Prognostic value of left gastric artery lymph node metastasis in patients with thoracic esophageal squamous cell carcinoma: a retrospective cohort study

Introduction

Esophageal cancer (EC), a common malignant tumor, is associated with a persistently high incidence and mortality rates, rapid growth in both new cases and deaths, and poor overall prognosis. EC is the 11th most common cancer and the 7th leading cause of cancer-related death worldwide, with the number of new global cases reaching 511,000 and the number of death cases standing at 445,000 in 2022 (1). In terms of histological subtype, EC is primarily classified into squamous cell carcinoma (SCC) and adenocarcinoma. Esophageal SCC (ESCC) is the dominant histological type, particularly in developing countries, with China having the greatest ESCC disease burden in the world (2). Patients with ESCC have a poor prognosis for two primary reasons: The tumor gradually invades the outer layers of the esophageal wall from the inner layer, which leads to insidious early symptoms and thus the majority of patients being diagnosed at an advanced stage (3). Moreover, a considerable portion of patients experience tumor recurrence even following radical esophagectomy, with a high complication rate and perioperative mortality risk persisting throughout the entire treatment course (4,5). For resectable ESCC, esophagectomy is currently recognized as the standard treatment modality; however, the postoperative 5-year overall survival (OS) of patients treated with esophagectomy remains unsatisfactory (6,7). Treatment for ESCC is administered under the guidance of precision staging with combined therapy. Patients with early-stage lesions are primarily subjected to endoscopic minimally invasive therapy, those with locally disease are administered neoadjuvant chemoradiotherapy combined with surgery as the core strategy, and those with advanced-stage disease undergo comprehensive regimens of immunotherapy combined with chemotherapy. However, the overall prognosis of patients with ESCC remains inadequate and further innovation and research are warranted (8). Specifically, there is a need to refine precision treatment and identify independent risk factors that can predict the prognosis of ESCC, which may aid in improving patients’ survival outcomes.

Lymph node (LN) metastasis (LNM) is widely recognized as the most important independent prognostic factor for patients with EC. The survival prognosis of patients with EC and LNM is significantly worse than that of those without LNM (9). Further exploration of the prognostic value of specific LNs in ESCC can provide a basis for optimizing station-based nodal staging system, thereby improving the precision of treatment regimens and the accuracy of prognostic assessments (10). Left gastric artery lymph nodes (No. 7) serve as a crucial hub for abdominal metastasis in ESCC and are one of the primary sites for the lymphatic drainage of the lower thoracic esophagus. No. 7 LNs have one of the highest metastasis rates among the sites of LNM in EC and are also the most common site of abdominal LNM in patients with lower thoracic EC, making dissection of the No. 7 LNs clinically necessary to avoid residual tumor and recurrence of ESCC (11). Anatomically, the submucosa of the esophagus is rich in a lymphatic network, through which cancer cells can spread extensively, resulting in the potential involvement of the cervical, mediastinal, and abdominal LNs (12). Moreover, the longitudinal lymphatic vessels in the esophageal submucosa can directly communicate with the abdominal cavity and are directly connected to the lymphatic network in the left gastric artery region. In ESCC, cancer cells can metastasize directly to this LN region along the lymphatic pathways within the esophageal mesentery, further highlighting the prominence of No. 7 LNs in the lymphatic metastasis pathway (13-15). Clinically, No. 7 LNs, along with other key regional LNs such as recurrent laryngeal nerve (RLN) LNs (No. 106rec), subcarinal LNs (No. 107), are generally recognized as high-risk regions and are commonly incorporated into the treatment planning for thoracic ESCC (16). However, significant heterogeneity exists in the prognostic value among these LNs. In ESCC patients who undergo neoadjuvant chemoradiotherapy followed by surgery, No. 7 LNM has been confirmed as an independent poor prognostic factor, whereas 106rec and 107 LNM occur only in a small subset of patients and exert no significant impact on prognosis (17). No. 7 LNs are a core component of celiac lymph nodes (CLN). A study has classified CLN metastasis as M1, and patients with such LNM have a significantly poorer prognosis than those without CLN involvement (18). Furthermore, No. 7 LNM is significantly associated with poor prognosis in patients with gastric cancer, and the implementation of No. 7 lymphadenectomy following radical resection can significantly improve patients’ survival outcomes (19). However, studies on the association between No. 7 LNM and the prognosis of patients with ESCC remain relatively limited. Furthermore, the pattern of LNM in ESCC remains uncertain, with a current lack of research focusing on the prognostic differences and underlying mechanisms of No. 7 LNM combined with metastasis to other regional lymph nodes. Owing to the complex anatomical structure of esophageal lymphatic drainage and the unclear anatomical mechanisms underlying metastasis, it remains clinically challenging to develop individualized prognostic assessment and treatment strategies based on LNM.

Therefore, this study aimed to systematically evaluate the independent prognostic value of No. 7 LNM and, as per the theory of membrane anatomy, analyze the prognostic differences between patients with No. 7 LNM alone and those with No. 7 LNM and LNMs to other sites. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2300/rc).

Methods

Study population and study design

This study retrospectively analyzed the clinical data of 144 patients with ESCC who underwent radical esophagectomy at the Department of Esophageal Surgery, Cancer Hospital of the Chinese Academy of Medical Sciences, between 2019 and 2021. The patients’ baseline data included information on age, gender, smoking and drinking history, Eastern Cooperative Oncology Group (ECOG) performance status, comorbidities, surgical approach, and nutritional status, among other characteristics. According to the eighth edition staging criteria of the American Joint Committee on Cancer (AJCC) (20), preoperative and postoperative tumor-node-metastasis (TNM) staging was completed for all enrolled patients. After resection of the tumor specimens, their three-dimensional size parameters were accurately measured and recorded; postoperatively, tumor characteristics were described by pathologists, including maximum tumor diameter, differentiation grade, depth of invasion, and location of the primary tumor. In accordance with the Japanese classification criteria for LNs in ESCC (21), LN dissection was performed for the left gastric artery LNs (No. 7), RLN LNs (No. 106rec), subcarinal LNs (No. 107), and main bronchial LNs (No. 109 LN) in the corresponding regions of the thoracic cavity, abdominal cavity, and neck. After postoperative specimens were fixed with formalin, they were stained with hematoxylin-eosin (HE) staining. Two pathologists independently evaluated the specimens to determine LNM status, which was defined as the presence of ≥1 cluster of tumor cells. Patients with unrecovered or unidentifiable LNs during surgery were defined as non-metastatic in the absence of definitive metastatic evidence. Subsequently, patients were divided into a positive group (No. 7 LN+) and a negative group (No. 7 LN−) based on the pathological results of No. 7 LNM. All enrolled patients underwent regular postoperative follow-up, during which the time of recurrence, location of recurrence, and time of death were recorded in detail.

Inclusion and exclusion criteria

The inclusion criteria were as follows: ESCC confirmed by histology or cytology (cT1b–cT4a N any M0); complete imaging examination data; disease assessed as resectable by thoracic surgeons; completion of radical esophagectomy; age ≥18 years; at least one measurable lesion identified as per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; no prior history of any systemic antineoplastic therapy, including surgery, chemotherapy, radiotherapy, targeted therapy, or immunotherapy; ECOG performance status of 0–1; expected survival time ≥12 weeks; normal bone marrow, liver, and renal function (with no blood transfusion, growth factor administration, or blood component support within 14 days before enrollment); for women of childbearing potential, completed serum or urine pregnancy test with a negative result within 14 days before enrollment and willingness to use appropriate contraceptive measures during the observation period and within 8 weeks after the last administration of the study drug; and for male patients, surgical sterilization or willingness to use appropriate contraceptive measures during the observation period and within 8 weeks after the last administration of the study drug.

The exclusion criteria were as follows: a history of surgery for malignant tumors of the chest or gastrointestinal tract; reoperation due to recurrence after radical esophagectomy; administration of palliative surgery without R0 resection and without standardized two-field or three-field LN dissection; incomplete follow-up data; and systematic dissection of No. 7, 106, 107, and 109 LNs was not performed during radical esophagectomy.

Patient follow-up

The postoperative follow-up protocol of this study was as follows: postdischarge follow-up examinations were conducted in phases after surgery. For the first 2 years, routine examinations including computed tomography (CT) scans of the chest, head, and abdomen, as well as neck and abdominal ultrasound, were performed every 3 months; thereafter, examinations were conducted once every 6 months for the following 5 years, and annual evaluations were performed subsequently. Annual follow-up was carried out via outpatient reviews or telephone follow-up. To reduce selection bias and ensure the accuracy of survival analysis results, standard right-censoring techniques were applied to lost-to-follow-up cases, with the last effective follow-up time defined as the censoring point. All censored data were retained and incorporated into the final statistical analysis. In this study, OS and disease-free survival (DFS) were the key indicators for evaluating the prognosis of ESCC. OS was defined as the time from the implementation of radical esophagectomy to all-cause death or the last follow-up; DFS was defined as the time from the implementation of radical esophagectomy to tumor recurrence or the last follow-up.

Statistics analysis

Statistical analyses were performed with SPSS v. 27.0 (IBM Corp., Armonk, NY, USA). Continuous data with a normal distribution are presented as the mean ± standard deviation (x¯±s), and comparisons of intergroup differences were conducted via the independent samples t-test. Categorical data are expressed as percentages, and intergroup comparisons were conducted via the Chi-squared test (χ² test) or Fisher exact test. The Kaplan-Meier method was used to plot survival curves for patients’ OS and DFS, and the log-rank test was applied to compare survival differences between groups. Moreover, a Cox proportional hazards regression model was used for univariate and multivariate analyses to identify risk factors influencing OS and DFS in patients with ESCC. Variables with a P<0.1 in univariate analysis, combined with covariates selected based on clinical relevance and existing literature evidence, were included in the multivariate analysis to determine the independent prognostic factors for ESCC (22,23). All statistical tests were two-tailed, with a P value <0.05 being considered statistically significant.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. It was approved by the Ethics Review Committees of Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No. 24/383-4663) and Peking University Cancer Hospital (Inner Mongolia Campus) (No. WZ202528). Given the retrospective nature of the study, individual informed consent for this analysis was waived by the Ethics Review Committees.

Results

Participant characteristics

A total of 144 patients with thoracic ESCC were enrolled in this study, including 124 males and 20 females; the tumor was located in the upper-middle thoracic segment in 69 cases, and lower thoracic segment in 75 cases; the treatment regimens included neoadjuvant chemoradiotherapy in 7 cases, neoadjuvant chemotherapy in 64 cases, and neoadjuvant immunochemotherapy in 52 cases; 115 patients were diagnosed with stage N0–N1 disease; all patients achieved R0 resection. Postoperative pathological findings were used as the basis for grouping: 25 patients with pathologically confirmed No. 7 LNM after surgery were assigned to the No. 7 LN+ group, while 119 patients without No. 7 LNM were assigned to the No. 7 LN− group, with the overall metastasis rate of No. 7 LNs being 17.4% (25/144). Analysis of baseline characteristics showed that among the 144 patients, the overall positive rate of metastasis to the No. 106rec LNs was 28.47% (41/144), and the overall positive rate of metastasis to the No. 107/109 LNs was 12.5% (18/144); only the distribution of No. 106rec LNs and the. No. 107/109 LNs between the two groups showed a significant statistical difference (P<0.05). Other baseline characteristics, including age, gender, body mass index (BMI), preoperative nutritional intervention, smoking and drinking history, T stage, N stage, clinical stage, primary tumor location, preoperative treatment modality, the number of examined lymph nodes, and nutritional score, showed no statistical difference in distribution between the two groups (P>0.05) (Table 1).

Analysis of OS and DFS in the No. 7 LN+ group and No. 7 LN− group

To examine the influence of No. 7 LNM on the prognosis of patients with ESCC, this study compared the OS and DFS between the No. 7 LN+ group and the No. 7 LN− group (Figure 1). Results showed significant differences in Kaplan-Meier curves between the two groups for OS (P=0.007) and DFS (P=0.009). Specifically, the No. 7 LN+ group had notably poorer survival outcomes, with the 1- and 3-year OS (84.0% and 55.7%, respectively), being significantly lower than the those of the No. 7 LN− group (89.9% and 81.5%, respectively). Survival analysis revealed that the mortality risk of the No. 7 LN+ group was 2.6 times higher than that of the No. 7 LN- group [hazard ratio (HR) =2.6, 95% confidence interval (CI): 1.26–5.36], indicating a significantly higher mortality risk and poorer prognosis in the No. 7 LN+ group. In terms of DFS, the 1- and 3-year DFS rates of the No. 7 LN− group were 89.6% and 85.9%, respectively, while those of the No. 7 LN+ group were 71.8% and 62.8%, respectively. Survival analysis showed that the disease recurrence risk of the No. 7 LN+ group was 2.82 times that of the No. 7 LN− group (HR =2.82, 95% CI: 1.25–6.4). The median follow-up duration was 34 months.

Figure 1 Kaplan-Meier curves for overall survival (A) and disease-free survival (B) among patients with ESCC. Patients were divided into group A (absence of left gastric artery lymph nodes metastasis) and group B (left gastric artery lymph nodes metastasis). CI, confidence interval; ESCC, esophageal squamous cell carcinoma; HR, hazard ratio.

Univariate and multivariate regression analysis of OS and DFS in patients with ESCC

A Cox regression model was to analyze the influencing factors of OS and DFS among the 144 enrolled patients with ESCC. For the univariate Cox analysis of OS, the P values of smoking, alcohol consumption, T stage, clinical stage, neoadjuvant chemoradiotherapy, and No. 7 LNM were all <0.1, which met the preset variable inclusion criterion. Thus, these variables were included in the multivariate Cox regression analysis to exclude the influence of confounding factors. Meanwhile, based on clinical significance and existing literature evidence, age, gender, N stage, primary tumor location, and the number of examined lymph nodes were supplementarily included in the multivariate Cox regression model to enhance the reliability of the analysis results. The results indicated that No. 7 LNM was an independent risk factor influencing patients’ OS (HR =2.36, 95% CI: 1.07–5.18; P=0.03) (Table 2). For DFS, variables with P<0.1 in univariate analysis, as well as clinically meaningful and literature-supported covariates including age, gender, N stage, primary tumor location, and the number of examined lymph nodes, were included in the multivariate regression analysis. The results confirmed that No. 7 LNM was also an independent risk factor affecting patients’ DFS (HR =2.5, 95% CI: 1.02–6.1; P=0.04) (Table 3).

Analysis of OS and DFS in patients with No. 7 LNM with or without No. 106rec LNM

To systematically evaluate patient prognosis, we conducted a subgroup analysis of patients with No. 7 LNM, examining those with No. 106rec LNM (No. 106rec LN+ group; n=14) and those without No. 106rec (106rec LN− group; n=11) and using the Kaplan-Meier method to analyze the OS and DFS of these two subgroups (Figure 2). In terms of OS, the No. 106rec LN+ group showed a markedly lower survival probability, with a median OS of 28 months, while the median OS of the No. 106rec LN− group was not reached. This suggests that the mortality risk associated with No. 106rec LNM may be higher, but the difference in OS between the two groups was not statistically significant (HR =1.83, 95% CI: 0.53–6.28; P=0.33). In terms of DFS, the No. 106rec LN+ group had a lower DFS probability than did the No. 106rec LN− group. However, the difference in DFS between the two groups was also not statistically significant (HR =1.89, 95% CI: 0.47–7.56; P=0.37).

Figure 2 Kaplan-Meier curves for overall survival (A) and disease-free survival (B) among patients with ESCC with left gastric artery lymph node metastasis. Patients were divided into group A (isolated left gastric artery lymph nodes metastasis) and group B (left gastric artery lymph nodes metastasis accompanied by recurrent laryngeal nerve lymph nodes metastasis). CI, confidence interval; ESCC, esophageal squamous cell carcinoma; HR, hazard ratio.

Analysis of OS and DFS in patients with No. 7 LNM with and without No. 107 LNM or No. 109 LNM

The Kaplan-Meier method was used to analyze the OS and DFS of two groups of patients with No. 7 LNM: one with concurrent No. 107 or No. 109 LNM (n=9) and the other without such involvement (n=16) (Figure 3). The results demonstrated that among these patients, the OS (P=0.02) and DFS (P=0.03) of the group with concurrent No. 107 or No. 109 LNM were significantly inferior to those of the group without such concurrent involvement. Further risk analysis revealed that the mortality risk of patients with such concurrent involvement was significantly increased by 306% (HR =4.06, 95% CI: 1.18–14.01), while their risk of disease recurrence was significantly increased by 326% (HR =4.26, 95% CI: 1.06–17.08).

Figure 3 Kaplan-Meier curves for overall survival (A) and disease-free survival (B) among patients with ESCC with left gastric artery lymph node metastasis. Patients were divided into group A (isolated left gastric artery lymph nodes metastasis) and group B (left gastric artery lymph nodes metastasis accompanied by subcarinal or main bronchial lymph nodes metastasis). CI, confidence interval; ESCC, esophageal squamous cell carcinoma; HR, hazard ratio.

Impact of No. 7 LNM on prognosis across different thoracic tumor locations

The study cohort was further analyzed based on differences in primary tumor location (Figure 4). There were 69 patients with ESCC whose tumors were located in the upper or middle thoracic segments, among whom 58 were in the No. 7 LN− group and 11 in the No. 7 LN+ group. Kaplan-Meier curves indicated that the No. 7 LN+ group, as compared with the No. 7 LN−, had lower an OS, but this difference was not significant (HR =2.62, 95% CI: 0.79–8.71; P=0.11). Similarly, the DFS in the No. 7 LN+ group was also lower but not significantly so (HR =2.99, 95% CI: 0.71–12.5; P=0.12). Among the 75 patients with ESCC with tumors in the lower thoracic segment, there were 14 cases in the No. 7 LN+ group and 61 cases in the No. 7 LN−. Kaplan-Meier survival analysis of these patients indicated that No. 7 LN+ group had a significantly shorter OS (HR =2.49, 95% CI: 1.02–6.18; P=0.04) and DFS (HR =2.76, 95% CI: 1.02–7.48; P=0.04) compared to No. 7 LN− group.

Figure 4 Kaplan-Meier curves for overall survival (A,C) and disease-free survival (B,D) among patients with ESCC with left gastric artery lymph node metastasis. Patients were divided into group A (absence of left gastric artery lymph nodes metastasis) and group B (left gastric artery lymph nodes metastasis). (A,B) The upper and middle thoracic segments. (C,D) Lower thoracic segment. CI, confidence interval; ESCC, esophageal squamous cell carcinoma; HR, hazard ratio.

Sensitivity analysis of No. 7 LNM prognostic impact in ESCC patients with neoadjuvant therapy

To confirm the stability of the study results, we performed a sensitivity analysis involving 124 neoadjuvant-treated patients, excluding those who did not receive neoadjuvant therapy (Table S1). Kaplan-Meier survival analysis indicated that OS (HR =2.46, 95% CI: 1.18–5.14; P=0.01) and DFS (HR =3.03, 95% CI: 1.12–5.87; P=0.02) were significantly shorter in the No. 7 LN+ group as compared to the No. 7 LN− group (Figure S1). In the multivariate Cox regression model, after adjusting for the same covariates as those used in the overall population analysis, the results indicated that No. 7 LNM remains an important adverse prognostic factor for patients with ESCC (Tables S2,S3).

Discussion

LNM is a key independent factor in the clinical prognostic assessment of ESCC, and its status is directly associated with patients’ survival outcomes and the selection of treatment strategies (24). In ESCC, left gastric artery LNs (No. 7) have a relatively high metastatic rate, and thus are critical to LNM evaluation and clinical decision-making for ESCC, warranting particular consideration (25). A study using carbon nanoparticle lymphatic tracing experiments found that when the carbon nanoparticle tracer was injected into the submucosa of the upper and middle thoracic esophagus to trace the natural drainage pathway of esophageal lymph fluid, clear visualization was observed in the No. 7 LNs (26). This result suggests that the No. 7 LNs may be the terminal endpoint of esophageal lymphatic drainage and that the root of the esophageal mesentery may lie within the left gastric mesentery. Although the No. 7 LNs have a relatively high metastatic rate with implications for ESCC clinically, their link to the postoperative prognosis of patients with ESCC has not been extensively investigated. Liu et al. reported that patients with ESCC but without No. 7 LNM had significantly better survival outcomes than did those with LNM at this site (27). A retrospective cohort study indicated that during radical esophagectomy for EC, dissection of the No. 7 LN is a necessary measure to prevent residual ESCC or metastasis (11). However, other related studies have reported inconsistent results. For instance, a study on patients with thoracic ESCC who received definitive chemoradiotherapy found that No. 7 LNM had no significant correlation with survival rates (28). Additionally, Cho et al. observed that abdominal LNM did not affect the survival rate of patients with thoracic ESCC who underwent neoadjuvant chemoradiotherapy followed by surgery (29). Since a consistent understanding of the association between No. 7 LNM and ESCC prognosis has not yet been established, our findings may further clarify this relationship and provide a reference for refining the diagnosis and treatment strategies for ESCC.

In our study, No. 7 LNM was closely associated with the prognosis of patients with ESCC: the No. 7 LN+ group had a significantly higher risks of death and disease recurrence than did the No. 7 LN− group. Furthermore, No. 7 LNM exerted significant adverse effects on both OS (HR =2.36, 95% CI: 1.07–5.18; P=0.03) and DFS (HR =2.5, 95% CI: 1.02–6.1; P=0.04) in patients with ESCC and served as an independent risk factor in the prognosis of patients with ESCC. The core findings of this study regarding the impact of No. 7 LNM on the prognosis of patients with ESCC are consistent with those of some previous studies but differ from those of others (27-29). The reasons for these discrepancies in ESCC research may be attributed to multiple factors: differences in treatment modalities mean that with definitive chemoradiotherapy, surgery achieves more thorough local LN clearance, and this difference renders the independent prognostic impact of No. 7 LNM more prominent; additionally, variations in the subclassifications of No. 7 LN across studies hinders the uniformity and comparability of the research data; furthermore, factors including tumor stage and primary tumor location in patients with ESCC are the principal variables highly correlated with prognosis and LNM, and the inconsistent distribution of these variables across study cohorts exerts a direct confounding effect on the prognostic impact of No. 7 LNM.

Professor Daiko from the National Cancer Center Japan proposed the concentric circle theory, which divides the esophagus and its surrounding structures into the visceral layer, vascular layer, and parietal layer. Moreover, the theory of esophageal mesentery holds out that the esophageal mesentery is composed of two layers of connective tissue membranes, which can enwrap the esophagus and surrounding adipose tissue to form a relatively closed lymphatic drainage system; although the No. 106rec and No. 7 LNs belong to different body cavities, and the rates of No. 106rec LNM and No. 7 LNM vary among patients with different tumor locations, both the No. 106rec and No. 7 LNs are located in the visceral layer in concentric circle theory, while according to the theory of esophageal mesentery, No. 106rec and No. 7 LNs belong to the esophagus’s intramesenteric lymphatic system, with mesenteric structural continuity maintained by the visceral fascia to form an uninterrupted drainage pathway (30). Lymphatic fluid from No. 106rec LNs drains to No. 7 LNs via the intramesenteric lymphatic network; cancer cells metastasizing between these two stations remain enclosed by the mesenteric fascial barrier without crossing anatomical boundaries, representing intramesenteric metastasis (21,31). This suggests that the No. 106rec and No. 7 LNs are not independent distant metastatic sites in the conventional sense; rather, their metastatic nature is more likely to involve a regional spread within the unified lymphatic diffusion system around the esophagus. Therefore, in patients with No. 7 LNM, the presence or absence of No. 106rec LNM is not significantly associated with the OS (HR =1.83, 95% CI: 0.53–6.28; P=0.33) and DFS (HR =1.89, 95% CI: 0.47–7.56; P=0.37). However, patients with the No. 106rec LNM nonetheless tend to have a poorer prognosis. This may be because No. 106rec LNM is one of the independent prognostic risk factors for ESCC; additionally, it is significantly associated with the primary tumor location, depth of invasion, and degree of differentiation of ESCC. Therefore, No. 106rec LNM may represent a biological manifestation of the tumor’s stronger invasive and metastatic potential, which is directly associated with shorter OS in patients (32,33). A retrospective study involving 688 patients with ESCC found that patients with LNM confined to a single region had significantly better survival rates than did those with multiregional LNM; moreover, multiregional LNM was often accompanied by a greater number of positive LNs (34). It has been established that the number of positive LNs is an independent predictor of prognosis for patients with ESCC (35), which further suggests that multiregional LNM may impact patients’ survival outcomes by increasing the number of positive LNs.

Subsequently, we further investigated the influence of 107 LNM or 109 LNM on the prognosis of patients with ESCC and No. 7 LNM. In our study, patients with No. 107 LNM or No. 109 LNM had significantly poorer OS (HR =4.06, 95% CI: 1.18–14.01; P=0.02) and DFS (HR =4.26, 95% CI: 1.06–17.08; P=0.03) than did those without such metastases. According to the theory of esophageal mesentery, No. 7 LNs lie within the esophageal mesentery, while No. 107 and 109 LNs are separated by independent membranous structures outside the mesentery and located in the extramesenteric region. Thus, no direct intramesenteric pathway exists between No. 107/109 LNs and No. 7 LNs, as they are separated by the visceral fascia barrier. No. 7 LNM remains confined within the mesentery, whereas No. 107/109 LNM signifies breach of the mesenteric barrier and tumor progression into the peripheral lymphatic system (36,37). According to the concentric circle theory, the esophageal submucosa contains dense longitudinal lymphatic networks that drain directly to the No. 7 LNs in the visceral layer, while the No. 107 or 109 LNs lie in the vascular layer; thus, tumor cells must first break through anatomical barriers to spread to these nodes, leading to a relatively low probability of metastasis (15). This phenomenon of cross-regional metastases clearly reflects the strong invasive and metastatic potential of tumor cells, suggesting that the tumor has broken through local constraints and entered the stage of systemic spread. When patients exhibit severe vascular invasion and tumor infiltration, the disease is likely to be at an advanced stage, and the prognosis is often poorer (38,39).

We further investigated the impact of No. 7 LNM on patient prognosis across different primary tumor locations in the thoracic esophagus. The results showed that No. 7 LNM has limited prognostic predictive value for patients with upper and middle thoracic ESCC, with no significant differences in OS (HR =2.62, 95% CI: 0.79–8.71; P=0.11) or DFS (HR =2.99, 95% CI: 0.71–12.5; P=0.12) between patients with and without No. 7 LNM. However, in patients with lower thoracic ESCC, compared with No. 7 LN− group, No. 7 LN+ group had a significantly poorer OS (HR =2.49, 95% CI: 1.02–6.18; P=0.04) and DFS (HR =2.76, 95% CI: 1.02–7.48; P=0.04). Therefore, we can conclude that No. 7 LNM can serve as an effective predictive indicator for OS and DFS in patients with lower thoracic ESCC. No. 7 LNs represent the most commonly involved abdominal lymph node station in lower thoracic ESCC, and their metastatic characteristics exhibit significant differences among different segments of thoracic ESCC; specifically, the metastatic rate of No. 7 LNs in lower thoracic ESCC is significantly higher than that in middle and upper thoracic ESCC (40). The relatively high incidence rate endows it with stable distribution characteristics in clinical samples, thus enabling it to more reliably reflect the association with prognosis. Furthermore, the number of LNMs is also one of the independent prognostic risk factors for ESCC (41). Given that the lymphatic drainage of the lower thoracic esophagus is highly concentrated in No. 7 LNs, which facilitates the accumulation of cancer cells at this site, patients with lower thoracic ESCC may also have a greater number of No. 7 LNMs (17).

This study initially included thoracic ESCC patients who received neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, or no neoadjuvant therapy, among other treatment groups. However, neoadjuvant therapy can induce a significant lymph node downstaging effect. Additionally, population heterogeneity caused by different treatment modalities may introduce bias and affect the robustness of the core conclusions. Therefore, this study conducted a sensitivity analysis by excluding patients who did not receive neoadjuvant therapy, aiming to reduce treatment-related confounding effects. The results demonstrated that No. 7 LNM remained associated with poor prognosis in the neoadjuvant therapy cohort.

This study serves as an important reference for the individualized precision diagnosis and treatment of thoracic ESCC. No. 7 LNM should be incorporated into the routine clinical prognostic evaluation system, and patient risk should be assessed in combination with esophageal mesentery anatomy. In patients with No. 7 LNM combined with extramesenteric LNM, this finding indicates that the tumor has breached anatomical barriers. On the basis of routine complete dissection of No. 7 LNs, exploration of peripheral lymphatic regions may be enhanced when necessary. In terms of treatment strategy, it is recommended that such patients receive combined neoadjuvant chemoradiotherapy or postoperative adjuvant therapy to reduce the risk of recurrence and metastasis. For follow-up management, the frequency of postoperative follow-up and monitoring for these patients should be heightened, with a focus on signs of distant metastasis. This study involved several limitations that should be acknowledged. First, we employed a single-center, retrospective design, and the data collection relied on historical clinical records, makes it difficult to fully avoid selection bias and information bias. Furthermore, all patients were recruited from this single center, and its treatment protocols, pathological assessment criteria, and patient baseline characteristics were specific to this center, limiting the direct generalizability of the conclusions to ESCC populations in other centers or different regions. Second, the total sample size was only 144 cases, among which only 25 were patients with No. 7 LNM, compromising the stability and reliability of the conclusions. Additionally, while Xia et al. confirmed that neoadjuvant therapy improves long-term survival in certain populations (42), patients in this study who received neoadjuvant chemoradiotherapy or combined immunotherapy tended to have poorer prognoses. This may be attributed to the advanced disease stages or extensive LNM in these patients, rather than the treatment regimen itself, making it challenging to clearly isolate the independent prognostic effects of treatment from the underlying disease status. Future research will adopt a prospective multicenter design, establish a network of multiple centers at all levels, and increase the sample size through multicenter collaboration and extended enrollment periods to enhance the generalizability of the conclusions.

Conclusions

Our study demonstrates that No. 7 LNM is an independent risk factor for OS and DFS in patients with thoracic ESCC and holds more significant prognostic value in patients with lower thoracic ESCC. Additionally, we further examine the prognostic differences among No. 7 LNM with and without other regional LNMs, deepening the understanding of the LNM pattern in ESCC. Based on the results of this study, routine dissection of No. 7 LNM should be performed intraoperatively. For patients with No. 7 LNM, especially those with concurrent other regional LNs, adjuvant therapy and targeted follow-up should be considered to improve survival. It should be noted that the study had limitations, such as the single-center, retrospective design and a limited sample size. In the future, multicenter, prospective studies can be conducted to validate our findings, and the research scope can be further expanded to enrich the evidence base.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2300/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2300/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2300/prf

Funding: This work was supported by the Beijing Medical Award Foundation (No. YXJL-2020-0785-0351), the Wu Jieping Medical Foundation (No. 320.6750.202219-88), the Science and Technology Program of the Joint Fund of Scientific Research for the Public Hospitals of the Inner Mongolia Academy of Medical Sciences (Nos. 2023GLLH0123 and 2024GLLH0384), the Inner Mongolia Medical University Joint Project (Nos. YKD2024LH021 and YKD2022LH005), the Beijing University Cancer Hospital Inner Mongolia Hospital “Qingmiao” Talent Plan (Nos. QM202325 and QM202312), and Inner Mongolia Hospital of Peking University Cancer Hospital - Demonstration Project for the Reform and High-quality Development of Public Hospitals (Gastrointestinal Tumors + Thoracic Tumors) Construction of Clinical Key Specialties (No. 12024YNQN013).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2300/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 and its subsequent amendments. It was approved by the Ethics Review Committees of Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No. 24/383-4663) and Peking University Cancer Hospital (Inner Mongolia Campus) (No. WZ202528). Given the retrospective nature of the study, individual informed consent for this analysis was waived by the Ethics Review Committees.

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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(English Language Editor: J. Gray)