Lymph Node Status After Chemoimmunotherapy Predicts Survival in Esophageal Cancer

For patients with locally advanced esophageal squamous cell carcinoma, treatment increasingly begins not with surgery but with neoadjuvant chemoimmunotherapy, a combination of chemotherapy and immune checkpoint inhibitors given before the operation. This approach has emerged as a standard treatment for this disease. But a central question has lingered: once the pathology report comes back after surgery, which measure of lymph node status actually predicts how long a patient will live and remain free of recurrence?

A retrospective study from the First Medical Center of Chinese PLA General Hospital in Beijing, published in Frontiers in Oncology, addresses that question directly. The researchers analyzed 194 patients with esophageal squamous cell carcinoma who received neoadjuvant chemoimmunotherapy followed by radical esophagectomy between January 2019 and December 2024. Their goal was twofold: to establish whether the postoperative pathological N stage, abbreviated ypN, carries independent prognostic weight, and to test whether the pre-treatment clinical N stage, or cN, adds any additional predictive information for patients whose postoperative nodes show no residual cancer.

The team sorted patients into three groups based on the combination of their clinical and pathological nodal findings. One hundred four patients had no clinical node involvement before treatment and no pathological node involvement after surgery, the cN0/ypN0 group. Thirty-two patients had clinical node involvement before treatment but achieved a pathological nodal response, the cN+/ypN0 group. Fifty-eight patients still had cancer in their lymph nodes after neoadjuvant therapy, the ypN+ group. Survival was assessed with Kaplan-Meier analysis and Cox proportional hazards models, and the multivariable models were built using a clinically informed variable-selection strategy constrained by the number of events, a safeguard against overfitting in a cohort of this size.

During a median follow-up of 34.0 months, calculated by reverse Kaplan-Meier, the cohort recorded 31 deaths and 37 recurrences. The headline result was unambiguous. Patients with residual nodal disease after surgery, the ypN+ group, had significantly worse overall survival and recurrence-free survival than patients without nodal involvement, with log-rank P values below 0.001 for both endpoints.

The multivariable analysis strengthened the finding. After adjusting for other clinical factors, ypN+ remained an independent adverse prognostic factor for overall survival, with a hazard ratio of 3.204 (95% confidence interval 1.563 to 6.568, P=0.001), and for recurrence-free survival, with a hazard ratio of 3.780 (95% confidence interval 1.943 to 7.356, P<0.001). The result held up across extended models, cycle-adjusted analyses, and landmark sensitivity analyses, suggesting the association is not an artifact of how the follow-up window is defined or how many treatment cycles patients completed.

The three-group comparison then probed the more subtle question: does knowing what the nodes looked like before treatment matter once the pathology after surgery is clear? For overall survival, the ypN+ group fared significantly worse than both ypN0 groups, with P=0.002 against the cN0/ypN0 group and P=0.008 against the cN+/ypN0 group, both comparisons surviving a Bonferroni-adjusted significance threshold of 0.017 set for the three pairwise tests. For recurrence-free survival, the ypN+ group was again significantly worse than the cN0/ypN0 group, with P<0.001.

Between the two node-negative groups, however, the picture changed. Overall survival did not differ significantly between patients who were node-negative before and after treatment and those who had clinical node involvement before treatment but cleared their nodal disease after chemoimmunotherapy, with P=0.259. The recurrence-free survival comparison between these groups was nominally significant, with a hazard ratio of 2.799 (95% confidence interval 1.048 to 7.479, unadjusted P=0.040), but it did not survive the Bonferroni correction, meaning the apparent signal could reflect chance in a dataset of this size.

The authors conclude that the postoperative pathological N stage is the core prognostic determinant in esophageal squamous cell carcinoma treated with neoadjuvant chemoimmunotherapy, and that pre-treatment clinical node status did not demonstrate statistically significant additional prognostic discrimination among patients achieving ypN0 in this cohort. In practical terms, once the surgical specimen shows the nodes are clear, the prior clinical stage did not add statistically significant independent predictive power for survival in this dataset.

The researchers are careful about the limits of their evidence. The study is retrospective and conducted at a single center, and the cN+/ypN0 subgroup contained only 32 patients with few events, so the estimates for that comparison were imprecise. The authors state that their findings require validation in larger, preferably multicenter, cohorts before firm conclusions can be drawn about the value of clinical nodal staging in the node-negative post-treatment setting. Even with those caveats, the study offers a clear message for clinicians managing this disease: in the era of chemoimmunotherapy, postoperative risk assessment should be based primarily on ypN status.

Subject of Research: Prognostic value of pathological and clinical lymph node staging in esophageal squamous cell carcinoma after neoadjuvant chemoimmunotherapy

Article Title: Prognostic significance of lymph node staging in esophageal squamous cell carcinoma after neoadjuvant chemoimmunotherapy

Article References: Han, H., Hou, X., Liu, Y., Cai, W., Jin, J., Qiu, X., Zhu, Z., Zhao, K., Hu, M., & Xue, Z. (2026). Prognostic significance of lymph node staging in esophageal squamous cell carcinoma after neoadjuvant chemoimmunotherapy. Frontiers in Oncology, 16, Article 1931817. https://doi.org/10.3389/fonc.2026.1931817

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1931817

Keywords: esophageal squamous cell carcinoma, lymph node staging, neoadjuvant chemoimmunotherapy, ypN stage, clinical N stage, overall survival, recurrence-free survival, prognosis, esophagectomy, retrospective cohort study, immunotherapy, surgical oncology