Patterns of Site and Timing of Recurrence After Curative Resection in Single and Multiple Large Hepatocellular Carcinoma: A Multicenter International Comprehensive Analysis

Background: Curative options for large hepatocellular carcinoma (LHCC) are limited because of the high risk of early and extrahepatic recurrence. However, only a few studies report data on long-term outcomes in large cohorts of resected LHCC. We therefore investigated timing and site of recurrence of LHCC and assessed factors strictly associated with adverse patterns. Patients and Methods: This was a retrospective, international, multicenter study of patients undergoing anatomic resection of HCC ≥ 5 cm at 12 hepatobiliary high-volume centers. Extrahepatic recurrence was defined as any distant site of metastasis, while recurrence within 2 years after surgery was classified as early recurrence. Results: A total of 869 patients were included. Recurrence was observed in 487 (56%) cases. Patterns associated with reduced overall survival were early (p < 0.001) and simultaneous intrahepatic and extrahepatic recurrence (p = 0.038). Variables independently associated with early recurrence were age (p = 0.037), major hepatectomy (p = 0.023), microvascular invasion (p = 0.011), satellites nodules (p = 0.005), and open approach (p = 0.025). Variables correlated with simultaneous intra- and extrahepatic relapse were age (p < 0.001), preoperative transarterial chemoembolization (TACE) (p < 0.001), microvascular invasion (p < 0.001), and satellite nodules (p = 0.026). Conclusions: Surgery for LHCC is associated with a high risk of early recurrence. Apart from pathological variables, factors independently associated with adverse patterns were open approach and age for the early recurrence and preoperative TACE and age for simultaneous intra-extrahepatic relapse. BCLC stage was not associated with timing nor with site of recurrence.