Routine H&E Histology Encodes Postoperative Risk Heterogeneity in Resected Pancreatic Ductal Adenocarcinoma: A Multicohort Evaluation of TIGERS.

Abstract

Patients with resected pancreatic ductal adenocarcinoma (PDAC) can have different outcomes despite similar TNM stage. We developed TIGERS (Tumor Intelligence Grading and Evaluation Risk Score), a nine-feature prognostic biomarker derived from routine hematoxylin and eosin (H&E) whole-slide images. TIGERS quantifies tumor burden, glandular and nuclear morphology, chromatin texture, and tumor-stroma topology. The score was trained in 644 treatment-naive cases and evaluated in an internal validation cohort (n = 385), a separate post-neoadjuvant cohort (n = 275), two external cohorts (n = 260 and n = 235), the TCGA-PAAD cohort (n = 133), and a prospectively accrued external cohort (n = 155) with subsequent offline inference. Overall survival was the primary endpoint; the same formula and locked cutoff were applied throughout. The cutoff stratified survival in the internal validation cohort and three of four retrospective test cohorts. In the remaining external cohort, 226 of 235 patients (96.2%) were classified as high risk, showing limited transportability of the fixed threshold. Adding TIGERS to the clinicopathologic model increased Harrell's C-index in all six retrospective cohorts (range 0.015-0.047). In the prospectively accrued cohort, mortality was 47.5% in the high-risk group and 22.7% in the low-risk group; high risk remained associated with worse survival after adjustment (hazard ratio, 4.45; 95% confidence interval, 2.28-8.70; P < .001). Automated quality control passed 92.3% of screened cases, and scoring was completed in all included cases with a median turnaround time of 13.5 minutes. TIGERS assigned 43.2% of patients to a different risk category than the prespecified stage-based definition. Higher TIGERS correlated with a more basal-like proteomic profile in both the training and internal validation cohorts, supporting a molecular basis for its prognostic value. Routine H&E histology may therefore provide prognostic information complementary to conventional clinicopathologic assessment. Prospective interventional studies are needed before TIGERS can guide treatment or surveillance.