Beyond TNM Staging: Exploratory Integration of HALP, Prognostic Nutritional Index, and Lymph Node Ratio for Prognostic Assessment After Resection of Ampullary Adenocarcinoma

Background: This study investigated an exploratory Combined Biomarker Score (CBS)—integrating the Hemoglobin-Albumin-Lymphocyte-Platelet (HALP) score, Prognostic Nutritional Index (PNI), and lymph node ratio (LNR)—in resected ampullary adenocarcinoma, with methodological emphasis on censoring, score construction, collinearity, and internal validation. Methods: Data from 98 patients undergoing pancreaticoduodenectomy were analyzed retrospectively. The PNI was determined using the standard formula: (10 × albumin [g/dL]) + (0.005 × lymphocyte count [/mm3]), equivalent to albumin [g/L] + 5 × lymphocytes [×109/L]. Thirty-six-month cumulative/dynamic time-dependent ROC analysis with inverse-probability-of-censoring weighting was utilized to derive exploratory HALP, PNI, and LNR thresholds. Overall survival (OS) was evaluated using Kaplan–Meier and Cox proportional hazards regression. Spearman correlations, variance inflation factors, proportional-hazards diagnostics, alternative model specifications, apparent calibration, and 1000-resample full-procedure bootstrap validation were performed. Results: The mean PNI was 47.92 ± 6.36 (median 48.05, IQR 42.66–52.06). At 36 months, time-dependent AUCs were 0.579 for HALP, 0.567 for PNI, 0.512 for LNR, and 0.699 for the exploratory CBS. Optimized thresholds were established at HALP ≤ 26.784, PNI ≤ 46.20, and LNR ≥ 0.395. A high-risk CBS (2–3 adverse components) was observed in 27 of 98 patients and showed no statistically significant association with OS by log-rank testing (p = 0.142) or after adjustment for age and dichotomized stage (adjusted HR = 1.28, 95% CI: 0.58–2.80; p = 0.539). Age remained independently associated with OS (adjusted HR = 1.06 per year, p = 0.004). Model 4 (incorporating age, stage, and CBS) yielded an apparent Harrell C-index of 0.674 and a 36-month time-dependent AUC of 0.806; however, adding the CBS to age and stage did not significantly improve overall model fit (LR p = 0.543). Full-procedure bootstrap validation yielded an optimism-corrected C-index of 0.638. Conclusions: Evaluated via rigorous censoring-aware methodologies, the CBS currently serves as an exploratory framework rather than a validated clinical tool. While the score demonstrates moderate 36-month discrimination within this development cohort, it does not provide a statistically significant independent or incremental survival contribution beyond age and standard clinical variables. External validation and comprehensive clinicopathological adjustment are mandatory prior to any clinical translation.