Lymphovascular and Perineural Invasion Guides Adjuvant Therapy after Neoadjuvant Chemoimmunotherapy in Esophageal Squamous Cell Carcinoma

BACKGROUND: Lymphovascular (LVI) and perineural invasion (PNI) are adverse pathological features in esophageal squamous cell carcinoma (ESCC). We evaluated the prognostic significance of combined LVI/PNI (LNI) after neoadjuvant chemoimmunotherapy (nCIT) and the potential benefit of adjuvant therapy. METHODS: We retrospectively analyzed 473 ESCC patients undergoing nCIT followed by curative resection. LNI status was assessed in resected specimens. Survival outcomes were compared between LNI-positive and -negative patients using propensity score matching and multivariable Cox models. External validation was performed using an independent patient-level dataset. RESULTS: LNI was present in 21% of patients. LNI-positive patients had worse 3-year OS (49.8% vs 76.4%) and DFS (41.7% vs 69.3%), which remained significant after matching. LNI independently predicted inferior OS (HR 1.52, P = 0.022) and DFS (HR 1.40, P = 0.045). Recurrence occurred more frequently in LNI-positive patients (39.4% vs 19.8%, P < 0.001), predominantly locoregional. Among LNI-positive patients, adjuvant therapy improved 3-year OS (56.8% vs 32.4%) and DFS (49.7% vs 20.7%; adjusted HR 0.43, P = 0.002). External validation confirmed these findings, with independent prognostic impact of LNI and benefit from adjuvant therapy. CONCLUSIONS: LNI after nCIT is an independent adverse prognostic factor in ESCC. Patients with these high-risk pathological features have markedly worse outcomes but appear to derive significant benefit from adjuvant therapy, supporting its incorporation into postoperative management.