The Prognostic Value Of Tumor-infiltrating Neutrophils In Adenocarcinoma Of The Esophagogastric Junction

Background:The incidence of adenocarcinoma of the esophagogastric junction (AEG) has increased steadily, and its mortality has also increased from 2 to 15 deaths per 100,000 over the past 30 years. Several etiological risks such as Barrett’s esophagus, gastroesophageal reflux disease (GERD), acid-suppressive medication use, obesity, and possible genetic and epigenetic alterations might be involved in this development. Recently, many studies have been conducted to investigate the molecular mechanisms of AEG formation and progression. However, the causal relationships between them have not been clarified.Studies suggested that tumor microenvironment played an important role in tumorigenesis and progression. Inflammation has become an important hallmark of cancer. Recently, the relationship between tumor-infiltrating neutrophil (TIN) and tumor outcome has become a research hotspot. Studies showed that high expression of TIN in tumor nest was associated with poor clinical outcome in several human cancers such as renal cell carcinoma (RCC), melanoma, colorectal cancer (CRC), and so on. However, TIN and its role in AEG have not been investigated.Objectives:In this study, we evaluated the expression of TIN in AEG tumor nest by immunohistochemical staining to investigate the possible relationship between TIN and the outcome of AEG patients. Ki-67 was also stained to explore the relationship between TIN and Ki-67.Methords:We conducted a retrospective study on consecutive AEG patients from Shandong Provincial Hospital Affiliated to Shandong University, who underwent complete resection between June 2007 and July 2009. The main inclusion criteria were histological diagnosis of primary AEG and complete surgical resection. The clinicopathological characteristics of the patients were collected and immunohistochemical staining of CD66b and Ki-67 were conducted. The prognostic value and its relationship with clinicopathological characteristics and Ki-67 (a proliferation-associated antigen) expression were analyzed. Statistical analyses were performed using SPSS software program (version20.0; SPSS Inc., Chicago, IL, USA).Results:The relationship between TIN and clinicopathological parameters of 113 AEG patients was analyzed. High level of TIN was found to be associated with T stage (p=0.006), positive lymph node metastasis (N status, p=0.03), and high expression of Ki-67 (p=0.008). Kaplan-Meier survival curves demonstrated a high level of TIN expression to be a significantly unfavorable prognostic factor for overall survival. According to univariate Cox regression analysis, the overall survival was correlated with TNM stage (hazard ratio (HR)=1.93, p=0.02), grade of tumor differentiation (HR=2.10, p=0.002), Ki-67 expression (HR=2.15, p=0.001), and TIN expression (HR=3.93, p<0.001). Further multivariate analysis using a Cox regression model indicated that high grade of tumor differentiation (HR=2.28, p=0.001), Ki-67 expression (HR=1.94, p=0.007), and high level of TIN expression (HR=3.44, p<0.001) were independent prognostic factors for overall survival.Conclusion:In conclusion, our study demonstrated that TIN was an independent unfavorable predictor in the AEG patients. Furthermore, we found that TIN was associated with tumor proliferation and this provides a mechanism for the interaction between TIN and tumor cells.