Early extrahepatic recurrence as a pivotal factor for survival after hepatocellular carcinoma resection: A 15-year observational study

Abstract

Background: Surgical resection is one of the most widely used modalities for the treatment of hepatocellular carcinoma (HCC). Early extrahepatic recurrence (EHR) of HCC after surgical resection is considered to be closely associated with poor prognosis. However, data regarding risk factors and survival outcomes of early EHR after surgical resection remain scarce.

Aim: To investigate the clinical features and risk factors of early EHR and elucidate its association with survival outcomes.

Methods: From January 2004 to December 2019, we enrolled treatment-naïve patients who were ≥ 18 years and underwent surgical resection for HCC in two tertiary academic centers. After excluding patients with tumor types other than HCC and/or ineligible data, this retrospective study finally included 779 patients. Surgical resection of HCC was performed according to the physicians' decisions and the EHR was diagnosed based on contrast-enhanced computed tomography or magnetic resonance imaging, and pathologic confirmation was performed in selected patients. Multivariate Cox regression analysis was performed to identify the variables associated with EHR.

Results: Early EHR within 2 years after surgery was diagnosed in 9.5% of patients during a median follow-up period of 4.4 years. The recurrence-free survival period was 5.2 mo, and the median time to EHR was 8.8 mo in patients with early EHR. In 52.7% of patients with early EHR, EHR occurred as the first recurrence of HCC after surgical resection. On multivariate analysis, serum albumin < 4.0 g/dL, serum alkaline phosphatase > 100 U/L, surgical margin involvement, venous and/or lymphatic involvement, satellite nodules, tumor necrosis detected by pathology, tumor size ≥ 7 cm, and macrovascular invasion were determined as risk factors associated with early EHR. After sub-categorizing the patients according to the number of risk factors, the rates of both EHR and survival showed a significant correlation with the risk of early EHR. Furthermore, multivariate analysis revealed that early EHR was associated with substantially worse survival outcomes (Hazard ratio, 6.77; 95% confidence interval, 4.81-9.52; P < 0.001).

Conclusion: Early EHR significantly deteriorates the survival of patients with HCC, and our identified risk factors may predict the clinical outcomes and aid in postoperative strategies for improving survival.

Keywords: Early extrahepatic recurrence; Hepatocellular carcinoma; Prognosis; Surgery; Survival.

Figure 1

Both the cumulative rates of recurrence and the overall survival rates after surgical resection of hepatocellular carcinoma showed stepwise correlations with the interval to extrahepatic recurrence. A: Cumulative rate of the first recurrence of hepatocellular carcinoma after curative surgical resection; B: Overall survival rates stratified by the characteristics of extrahepatic recurrence. EHR: Extrahepatic recurrence.

Figure 2

Patients were classified according to the number of eight risk factors related to early extrahepatic recurrence, and the probability of extrahepatic recurrence and overall survival rate was evaluated. A: Cumulative rates of extrahepatic recurrence; B: Cumulative rates of overall survival after surgical resection; C: The cumulative rates of extrahepatic recurrence; D: The cumulative rates of overall survival. EHR: Extrahepatic recurrence.