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-poorlydifferentiated 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 nonalcoholic fatty liver disease-related and/or malignant transformation of hepatocellular adenoma.

Long-term outcomes following resection of hepatocellular adenomas with small foci of malignant transformation or malignant adenomas

“…Recently, a new subtype of HCC defined as "atypical large well-differentiated HCC" beyond 3 cm was reported (19). In typical HCC, tumour evolution follows an increase in size and a dedifferentiation stage (20).…”

Hepatocellular adenoma: what we know, what we do not know, and why it matters

“…However, the evaluation is biased, owing to the inclusion of only surgical samples. In addition, the presence of an HCA in an HCC, or a history of incomplete resection of an HCA, is a prerequisite for the diagnosis of HCA‐derived HCC; therefore, the precise frequency of pre‐existing HCA behind a fully developed HCC in a non‐cirrhotic liver is unknown 67,81 …”

“…The identification and the significance of a histological ‘borderline’ lesion still represent an enigma, partly because of the absence of clear‐cut criteria and helpful markers. TERT promoter mutation is thought to represent an irreversible step towards malignancy in CTNNB1 ‐mutated HCA 81 . However, the evolution and exact prognosis of the malignant transformation of HCA at different stages up to a well‐differentiated HCC are still issues that need further study, which may lead us to abandon the term ‘hepatocellular neoplasm of uncertain malignant potential’ 136–138 …”

“…In addition, the presence of an HCA in an HCC, or a history of incomplete resection of an HCA, is a prerequisite for the diagnosis of HCA-derived HCC; therefore, the precise frequency of pre-existing HCA behind a fully developed HCC in a non-cirrhotic liver is unknown. 67,81 The reported risk factors for malignant transformation of HCA are male sex, size (>50 mm), CTNNB1 mutation, in particular in exon 3, and concurrent liver diseases, particularly glycogen storage disorders (GSDs) and VLD. 78 The higher risk of NT malignant transformation in male patients has been well recognised since the work by Dokmak, who showed a 10-fold higher risk in men than in women, 6 leading to the recommendation in clinical guidelines to remove or ablate any HCA in men.…”

Antitumoral and Anti-inflammatory Roles of Somatostatin and Its Analogs in Hepatocellular Carcinoma

“…This etiological variety implies that patients with HCC will also carry the burden of the underlying disease, and their management will require a more complex approach, often involving an interdisciplinary team to address cardiovascular, neurological, metabolic, or renal complications as well as any other associated pathologies [ 9 – 11 ]. Also, the presence of rare subtypes of HCC or atypical presentations can further delay the treatment and worsen patient prognosis [ 12 , 13 ].…”