Worldwide, neoadjuvant therapy is increasingly being advocated to treat patients with gastric cancer, showing a survival advantage compared with surgery only, without increasing postoperative morbidity and mortality 8,27–29. The theoretical benefits of neoadjuvant therapy have been analyzed in previous studies 30,31. The potential of LN metastasis is a crucial preoperative consideration in administering this type of treatment. Increasingly more clinical experts have recommended preoperative therapies for gastric cancer patients with nodal involvement 6,7,32. Findings have indicated that preoperative therapies are effective in controlling LN metastasis in gastric cancer, thereby reducing tumor N stage and increasing complete resection 32–34. Therefore, the estimation of LN status before surgery seems to be critical to select a reasonable therapeutic schedule for patients. In addition, in terms of the lymphadectomy, although D2 LN dissection is considered the standard care, it is not performed uniformly under all conditions. Some previous RCTs have shown that extended (D2) lymphadectomy was related to a higher possibility of reoperation, morbidity, and mortality and no prolonged survival was observed compared with D1 lymphadectomy 35,36. Another recent Italian RCT suggested that D2 resection may be more suitable than D1 resection for advanced gastric cancer patients with LN metastasis 37. In USA, a D1 or modified D2 gastrectomy (≥15 LNs harvested) was recommended by the National Comprehensive Cancer Network guidelines 11. Therefore, we believe that D1 gastrectomy may be appropriate for localized gastric cancer without LN metastasis, especially for early-stage gastric cancer; suitable cases can also be cured by endoscopic resection. However, for other curable disease, D2 gastrectomy may be necessary.
Given the above, it is clear that identification of a preoperative model to discriminate the metastasis of LN in gastric cancer is valuable to establish a personalized treatment plan in clinical work. Nowadays, EUS is a very commonly studied instrument for local staging of gastric cancer, showing a powerful ability to describe T stages and a less reliable performance in predicting LN status 26. Similar to EUS, all of other current imaging modalities achieved limited success in staging preoperative LN status 12,14. As a result, numerous methods including gene microarray, comparative proteomic, and histological analysis have been used to discover new biomarkers recognizing the LN metastasis and several predictive markers have been found successfully, such as miR-1207-5p expression, LYVE-1 antibody, 14-3-3β and profilin-1 protein, suppressor of cytokine signaling-3, and so on 15,16,38,39. However, the usefulness of these assessments depends on expensive equipment, difficult technology, and some biomarkers that cannot be detected before surgery. The search for a reliable and affordable preoperative biomarker to predict this clinical behavior of gastric cancer is still ongoing.
Our current research showed the significance of preoperative PLR and NLR in the peripheral blood on LN metastasis in gastric cancer. The ROC curve indicated that the utility of the PLR and NLR as predictive markers for LN metastasis in gastric cancer is the best among all preoperative SIR makers. Given the fact that platelet and neutrophil showed a positive link with LN metastasis and lymphocyte showed a negative link with LN metastasis, it is not difficult to understand that combining a positive indicator with a negative indicator together is better than just using one of them. Although preoperative NLR and PLR were significant in terms of the number of dissected positive LNs and metastatic ratio of LNs, the total number of LNs dissected in surgeries showed no obvious difference, thereby indicating that NLR and PLR have a close relationship with the metastatic LNs. In our research, a significant correlation was found between NLR and age, whereas PLR showed no statistically significant difference, which is in agreement with a previous study that found that older age was an independent risk factor for high NLR 40. This change may be because of an age-related dysfunction of immunosurveillance for cancers 41,42. Moreover, comparison between NLR and PLR with other clinical characteristic has shown that both elevated NLR and PLR was statistically significant in terms of larger tumor size, advanced TNM stage, poorly differentiated, higher node status, and depth of invasion, reflecting aggressive behaviors of gastric cancer. Consistent with previous studies 43,44, lymphatic invasion, macroscopic type, depth of invasion, and tumor size retained significance in the logistic regression model in our study. Importantly, the model first identified that both PLR and NLR are independent predictors of LN metastasis in gastric cancer.
Concurrent with GPS, NLR and PLR are gaining interest as SIR markers in various clinical circumstances 45. Numerous causes of cancer development show an essential relationship with the condition of inflammation. Tumor cells have been shown to overproduce proinflammatory mediators, such as tumor necrosis factor-α, interleukin-3 (IL-3), and IL-6 46, which stimulate the hepatic production of CRP 47,48, increase peripheral blood neutrophil and platelet counts, and decrease lymphocyte counts, thus leading to a relative neutrophilia, thrombocytosis, and lymphocytopenia 49,50. The lymphocyte response plays a pivotal role in the suppression of cancer progression 51. Cancer with lymphocytopenia has been linked to the status of innate cellular immune defects 52. Because of the antitumor activities of lymphocytes, a better prognosis was found in patients with peritumoral lymphocytes infiltration 53. In contrast, the presence of neutrophilia may antagonize the antitumor immune response by impairing the antitumor effect of lymphocyte or provide a conductive tumor microenvironment, thereby promoting tumor growth and metastasis 54–56. It has been noted that circulating vascular endothelial growth factors are mostly secreted by neutrophil, which is of crucial importance in relation to tumor angiogenesis 57. In addition, neutrophilia is considered an index of poor prognosis in some types of cancer 58,59. Platelet count is also a member of SIR markers associated with the tumor 60. Studies have already reported that platelets have the ability to protect tumor cells from immune responses and promote tumor cell growth, extravasation, and migration 61,62. Furthermore, it was observed that platelet count shows a significant relationship with nodal involvement in patients with gastric cancer, colon cancer, and non-small-cell lung cancer 49,63,64.
The role of PLR or NLR in nodal staging of cancer has been investigated in a few studies. Recently, a study of 353 non-small-cell lung cancer patients recommended a novel preoperative COCT-NLR model (a combination of NLR and contrast-enhanced computed tomography) to detect LN metastasis with a high sensitivity (70.59%) and specificity (74.89%) 65. Ertas et al. 66 carried out a study to determine whether preoperative NLR and PLR could provide useful information on LN metastasis in 64 vulvular squamous cell sarcoma patients, concluding that NRL higher than 2.81 and PRL more than 139.5 had a significant independent effect on the LN metastasis (odds ratio 14.18, 95% CI 2.54–79.03, P=0.002; odds ratio 10.4, 95% CI 1.82–59.39, P=0.008, respectively). Another study comprising data on 319 endometrial adenocarcinoma patients concluded that the predictive accuracy of the nodal involvement of NLR and PLR is not better than serum CA125, although PLR and NLR values were significantly elevated in the LN-positive group (P=0.003, 0.012, respectively) 67. Several studies have attempted to explore the relationship between gastric cancer and PLR, NLR. Most of them were designed to determine their roles in the prognosis or chemotherapeutic response rather than LN metastasis 21,50,56,68,69. This is the first research that has attempted to evaluate whether PLR and NLR can be used as predictive indicators for LN metastasis in gastric cancer and to test the clinical utility of a new method with combined tumor-related and host-related factors to identify the risk of LN metastasis.
Several other score models have been developed by researchers to detect LN metastasis in gastric cancer. For example, a nodal status predictive score system including those differentially expressed proteins in pT3 stage gastric cancer with LN metastasis was established by Li et al. 70. The limitation of specific materials and a complex procedure influenced the clinical use of this model and the requirement of more tumor tissues and detecting lymphatic/vascular invasion made its use before surgery difficult. Recently, Shida et al. 71 recommended a preoperative score system to predict LN metastasis in early gastric cancer. Only tumor-related factors were analyzed and the accuracy, specificity, and sensitivity rates of the model were only 70, 61.6, and 63.2%, respectively. In comparison with the above studies, the score system devised in the present study, which included more convenient and available preoperative variables of tumor size, macroscopic type, depth of invasion, PLR, and NLR, showed a reliable and stable power (AUC 0.830, 95% CI 0.782–0.878) to predict LN metastasis with a relatively moderate specificity (72.4%) and a high sensitivity (82.7%), which was also definitely superior to the unstable performance of EUS and other imaging tools, with inconsistent sensitivities, specificities, and accuracies reported in various studies 12,72. However, our score system was only a complementary tool for the prediction of nodal involvement. Given that the positive and negative predictive values of the model were 88.7 and 61.5%, respectively, its clinical application should be combined with traditional imaging protocols to decrease false estimations. Moreover, for those patients who were understaged before the surgery, salvage treatment of adjuvant therapy was urgently needed 7.
In terms of the cutoff value of PLR and NLR, the optimal cutoff levels identified in the previous studies are inconsistent 22,23. Various methods have been used to calculate the cutoff value in different tumors. For gastric cancer, some studies just used their best cutoff values according to the median value 69 or previous studies 68,73. However, several studies applied the ROC curve to assess the ideal cutoff value. For instance, a retrospective study of 1986 patients found that both PLR and NLR can predict the overall survival and recurrence of gastric cancer with a cutoff level for PLR of 126 and 200, respectively, and NLR of 2, 3, respectively, by constructing the ROC curve 50. In contrast, Lee et al. 60 suggested a PLR of 160 and an NLR of three as the optimal threshold as a prognostic indicator by selecting values with the most remarkable difference in the univariate analysis of overall survival curves. However, in the same way, Shimada et al. 40 reported that the ideal cutoff value of NLR was 4.0. Considering the heterogeneity of thresholds proposed in previous studies and the fact that this is the first research to evaluate optimal thresholds according to the nodal involvement of gastric cancer, we established a PLR of 155.67 and an NLR of 1.59 as the ideal cutoff value using the ROC curve. On the basis of our cutoff values, although a slight trend of increased number of patients was noted in line with the extent of nodal metastasis, it did not reach significance among N1, N2, and N3 (data not shown). This result may be attributed to the small number of samples with LN metastasis in our study classified as three different groups. It is obvious that more verification is warranted to confirm these cutoff values, but our study suggested that a PLR of 155.67 and an NLR of 1.59 may be reliable thresholds to detect nodal involvement in gastric cancer patients.
The current study also had some limitations that should not be ignored. First, this was a retrospective study carried out in a single hospital to search the date from a collected computerized database. Second, after excluding lymphatic invasion, the variables of depth of invasion and macroscopic type in the score system were also observed from postoperative specimen examinations. Although we could obtain these tumor variables before surgery, it may have influenced the accuracy of our results. Finally, the relationship between intratumor inflammatory reaction and peripheral hematological component alteration of the SIR was not assessed in our study. Therefore, our results need to be confirmed in further large-scale prospective studies.
The present study showed that NLR and PLR could be simple, repeatable, and inexpensive preoperative indicators of LN metastasis in gastric cancer patients. As a potential therapeutic target, knowledge of their mechanisms may be useful for cancer prevention and therapy. In addition, the score system that combined PLR and NLR and tumor-related factors is a reliable and economical predictive tool to distinguish gastric cancer patients with nodal involvement between those without nodal involvement in the study, which is useful for further planning of selective neoadjuvant therapy or nodal dissection before surgery. In future, more studies on clinically available preoperative NLR and PLR, together with our score system, such as in combination with imaging systems and other known sera markers, should be explored to find a more accurate preoperative strategy to predict LN metastasis in patients with gastric cancer.
Authors contribution: Wenyang Pang: acquired data, analyzed, and interpreted the data, and drafted the manuscript; Neng Lou: acquired data; Cancan Jin, Changyuan Hu: carried out the statistical analysis; Chandoo Arvine: analyzed and interpreted the data, and revised the manuscript; Guangbao Zhu: designed the study, analyzed, and interpreted the data, supervised the study, revised the manuscript, and finally approved the version of the manuscript for publication; Xian Shen: contributed toward the conception of the study, designed the study, analyzed, and interpreted the data, revised the manuscript, and finally approved the version of the manuscript for publication.
There are no conflicts of interest.
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