Background/Objectives: Extrahepatic recurrence (EHR) is a significant negative prognostic factor in hepatocellular carcinoma (HCC). Although EHR is commonly observed in high-risk patients following HCC hepatectomy, its occurrence without concurrent intrahepatic HCC remains poorly understood. Therefore, this study aims to examine the clinical characteristics and risk factors associated with EHR in patients without intrahepatic HCC at diagnosis. Methods: This study included 1066 treatment-naïve patients who underwent curative hepatectomy for HCC at four tertiary academic centers between January 2004 and December 2019. After excluding those with intrahepatic recurrence (IHR), concurrent EHR, or incomplete clinical records, 569 patients were included in the final analysis. Risk factors for EHR were assessed using multivariate Cox regression over a median follow-up period of 3.91 years. Results: Among the cohort, 38 patients developed EHR post-surgery without residual intrahepatic HCC, with a median follow-up of 1.04 years. These patients experienced earlier initial HCC recurrence than those without EHR (1.73 vs. 4.43 years). Multivariate analysis revealed significant associations between EHR and microvascular invasion (hazard ratio [HR]: 2.418,p= 0.020), tumor necrosis (HR: 2.592,p= 0.009), and initial tumor staging beyond the Milan criteria (HR: 3.008,p= 0.001). Moreover, Cox regression analysis revealed that EHR strongly correlated with decreased post-hepatectomy survival (HR: 14.044,p< 0.001). Cumulative EHR and survival rates were closely linked to the number of risk factors present. Conclusions: EHR without detectable IHR is significant and warrants close monitoring in high-risk patients.
背景/目的：肝外复发是肝细胞癌的重要不良预后因素。尽管肝细胞癌肝切除术后高风险患者中常见肝外复发，但其在不伴肝内肝细胞癌复发情况下的发生机制尚不明确。因此，本研究旨在探讨诊断时无肝内肝细胞癌患者的肝外复发临床特征及相关危险因素。方法：本研究纳入2004年1月至2019年12月期间在四家三级学术中心接受根治性肝切除术的1066例初治肝细胞癌患者。排除肝内复发、同期肝外复发或临床资料不完整的患者后，最终纳入569例进行分析。通过中位3.91年的随访期，采用多变量Cox回归评估肝外复发的危险因素。结果：队列中38例患者在术后出现肝外复发且无残留肝内肝细胞癌，中位随访时间为1.04年。这些患者的首次肝细胞癌复发时间早于无肝外复发患者（1.73年 vs 4.43年）。多变量分析显示，肝外复发与微血管侵犯（风险比[HR]：2.418，p=0.020）、肿瘤坏死（HR：2.592，p=0.009）以及超出米兰标准的初始肿瘤分期（HR：3.008，p=0.001）显著相关。此外，Cox回归分析表明肝外复发与肝切除术后生存率降低密切相关（HR：14.044，p<0.001）。累积肝外复发率和生存率与现存危险因素数量呈显著关联。结论：不伴可检测肝内复发的肝外复发具有重要临床意义，需对高风险患者进行密切监测。
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