S100A6 expression in resected specimens predicts lymph node metastasis in small pancreatic ductal adenocarcinoma: A retrospective cohort study.

Lymph node metastasis is a major prognostic determinant in patients with pancreatic ductal adenocarcinoma. Accurate preoperative prediction of lymph node metastasis remains challenging, particularly in small pancreatic ductal adenocarcinoma. We retrospectively analyzed 227 patients with pancreatic ductal adenocarcinoma who underwent upfront resection at a single center (2012-2021). Small pancreatic ductal adenocarcinoma was defined as a pathologically confirmed tumor ≤20 mm. Clinicopathologic factors associated with lymph node metastasis were identified, and immunohistochemistry for S100A6 and S100A4 was performed on resected specimens to identify potential predictors of lymph node metastasis. Lymph node metastasis was detected in 140 patients (62%) and was independently associated with worse survival (hazard ratio, 1.64; 95% confidence interval, 1.07-2.51). Prognostic separation by lymph node metastasis was most pronounced in pT1 tumors (median overall survival, 24.2 vs 121.0 months; P < .001). Both tumor size and elevated carbohydrate antigen 19-9 levels were significant preoperative predictors of lymph node metastasis but were not associated with pT1 tumors. High S100A6 expression (≥2+) predicted lymph node metastasis-negative status with 86.7% sensitivity and 86.5% specificity. A composite criterion of high S100A6 expression or the absence of S100A4 expression further improved specificity (91.9%). Lymph node metastasis remains a key prognostic determinant, especially in small pancreatic ductal adenocarcinoma. S100-protein-based immunohistochemistry may enhance preoperative risk stratification for nodal involvement. Prospective validation using preoperative biopsy specimens is required before clinical implementation.