Inflammatory hepatocellular adenomas developed in the setting of chronic liver disease and cirrhosis

Abstract

Hepatocellular adenoma is considered to occur exclusively in non-fibrotic livers. It is a heterogeneous entity and a molecular classification is now widely accepted. The most frequent hepatocellular adenoma subtype, namely inflammatory adenoma, harbor somatic activating mutations of genes involved in the interleukin-6 pathway that lead to high C-reactive protein and serum amyloid A expression. The aim of our study was to investigate a series of benign hepatocellular neoplasms developed on cirrhotic livers and characterized by an unequivocal histological diagnosis. We performed a clinical, pathological, and molecular study of 10 benign hepatocellular neoplasms developed in three patients with cirrhosis. Markers allowing hepatocellular adenoma classification were assessed by quantitative real-time PCR and immunohistochemistry. Samples were sequenced for CTNNB1, HNF1A, IL6ST, GNAS, STAT3, and TERT (promoter) mutations. A control series of 32 classical macronodules developed in cirrhosis related to various etiologies was screened by immunohistochemistry and gene sequencing. The three patients had cirrhosis related to metabolic syndrome and/or alcohol intake; two had a single tumor, while the third developed more than 30 lesions. Microscopic examination showed welldifferentiated neoplasms sharing features with inflammatory adenoma including inflammatory infiltrates, sinusoidal dilatation, and dystrophic vessels. Sequencing revealed classical hotspot somatic mutations (IL6ST, n = 8; STAT3, n = 1; and GNAS, n = 1) known to be responsible for IL-6/JAK/STAT pathway activation. Two classical high-grade macronodules demonstrated high serum amyloid A and/or C-reactive protein expression, without gene mutations. Altogether, our findings support the existence of rare inflammatory adenoma developed in cirrhosis.

Molecular classification of hepatocellular adenoma in clinical practice

“…13 We also identified rare cases of IHCA harbouring activating mutations in IL6ST or STAT3 developed on cirrhosis, related to metabolic syndrome or chronic alcohol intake. 34,35 The same observations have also been described on cirrhosis in Japan. However, additional data are warranted to confirm that HCA can arise on cirrhotic liver.…”

Benign Hepatocellular Nodules: Hepatobiliary Phase of Gadoxetic Acid–enhanced MR Imaging Based on Molecular Background

“…The details of the clinicopathologic differences between SAA-HN and FNH-like nodule are now under investigation. On the other hand, a recent study also supports the existence of I-HCA occurring in cirrhosis (54). Therefore, SAA-HN will be classified as I-HCA in the near future.…”

Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation

“…The non-tumor liver parenchyma was steatotic in 42 patients (12%) and fibrotic (F2ÀF4) in 24 patients (7%) (Supplementary Table 2). 39 Six patients died, 3 due to a malignant transformation, 1 from HCA bleeding, 1 after liver resection for multiple HCA developed on cirrhosis, and 1 after liver transplantation for HCA developed on glycogenosis.…”