Systemic inflammation markers have been linked to increased cancer risk and mortality in a number of studies. According to the studies, NLR, PLR, SII and FAR played an important role in the diagnosis, prognosis and recurrence of tumors. Routine blood test is an essential, non-extra cost component of the preoperative diagnostic workup for all patients scheduled for surgical intervention. Given this, NLR, PLR, SII and FAR may serve as robust, efficacious and reproducible biomarkers for the diagnosis of EC. Therefore, this study assessed the level changes of NLR, PLR, SII and FAR between EEC and endometrial polyps. Additionally, the correlations between these ratios and the clinicopathological characteristics of EEC were analyzed, in order to provide reference for the auxiliary diagnosis and treatment monitoring in EC.
1.NLR
The NLR is the ratio of the number of neutrophils to lymphocytes in the blood, often used as a metric for assessing disease severity, prognostication, and guiding therapy. Qin L et al reported that [10] the best cut-off value of NLR for EC diagnosis was 2.2, and the area under the curve was 0.777. Acmaz G et al showed that the boundary value of NLR was 2.89 in the EC group [11]. Abu-Shawer O et al showed that [12] NLR had a certain role in evaluating the progression and metastasis of EC. However, Firat A et al showed that [13] there was no statistical difference in NLR between patients with benign endometrial diseases and those with EC.
In our study, the NLR levels in EEC group were significantly higher than those in endometrial polyp group (P<0.05, Table 2). And NLR had diagnostic efficacy for EEC, with a critical value of 1.658, AUC of 0.622, sensitivity of 66.4% and specificity of 54.9% (Table 3, Figure1). Our study results were slightly lower than those of the mentioned studies, which may be related to the histological result of the patients included in our study was EEC only.
Moreover, comparative analysis of peripheral blood NLR among patients with EEC, stratified by clinical staging and LNM, has revealed statistically significant differences. These findings suggested a positive correlation between elevated NLR levels and the clinicopathological characteristics of EEC (P<0.05, Table 4). Similar results also had been found in studies of cervical cancer [14].
Several studies have indicated that elevated NLR in patients with EC are correlated with unfavorable prognostic outcomes [15,16]. Barrington DA et al [8] demonstrated that a pre-treatment NLR below 6 was linked to enhanced overall survival (OS) in patients with recurrent EC undergoing immunotherapy. This finding suggested that NLR could serve as a predictive biomarker for post-immunotherapy survival in this patient cohort. Prognosis was not analyzed in our study, but can be evaluated in the later stage.
2.PLR
The PLR has emerged as a novel prognostic biomarker in oncology. Accumulating data suggests that a heightened serum PLR could serve as an indicator of adverse tumor features [17-19]. PLR encompass platelet and lymphocyte counts as key blood cell parameters. Dong Soo Lee et al showed that [19] Baseline PLR significantly associated with overall survival (OS). The PLR exhibited a significant association with LNM and the presence of distant organ metastasis. A pretreatment PLR greater than 148 was found to be associated with poorer OS, but this correlation was observed solely in the context of univariate analysis [20]. A study covering 3,390 patients showed that pre-treatment elevated NLR and PLR are biomarkers of poor prognosis in patients with EC [21].
In our study, the level of PLR in EEC group was higher than that in endometrial polyp group, but the difference was not statistically significant (P>0.05, table2). The observed outcomes may be attributed to the relatively small sample size collected in our study. Upon expansion of the sample cohort, the significance of these differences is anticipated to emerge more distinctly. Vasilios Pergialiotis et al shared [22] the same view with us.
However, our study demonstrated that PLR, similar to NLR, exhibited a strong correlation with FIGO stage and LNM following surgery for EEC (P<0.05, Table4). Teerapat Muangto et al concluded that [23] NLR and PLR was statistically associated with the depth of myometrial invasion in endometrial cancer cases. An NLR of 1.93 or higher and a PLR of 134.95 or higher predicted a depth of invasion exceeding half, which contradicts with our findings. This discrepancy may be attributed to significant statistical differences in the average age, menopausal status, and underlying health conditions between the endometrial cancer and control groups in their study. However, it was noteworthy in our research(P>0.05, table1).
3.SII
SII, which is calculated using absolute platelet, neutrophil, and lymphocyte counts, has recently attracted attentions as a prognostic indicator in patients with malignancies [24]. It may provide a more comprehensive elucidation of the associations between cancer cells and systemic inflammatory environments.
Sho Matsubara et al showed that [25] SII was an independent prognostic factor in EC patients, allowing more precise survival estimation than PLR or NLR. Lei Het al found that [26] elevated SII was an independent risk factor for LNM in patients with EC. In addition, the SII could be used as a predictor of higher pathological grade in young premenopausal EC patients. Similar results have also been found in another study, and the optimal cut-off points for SII was 508.4 (AUC=0.615; sensitivity, 52.4%; specificity, 66.3%) [27].
In our study, SII also showed good diagnostic value. The level of SII was higher in patients with EEC than in the control group (P<0.05, Table2). Compared with NLR and FAR, its AUC value was larger, and it was highly correlated with postoperative FIGO stage and LNM (P<0.05, Table4), which suggesting that SII may better-predicted diagnosis than NLR or PLR in EEC. The results were consistent with previous researches.
Sho Matsubara et al also found that [25] high SII was associated with advanced FIGO stage, higher histological grade and LVSI. However, the same results were not found in our study(P>0.05, Table4). The positive rate of LVSI in our study was 3.52%, which was lower than the study of Feng J et al [28], which showed that the overall positive rate of LVSI in endometrial cancer was 9.31%. This may be due to the high proportion of FIGO I stage patients in our study and that histopathological type was endometrioid carcinoma only, thus the incidence of LVSI positivity was relatively low. As a result, the differences of NLR, PLR, SII and FAR between groups with and without LVSI was not significant.
4.FAR
The fibrinogen-to-albumin ratio (FAR) is a metric derived from the serum levels of fibrinogen (FIB) and albumin (ALB). FIB and ALB are two acute-phase proteins induced in response to systemic inflammation but show opposite abundance trends under cancer inflammatory stimulation. Numerous investigations had demonstrated that FAR correlates with diminished overall survival, recurrence-free survival, progression-free survival, disease-free survival, and time to recurrence [29-31]. Song L et al found that [6] compared to the early-stage ovarian cancer (OC) group, the advanced-stage OC group had significantly higher levels of FAR. Moreover, the OC group with lymph node metastasis exhibited significantly higher levels of FAR, in contrast to the non-metastatic group. Among the six inflammatory-nutritional markers including CA125, HE4, SII, NLR, PLR, and FAR, the FAR displayed the greatest diagnostic value. Onoprienko A et al found that [32] FAR could predict disease-specific survival (DSS) and progression-free survival (PFS) of vulvar cancer, outperforming FIB and ALB alone.
Huayan Li et al [33] reported that, in comparison to the healthy control group, the EC group exhibited a general upward trend in coagulation function indicators, with FIB levels notably increased. They also found that an increase in FIB levels was observed with advancing stages of the disease, suggesting that elevated FIB may serve as a prognostic indicator for endometrial cancer. Seebacher V et al [34] identified that pre-treatment ALB levels constituted independent prognostic factors for both DFS and PFS in patients with EC. Wang F et al found that [35] the levels of FIB and ALB in LVSI group were higher than those in non- LVSI group, and FIB and ALB were independent risk factors for LVSI in EC. Rong Cong et al revealed that [16] high FIB and low ALB were significant prognostic factors for EC patients, and the cut-offs for the indicators were FIB≥3.10g/L, ALB≤42.45g/L for OS and 3.10g/L, 42.45g/L for PFS.
In our study, there were significant differences in FIB and FAR between patients with EEC and endometrial polyps (P<0.05, Table2). ALB in EEC group was higher than that in polyp group, but the difference was not statistically significant(P>0.05, Table2). In the study of Zhang Q et al, 97 patients with EC and 74 patients with endometrial polyps showed [36] statistically significant differences in preoperative high FIB, high FAR, and low ALB between the two groups. The sensitivity, specificity, and AUC of FAR in the diagnosis of endometrial cancer were 60.8%, 93.2%, and 0.796, respectively, higher than 0.590 in our study (Table3), which may be related to the fact that our study did not include other types of EC. They also found that FAR was correlated with LNM and histological grade. However, in our study, FAR was only found to be associated with FIGO stage. The level of FAR in patients with advanced (III/IV) EEC was significantly higher than that in patients with early (I/II) EEC (P<0.05, Table4). The incidence of LNM in patients with early-stage EEC was 3.4%, approximately 97% of early-stage endometrioid EC patients did not have LNM. The results were consistent with previous studies [37].
Although there is an existing body of research concerning the relationship between FIB, ALB and endometrial cancer, there is a relative scarcity of literature on the diagnostic and prognostic implications of the FAR in this context.