ABSTRACT
Objectives
To investigate the lymph node metastasis (LNM) pattern of esophageal squamous cell carcinoma (ESCC) and identify factors associated with LNM:
Methods
A retrospective study was conducted including 388 patients with ESCC who underwent curative resection at the First Affiliated Hospital of Nanjing Medical University between January 2020 and December 2022. Clinicopathological characteristics and lymph node metastasis patterns were analyzed. Univariate and multivariate analyses were performed to identify factors associated with LNM.
Results
Among the 388 patients, 144 (37.11%) had lymph node metastasis. The total number of dissected lymph nodes was 8546, with 341 positive nodes, yielding an LNM degree of 3.99%. Upper thoracic ESCC was more likely to metastasize to upper right paratracheal lymph nodes, while lower thoracic ESCC showed a higher rate of paracardial lymph node metastasis. Tumor differentiation, tumor size, invasion depth, age, and intravascular tumor thrombus were associated with LNM. Multivariate logistic regression analysis revealed that tumor diameter ≥ 3 cm (OR = 2.485, 95% CI 1.483–4.165, p = 0.001) and intravascular tumor thrombus (OR = 7.123, 95% CI 3.101–16.362, p < 0.001) were independent risk factors.
Conclusions
Upper esophageal SCC tends to metastasize to upper mediastinal lymph nodes, whereas abdominal and paracardial lymph node metastasis is more common in lower esophageal SCC. Tumor size and intravascular tumor thrombus are independent risk factors for lymph node metastasis.
Keywords: esophageal squamous cell carcinoma, influencing factors, lymph node metastasis
Among 388 patients with esophageal squamous cell carcinoma who underwent curative resection, 144 (37.1%) developed lymph node metastasis. Upper thoracic tumors mainly involved upper mediastinal and upper right paratracheal nodes, whereas lower thoracic tumors more often involved paracardial and abdominal nodes. Poor differentiation and metastasis in subcarinal, paraesophageal, or right gastric nodes were associated with left gastric lymph node involvement. Tumor diameter ≥ 3 cm and intravascular tumor thrombus independently predicted metastasis, supporting individualized risk assessment and risk‐adapted lymphadenectomy.
Abbreviations
- ESD
endoscopic mucosal dissection
- LNM
lymph node metastasis
- NSM
nodal skip metastasis
- SCC
squamous cell carcinoma
1. Background
Esophageal cancer represents a prevalent malignancy within the digestive tract. According to the 2020 global cancer statistics report [1], it ranks eighth in incidence and sixth in case fatality rates among all cancers. Squamous cell carcinoma (SCC) constitutes the predominant histological type, accounting for approximately 85% of cases [2]. The incidence of lower esophageal cancer continues to escalate annually [3]. Despite numerous therapeutic interventions, the 5 year survival rate remains low [4]. Hence, there is a pressing need to delve into esophageal SCC and identify suitable methods for prognosis improvement. Several risk factors, including lymph node metastasis (LNM), significantly impact prognosis. Although lymphadenectomy has been adopted in certain esophageal SCC cases, a study by Li revealed a 25.9% prevalence of LNM [5]. Therefore, understanding the lymph node metastasis patterns in esophageal SCC patients is crucial for comprehending the high recurrence rates and enhancing treatment strategies.
Currently, endoscopic mucosal dissection (ESD) is primarily employed for early esophageal cancer (confined to the mucosal layer), yet lymph node dissection is not typically performed with this approach. However, the possibility of LNM in early submucosal or intramucosal esophageal cancer cannot be discounted [6, 7]. Missed LNM adversely affects patient survival; hence, early LNM detection in esophageal SCC patients holds significant clinical value. Zhou et al. developed an LNM risk prediction model based on clinical data, achieving an AUC of 0.80 (95% CI, 0.74–0.86) and excellent calibration curves [8]. Similarly, Pan et al. devised an automatic LNM segmentation algorithm based on hematoxylin–eosin‐stained slices with an accuracy exceeding 90% [6]. While these studies addressed LNM‐related issues, they exhibited certain limitations, primarily focusing on their datasets rather than underlying pathological and physiological characteristics. Despite decades of development in intra‐operative metastasis detection methods, LNM prevalence remains high. Furthermore, LNM serves as a significant pathway for esophageal cancer metastasis and significantly impacts prognosis [7]. Understanding LNM mechanisms in esophageal cancer is pivotal for guiding lymph node dissection. Therefore, this study aimed to investigate LNM patterns and influencing factors across different esophageal locations.
2. Methods
2.1. Study Design and Subjects
Patients who underwent curative resection for esophageal cancer between January 2020 and December 2022 at the First Affiliated Hospital of Nanjing Medical University were retrospectively collected. The inclusion criteria were: (1) patients who underwent radical resection of esophageal cancer; (2) absence of other concomitant tumors; (3) histologically confirmed squamous cell carcinoma. Exclusion criteria were: (1) patients undergoing palliative surgery; (2) presence of positive margins; (3) receipt of neoadjuvant chemotherapy; (4) absence of clinicopathological data; (5) undergoing ESD procedures. This study received approval from the Medical Ethics Committee of the First Affiliated Hospital of Nanjing Medical University. All participants provided informed consent.
2.2. Typical Surgical Approach
The included patients underwent one of four surgical modalities (Sweet, Ivor Lewis, McKeown, thoracic laparoscopic combined with esophagectomy) for cancer treatment, with the choice of procedure based on preoperative evaluation.
In the Sweet operation, the azygos vein arch was cut to expose the upper and middle mediastinum. Peritracheal and cervical lymph nodes were dissected, followed by freeing the esophagus from the aortic arch to the carina level. Dissection of cervical and middle mediastinal lymph nodes, vagus nerve division, thoracic duct ligation, and esophageal dissection at the cardia level ensued. Subsequently, the stomach was mobilized and brought up to the neck for anastomosis through the phrenoesophageal hiatus after gastric tube formation. The Ivor Lewis procedure involved shaping a gastric tube at an advanced stage, followed by thoracoabdominal lymph node dissection. The gastric tube was then elevated to the right chest apex through the hiatus for re‐anastomosis. In the McKeown procedure, the esophagus was freed, and lymph node dissection was performed. Subsequently, the cervical esophagus was separated, followed by cervical lymph node dissection. The stomach and lymph node dissection were extracted through a 4 cm median incision under the xiphoid process. A tubular stomach was fashioned and elevated for posterior cervical anastomosis.
In thoracic laparoscopic combined esophageal cancer resection, thoracoscopic esophagus liberation was initially performed, along with cervical and thoracic lymph node dissection. Subsequent laparoscopy freed the stomach, and abdominal lymph nodes were dissected. A gastric tube was then fashioned extracorporeally, followed by cervical anastomosis.
2.3. Data Collection
Data collection involved classifying lymph nodes according to the AJCC criteria [8]. Clinical data analyzed included age, sex, tumor differentiation, size, location, presence or absence of vascular tumor thrombus, and LNM status.
The lymph node metastasis (LNM) rate was defined as the proportion of patients with metastatic lymph nodes among the total number of patients. The degree of LNM was defined as the ratio of metastatic lymph nodes to the total number of dissected lymph nodes.
2.4. Statistical Analysis
Statistical analysis was conducted using SPSS software (version 22.0, IBM Corp., Armonk, N.Y., USA). Initially, the Chi‐square test or Fisher's exact probability was employed to examine the relationship between LNM areas and esophageal cancer occurrence sites. Subsequently, another Chi‐square test or Fisher's exact probability was utilized to investigate risk factors for developing left gastric LNM. Further, the Chi‐square test or Fisher's exact probability was applied to explore risk factors for any LNM, and variables with p < 0.05 were included in a multivariate analysis to determine independent risk factors. A significance level of p < 0.05 was considered statistically significant.
3. Results
3.1. Participants
A total of 388 patients (average age: 66.7 ± 6.4 years, ranging from 51 to 83 years) who underwent curative resection for esophageal cancer at the First Affiliated Hospital of Nanjing Medical University between January 2020 and December 2022 were included.
3.2. Lymph Node Metastasis Status
Among the 388 cases, 144 (37.11%) had LNM. The total number of dissected lymph nodes was 8546, averaging 22.03 lymph nodes per patient, including 341 positive lymph nodes. The LNM rate was 3.99%.
3.3. Association Between Esophageal Cancer Location and LNM
Table 1 shows that among the 388 patients, upper right paratracheal LNM (metastatic rate of 12.63%) and paraesophageal LNM (metastatic rate of 11.60%) were most common. Esophageal cancer in the upper segment was more likely to metastasize to the upper right paratracheal lymph nodes compared to the middle and lower segments (62.5% vs. 55.0% [middle segment] and 22.9% [lower segment], p = 0.008). Conversely, esophageal cancer at the lower segment was more prone to metastasize to the paracardial lymph nodes (28.1% vs. 0.0% [upper segment] and 12.5% [middle segment], p = 0.012).
TABLE 1.
Univariate analysis of lymph node metastasis in esophageal cancer with different locations.
| Upper segment (n = 8) | Middle segment (n = 40) | Lower segment (n = 96) | Total (n = 144) | χ 2 | p | |
|---|---|---|---|---|---|---|
| Upper right paratracheal | 5 | 22 | 22 | 49 | 9.85 | 0.008 |
| Upper left paratracheal | 2 | 6 | 12 | 20 | 0.619 | 0.79 |
| Lower paratracheal | 0 | 0 | 1 | 1 | 1.74 | 1 |
| Subcarinal | 0 | 5 | 19 | 24 | 4.689 | 0.119 |
| Paraesophageal | 0 | 13 | 32 | 45 | 5.955 | 0.073 |
| Left lower pulmonary ligament and right inferior pulmonary ligand | 0 | 0 | 0 | 0 | ||
| Paracardial | 0 | 5 | 27 | 32 | 9.179 | 0.012 |
| Left gastric artery | 2 | 6 | 26 | 34 | 3.432 | 0.251 |
| Common hepatic artery | 0 | 0 | 2 | 2 | 1.273 | 1 |
| Abdominal aorta | 0 | 0 | 3 | 3 | 1.385 | 0.626 |
3.4. Factors Influencing Left Gastric LNM
In the univariate analysis of potential influencing factors on left gastric LNM, we observed an association between tumor differentiation degree and left gastric artery LNM (p = 0.018). Notably, lower differentiation degrees correlated with a higher likelihood of left gastric LNM. Additionally, subcarinal, paraesophageal, and right gastric LNMs exhibited associations with left gastric LNM (p values were 0.001, 0.001, and < 0.001, respectively) (Table 2).
TABLE 2.
Univariate analysis of lymph node metastasis affecting left stomach [(n%)].
| Variables | Left gastric artery lymph node positive (n = 34) | Left gastric artery lymph node negative (n = 354) | χ 2 | p |
|---|---|---|---|---|
| Sex | 0.538 | 0.311 | ||
| Male | 28 (82.4) | 272 (76.8) | ||
| Female | 6 (17.6) | 82 (23.2) | ||
| Age | 0.231 | 0.385 | ||
| > 60 | 26 (76.5) | 283 (79.9) | ||
| ≤ 60 | 8 (23.5) | 71 (20.1) | ||
| Cancer location | 3.432 | 0.251 | ||
| Upper segment | 2 (5.9) | 20 (5.6) | ||
| Middle segment | 6 (17.6) | 114 (32.2) | ||
| Lower segment | 26 (76.5) | 220 (62.1) | ||
| Tumor differentiated | 10.635 | 0.018 | ||
| Low | 8 (23.5) | 36 (10.2) | ||
| Moderately | 24 (70.6) | 239 (67.5) | ||
| Well | 2 (5.9) | 57 (16.1) | ||
| Carcinoma in situ | 0 (0.0) | 22 (6.2) | ||
| Cancer length (cm) | 2.542 | 0.078 | ||
| < 3 cm | 13 (38.2) | 186 (52.5) | ||
| ≥ 3 cm | 21 (61.8) | 168 (47.5) | ||
| Infiltration depth | 4.363 | 0.193 | ||
| Tis | 0 (0.0) | 8 (2.3) | ||
| T1 | 6 (17.6) | 115 (32.5) | ||
| T2 | 19 (55.9) | 139 (39.3) | ||
| T3 | 9 (26.5) | 92 (26.0) | ||
| Intravascular tumor thrombus | 1.433 | 0.159 | ||
| Y | 6 (17.6) | 37 (10.5) | ||
| N | 28 (82.4) | 317 (89.5) | ||
| Subcarinal lymph node metastasis | 8 (23.5) | 17 (4.8) | 11.962 | 0.001 |
| Paraesophageal lymph node metastasis | 11 (32.4) | 35 (9.9) | 11.293 | 0.001 |
| Paracardia lymph node metastasis | 12 (35.3) | 20 (5.6) | 23.043 | 0 |
3.5. Factors Associated With LNM
Univariate analysis results indicated that LNM, age, differentiation grade, tumor diameter, depth of invasion, and intravascular tumor thrombus were statistically significant factors influencing LNM in esophageal cancer (p < 0.05). However, patient sex (p = 0.215) and cancer location (p = 0.572) did not show statistical differences in LNM (Table 3). Subsequent binary logistic regression analysis revealed tumor diameter > 3 cm (OR = 2.485, 95% CI: 1.483–4.165) and the presence of intravascular tumor thrombus (OR = 7.123, 95% CI: 3.101–16.362) as independent factors for LNM (Table 4).
TABLE 3.
Univariate analysis influencing lymph node metastasis.
| Variables | Total cases, n = 388 | Lymph node metastasis, n = 144 | Metastasis vs. Non‐metastasis | |
|---|---|---|---|---|
| χ 2 | p | |||
| Sex | 0.843 | 0.215 | ||
| Male | 300 | 115 (38.3) | ||
| Female | 88 | 29 (33.0) | ||
| Age | 5.131 | 0.017 | ||
| > 60 | 309 | 106 (34.3) | ||
| ≤ 60 | 79 | 38 (48.1) | ||
| Cancer location | 1.125 | 0.572 | ||
| Upper segment | 22 | 8 (36.4) | ||
| Middle segment | 120 | 40 (33.3) | ||
| Lower segment | 246 | 96 (39.0) | ||
| Tumor differentiated | 27.659 | 0.000 | ||
| Carcinoma in situ | 22 | 0 (0.0) | ||
| Low | 44 | 22 (50.0) | ||
| Moderately | 263 | 111 (42.2) | ||
| Well | 59 | 11 (18.6) | ||
| Cancer length (cm) | 29.549 | 0.000 | ||
| < 3 cm | 199 | 48 (24.1) | ||
| ≥ 3 cm | 189 | 96 (50.8) | ||
| Infiltration depth | 26.159 | 0.000 | ||
| Tis | 8 | 0 (0.0) | ||
| T1 | 121 | 28 (23.1) | ||
| T2 | 158 | 66 (41.8) | ||
| T3 | 101 | 50 (49.5) | ||
| Intravascular tumor thrombus | 40.630 | 0.000 | ||
| Y | 43 | 35 (81.4) | ||
| N | 345 | 109 (31.6) | ||
TABLE 4.
Multivariate logistic regression analysis.
| Variables | Regression coefficient | Standard error | Wald | p | OR | 95% CI |
|---|---|---|---|---|---|---|
| Diameter ≥ 3 cm | 0.91 | 0.263 | 11.943 | 0.001 | 2.485 | 1.483–4.165 |
| Intravascular tumor thrombus | 1.963 | 0.424 | 21.409 | 0 | 7.123 | 3.101–16.362 |
4. Discussion
This study revealed that esophageal cancer originating in the upper segment exhibited a propensity to metastasize to the upper right paratracheal region, whereas cancer in the lower segment had a higher likelihood of metastasizing to the para cardia region. Single variate and multivariate analyses identified tumors larger than 3 cm and the presence of intravascular tumor thrombus as independent risk factors for metastasis. The findings of this study underscore the importance of assessing tumor size and the presence of intravascular tumor thrombus as potential indicators for predicting lymph node metastasis in esophageal squamous cell carcinoma, aiding in treatment decision‐making and patient management strategies.
The findings of this study regarding the LNM patterns in esophageal cancer at different segments revealed that esophageal SCC in the upper segment exhibited a tendency to metastasize to upper right paratracheal lymph nodes (p = 0.008), while lower esophageal cancer showed a predilection for metastasis to paracardial lymph nodes (p = 0.012). Although no significant difference (p = 0.626) was observed in abdominal aortic LNM states, our results indicated that only esophageal SCC occurring in the lower segment metastasized to abdominal aortic lymph nodes. This phenomenon could be partially attributed to the lymphatic drainage characteristics of the esophagus, wherein lymph from the upper segment primarily drains to the neck, lymph from the middle segment drains bidirectionally, and lymph from the lower segment mainly drains to the abdominal cavity [9]. While the majority of lymph nodes did not exhibit a clear relationship with esophageal SCC occurrence, nodal skip metastasis (NSM) was observed in many patients. Lower thoracic esophageal cancer could develop metastasis to cervical lymph nodes, while upper thoracic esophageal cancer could develop metastasis to abdominal lymph nodes. Metastasis was often observed in distant regional lymph nodes rather than lymph nodes near the primary tumor site, which, in our study, was associated with the complex lymphatic drainage in esophageal cancer. As described by Wang et al. [10], esophageal lymphatic drainage is primarily categorized into three types: transverse, longitudinal, and circular. Lymph containing tumor cells drains longitudinally within the full thickness of the esophageal wall before transversely penetrating the esophageal wall, thus bypassing lymph nodes near the primary tumor for metastasis to distant lymph nodes, leading to NSM [11]. Additionally, cervical and upper thoracic esophageal cancer is considered the most aggressive due to multiple involvements of adjacent structures such as the airways, aortic arch, or recurrent laryngeal nerve, often hindering complete resection of locally advanced tumors [12].
The lymph node of the left gastric artery in the abdominal region serves as the final station of regional LNM in esophageal SCC. Further metastasis to distant sites progresses to stage IV esophageal cancer, significantly impacting patient prognosis. Previous studies have indicated that moderately to poorly differentiated esophageal cancer is more prone to developing left gastric LNM (p = 0.018), with metastasis occurring in the subcarinal, paraesophageal, and cardia lymph nodes often combined with left gastric LNM [13, 14]. However, in our study, the number of patients with left gastric LNM is relatively small (n = 34); therefore, a larger cohort is necessary to validate our hypothesis. Additionally, NSM occurred in patients with left gastric LNM; some patients who did not develop metastasis in the subcarinal, paraesophageal, or right gastric lymph nodes still presented with left gastric LNM.
Irrespective of the esophageal SCC location, performing cervical, thoracic, and abdominal three‐field lymph node dissection is essential, and left gastric lymph node resection should be considered a routine step in esophageal SCC radical surgery procedures. Previous studies have demonstrated its efficacy in improving prognosis [15]. However, it has also been reported that three‐field lymph node dissection may lead to a higher incidence of anastomotic leakage and recurrent laryngeal nerve injury [16]. Thus, surgeons should possess a thorough understanding of neck dissection to reduce complication rates. Previous studies have suggested that fluorescent thoracoscopic surgery or carbon nanoparticle tracing techniques can accurately locate metastatic lymph nodes and achieve efficient lymph node dissection [17, 18, 19]. Additionally, according to Hosch et al. [20], routine pathological biopsies may primarily miss micrometastases, affecting examination results. The detection rate of lymph nodes can be improved by using the monoclonal antibody Ber‐EP4.
In this study, factors influencing esophageal SCC metastasis included age (p = 0.017), tumor differentiation grade (p < 0.001), tumor diameter, infiltration depth (p < 0.001), and vascular tumor thrombus (p < 0.001), while sex and cancer location were not associated with esophageal SCC LNM. Among these factors, tumor diameter and infiltration depth have been subjects of controversy. Vos demonstrated that tumor size was an independent risk factor for LNM in T1b gastric cancer patients [21], and Machens showed that primary tumor size could contribute to distant metastasis. However, some scholars have declared no clear relationship between tumor size and LNM [22]. Regarding infiltration depth, it is generally believed that as infiltration depth increases, the lymphatic network becomes more abundant, thereby increasing the probability of metastasis [23, 24], which aligns with our results. Nevertheless, some scholars argue that once the tumor has infiltrated the submucosa, it is within the same lymphatic drainage system, and changes in infiltration depth do not affect LNM. Additionally, most previous studies have suggested that age is not a factor affecting LNM [25], which contrasts with our findings identifying age as a risk factor for LNM. This discrepancy could be partially explained by the fact that patients under 60 years old typically experience higher levels of stress from multiple sources, and chronic stress states may facilitate tumor dissemination [26]. Further multivariate analysis revealed that intravascular tumor thrombus and tumor diameter greater than 3 cm were independent influencing factors for LNM. Specifically, patients who developed intravascular tumor thrombus had approximately twice the probability of developing LNM compared to those who did not, and the presence of tumor thrombus indicated a seven‐fold increase in LNM.
However, this study has several limitations. Firstly, it was a single‐center study lacking multicenter collaborative data diversity support. Secondly, the number of patients developing LNM was relatively small, indicating some insufficiency in comprehensively characterizing LNM in esophageal cancer. Thirdly, molecular experiments were not conducted to validate our results or explore the mechanism underlying the NSM phenomenon. Nevertheless, the study still provides relevant data for guiding clinical lymph node dissection and risk factor assessment in patients with esophageal SCC.
5. Conclusions
In conclusion, upper esophageal SCC demonstrated a propensity to metastasize to the upper mediastinal lymph nodes, while abdominal and paracardial LNM were more common in patients with lower esophageal SCC. This metastasis pattern suggests potential benefits from cervical, thoracic, and abdominal lymph node dissection. Furthermore, this study identified tumor size and intravascular tumor thrombus as independent factors for tumor LNM. Hence, comprehensive preoperative and intraoperative evaluation of patients' tumors using imaging and molecular tracing methods could aid in predicting and managing LNM more accurately.
Author Contributions
Yuheng Wang and Qingqing Ding carried out the studies, participated in collecting data, and drafted the manuscript. Lei Xue and Yuheng Wang performed the statistical analysis and participated in its design. Yuheng Wang and Jinhua Luo participated in the acquisition, analysis, or interpretation of data and drafted the manuscript. All authors read and approved the final manuscript.
Funding
The authors have nothing to report.
Ethics Statement
This study received approval from the Medical Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (Approval No. 2025‐SRFA‐733).
Consent
All participants provided informed consent.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
The authors have nothing to report.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.