Systemic Immune-Inflammation Index Predicts Prognosis of Patients with Esophageal Squamous Cell Carcinoma: A Propensity Score-matched Analysis

Systemic immune-inflammation index (SII), based on peripheral lymphocyte, neutrophil, and platelet counts, was recently investigated as a prognostic marker in several tumors. However, SII has not been reported in esophageal squamous cell carcinoma (ESCC). We evaluated the prognostic value of the SII in 916 patients with ESCC who underwent radical surgery. Univariate and multivariate analyses were calculated by the Cox proportional hazards regression model. The time-dependent receiver operating characteristics (ROC) curve was used to compare the discrimination ability for OS. PSM (propensity score matching) was carried out to imbalance the baseline characteristics. Our results showed that SII, PLR, NLR and MLR were all associated with OS in ESCC patients in the Kaplan-Meier survival analysis. However, only SII was an independent risk factor for OS (HR = 1.24, 95% CI 1.01–1.53, P = 0.042) among these systemic inflammation scores. The AUC for SII was bigger than PLR, NLR and MLR. In the PSM analysis, SII still remained an independent predictor for OS (HR = 1.30, CI 1.05–1.60, P = 0.018). SII is a novel, simple and inexpensive prognostic predictor for patients with ESCC undergoing radical esophagectomy. The prognostic value of SII is superior to PLR, NLR and MLR.

Scientific RepoRts | 6:39482 | DOI: 10.1038/srep39482 been reported in ESCC. In this study, we evaluated the prognostic value of SII in patients with ESCC who underwent radical surgery. We also explore whether SII has more advantages to predict the survival of ESCC population than NLR or PLR. To increase statistical power and to further elaborate on the possible prognostic impact of SII, both Cox's proportional hazards model analysis as well as propensity score matching (PSM) were applied.

Results
Clinicopathological characteristics of Patient. There were 696 males (76.0%) and 220 females (24.0%) with an age range of 37-84 years (median 60.0 years), of which 46 patients were well differentiated, 450 patients were moderately differentiated, and 420 patients were poorly differentiated. According to the 7th AJCC standard, there were 168 patients at stage 0-I, 395 patients at stage II and 353 patients at stage III. Other clinicopathological features are shown in Table 1. The median OS was 42 months (range, 3 to 146 months) and the rate of 3-and 5-year OS was 52.5% and 44.2%, respectively. Patients with SII > 307 in complete datasets were more likely to be men (P = 0.022), poor differentiation (P = 0.004), advanced T stage (P < 0.001), advanced N stage (P < 0.001) and advanced AJCC TNM stage (P < 0.001) ( Table 1). Patients with NLR > 1.7 showed the similar results. PLR > 120 was only associated with advanced AJCC TNM stage (P = 0.015). MLR was associated with sex (P < 0.001), T stage (P = 0.002) and AJCC TNM stage (P < 0.001) in complete datasets ( Table 2).
The prognostic significance of SII, NLR, PLR and MLR. The Kaplan-Meier survival analysis showed that high SII, PLR, NLR and MLR scores were all associated with poor OS in ESCC patients (P < 0.001, P = 0.017, P = 0.001, P = 0.009, respectively) (Fig. 1)  in patients with ESCC in 3-years and 5-years ( Fig. 2). It means SII is superior to NLR, PLR or MLR as a predictive factor in ESCC patients.
Propensity score matching analysis. Considered the sex, histological grade, T stage, N stage and AJCC TNM stage were imbalance between SII ≤ 307 and SII > 307 ESCC patients (Table 1), we applied a 1:2 PSM ratio to minimize these differences. In the PSM analysis, we selected 253 patients from SII ≤ 307 group with matched pairings of the 506 SII > 307 patients using a nearest-neighbour algorithm. These clinicopathological characteristics were balanced and evenly distributed between these groups (all P > 0.1) (

Discussion
Inflammation has been known as a hallmark feature of tumor 15 . The correlation between inflammation and tumor was first reported by Rudolf Virchow in 1863 16 . Recently, accumulating evidence has indicated that inflammation contributes to tumor development, progression and metastasis. Systemic inflammatory scores such as NLR, PLR and MLR have been found to be independent markers of prognosis in a variety of cancers, including ESCC 7-10 .
A novel systemic inflammation score-SII, based on neutrophil, platelet, and lymphocyte counts, was shown to be an independent risk of recurrence and survival for hepatocellular carcinoma, small cell lung cancer, colorectal cancer and gastric cancer patients [11][12][13][14]17 . It was considered to be better than PLR and NLR, and was associated with higher circulating tumor cells (CTCs) levels. In the present study, SII was confirmed to be a novel independent predictor of survival for patients with resectable ESCC by a multivariable Cox regression analysis and PSM analysis. It was shown to be superior to NLR, PLR and MLR as a predictive factor in ESCC patients. Compared with other prognostic factors, the inflammation-based prognostic scores are simple, inexpensive and routinely performed in clinical practice. Meanwhile, SII based on standard laboratory measurements of total platelet, neutrophil, and lymphocyte counts is simple, inexpensive and routinely performed in clinical practice. Thus, there is a potential for SII to be used as a marker for prognosis and treatment response surveillance. Several potential mechanisms may be used to explain the prognostic values of SII in tumor. Cancer-mediated myelopoiesis has been recognised in the promotion of tumor angiogenesis, cell invasion, and metastasis in recent years. In contrast with myelopoiesis during acute infection, stress, or trauma in which circulating immune cells are transient increase, cancer myelopoiesis is associated with persistence of immature myeloid cells 18 . Firstly, neutrophils are not released from the bone marrow until mature ordinarily, however, in the context of inflammation, they were triggered by secretion of cytokines and chemokines, such as interleukin-6 (IL-6), tumor necrosis factor (TNF) and myeloid growth factors 19 . These inflammatory mediators enhance the invasion, proliferation, and metastasis of cancer cell, aid cancer cells to evade immune surveillance, and induce the resistance to cytotoxic drugs 6,20 . The elevated neutrophils can also release plenty of nitric oxide, arginase, and reactive oxygen species (ROS), leading to T cell activation disorders 21 . Secondly, platelets can protect CTCs from shear stresses during circulation, induce epithelial-mesenchymal transition, and promote tumor cell extravasation to metastatic sites 4,22 . Meanwhile, platelets and neutrophils have been reported to promote adhesion and seeding of distant organ sites through secreting vascular endothelial growth factor (VEGF) 5,11,23 . Thirdly, lymphocytes can also secrete several cytokines, such as IFN-γ and TNF-α , to control tumor growth and improve prognosis of cancer patients 24 , and the decreased lymphocyte count and function will impair cancer immune surveillance and defense 6,24 .
Based on the above theory, SII should be a more objective marker that reflects the balance between host inflammatory and immune response status than all the other systemic inflammation index such as the PLR and NLR. In fact, our results confirmed that SII is indeed superior to PLR, NLR and MLR. In addition, many studies have confirmed that non-steroidal anti-inflammatory drugs (NSAIDs) are associated with improved survival outcomes in patients with cancer, including esophageal cancer 25,26 . The patients with ESCC who have a high SII maybe especially benefit from targeted anti-inflammatory with aspirin and non-steroidal anti-inflammatory drugs (NSAIDs).  Although our results demonstrated the prognostic value of SII in ESCC, there are still several limitations in this study. First, it should be noted that most patients with esophageal cancer in China are squamous cell carcinoma, while the most esophageal cancer is adenocarcinoma in western. Therefore, the prognostic significance of SII needs to be validated in patients with esophageal adenocarcinoma. Second, our study was a retrospective study, and there may be selection bias during retrospective data collection. However, we used PSM analysis which can minimize group differences in the baseline characteristics. Third, the majority (77.8%) of patients enrolled in this study had dissected lymph nodes with < 15, so further studies for patients with adequate lymphadenectomy are needed to confirm our results. Fourth, our study is a single retrospective center research study. Thus, a multicenter collaborative prospective study is required to be further verified in a prospective, large-scale collaborative study.
In conclusion, SII is a novel independent prognostic predictor for patients with ESCC undergoing radical esophagectomy. The prognostic value of SII is superior to PLR, NLR and MLR. Based on simple and inexpensive standard laboratory measurements, SII will be a potential marker for ESCC prognosis and treatment response surveillance.

Materials and Methods
Patients. A retrospective analysis was conducted in patients who underwent radical esophagectomy at the Third Affiliated Hospital of Soochow University (Changzhou, China) from January 2002 to December 2012. The dissection area for lymphadenectomy was described as our previous article 27 . All patients received transthoracic radical esophagectomy with mediastinal and abdominal two-field lymphadenectomies. The scope of mediastinal lymphadenectomies included subcarinal, left and right bronchial, lower posterior mediastinum, pulmonary ligament, and paraesophageal and thoracic duct nodes. The scope of abdominal lymphadenectomies included the paracardial, lesser curvature, left gastric, common hepatic, celiac, and splenic nodes. The paratracheal and recurrent laryngeal nerve LNs were also dissected. Cervical lymphadenectomy was not conventionally performed, except for cases of suspicious cervical lymphadenopathy. The inclusion criteria were as  follows: ESCC was confirmed by histopathology, R0 resection, no preoperative or postoperative radiotherapy and/or chemotherapy. At last, 916 patients were enrolled in the current study. The patient follow-up started from the date of surgery and continued up until December 2014 or patients' death. All the patients received postoperative follow-up every 3 months within two years after the operation, and the median follow-up time was 39 months (3-146 months). This study was undertaken according to the Declaration of Helsinki and was approved by the Ethics Committee of Third Affiliated Hospital of Soochow University. Written informed consent was obtained from all participants.
Statistical Analysis. Statistical analysis was conducted with SPSS 22.0 (SPSS, Chicago, IL), Graphpad Prism 6.01 (La Jolla, CA, USA) and R software 3.2.5 (http://www.r-project.org/) with MatchIt packages. The correlations between the inflammation-based prognostic scores and clinicopathological characteristics were analyzed by the χ 2 test. Correlation analysis is using Person's correlation test. Survival curves were plotted using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were calculated by the Cox proportional hazards regression model. The time-dependent receiver operating characteristics (ROC) curve was  used to compare the discrimination ability for OS. PSM was carried out because of imbalance in the baseline characteristics. PSM was done with a nearest-neighbour matching algorithm, allowing a maximum tolerated difference between propensity scores less than 30% of the propensity score SD. A P value less than 0.05 was considered to be statistically significant unless otherwise specified.