Characteristics of atypical large well-differentiated hepatocellular carcinoma: a specific subtype of hepatocellular carcinoma?

Abstract

Background: Hepatocellular carcinoma (HCC) de-differentiation is thought to correlate with size, therefore well-differentiated HCC ≥3 cm are considered rare and not fully understood.

Methods: Patients who underwent hepatectomy for HCC between 1998-2016 were retrospectively analyzed. Patient's characteristics and recurrence-free (RFS) and overall (OS) survival were compared between those with atypical- (well-differentiated-HCC ≥3 cm) and typical-HCC (moderate-to-poorly-differentiated HCC ≥3 cm).

Results: Of 176 patients included in this study, 37 (21%) had atypical-HCC. Patients with atypical-HCC were less likely to be Asian ethnicity (3% vs. 17%, p = 0.062), have lower rate of viral infection (14% vs. 43%, p = 0.003), cirrhosis (8% vs. 27%, p = 0.015). The tumors were less likely to demonstrate vascular invasion (30% vs. 59%, p = 0.002), and were associated with a lower alpha-fetoprotein level (3.5 ng/ml vs. 33.2 ng/ml, p < 0.001). Patients with atypical-HCC had a longer RFS (5-y RFS: 58.3% vs. 35.7%, p = 0.016) and OS (5-y OS: 79.1% vs 53.3%, p = 0.029) as compared to those with typical-HCC following univariate analysis, however this did not appear following multivariate analysis.

Conclusion: Patients with atypical-HCC have different characteristic in terms of epidemiology, etiology, cirrhosis and vascular invasion as compared to typical-HCC. The etiology of atypical-HCC may be non-alcoholic fatty liver disease-related and/or malignant transformation of hepatocellular adenoma.

Fig. 1. Progression process of hepatocellular carcinoma (HCC).

Typically, HCC develop from pre-neoplastic lesions (dysplastic nodule) to early HCC. Majority of early HCC consist of well-differentiated tissues, and then, de-differentiate to moderate-to-poor-differentiated HCC along with enlargement, which is called as “multistep progression”. Well-differentiated HCC beyond a diameter of 3 cm is considered to be rare and referred to as “atypical large well-differentiated HCC”.^, HBV, hepatitis B virus; HCV, hepatitis C virus; NAFLD, non-alcoholic fatty liver disease.

Fig. 2

(a) Recurrence-free survival and (b) overall survival after hepatectomy according to the type of HCC.

Fig. 3

(a) Recurrence-free survival and (b) overall survival after hepatectomy according to the type of HCC only in patients with stage I and II (TNM classification in AJCC 8^th edition).