Background
Esophageal cancer (EC) is characterized by its high aggressiveness and poor survival, which caused approximately 508 000 deaths worldwide in 2018. Among cancers, EC is the seventh most common cause of morbidity and the sixth most common cause of cancer-associated mortality [ 1 ]. Early esophageal cancer (EEC) has a good prognosis and can have a 5-year survival rate of up to 90% [ 2 ]. Currently, surgical treatment is the first choice for clinical treatment of esophageal cancer; however, traditional surgical operations are traumatic, costly, have a slow postoperative recovery, and can lead to more complications. In recent years, endoscopic submucosal dissection (ESD) has become a preferred treatment method for patients with EEC. It has the advantages of a high resection rate, small wound, less bleeding, good curative effect, and rapid postoperative recovery, but it is difficult to operate and can easily lead to esophageal stricture. Post-ESD esophageal strictures in EEC can cause dysphagia of varying severity and reduce the quality of life of patients [ 3 , 4 ]. However, most patients are discovered to have esophageal stricture after presenting with dysphagia. Therefore, early detection of patients with potential esophageal strictures is essential. The mechanism of post-ESD esophageal strictures in EEC has not yet been clarified. Research has shown that the formation of esophageal strictures can be attributed to mechanical and chemical factors stimulating the wound, leading to an aggravated inflammatory response, mainly manifested by inflammatory cell infiltration and the formation of new vessels, and highly contracted muscle fibroblasts, eventually resulting in scar formation. It can be seen that the inflammatory response plays an important role in the formation of esophageal strictures [ 5 , 6 ]. Thus, inflammatory reaction plays an important role in the formation of post-ESD esophageal strictures. Some inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) [ 7 ], are used for measuring systemic inflammation. However, the predictive value of NLR, PLR, and MLR in post-ESD esophageal strictures of EEC has not been confirmed. Therefore, we evaluated the predictive values of NLR, PLR, and MLR in post-ESD esophageal strictures of EEC. The innovative points and the aim of this study were to find out the predictive value of NLR, PLR, and MLR in the post-ESD esophageal strictures of EEC and to analyze the correlations of stricture severity.
Material and Methods
Participants
Patients with EEC who underwent endoscopic treatment in the Department of Gastroenterology, Second Affiliated Hospital of Harbin Medical University from January 2016 to December 2021 were evaluated. All patients were hospitalized. Inclusion criteria were as follows: (1) pathological diagnosis of EEC; (2) submucosal involvement of no more than sm1 (infiltration of the submucosal layer of ≤200 μm); (3) absence of lymph node metastasis; and (4) patients who only underwent ESD treatment and the treatment was successful. The exclusion criteria were as follows: (1) patients who had received chemotherapy and/or radiotherapy before ESD; (2) patients with underlying serious cardiovascular diseases and pulmonary, intestinal, abdominal, or other systemic infections; (3) patients who had received antiplatelet treatment in the past 3 months; (4) patients who had received steroid treatment after admission; (5) patients with relapsed EC; (6) patients with multiple myeloma or blood cancers; and (7) patients who had developed distant metastases. A total of 285 patients who met any of the above criteria were included in the study. We obtained prior informed consent from all participants and received approval from the Ethics Committee of the hospital.
ESD Method
Preoperative routine assessment of patients is conducted, including general condition and local tumor condition. Endoscopy can be used to understand the size and type of the tumor, and ultrasonography endoscopy or chest enhanced computed tomography scan can be used to obtain information such as tumor infiltration depth. Preoperative biopsy pathology can determine the histological type, and comprehensive evaluation is used to determine whether the patient meets the indications for ESD treatment. The patient receives ESD treatment under tracheal intubation anesthesia. Indigo carmine staining is used to confirm the lesion and range, and the Olympus GIF-260 or GIF-290 endoscope (with a transparent cap at the front end) is used. Argon gas is marked 5 mm outside the lesion, and the electric knife is used to mark the tumor margin outside the mark. Physiological saline or sodium hyaluronate is injected along the tumor margin to lift the tumor, making it easier to completely remove the tumor and ensure that the depth of removal does not exceed the muscle layer. The Dual knife or IT knife is used to peel off the submucosal layer of the lesion along the marked margin, and the good cutting angle and field of view can be ensured by pulling the esophageal wall, adjusting the body of the endoscope, and changing the body position. Hemostasis should be timely and effective during the operation, and the vision should be kept clear. The lesion should be removed completely at one time. If it cannot be completely removed, it should be removed in stages under the premise of ensuring clean removal. After marking the range of the lesion with the above methods, indigo carmine solution is injected at multiple points under the mucosa outside the lesion to lift the lesion, and then the Dual knife or IT knife is used to cut the edge of the lesion and peel off the submucosa, and the lesion is completely removed in large pieces. For small bleeding, local spraying hemostatic drugs or electrocoagulation hemostasis can be used, which can generally achieve the effect. If the exposed blood vessels are thick or the amount of bleeding is large, metal clamps can be used to stop the bleeding, and the metal clamping site should be accurate and reliable. After the excised tissue specimen is fixed, it is immersed in 5% to 10% formalin for inspection.
Follow-Up
All patients were followed up at 3, 6, and 12 months after ESD and annually thereafter. Follow-up was completed on August 31, 2022. The outcome of interest was the presence of esophageal stricture at follow-up. The severity of esophageal stricture was assessed by the Stooler classification of dysphagia and esophageal stricture (grade I: soft food can be eaten smoothly, with an inner diameter of more than 13 mm; grade II (mild stricture): semi-liquid food, with an anastomotic diameter of 8–13 mm; grade III (moderate stricture): only liquid food can be eaten, with an anastomotic diameter of 3–8 mm; and grade IV (severe stricture): it is difficult to eat liquid food, with an anastomotic diameter less than 3 mm).
Hematology Analysis
Patients with EEC after ESD were required to abstain from food and water for 3 days. Patients should be given acid suppression and fluid rehydration therapy within 3 days. After 3 days, the patients were discharged, with no obvious discomfort after taking liquid food. All participants underwent a complete blood count (CBC) and an automatic differential count. Peripheral fasting blood samples (2 mL each) were collected from the cubital vein on the morning of the third day after ESD. The CBC tests were conducted within 4 hours. The counts of peripheral blood white blood cells, neutrophils, lymphocytes, monocytes, and platelets were detected using a blood counting instrument (Sysmex XE-2100, Sysmex Corporation, Japan). Then, different ratios, including the NLR, PLR, and MLR, were determined. During the test, all procedures were conducted in strict accordance with the operating procedures, and all experimental reagents (Sigma, Japan) were matched with the instrument (Sysmex XE-2100, Sysmex Corporation, Japan).
Statistical Analysis
A t test or chi-squared test was used to compare the clinical differences in different subgroups. The continuous variables were represented as the mean±standard deviation (SD). Next, receiver operating characteristic (ROC) curves were plotted to determine and compare the predictive value of inflammatory biomarkers in post-ESD esophageal stricture of EEC. The area under the ROC curve (AUC) was also determined. The Spearman correlation test was used to detect the relationship between inflammatory biomarkers and the severity of esophageal stricture. Kaplan-Meier survival analysis was used to evaluate the relationship between different levels of inflammatory biomarkers and the time of occurrence of post-ESD esophageal stricture. SPSS v22.0 (IBM Corp, Armonk, NY, USA) and GraphPad Prism 8 (GraphPad Prism Software Inc, San Diego, CA) were used for generated graphs and statistical analyses. Statistical significance was determined at P <0.05.
Results
Clinical Baseline Characteristics
The factors affecting the post-ESD esophageal strictures in EEC patients include circumferential resection range, longitudinal length of lesion, and tumor depth ( P <0.05), with no correlation to age, sex, residential address, body mass index, history of drinking, smoking, family history, extent of resection, pathological differentiation, pathological type, and pairs type ( P >0.05; Table 1 ).
Comparison of NLR, PLR, and MLR in the Stricture Group and Non-Stricture Group
The NLR, PLR, and MLR values in the stricture group were higher than those in the non-stricture group ( P <0.05; Figure 1 ).
Predictive Significance of NLR, PLR and MLR in Post-ESD Esophageal Strictures in EEC
ROC analysis showed that the cut-off value for NLR was 2.058 (AUC=0.792, 95% confidence interval (CI)=0.729–0.855, Se=64.4%, Sp=82.5%). The cut-off value for PLR was 100.718 (AUC=0.774, 95% CI=0.710–0.839, Se=94.1%, Sp=52.5%). The cut-off value for MLR was 0.168 (AUC=0.768, 95% CI=0.703–0.834, Se=62.7%, Sp=81.2%). The cut-off value for the combination of NLR, PLR, and MLR was 0.409 (AUC=0.850, 95% CI, 0.797–0.903, Se=93.2%, Sp=60%; Figure 2A–2D and Table 2 .
Inflammatory Biomarkers and the Severity of Post-ESD Esophageal Strictures in EEC
Based on the Stooler classification of dysphagia and esophageal stricture, esophageal stricture is divided into 4 grades ( Figure 3 ). Spearman correlation test revealed that NLR was generally positively correlated with the severity of esophageal stricture ( r =0.501, P <0.0001). PLR was not related to the severity of esophageal stricture ( P >0.05). MLR was significantly positively correlated with the severity of esophageal stricture ( r =0.736, P <0.0001; Figure 4 ).
Effects of Inflammatory Biomarkers on the Stricture Rate of Patients with Post-ESD Esophageal Strictures in EEC
According to the cut-off values of NLR, PLR, and MLR, the stricture group was divided into high- and low-level subgroups. Kaplan-Meier survival analysis indicated that compared to the group with a low NLR level, the group with a high NLR level had a higher rate of stricture ( P <0.05; Figure 5A ). Compared to the group with a low MLR level, the group with a high MLR level had a significantly higher rate of stricture ( P <0.05; Figure 5B ). However, there was no significant difference between the group with a high PLR level and the group with a low PLR level ( P >0.05).
Discussion
EC is highly invasive and has a close mortality to morbidity ratio because it progresses rapidly. It is usually diagnosed at an advanced stage and has poor prognostic outcomes [ 8 , 9 ]. However, overall survival increases significantly if EC is diagnosed at an early stage, with the 5-year survival rate of EEC as high as 90% [ 10 ]. For EEC, ESD is the preferred treatment [ 11 ], with advantages of high resection rate, high cure rate, and low recurrence rate [ 12 – 14 ]. Esophageal stricture is a common complication in post-ESD of EEC, which significantly affects the quality of life and long-term prognosis of patients. Therefore, early detection and prevention of post-ESD esophageal stricture of EEC is particularly important. Funakawa et al reported that lesions more than three-quarters of the circumference of the esophagus or the depth of tumor invasion more than the lamina propria of the esophageal mucosa are risk factors for post-ESD stricture [ 15 ], which is consistent with our results. The main purpose of the present study was to predict the occurrence and severity of post-ESD esophageal stricture in EEC by detecting inflammatory biomarkers, so as to provide early intervention treatment. Kim et al reported that early intervention treatment for high-risk patients with esophageal stricture can achieve remission of dysphagia or reduce the recurrence of esophageal stricture, mainly by endoscopic balloon dilation and intralesional steroid injections or oral steroids [ 16 ]. Most patients are diagnosed with esophageal stricture after experiencing symptoms of difficulty swallowing, which leads to repeated balloon dilation treatment, not only seriously affecting the quality of life of patients, but also increasing their economic burden. If we can predict the occurrence of esophageal stricture through calculating a simple blood cell count and provide early intervention treatment, the patients can benefit from it.
White blood cells and its classification count (including lymphocytes, neutrophils, eosinophils, and monocytes) are related to inflammation and the immune system. Platelets are anucleated blood cells produced by megakaryocytes in the bone marrow and play an important role in the regulation of host inflammation and immune response, as well as hemostasis and thrombosis formation [ 17 , 18 ]. Current research has emphasized that the NLR, PLR, and MLR can predict systemic inflammatory reactions with the calculation of simple blood cell counts. The use of these ratios has the advantages of being cost-effective, potent, and quantitative, so it has attracted wide attention [ 19 , 20 ]. At present, studies have found that the NLR, PLR, and MLR can be used in the diagnosis, treatment, and prognosis of inflammatory diseases, autoimmune diseases, tumors, and respiratory diseases, such as COVID-19, autoimmune liver diseases, esophageal squamous cell carcinoma, and colorectal cancer. At the same time, the NLR, PLR, and MLR have gradually become predictive factors to evaluate the severity of disease [ 21 – 25 ]. To the best of our knowledge, this is the first study to investigate the predictive value of the NLR, PLR, and MLR in post-ESD esophageal strictures of EEC. In this study, we determined the predictive values of NLR, PLR, and MLR indices for post-ESD esophageal strictures of EEC and performed ROC analysis of these indices. We found that NLR, PLR, and MLR values were higher in post-ESD stricture patients than in post-ESD non-stricture patients, and there was a positive correlation between NLR, MLR, and the severity of the stricture. ROC analysis also showed that the AUC value of the combination of NLR, PLR and MLR (0.850) was higher than that of the NLR (0.792), PLR (0.774), and MLR (0.768), thus indicating that the combination of the 3 indices was superior to NLR, PLR, and MLR in predicting post-ESD esophageal strictures of EEC. Meanwhile, our research found that high NLR and MLR levels can indicate that post-ESD patients of EEC are more likely to develop esophageal stricture than those with low NLR and MLR levels.
Conclusions
Post-ESD esophageal strictures of EEC patients had obviously higher NLR, PLR, and MLR values than post-ESD non-stricture of EEC patients. There was a positive correlation between NLR and MLR and the severity of stricture. Furthermore, ROC analysis indicated that the AUC of the combination of the 3 indices was significantly greater than the AUCs of NLR, PLR, and MLR, and thus the predictive capacity of the combination of the 3 indices for post-ESD esophageal stricture was better than the other 3 indices alone. Consequently, the combination of NLR, PLR, and MLR could help clinicians to predict post-ESD esophageal stricture in the early stage, particularly NLR and MLR, which can also predict the severity and the probability of esophageal stricture, so that we can make a closer follow-up and provide appropriate treatment early to maximize the benefits for patients.
Conflict of interest: None declared
Publisher’s note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher
Declaration of Figures’ Authenticity
All figures submitted have been created by the authors, who confirm that the images are original with no duplication and have not been previously published in whole or in part.
Financial support: This work was supported by Harbin Medical University (no. YJSCX2015-24HYD)
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