Background: The role of autophagy-related markers as the prognostic factor of post-operative hepatocellular carcinoma (HCC) recurrence remained controversial. Methods: Overall, 535 consecutive HCC patients undergoing curative resection from 2010 to 2014 were followed and classified with early (ER, <2 years) or late recurrence (LR). Autophagy-related markers, LC3, Beclin-1, and p62 expression was immunohistochemically assessed in HCC and adjacent non-tumor (ANT) tissues. Results: HCC recurred in 245 patients: 116 with ER and 129 with LR. The cumulative incidence of recurrence at 1, 3, 5, and 7 years was 9.7%, 33.9%, 53.3%, and 66.3%, respectively. In multivariate analysis, HCC recurrence was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (hazard ratio/95% confidence interval: 6.12/2.473-17.53, 4.18/1.285-13.61, and 1.89/1.299-2.757) and macrovascular invasion (1.63/1.043-2.492) and cirrhosis (1.59/1.088-2.326). ER was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (6.54/2.934-15.81, 3.26/1.034-10.27, and 2.09/1.313-3.321) and macrovascular and microvascular invasion (2.65/1.306-5.343 and 2.55/1.177-5.504). LR was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (5.02/1.372-18.83, 3.19/1.13-12.09, and 1.66/1.051-2.620) and cirrhosis (1.66/1.049-2.631). Patients with low and high LC3 expression in tumor and ANT tissues showed a 5-year cumulative recurrence of 94.3% and 41.7%, respectively (p < 0.001). Conclusions: The high LC3 expression in the tumor and liver microenvironments is significantly associated with lower HCC recurrence. Furthermore, tumor characteristics and liver microenvironment were also significantly associated with ER and LR, respectively. Translational impact: The analysis for LC3 expression in both the HCC and ANT tissues could identify patients at risk of HCC recurrence.
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