Direct Tumor-Adipocyte Contact as a Prognostic Biomarker in Resected Pancreatic Ductal Adenocarcinoma

Direct tumor-adipocyte contact (TAC), also referred to as Stroma AReactive Invasion Front Areas (SARIFA), is an emerging histomorphologic biomarker, defined by histologically visible direct tumor-adipocyte interaction. Its prognostic relevance in pancreatic ductal adenocarcinoma (PDAC) has not been investigated across independent cohorts.

In this international, real-world, multicenter study, TAC/SARIFA was assessed on 941 resected PDAC cases across five cohorts (Munich n = 400, Bern n = 215, Graz n = 111, Erlangen n = 101, TCGA n = 114). Clinicopathological correlations, survival analyses, and differential gene expression analyses were performed.

TAC/SARIFA positivity was present in 53% of evaluable cases and showed substantial interobserver agreement across seven pathologists (mean Cohen's kappa: 0.71). TAC/SARIFA-positive tumors were associated with higher nodal (pN) stage, higher tumor grade, and older patient age (each p < 0.01). TAC/SARIFA positivity was significantly associated with reduced overall survival (pooled median OS: 14.1 vs. 28.0 months, p < 0.001) and remained an independent prognostic factor in multivariate analysis (pooled HR 1.84, 95% CI 1.59-2.14, p < 0.001). A significant interaction between TAC/SARIFA and sex was identified (p < 0.001), with a stronger prognostic effect in males (HR 2.46) than in females (HR 1.50). Adjuvant chemotherapy was associated with longer OS in both TAC/SARIFA subgroups, with a greater absolute survival difference in TAC/SARIFA-positive patients. Bulk transcriptomic profiling revealed upregulation of leptin (LEP) and the basal-like marker KRT14 in TAC/SARIFA-positive tumors.

TAC/SARIFA is a robust, independent prognostic histomorphologic biomarker in PDAC with a sex-dependent effect. Its reproducible and quick assessment on routine H&E slides supports further investigation of its applicability for PDAC risk stratification.