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Prognostic significance of neutrophil-to-lymphocyte ratio in esophageal squamous cell carcinoma

OBJECTIVE: The purpose of the study was to assess the effect of neutrophil-to-lymphocyte ratio (NLR) on recurrence and survival in patients with Esophageal Squamous Cell Carcinoma (ESCC) undergoing surgery. METHODS: This was a retrospective analysis of the 80 resectable ESCC patients who underwent surgery at Yuzuncu Yil University Faculty of Medicine between 2008 and 2018. Receiver operator characteristics curve of NLR was plotted for disease-free survival (DFS). The area under the curve of NLR was 0.692 (p=0.008) with 65.2% sensitivity and 2.8 with 69.5% specificity. Patients were divided into two groups based on the NLR as follows: NLR <2.8 and NLR ≥2.8. RESULTS: Among 80 ESCC patients, 54 (65.5%) were female. The median age was 55 years (range, 26–77). The NLR was <2.8 in 47 (58.7%) patients. Median DFS was 55 months in patients with NLR ≥2.8, whereas it was not reached in those with NLR <2.8 (p=0.008), with corresponding overall survival (OS) durations of 71 months and not reached (p=0.027). Eastern Cooperative Oncology Group performance score 2, presence of obstruction at diagnosis, lower 1/3 esophageal localization, neoadjuvant treatment, and NLR ≥2.8 were found to be the factors related to survival. CONCLUSION: The present study demonstrated that high pre-treatment NLR was associated with worse DFS and OS in patients with resectable esophageal cancer. We believe that pre-treatment NLR may help guide predicting treatment outcomes in non-metastatic resectable ESCC patients.

Patients' performance status and other clinical features such as weight loss, tumor stage, tumor localization, tumor grade, extent of surgical resection, pre-operative chemoradiotherapy (CRT), and response to pre-operative CRT as well as molecular markers including vascular endothelial growth factor, epidermal growth factor, and p53 have been shown to have prognostic value in EC patients [5][6][7].
Systemic inflammatory response (SIR) is associated with tumor development, apoptosis inhibition, and angiogenesis. In addition, SIR has been shown to be an important factor, leading to tumor progression and metastasis [8]. The neutrophil-to-lymphocyte ratio (NLR), which is an inflammatory-and immunological-based score, can be easily obtained by dividing the total neutrophil count (TNC) by the total lymphocyte count (TLC). Its prognostic value has previously been investigated in a variety of cancers such as lung, stomach, pancreas, hepatocellular, colorectal, and ovarian cancer [9][10][11]. The aim of this study was to investigate the relation of pre-treatment NLR with recurrence and survival in operated ESCC patients.

Study Population
After analyzing the medical records of 430 EC patients who were followed up and treated at the Department of Medical Oncology, Yuzuncu Yil University Faculty of Medicine from 2008 to 2018, a total of 80 patients were included in the final analysis, excluding the patients with the following criteria; age <18 years, benign or malignant hematologic disease, chronic or acute infection, history of immunosuppressive drug use, non-squamous histology (adenocarcinoma, undifferentiated, and small cell carcinoma), unoperated patients, multiple primary tumors, and cases with incomplete data (Fig. 1).

Data Collection
The demographic features including age, gender, comorbid disease (essential hypertension [HT], diabetes mellitus [DM], chronic obstructive pulmonary disease [COPD], chronic ischemic heart disease [CIHD], and initial symptoms, e.g., obstruction, dysphagia, abdominal pain, and weight loss), Eastern Cooperative Oncology Group performance score (ECOG PS), tumor localization (middle 1/3 vs. lower 1/3), tumor grade, disease stage, neoadjuvant chemoradiotherapy (NA-CRT), adjuvant treatment, recurrence and site of recurrence, final status (dead or alive) of patients, and initial laboratory data including carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), hemoglobin (Hb), TLC, total monocyte count (TMC), TNC, and total platelet count (TPC), were obtained from hospital medical records. In all patients, we utilized the initial laboratory data which were obtained after the first diagnosis. NLR was calculated by dividing the TNC by TLC. The platelet-to-lymphocyte ratio (PLR) was found by dividing the TPC by TLC. Patients were grouped according to ECOG PS as 0-1 and 2. Tumor localization was classified as middle 1/3 and lower 1/3. Tumor grade was categorized into two groups as good (1) + moderate (2) and poorly differentiated (3). Receiver operator characteristics curve of NLR was plotted for disease-free survival (DFS). The area under the curve of NLR was found to be 0.692 (95% confidence interval [CI] =0.569-0.812, p=0.008) with 65.2% sensitivity and 2.8 with 69.5% specificity (Fig. 2). Patients were categorized into two groups according to NLR as NLR <2.8 and NLR ≥2.8.

Highlight key points
• Esophageal cancer (EC) is the 6 th cause of cancer-related deaths worldwide.
• At the time of diagnosis, 50-80% of EC patients have locally advanced or metastatic disease.
• The neutrophil-to-lymphocyte ratio (NLR), which is an inflammatory-and immunological-based score can be easily calculated by total neutrophil count and the total lymphocyte count.
• Systemic inflammatory response has been shown to be an important factor, leading to tumor progression and metastasis.
• High pre-operative NLR was associated with worse survival in patients with ESCC.   Table 1). The NLR in 47 (58.7%) patients was <2.8, while it was ≥2.8 in 33 patients. There was no remarkable difference between NLR groups (<2.8 vs. ≥2.8) in regard to CEA, CA19-9, TMC, and TPC, whereas there was statistically significant difference between the groups in terms of TNC, TLC, Hb, and PLR (Table 2).

DISCUSSION
EC is a very aggressive disease with poor prognosis. Besides TNM staging to determine patients at high risk for recurrence, the identification of new markers augments the chances of early diagnosis and intervention, providing more favorable treatment outcomes. NLR can be easily calculated through a simple hemogram analysis, which is easy, affordable, and cost-effective blood test. The present study investigated the relation of NLR with recurrence and survival in non-metastatic ESCC patients treated with curative surgery and concluded that both DFS and OS were significantly lower in patients with NLR ≥2.8, with NLR ≥2.8 increasing the risk of recurrence by 5.4 times. Systemic inflammation can contribute to tumor development through some pathways such as genomic instability, genetic mutations, and epigenetic modification. Inflammation activates tissue repair responses that induce the proliferation of premalignant cells and ensure their survival. In addition, inflammation leads to immunosuppression, resulting in formation of microenvironments through which malignant cells can survive. Systemic inflammation also promotes metastatic spread by stimulating angiogenesis [8]. Systemic inflammatory markers such as NLR, which can reflect the inflammatory status of patients, have been shown to predict mortality and recurrence in various cancers in the previous studies [9][10][11][12][13]. In a study of 295 curatively operated EC patients, 75 of whom were ESCC, the cutoff value for NLR was found to be 5 and patients with high pre-     operative NLR were shown to have worse OS and DFS than those with low pre-operative NLR [12]. Duan et al. [14] found that patients with high pre-operative NLR had significantly worse tumor-specific survival and recurrence-free survival rates than those with low pre-operative NLR in ESCC patients who underwent curative surgery, indicating that NLR had the most significant predictive effect, particularly for patients with Stage IIIA disease. Similarly, Xu et al. [15] reported the cutoff value for NLR to be 2.99 in their study with ESCC patients and concluded that pre-operative NLR was significantly associated with long-term prognosis, especially in patients with lymph node metastasis and Stage II-III disease. However, Rashid et al. [16] reported that NLR (cutoff; 3.5) was not associated with DFS in their study including 294 EC patients, only 50 of whom were ESCC. In our study, cutoff value of NLR for DFS was detected 2.8, with 65.2% sensitivity and 69.5% specificity. We found no significant difference between NLR groups in terms of disease stage and NACRT rates. Besides, the locoregional relapse rate was significantly higher in the patients with NLR ≥2.8. Similar to the findings observed in other studies, we showed that high pre-operative NLR negatively affected both DFS and OS [12,14,15].
In the neoplastic process, neutrophilia can be observed due to the granulocyte colony-stimulating factor produced by malignant cells. Moreover, myeloid growth factors are produced as a part of paraneoplastic syndrome, which can contribute to neutrophilia. Interleukin-6 and tumor necrosis factor-a secreted by tumor cells can also cause neutrophilia and therefore inflammation. In addition, a significant decrease in CD-4 helper lymphocytes and increase in CD-8 suppressor lymphocytes represent a depression in natural cellular immunity. For many types of cancer, lymphocytopenia indicates a general immunosuppression condition, which seems to affect survival. Depression in T-cell function can weaken the tumor-specific response [17][18][19][20][21]. These mechanisms above may explain, albeit partially, how NLR affects oncological results.
The strengths of our study were as follows; *follow-up period was relatively longer, *unlike other studies, only ESCC patients were included, *NLR groups were homogeneous [16,12], and *comorbidities and presenting symptoms were also analyzed. However, our study was designed as a retrospective and single-center study. In addition, our study was conducted in an area where ESCC is endemic; we, therefore, do not know how these conditions affect our results.

Conclusion
This study revealed that high pre-operative NLR was associated with worse DFS and OS in patients with ESCC. The determination of NLR is pretty simple, cost effective, and easily available in daily oncological practice. Based on the findings mentioned above, we believe that pre-treatment NLR can provide important information to predict treatment outcomes in non-metastatic operable ESCC patients.

Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study has received no financial support.