The value of perioperative neutrophil-to-lymphocyte ratio combined with the prognostic nutritional index for predicting anastomotic leakage after minimally invasive esophagectomy

Introduction

Esophageal cancer remains one of the most common malignant tumors of the digestive system in the world. According to the 2020 GLOBOCAN report, the global incidence and mortality of esophageal cancer rank seventh and sixth, respectively (1,2). The present treatment strategy for patients with resectable esophageal cancer is still based on surgical resection (3). Despite significant advancements in surgical techniques and perioperative management in recent years, anastomotic leakage, a severe complication, remains unavoidable in clinical practice (4,5). The occurrence of anastomotic leakage is not only associated with prolonged hospital stays, wastage of medical resources, and increased perioperative mortality but may also leaded to tumor recurrence and a decline in long-term survival (6,7). Therefore, the early postoperative prediction of anastomotic leakage holds significant clinical value. Currently, there is a wealth of research on risk factors for anastomotic leakage after minimally invasive esophagectomy (MIE), including age, diabetes, anastomotic technique, and others (8-11). However, they failed to consider the patients’ own inflammatory levels and nutritional status. The etiology of anastomotic leakage is complex and may result from the combined effects of inflammation, immune system factors, and nutritional status (12-16). In recent years, the neutrophil-to-lymphocyte ratio (NLR) has emerged as an important indicator of systemic inflammation and immune levels, garnering widespread attention (17). Previous studies have shown that NLR is associated with the prognosis of various malignant tumors and postoperative complications (18,19). Meanwhile, the prognostic nutrition index (PNI) is a nutritional marker based on serum albumin and lymphocyte levels and has been reported to be a good predictor of complications following operation on the digestive system (20-22). The NLR and PNI are relatively easy to obtain in clinical practice. Therefore, this study aimed to assess the value of perioperative NLR combined with PNI in predicting anastomotic leakage after minimally invasive resection of esophageal cancer. We present this article in accordance with the TRIPOD reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-302/rc).

Methods

Patient selection

A retrospective analysis was conducted on patients who underwent minimally invasive esophageal cancer resection at the Department of Thoracic Surgery of The Affiliated Lihuili Hospital of Ningbo University from January 2019 to May 2023. A total of 232 cases were included, comprising 214 males and 18 females, with a median age of 67 years (range, 47–83 years). The inclusion criteria were as follows: (I) pathologically confirmed with primary esophageal cancer; (II) completion of minimally invasive esophageal resection; (III) availability of complete clinical and pathological data; and (IV) availability of complete perioperative peripheral blood data. Meanwhile, the exclusion criteria were as follows: (I) preoperative neoadjuvant therapy or anti-inflammatory treatment; (II) liver, kidney, or hematologic diseases; (III) patients with distant metastasis; (IV) severe lung infection within 1 week after surgery (definition of severe pneumonia: postoperative CT shows newly developed pulmonary infiltrates that are extensive in scope, such as involving multiple lung lobes or associated with lung consolidation); and (V) presence of other severe postoperative complications, such as chylothorax or cerebral infarction. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Ethics Committee of The Affiliated Lihuili Hospital of Ningbo University (No. KY2019PJ058) and informed consent was taken from all the patients.

Data collection

The clinical and pathological characteristics of patients, including sex, age, smoking history, alcohol consumption history, history of hypertension, history of diabetes, surgical method, maximum tumor diameter, tumor location, depth of infiltration, lymph node metastasis, and routine perioperative laboratory tests, were recorded. Within 1 week before surgery, serum albumin levels, neutrophil count, lymphocyte count, platelet count, and monocyte count were collected via routine blood tests. The definitions of NLR and PNI are as follows: NLR = neutrophil count/lymphocyte count; PNI = serum albumin + 5 × lymphocyte count.

Definition and assessment of anastomotic leakage

According to the consensus of the Esophagectomy Complications Consensus Group (ECCG), in this study, anastomotic leakage was defined as a full-thickness defect involving the esophagus, anastomosis site, suture line, or tubular stomach. Postoperatively, we closely monitored patients, and postoperative anastomotic leakage was diagnosed if any of the following occurred: (I) extravasation of contrast agent on gastrointestinal contrast radiography; (II) endoscopic confirmation of anastomotic leakage; (III) computed tomography scan suggesting anastomotic leakage; and (IV) drainage tube discharge of purulent or feculent fluid.

Statistical analysis

Data analysis was performed with SPSS 26.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism 10.1.2 (GraphPad Software, San Diego, CA, USA). Normally distributed continuous data are described as the mean ± standard deviation, and intergroup comparisons were made with the t-test. Nonnormally distributed continuous data are described as the median and interquartile range, while intergroup comparisons were made with nonparametric tests. Categorical data are expressed as frequency and percentage, and intergroup comparisons were made with the chi-square test or Fisher exact test. Univariate and multivariate logistic regression analyses were conducted to identify the risk factors of anastomotic leakage in patients with esophageal cancer. The value of NLR and PNI for predicting anastomotic leakage was assessed with receiver operating characteristic (ROC) curves. Then, NLR and PNI were combined to evaluate their predictive value for anastomotic leakage. A two-tailed P value <0.05 was considered statistically significant.

Results

Clinical and pathological characteristics

A total of 232 patients met the inclusion and exclusion criteria in this study, as shown in Figure 1. The clinical and pathological characteristics of 232 patients with esophageal cancer are shown in Table 1, including 214 males (92.2%) and 18 females (7.8%), with a median age of 67 years (range, 47–83 years). Among them, 162 had a history of smoking (69.8%), 168 had a history of alcohol consumption (72.4%), 90 had a history of hypertension (38.8%), and 23 had a history of diabetes (9.9%). Among the cases, 178 (76.7%) underwent cervical anastomosis, while 54 (23.3%) underwent thoracic anastomosis. The tumor locations were as follows: upper, middle, and lower esophagus in 17 (7.3%), 136 (58.6%), and 79 (34.1%) cases, respectively. The median tumor maximum diameter was 3.5 cm (range, 2.5–4.5 cm). According to the eighth edition of the tumor-node-metastasis (TNM) staging system, the distribution of tumor infiltration depth among patients was as follows: T1 in 51 (22.0%) cases, T2 in 45 (19.4%) cases, and T3 in 136 (58.6%) cases. Meanwhile, N0 lymph node metastasis was observed in 120 (51.7%) cases while N+ was observed in 112 (48.3%) cases.

Figure 1 Flowchart of patient selection.

Univariate analysis of anastomotic leakage in patients with esophageal cancer after surgery

Patients were divided into two groups based on whether anastomotic leakage occurred postoperatively, with 35 (15.1%) cases experiencing anastomotic leakage. Among them, there were 29 (82.9%) cases of cervical anastomotic leakage and 6 (17.1%) cases of thoracic anastomotic leakage. There were 30 (85.7%) cases of anastomotic leakage occurring within 10 days after surgery. Results of the univariate analysis of the general clinical and pathological characteristics (Table 2) only identified a history of diabetes as being significantly associated with postoperative anastomotic leakage (P=0.003). Age, sex, smoking history, alcohol consumption history, history of hypertension, surgical method, tumor location, tumor maximum diameter, depth of infiltration, and lymph node metastasis showed no significant association with postoperative anastomotic leakage (all P values >0.05). Univariate analysis of perioperative blood indicators (Table 3) revealed that the factors significantly associated with postoperative anastomotic leakage were higher neutrophil levels on postoperative days 1, 3, and 5 (P=0.01, P<0.001, and P<0.001, respectively); higher platelet levels on postoperative day 1 (P=0.01); higher NLR levels on postoperative days 3 and 5 (P<0.001 and P<0.001, respectively); and lower PNI levels on postoperative days 3 and 5 (P<0.001 and P<0.001, respectively).

Multivariate logistic regression analysis of anastomotic leakage in patients with esophageal cancer after surgery

To eliminate the influence of collinearity, a multivariate logistic regression analysis (Table 4) was conducted that included a history of diabetes, NLR levels on postoperative days 3 and 5, PLR levels on postoperative day 3, and PNI levels on postoperative days 3 and 5. The results showed that the independent influencing factors for postoperative anastomotic leakage were a history of diabetes (P=0.047), higher NLR levels on postoperative days 3 and 5 (P=0.048 and P=0.01, respectively), and lower PNI levels on postoperative day 3 (P=0.02).

Efficacy of NLR and PNI in predicting the development of anastomotic leakage in patients with esophageal cancer after surgery

Patients who developed anastomotic leakage after esophageal cancer surgery often exhibit persistently elevated NLR levels and persistently decreased PNI levels postoperatively. To further characterize the efficacy of NLR and PNI in predicting postoperative anastomotic leakage, we established ROC curves. The analysis results showed that at a cutoff value of 10.715, the area under the curve (AUC) of NLR on postoperative day 3 was 0.801, with a sensitivity and specificity of 0.829 and 0.756, respectively. At a cutoff value of 36.875, the AUC of PNI on postoperative day 3 was 0.737, with a sensitivity and specificity of 0.886 and 0.548, respectively. When NLR and PNI were combined, the AUC was 0.826 on postoperative day 3, with a sensitivity and specificity of 0.829 and 0.782, respectively, indicating a higher predictive efficacy when these two indicators were combined on postoperative day 3. At a cutoff value of 7.960, the AUC of NLR on postoperative day 5 was 0.772, with a sensitivity and specificity of 0.629 and 0.853, respectively. At a cutoff value of 34.225, the AUC of PNI on postoperative day 5 was 0.727, with a sensitivity and specificity of 0.429 and 0.898, respectively. When NLR and PNI were combined, the AUC was 0.777 [95% confidence interval (CI): 0.681–0.873] on postoperative day 5, with a sensitivity and specificity of 0.743 and 0.766, respectively, the AUC was 0.826 (95% CI: 0.754–0.898) on postoperative day 3, with a sensitivity and specificity of 0.829 and 0.782. See Table 5 and Figure 2 for further details.

Figure 2 ROC curves of NLR and PNI in predicting anastomotic leakage after minimally invasive esophagectomy. (A) Postoperative day 3. (B) Postoperative day 5. NLR, neutrophil-to-lymphocyte ratio; PNI, prognostic nutritional index; ROC, receiver operating characteristic.

Discussion

Minimally invasive esophageal cancer resection is the primary treatment modality for patients with esophageal cancer. Although surgical techniques are continuously evolving, the incidence of anastomotic leakage after surgery remains relatively high, ranging from 10% to 20%. In our study, the incidence of anastomotic leakage after esophageal cancer surgery was 15.1%, which is consistent with the literature (23,24). Anastomotic leakage, as one of the most serious postoperative complications of esophageal cancer surgery, may lead to fever, abscess formation, sepsis, or septic shock (25). This can result in prolonged hospital stays, higher hospitalization costs, and even secondary surgeries, thereby increasing perioperative mortality rates (26,27). Therefore, the early prediction of postoperative anastomotic leakage in patients is of significant clinical value.

According to a relevant study, anastomotic leakage is pathophysiologically associated with ischemia, hypoxia, infection, and inflammation (28). The main risk factors include advanced age, obesity, anastomotic site and technique, hypoalbuminemia, and a history of diabetes (29). Multifactorial logistic regression analysis in our study revealed that a history of diabetes, elevated NLR levels on postoperative days 3 and 5, and decreased PNI levels on postoperative day 3 were independent risk factors for anastomotic leakage. Diabetes, as a chronic debilitating disease, can lead to immunodeficiency in patients due to long-term metabolic disturbances, increasing the risk of anastomotic infection. Additionally, diabetes can slow down blood flow, impairing tissue-healing capabilities (30).

NLR is recognized as an inflammatory response marker associated with the activation and regulation of the body’s inflammatory response (31,32). Neutrophils, as key cellular components of the innate immune system, recruit, activate, and modulate other immune cells during early inflammation, secreting a series of proinflammatory cytokines, regulatory cytokines, and chemokines, thereby triggering a cascade of inflammatory reactions. Meanwhile, lymphocytes, as the main components of the adaptive immune system, suppress the body’s inflammatory response by secreting anti-inflammatory factors. Neutrophils and lymphocytes interact to maintain immune system balance. Previous studies have demonstrated a correlation between NLR and the occurrence of anastomotic leakage after gastrointestinal surgery. In a retrospective study by Radulescu et al. of 204 patients undergoing gastric cancer resection, there was a significant correlation between high preoperative NLR levels and anastomotic leakage, with preoperative NLR >3.54 being an independent risk factor for anastomotic leakage (33). However, in our study, there was no correlation between preoperative NLR levels and anastomotic leakage (P=0.96), suggesting that the correlation between preoperative NLR levels and postoperative anastomotic leakage still needs to be verified by multicenter studies. In a study by Paliogiannis et al., the optimal cutoff value for NLR on postoperative day 4 was 7.1, representing the best predictive ability for anastomotic leakage, with the maximum AUC being 0.744 (34). In our study, the NLR levels of patients who developed anastomotic leakage after surgery were basically the same as those who did not develop anastomotic leakage on the first day, but thereafter, the NLR levels declined slowly but remained elevated. We found that high NLR levels were mainly due to high neutrophil counts and not decreased lymphocyte counts, which may be attributed to neutrophils primarily relying on glycolysis and thus consuming more oxygen, thereby exacerbating tissue hypoxia at the anastomotic site.

Due to prolonged dietary restrictions, most patients with esophageal cancer have poor nutritional status. Studies have shown that patients’ nutritional status is associated with cancer prognosis and postoperative complications. Onodera et al. first proposed the concept of the PNI in 1984 (21). PNI, based on serum albumin and lymphocyte levels, has been proven to be a good predictor of complications after gastrointestinal surgery. Our findings indicated that patients who developed anastomotic leakage had consistently low PNI levels postoperatively, and low PNI levels on postoperative day 3 were an independent risk factor for anastomotic leakage. To further investigate the predictive value of NLR and PNI for postoperative anastomotic leakage in esophageal cancer, we established ROC prediction models. The ROC models showed that NLR on postoperative day 3 had good predictive value for anastomotic leakage, with an AUC of 0.801, a sensitivity of 82.9%, and a specificity of 75.6%. Furthermore, when NLR was combined with PNI on postoperative day 3, the AUC was 0.826, with a sensitivity of 82.9% and a specificity of 78.2%, indicating higher predictive value than NLR alone. The results on postoperative day 5 were similar to those on postoperative day 3, with the combined NLR and PNI showing better predictive value for anastomotic leakage.

To our knowledge, few studies have examined the correlation between inflammatory-nutritional markers such as NLR and PNI and postoperative anastomotic leakage after MIE. Therefore, our study has important clinical value and can inform the management of patients with esophageal cancer after surgery. Clinicians can predict the occurrence of anastomotic leakage postoperatively by monitoring patients’ NLR and PNI levels and then implement preventive measures such as prolonging fasting time, actively treating inflammation, and improving protein levels. In summary, persistently high NLR levels and persistently low PNI levels after surgery have certain predictive value for postoperative anastomotic leakage in patients with esophageal cancer. The combination of NLR and PNI on postoperative day 3 demonstrated the best predictive value, and postoperative NLR and PNI indicators are simple and easy to obtain, supporting there applicability in clinical practice.

It should be noted that our study involved certain limitations, including its single-center, retrospective design and a relatively small sample size, which inevitably introduced selection bias. Therefore, further large-scale, multicenter, prospective studies are needed to verify the results. What’s more, given that all surgeries were performed by the same team, the anastomotic technique remained nearly consistent. We used a circular stapler for esophago-tubular gastric end-side anastomosis, with manual interrupted sutures applied to reinforce the anastomosis. Looking forward, we hope to collaborate with other centers to explore the impact of different anastomotic techniques on anastomotic leakage in future studies.

Conclusions

Persistently high NLR levels and persistently low PNI levels in the postoperative period following MIE correlated with the development of anastomotic leakage, and NLR combined with PNI on postoperative day 3 demonstrated the best ability to predict anastomotic leakage after this procedure.

Acknowledgments

We would like to express our gratitude to our mentors and colleagues in the department for their guidance and support throughout this research and study collaboration process.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-302/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-302/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-302/prf

Funding: This study was funded by the Ningbo Clinical Research Center for Thoracic and Breast Neoplasms (No. 2021L002).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-302/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Ethics Committee of The Affiliated Lihuili Hospital of Ningbo University (No. KY2019PJ058) and informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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