Development and validation of the APTNM staging system: Integration of serum biomarkers with TNM classification for enhanced prognostic stratification following hepatectomy for hepatocellular carcinoma.

[BACKGROUND] Current tumour-node-metastasis (TNM) staging for hepatocellular carcinoma (HCC) relies primarily on anatomical factors without incorporating tumour biological characteristics, limiting prognostic precision. This study aimed to develop and validate a novel staging system integrating serum biomarkers alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) with conventional TNM classification to enhance prognostic stratification following hepatectomy.

[METHODS] This multicentre cohort study included patients undergoing curative hepatectomy for HCC at six hospitals in China. The APTNM staging system was constructed by combining preoperative AFP (≥200 μg/L = 1 point), PIVKA-II (≥400 mAU/mL = 1 point), and AJCC 8th edition TNM stage (stages I-III = 1-3 points). Patients were classified as APTNM stage I (1 point), stage II (2-3 points), or stage III (4-5 points). Prognostic performance was evaluated using Kaplan-Meier analysis, multivariate Cox-regression, net reclassification improvement (NRI), and time-dependent receiver operating characteristic (ROC) curves.

[RESULTS] Among 660 HCC patients, the APTNM staging system demonstrated clear stratification for 5-year overall survival (OS) [stage I (n = 195), 47.7 %; stage II (n = 316), 28.1 %; stage III (n = 149), 15.3 %; P < 0.001] and recurrence-free survival (RFS) (stage I, 29.4 %; stage II, 12.7 %; stage III, 0.0 %; P < 0.001). Multivariate analysis confirmed APTNM staging as an independent predictor of both OS (stage II: HR 1.592, 95 % CI 1.209-2.096; stage III: HR 2.314, 1.668-3.211; both P < 0.001) and RFS (stage II: 1.556, 1.230-1.969; stage III: 2.159, 1.623-2.872; both P < 0.001). Time-dependent NRI values ranged from 0.20 to 0.26 for OS and 0.18-0.31 for RFS across 5-year follow-up, demonstrating substantial improvement over conventional TNM staging. Time-dependent ROC analysis consistently showed superior performance for the APTNM staging.

[CONCLUSIONS] The APTNM staging system successfully integrates tumour biomarkers with anatomical factors, providing significantly enhanced prognostic stratification compared with conventional TNM staging. This biologically informed approach may facilitate more precise risk stratification and guide individualised postoperative surveillance and adjuvant therapy decisions for patients with HCC.