transformation, invasion and metastasis [15,16].The level of in ammation in the human body has an important impact on the risk of tumor development and the prognosis of cancer patients. Some in ammation indicators including NLR, PLR were considered as effective predictors for predicting the prognosis of malignant tumors in some studies [17,18]. Ferro et al demonstrated that NLR, PLR were predictors of Gleason upgrading but not with upstaging in low-risk PCa [19]. Gokce et al also proposed that higher GS was associated with higher NLR in patients with PCa [20].These conclusions seemed to indicate that in ammation may promote the occurrence and development of PCa. However, in our study, we found that NLR and PLR did not predict postoperative ISUP GG upgrading in patients with low-grade PCa. However, in multivariate analysis, we found that only PLR was inversely related to the risk of AP after RP. In addition to the in ammation indicators shown by blood, Sanguedolce et al reported a meaningful conclusion that low-grade in ammation of the bioptic tissue may increase the risk of postoperative AP in patients with low-grade PCa [21]. This opinion was similar to ours, the low-grade in ammation of prostate tissue may predict poor outcomes. Therefore, the role of in ammation in the occurrence and development of PCa remains controversial. Recently, some studies had found that PNI and SII were used as independent predictors to predict the prognosis of some tumors [9,10]. However, in our study, PNI could not play a role in predicting the risk of AP and ISUP GG upgrading in patients with low-grade PCa. However, in multivariate analysis, SII was an independent protective factor for the risk of ISUP GG upgrading.
There were few limitations in our study. First, our research was a retrospective study, so some information or data may be biased. Besides, other in ammatory factors may also affect the results of the study, but we did not include these factors. Furthermore, We have included a small number of population, and the results may be biased.

Conclusion
In conclusion, PLR is an independent predictor of AP in patients with low-grade PCa after RP. And also, SII may be an important predictor of ISUP GG upgrading. However, we still need further large research to identify our results.

Ethics approval and consent to participate
The study was approved by the Regional Ethical Review Board in Tianjin medical university second hospital. Written informed consent was obtained from all participants included in the study.

Consent for publication
Not applicable.

Availability of data and materials
All data generated or analyzed during this study are included in this

Competing interests
The authors declare no con ict of interest.

Funding
This project was support by: Tianjin Science and technology committee(19ZXDBSY00050). The founding bodies had no in uence on the design of the study, data collection, data analysis, and interpretation of data; or writing of the manuscript.