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Genetic and epigenetic analysis of hepatocellular adenomas with atypical morphological features.

Haefliger, Simon, Hench, Juergen, O'Rourke, Colm J, Meyer-Schaller, Nathalie, Uzun, Sarp, Saldarriaga, Joan, Weber, Achim, Mazzucchelli, Luca, Jermann, Philip, Frank, Stephan, Andersen, Jesper B, Terracciano, Luigi, Sempoux, Christine and Matter, Matthias S (2022) Genetic and epigenetic analysis of hepatocellular adenomas with atypical morphological features. Histopathology. ISSN 1365-2559



Hepatocellular adenoma (HCA) is a rare liver tumor, which can have atypical morphological features such as cytological atypia, pseudo-glandular architecture, and altered reticulin framework. Little is known about the genetic and epigenetic alterations of such HCAs and whether they show the alterations classically found in HCC or in HCA without atypical morphology.


We analyzed five HCAs with atypical morphological features and one HCA with transition to HCC. Every tumor was subtyped by immunohistochemistry, sequenced by a targeted NGS panel and analyzed on a DNA methylation microarray.


Subtyping of the five HCAs with atypical features revealed 2 β-catenin mutated HCA (b-HCA), 2 β-catenin mutated inflammatory HCA (b-IHCA), and 1 sonic hedgehog activated HCA (shHCA). None of them showed mutations typically found in HCC, such as e.g. TERT or TP53 mutations. The epigenomic pattern of HCAs with atypical morphological features clustered with reference data for HCAs without atypical morphological features but not with HCC. Similarly, phylo-epigenetic trees using the DNA methylation data reproducibly showed, that HCAs with morphological atypia are much more similar to non-malignant samples than to malignant samples. Finally, atypical HCAs showed no relevant copy number variations (CNV).


In our series, mutational, DNA methylation, as well as CNV analyses supported a relationship of atypical HCAs with non-atypical HCAs rather than with HCC. Therefore, in cases with difficult differential diagnosis between HCC and HCA, it might be advisable to perform targeted sequencing and/or combined methylation/copy number profiling.

Item Type: Article
Date Deposited: 17 Jan 2023 00:45
Last Modified: 17 Jan 2023 00:45


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