Lymph node metastases status in esophageal squamous cell carcinoma following neoadjuvant chemoradiotherapy: a single-center cross-sectional study
Anh Tuan Nguyen1
, Van Hiep Pham1
, Manh Thang Tran2
, Pham Nghia Do Nguyen3
Contributions: (I) Conception and design: AT Nguyen, VH Pham; (II) Administrative support: PND Nguyen; (III) Provision of study materials or patients: MT Tran; (IV) Collection and assembly of data: MT Tran, PND Nguyen; (V) Data analysis and interpretation: AT Nguyen, VH Pham; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Background: The status of lymph node (LN) metastases in esophageal squamous cell carcinoma (ESCC) following neoadjuvant chemoradiation (NCRT) is not well understood but significantly affects patient prognosis and treatment options. We conducted this study to evaluate the distribution of LN metastases in patients with ESCC who received NCRT combined minimally invasive esophagectomy (MIE).
Methods: From March 2019 to September 2023, patients with middle- and lower-third ESCC received NCRT, followed by MIE with two-field lymphadenectomy, were included in this study. The primary outcome was to examine the distribution of LN metastases and their correlation with the radiation fields. Secondary outcomes included identifying risk factors for LN metastases and their impact on long-term survival.
Results: One hundred consecutive patients were included, and 4.11% had LN metastases. The median number of positive LN and the rate of LN metastases in the thoracic LN stations was lower than that of the abdominal region (1.5 and 2.84% vs. 2 and 5.94%, respectively). Over half of the patients had LN metastases within the radiation field. The multivariate analysis found that the LN metastases were associated with the ycN-stage [hazard ratio (HR) =2.03, 95% confidence interval (CI): 1.02–4.04, P=0.04]. Although the LN metastases were not significantly associated with either overall survival (OS) or disease-free survival (DFS) (P=0.89 and P=0.65, respectively), the number of LN removal ≥15 LN removals was significantly improved both OS and DFS (P=0.040 and P=0.049, respectively).
Conclusions: In patients with middle- and lower-third ESCC who underwent NCRT followed by MIE, the rate of LN metastases in the abdominal region is higher than in the thoracic region. The majority of patients had LN metastases within the radiation field. Therefore, NCRT does not justify minimizing lymphadenectomy in ESCC; furthermore, a higher ycN-stage correlated with a higher incidence of LN metastases; higher ycN-stage correlates with higher LN metastases.
Keywords: Esophageal cancer; esophagectomy; lymphadenectomy; lymph node metastases (LN metastases); neoadjuvant therapy
Received: 19 June 2024; Accepted: 30 September 2024; Published online: 17 January 2025.
doi: 10.21037/tgh-24-76
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Key findings
• Abdominal lymph node (LN) metastasis is more common than thoracic LN metastasis in esophageal squamous cell carcinoma (ESCC) patients post-neoadjuvant chemoradiotherapy (NCRT) and minimally invasive esophagectomy (MIE).
• NCRT reduces LN metastasis rates but does not eliminate the need for systematic lymphadenectomy.
• Higher ycN-stage is linked to increased LN metastasis.
• Removing ≥15 LNs significantly improves overall survival and disease-free survival.
What is known and what is new?
• ESCC frequently metastasizes to LNs, impacting prognosis and treatment. NCRT enhances resectability and survival.
• Despite NCRT, extensive lymphadenectomy is crucial. The study highlights more frequent abdominal LN metastasis and links higher ycN-stage to increased LN metastasis. Adequate LN removal improves survival.
What is the implication, and what should change now?
• Comprehensive lymphadenectomy remains essential even with effective NCRT in ESCC.
• Ensure systematic dissection of at least 15 LNs during esophagectomy to optimize survival and disease management in ESCC patients.
Introduction
Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive cancers with a high propensity for lymph node (LN) metastases (1). LN metastases significantly impact staging, prognosis, and therapeutic decisions in ESCC (1,2). Neoadjuvant chemoradiotherapy (NCRT) followed by surgery has emerged as a standard treatment strategy for advanced disease, aiming to enhance resectability and improve survival outcomes.
Despite advancements in treatment protocols, the optimal extent of LN dissection during esophagectomy in the context of NCRT for ESCC continues to be debated. Studies have shown that NCRT reduces the number and distribution of LN metastases (3,4). Consequently, some authors advocate for a limited extent of lymphadenectomy after NCRT (5), while others suggest that extended lymphadenectomy improves survival, even in patients who have received NCRT (6). The lack of international consensus on this issue necessitates further investigation into the location of LN metastases to guide lymphadenectomy in esophageal cancer.
This study addresses this gap by investigating LN metastases’ location in ESCC patients undergoing NCRT following MIE with two-field lymphadenectomy. We present this article in accordance with the STROBE reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-76/rc) (7).
Methods
Patients
From March 2019 to September 2023, 104 patients with middle-lower third ESCC received NCRT followed by MIE with two-field lymphadenectomy. After excluding four patients [two with non-R0 resection and two who died from coronavirus disease 2019 (COVID-19)], 100 patients were included in the study (Figure 1). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of the 108 Military Central Hospital (Reference: 996/QĐ-BV, dated January 25th, 2019). Informed consent was obtained from all individual participants included in the study.
Treatment protocol
Patients were staged by American Joint Committee on Cancer 7th criteria. If the invasion was > T1b or LN metastases were suspected, NCRT was administered. The chemotherapy regimen included 5-fluorouracil, cisplatin, and docetaxel. The radiation oncologist determined the radiotherapy course, divided into 23 fractions with a total dose of 41.4 Gy. All patients received three-dimensional (3D) radiotherapy and radiation fields were determined according to the Japanese Esophageal Society guidelines (8).
Surgery and pathological evaluation
After NCRT, patients were checked by endoscopy and CT scanner. Patients deemed resectable underwent MIE with two-field lymphadenectomy. LN were dissected and numbered according to the Japanese Esophageal Society guidelines. LN were fixed in 10% formalin and sent for pathological examination by experienced pathologists.
Outcome parameters
Data on patient characteristics, chemoradiotherapy regimen, number, and location of metastatic LN were collected. The LN metastases rate was defined as the ratio of metastatic LN to the total number of LN removed. Postoperatively, the radiation oncologist—blinded from the pathological results—classified each LN station inside or outside the preoperative radiation field.
To evaluate the pathological response of tumors following NCRT, we applied the Mandard classification system. Based on these changes, the tumor regression was classified into five histological tumor regression grading (9).
Follow-up
Patients are monitored and evaluated periodically every three months for the first two years and every six months in the following years. If there is evidence of recurrence or distant metastases, adjuvant treatment continues to be considered.
Statistical analysis
Data were collected and processed using SPSS software (version 27.0; SPSS Inc.). For the descriptive statistics, the mean ± standard deviation was used to summarize variables with a normal distribution, while the median (range) was employed for variables with a skewed distribution. Univariate analysis was conducted to identify which factors were associated with the prevalence of LN metastases. To account for confounding factors, the multivariate binary regression analysis included variables with a P value <0.05 in the univariate analysis. Cox logistic regression modeling was used to assess the relationship between LN metastases and the number of LN removal with overall survival (OS) and disease-free survival (DFS), providing hazard ratios (HRs) with 95% confidence intervals (CIs). A P value of <0.05 was considered to be statistically significant.
Results
Patient
All patients were male, the mean age was 57.68±8.31 years. One hundred percent were irradiated with a total dose of 41.4 Gy. The middle third tumor accounts for the majority (65%). Details about patient characteristics are shown in Table 1. All patients underwent thoracolaparoscopy esophagectomy two-field lymphadenectomy without conversion in any case, the mean length of surgical time was 294.91±55.24 minutes. Postoperatively, the mean length of hospital stay was 15.52±6.81 nights. Among 30 patients with a complete response at the ypT0-stage, seven patients have LN metastases (23.3%). The results and characteristics of the surgical intervention are shown in Table 2.
Table 1
| Factor | Variation | N [%] |
|---|---|---|
| ASA | I | 45 [45] |
| II | 44 [44] | |
| III | 11 [11] | |
| Comorbidity | Yes | 18 [18] |
| No | 72 [72] | |
| Tumor location | Mid esophagus | 65 [65] |
| Low esophagus | 35 [35] | |
| ycT | T0 | 19 [19] |
| T1 | 6 [6] | |
| T2 | 15 [15] | |
| T3 | 34 [34] | |
| T4a | 26 [26] | |
| ycN | N0 | 47 [47] |
| N1 | 39 [39] | |
| N2 | 14 [14] |
ASA, American Society of Anesthesiologists.
Table 2
| Factor | Variation | N [%] |
|---|---|---|
| Mandard tumor regression score | 1 | 30 [30] |
| 2 | 18 [18] | |
| 3 | 18 [18] | |
| 4 | 20 [20] | |
| 5 | 14 [14] | |
| ypT | T0 | 30 [30] |
| T1 | 19 [19] | |
| T2 | 21 [21] | |
| T3 | 19 [19] | |
| T4a | 11 [11] | |
| ypN | N0 | 62 [62] |
| N1 | 27 [27] | |
| N2 | 10 [10] | |
| N3 | 1 [1] | |
| Postoperative complication | Anastomotic leakage | 13 [13] |
| Pneumonia | 11 [11] | |
| Vocal cord palsy | 9 [9] | |
| Pleural injury | 4 [4] | |
| Hemorrhage | 3 [3] | |
| Jejunostomy leak | 3 [3] | |
| Bowel obstruction | 2 [2] |
LNs status
The number of LN removed per region is displayed in Table 3. The total number of LN removed was 2,553 nodes, the number of metastatic LN was 105 nodes, and the LN metastases rate was 4.11%. Compared to the thoracic region, the abdominal LN had a higher median number of positive LN (2 vs. 1.5) and a higher rate of LN metastases (5.94% vs. 2.84%).
Table 3
| Location | Number of LN resected, median [range] | Number of positive LN†, median [range] | Ratio of LN metastases (%) | Number of patients with LN metastases, n [%] | Number of patients with in-field LN metastases‡, n [%] |
|---|---|---|---|---|---|
| Overall | 24 [8–58] | 2 [1–20] | 4.11 | 38 [38] | 22/38 [57.9] |
| Thoracic region | 14 [1–34] | 1.5 [1–6] | 2.84 | 22 [22] | 22/22 [100] |
| Upper mediastinal | 4 [0–23] | 1 [1–3] | 4.22 | 12 [12] | 12/12 [100] |
| Middle mediastinal | 8 [1–22] | 1.5 [1–3] | 1.88 | 10 [10] | 10/10 [100] |
| Lower mediastinal | 2 [0–10] | 1.5 [1–3] | 4.90 | 4 [4] | 4/4 [100] |
| Abdominal region | 10 [1–28] | 2 [1–14] | 5.94 | 25 [25] | 9/25 [36] |
| Perigastric | 6 [1–19] | 2 [1–14] | 8.97 | 22 [22] | 9/22 [40.9] |
| Celiac | 3 [0–15] | 2 [1–4] | 2.62 | 5 [5] | 0/5 [0] |
†, in positive stations; ‡, in patients with LN metastases. LN, lymph node.
Of all patients with LN metastases, 57.9% had LN metastases within the radiation field. In the thoracic region, all LN metastases occurred in-field, while in the abdominal LN station, this rate was 36%.
Risk factors for LN metastases
On univariate analysis, the incidence of LN metastases correlated with the ycN-stage, Mandard tumor regression score, and yPT-stage. We perform multivariate analysis on factors with P value <0.05 to exclude the bias on univariate analysis. On the multivariate analysis, we found that the LN metastases were associated with ycN-stage (HR =1.93, 95% CI: 1.02–3.65, P=0.04) (Table 4).
Table 4
| Factors | Variation/value | N | Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | ||||
| Age (years), mean ± SD | 57.68±8.31 | 100 | −0.001 (−0.012 to 0.011) | 0.91 | – | – | |
| ASA | 1 | 45 | 1.20 (0.66–2.20) | 0.55 | – | – | |
| 2 | 44 | ||||||
| 3 | 11 | ||||||
| Main tumor location | Mid esophagus | 65 | 1.23 (0.53–2.86) | 0.64 | – | – | |
| Distal esophagus | 35 | ||||||
| ycT-stage | 0 | 19 | 1.25 (0.92–1.68) | 0.15 | – | – | |
| 1 | 6 | ||||||
| 2 | 15 | ||||||
| 3 | 34 | ||||||
| 4a | 26 | ||||||
| ycN-stage | N0 | 47 | 2.28 (1.25–4.16) | 0.007 | 1.93 (1.02–3.65) | 0.04 | |
| N1 | 39 | ||||||
| N2 | 14 | ||||||
| Mandard tumor regression score | 1 | 30 | 1.63 (1.20–2.21) | 0.002 | 1.61 (0.99–2.63) | 0.05 | |
| 2 | 18 | ||||||
| 3 | 18 | ||||||
| 4 | 20 | ||||||
| 5 | 14 | ||||||
| ypT-stage | 0 | 30 | 1.46 (1.08–1.99) | 0.02 | 0.91 (0.55–1.52) | 0.73 | |
| 1 | 19 | ||||||
| 2 | 21 | ||||||
| 3 | 19 | ||||||
| 4a | 11 | ||||||
LN, lymph node; SD, standard deviation; ASA, American Society of Anesthesiologists; HR, hazard ratio; CI, confidence interval.
Long-term survival
The median follow-up duration for all patients was 23.3 months (range, 8.8–45.7 months). The 1-, 2-, and 3-year OS rates were 76%, 54%, and 30%, respectively. The median OS was 16.2 months (range, 8.8–31.9 months), and the median DFS was 21.0 months (range, 3.0–44.0 months).
Using the Kaplan-Meier estimator, the presence of LN metastases was not significantly associated with either OS or DFS (P=0.89 and P=0.65, respectively) (Figure 2). However, when the patients were divided into two groups based on the number of LN removals, this factor was found to be significantly associated with both OS and DFS (P=0.040 and P=0.049, respectively) (Figure 3).
Discussion
ESCC often metastasizes to LN at very early stages, with metastases sites ranging from the neck to the abdomen (10). Postoperative pathological results show a high rate of LN metastases, even in cases treated with NCRT, which is considered the most important prognostic factor for patients (1). Although there have been studies on the location of metastatic LN after neoadjuvant therapy in both squamous cell carcinoma and adenocarcinoma, treatment protocols vary among authors, resulting in inconsistent outcomes (11,12) and there also no focus on the group of patients like our study. Hagens et al. published an article about LN metastases after NCRT but in esophageal adenocarcinoma rather than ESCC, as in our study (11). Compared with Kim et al. (13) and Miyata et al. (14), about haft of patients in their study underwent three-field lymphadenectomy rather than two-field lymphadenectomy in our study.
In this study, the median number of dissected LN was 24 (range, 8–28), comparable to several other studies (3,12). NCRT reduces both the number of dissected LN and the number of metastatic LN. A recent study showed that the LN metastases rate was 74% for patients undergoing esophagectomy alone, compared to only 31% for those receiving neoadjuvant therapy (3). Our study observed a low LN metastases rate of 4.11% with a median of 2 metastatic LN (range, 1–20). Compared to Pan et al.’s study, the LN metastases rates for middle-third and lower-third ESCC were 30.7% and 15.7%, respectively (15). This demonstrates that NCRT significantly reduces the rate of LN metastases.
We cannot identify specific pattern of lymphatic metastasis, although some LN stations had high rate of metastasis after NCRT, such as in perigastric region (8.97%). When comparing the thoracic and abdominal regions, the abdominal LN had a higher median number of positive LN (2 vs. 1.5) and a higher rate of LN metastases (5.94% vs. 2.84%). This demonstrates the role of thoracic radiation in reducing the rate of chest LN metastases. Meanwhile, abdominal radiation is only considered when abdominal LN metastases are suspected—that is, when a computed tomography (CT) scan detects nodes with a short-axis diameter >1 cm, they are deemed metastatic and are then irradiated (8). However, abdominal LN often measure less than 1 cm but may still be metastatic. This indicates a gap in the treatment approach, suggesting that more attention should be paid to the radiation field in the abdominal area without considering LN size, given the high risk of metastasis in this region.
Although NCRT reduces the number of metastatic LN, it cannot replace systematic lymphadenectomy. One study reported that 7% of LN metastases within the radiation field, despite no suspected metastases on chest CT scans (13). Another study evaluated the correlation between LN metastases and radiation field in patients with a complete response to NCRT. The results showed that 11 patients (21%) had metastatic LN, with 8 of these having metastases outside the radiation field. The authors identified high-risk areas, including LN around the esophagus, along the aorta, and near the gastroesophageal junction (16). To evaluate the impact of the radiation field on LN metastases, we assessed abdominal LN metastases, as this area includes nodes outside and inside of the radiation field. Our results showed that LN metastases outside the radiation field were significantly higher than within the radiation field. This finding is consistent with Kim et al.’s study, where the rate of LN metastases within the radiation field was 3% compared to 11% outside the radiation field (13). Therefore, abdominal LN dissection is crucial, as the radiation field does not cover all these nodes, leading to a high risk of metastases outside the radiation field. In addition, in our study, among 30 patients with a complete response at the ypT0-stage, seven patients had LN metastases (23.3%). Therefore, systematic lymphadenectomy remains crucial and cannot be replaced by NCRT.
Although LN metastasis has a poor prognosis in esophageal cancer (1), extensive LN dissection is a complex surgery with risks and complications (17-19). Therefore, some studies have aimed to identify risk factors for LN metastasis to minimizing lymphadenectomy for patients without risk factors (13,20-22). However, the results remain inconclusive. In this study, based on multivariate regression analysis, we found that LN metastasis is closely associated with ycN-stage (HR =2.03, 95% CI: 1.02–4.04, P=0.04). However, similar to previous studies, this factor cannot be definitively identified clinically. Therefore, we cannot recommend minimizing lymphadenectomy based on this finding.
Regarding long-term results, the LN metastases were not significantly associated with OS or DFS (P=0.89 and P=0.65, respectively). However, we divided patients into two groups based on the number of LN removal and found that it was significantly associated with both OS and DFS (P=0.040 and P=0.049, respectively). Our findings align with the current literature (6,11,23). These results further reinforce the role of systematic lymphadenectomy in managing ESCC. Surgeons must ensure they dissect the necessary number of LN, as the number of LN is related to OS and DFS.
Our study, while insightful, is not without its limitations, which must be acknowledged to contextualize our findings accurately. Firstly, the relatively small cohort of patients limits the statistical power of our analysis and restricts our ability to detect smaller yet potentially significant differences in outcomes. A larger sample size would have enabled more robust conclusions and potentially unveiled subtler patterns and correlations that remain obscured in this study. Secondly, all patients included in our study were diagnosed with ESCC. This singular focus on ESCC limits the generalizability of our results across the broader spectrum of esophageal cancer types. Moreover, the study was conducted within a single institution, which may introduce institutional bias and limit the external validity of our findings. The surgical techniques, perioperative care protocols, and postoperative management strategies can vary widely between institutions. As a result, the outcomes observed in our study may reflect the specific practices and expertise of our institution rather than a universal standard. Multi-center studies would be beneficial in providing a more comprehensive picture and enhancing the generalizability of the results.
Conclusions
The abdominal LN metastases in patients with middle- and lower-third ESCC underwent NCRT followed by MIE, as it is more common than thoracic LN metastases. The majority of patients had LN metastases within the radiation field. Therefore, NCRT does not justify minimizing lymphadenectomy in ESCC. Moreover, a higher ycN-stage is associated with higher LN metastases. Although LN metastases are not associated with worse survival, systemic lymphadenectomy ensures a minimum of 15 LN removals to improve OS and DFS.
Acknowledgments
Funding: None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-76/rc
Data Sharing Statement: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-76/dss
Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-76/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-76/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 the Ethics Committee of the 108 Military Central Hospital (Reference: 996/QĐ-BV, dated January 25th, 2019). Informed consent was obtained from all individual participants included in the study.
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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Cite this article as: Nguyen AT, Pham VH, Tran MT, Nguyen PND. Lymph node metastases status in esophageal squamous cell carcinoma following neoadjuvant chemoradiotherapy: a single-center cross-sectional study. Transl Gastroenterol Hepatol 2025;10:8.
