In this analysis of 71 patients with ACC,we found that the preoperative NLR can be a predictive biomarker for OS in ACC and is related to TNM stage and the LNM.Participants were divided into two groups according to the cutoff value, and chi-squared tests were applied to evaluate the clinical and pathologic characteristics of patients with ACC.We found that the preoperative NLR l was closely related to the TNM stage and LNM (P <0.05). No obvious correlations with age, sex, location,treatment or perineural invasion were observed (P >0.05). We used Kaplan-Meier survival analysis to determine the relationship between the NLR and OS and the NLR and DFS. Patients with a NLR >2.071had a shorter OS (P <0.05), and the NLR was not associated with DFS (P >0.05).We used a Cox regression model and analyzed sex, age, TNM stage, nerve invasion, LNM and NLR of patients. We found that the NLR (HR 0.22, 95% CI [0.07–0.66]) and age(HR 0.31, 95% CI [0.12-0.81]) were independent risk factors for OS in patients with ACC. The finding that a high NLR (>2.071) was a strong indicator of OS in patients with ACC appears to be novel.
Neutrophils display a protumor phenotype that could be detrimental to the host. The tumor microenvironment controls neutrophil recruitment, and in turn, neutrophils can strengthen the biological behavior of the tumor, causing it to grow and metastasize16. The mechanisms for this phenotype are just beginning to be demonstrated,but some of them involve genotoxicity, angiogenesis, and immunosuppression.It can change the tumor microenvironment by producing cytokines and chemokines and can also promote the transformation of normal cells into tumor cells by secreting reactive oxygen species and proteases and promoting cell migration and diffusion17.Liu reported that tumor-infiltrating neutrophils were related to the OS of patients with non muscle invasive bladder cancer (NMIBC)18.
Lymphocytes are the strongest parts of the adaptive immune system, which upon invasion of the tumor manifest the formation of an effective antitumor cellular immune response19. Elevated CD4+and CD20+lymphocytes in tumors have a strong relationship with improved disease-specific survival in patients who have undergone wide resections20. Lymphocytic cytokines secreted by the tumor could lead to a decrease in lymphocyte counts in a cancer patient, where lymphocytes undergo activation-induced apoptosis21.Seoung Yoon Rho reported that the circulating total lymphocyte count alone could be associated with immunologic parameters in patients with left-sided pancreatic cancer. In addition, it may affect the oncological outcome, regardless of tumor biology22.
Higher neutrophil levels can upregulate the expression of growth factors, such as chemokines, which play an important role in tumor development and progression. The reduction in lymphocytes indicates that the body's immunity is reduced and its antitumor ability is weakened.An increased NLR indicates that the body's inflammatory response is increased, while the lymphocyte-mediated antitumor response is decreased, which can easily cause tumor deterioration and metastasis, ultimately leading to the poor prognosis of patients15,16,17,23,24.Takumi Hasegawa et al. reported that the NLR increased with the number of pathological lymph node metastases and shorter OS in patients with oral cancer, which was also an indication of a decrease in the lymphocyte count25. The results of a meta-analysis suggested that an elevated pretreatment NLR is a negative prognostic factor in patients with head and neck cancer 26.
One of the results of our study showed that the NLR had a relationship with the TNM stage,which confirmed the findings of Sibel Goksel,who was able to demonstrate that a higher NLR could be a robust predictor to distinguish advanced stages of lung cancers27. A high NLR implies relative lymphocytopenia and neutrophilic leukocytosis. The former indicates a decrease in lymphocyte-mediated anticancer effects17, and the latter indicates higher secretion of proangiogenic factors for tumor growth23,which may partly explain the connection between the NLR and TNM stage.
One point worth mentioning is that an association between the LMN and NLR has been found in our research,which is the first one that was illustrated in ACC. This relationship has already been demonstrated in many other cancers, such as esophageal squamous cellcarcinoma,endometrial cancer and resectable pancreatic neuroendocrine tumors28–30.This conclusion still needs to be further confirmed through more studies concerning the ACC to improve its validity.
Perineural invasion had no significant association with the preoperative NLR, which had been proved in published data31.
Chun-Ye Zhang et al. analyzed 218 cases of ACC of the head and neck(ACCHN)and reported that older age(>60 years)is a significant factor for predicting poor prognosis in Chinese patients with ACCHN32. Yunsuk Choiet al. also reported that older people with ACCHN tend to haveshorterOS33. Our multivariate analysis indicated that older age(>54 years) is an independent predictor for the low survival of patients with ACC, which is largely in concordance with the results mentioned above.Comorbidities and worse performance status may lead to a poorer prognosis for elderly patients.
Kizuki Yuzaet al. found that the TNM stage clearly predicted outcomes of postoperative patients with gallbladder carcinoma. This is not in accordance with our results, which showed that patients with advanced TNM stage were prone to shorter OS,but it had no statisticalsignificance34.Several studies have demonstrated a positive correlation between LNM and decreased survival in patients with ACC of the head and neck35–37.Although our univariate analysis showed that patients with LNM were prone to shorter OS, it had no statistical significance (Table 2). Therefore, more cases need to be enrolled to prove our findings of patients with ACC.
Our present study has several limitations. First,because the optimal cutoff values for the NLR vary according to the clinical and pathological characteristics of participants and the number of participants,the cutoff value we obtained from the ROC curve is not generalizable to all patients with ACC.Second, because of the single-center design and rarity of ACC,our findings involved a sample that was relatively small. Although multivariate analysis was performed to reduce the bias,caution should still be used when dealing with the results of our research.Therefore,further multicenter prospective studies are needed to validate the sensitivity and specificity of the NLR in evaluating the prognosis of ACC.
In conclusion,a high NLR was associated with advanced tumor stage and LNM, as well as correlated with a shorter OS. In multivariate Cox regression analysis, a high NLR and older age were independent risk factors predicting poorer outcomes in patients with ACC.Therefore,we hypothesized that the preoperative NLR was a useful biomarker for the prognosis of patients with ACC.