Clinical and prognostic significance of high-endothelial venule density in regional lymph nodes of esophageal adenocarcinoma.

BACKGROUND

Esophageal adenocarcinoma (EAC) is associated with poor prognosis despite advances in multimodal treatment. High endothelial venules (HEVs) facilitate lymphocyte trafficking and are linked to anti-tumor immunity. While HEVs have shown prognostic relevance in esophageal squamous cell carcinoma and gastric cancer, their role in regional lymph nodes of EAC patients remains unclear.

METHODS

This retrospective study included 199 patients with EAC who underwent Ivor-Lewis esophagectomy between 2013 and 2021. Patients received perioperative chemotherapy (FLOT), neoadjuvant chemoradiotherapy (CROSS), or primary surgery. Tumor-free regional lymph nodes were immunohistochemically stained using the MECA-79 antibody to detect HEVs. Whole-slide images were digitally analyzed to quantify HEV density. Associations with clinicopathological parameters, treatment modality, therapy response, and survival outcomes were assessed. An exploratory analysis was performed in an additional cohort of 58 patients receiving adjuvant nivolumab therapy.

RESULTS

HEVs were detectable in regional lymph nodes across all treatment groups. HEV density was significantly higher in patients older than 60 years compared to younger patients (p = 0.001) and was independent of treatment modality, pathological response, T-stage, and N-stage. No association was observed between HEV density and response to neoadjuvant therapy. Dichotomization into MECA-low and MECA-high groups confirmed age as the primary determinant of HEV density classification. Kaplan-Meier analyses showed no significant differences in overall or progression-free survival between MECA-low and MECA-high patients in the primary cohort. In the adjuvant nivolumab cohort, MECA-high patients demonstrated a non-significant trend toward improved two-year overall survival (90% vs. 67%).

CONCLUSIONS

HEV density in tumor-free regional lymph nodes of EAC patients is primarily age-dependent and independent of tumor stage, treatment response, and neoadjuvant therapy regimen. Although HEV density alone does not predict survival, observed trends in immunotherapy-treated patients suggest a potential modulatory role in immune responsiveness. These findings emphasize the importance of host-related immune architecture and support further investigation of lymph node-based immune biomarkers in EAC.