TY - JOUR

T1 - Genetic and epigenetic analysis of hepatocellular adenomas with atypical morphological features

AU - Haefliger, Simon

AU - Hench, Juergen

AU - O'Rourke, Colm J.

AU - Meyer-Schaller, Nathalie

AU - Uzun, Sarp

AU - Saldarriaga, Joan

AU - Weber, Achim

AU - Mazzucchelli, Luca

AU - Jermann, Philip

AU - Frank, Stephan

AU - Andersen, Jesper B.

AU - Terracciano, Luigi

AU - Sempoux, Christine

AU - Matter, Matthias S.

PY - 2023

Y1 - 2023

N2 - BackgroundHepatocellular adenoma (HCA) is a rare liver tumour, which can have atypical morphological features such as cytological atypia, pseudoglandular 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 hepatocellular carcinoma (HCC) or in HCA without atypical morphology. MethodsWe analysed five HCAs with atypical morphological features and one HCA with transition to HCC. Every tumour was subtyped by immunohistochemistry, sequenced by a targeted NGS panel, and analysed on a DNA methylation microarray. ResultsSubtyping of the five HCAs with atypical features revealed two beta-catenin mutated HCA (b-HCA), two beta-catenin mutated inflammatory HCA (b-IHCA), and one 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, phyloepigenetic trees using the DNA methylation data reproducibly showed that HCAs with morphological atypia are much more similar to nonmalignant samples than to malignant samples. Finally, atypical HCAs showed no relevant copy number variations (CNV). ConclusionIn our series, mutational, DNA methylation, as well as CNV analyses, supported a relationship of atypical HCAs with nonatypical 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.

AB - BackgroundHepatocellular adenoma (HCA) is a rare liver tumour, which can have atypical morphological features such as cytological atypia, pseudoglandular 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 hepatocellular carcinoma (HCC) or in HCA without atypical morphology. MethodsWe analysed five HCAs with atypical morphological features and one HCA with transition to HCC. Every tumour was subtyped by immunohistochemistry, sequenced by a targeted NGS panel, and analysed on a DNA methylation microarray. ResultsSubtyping of the five HCAs with atypical features revealed two beta-catenin mutated HCA (b-HCA), two beta-catenin mutated inflammatory HCA (b-IHCA), and one 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, phyloepigenetic trees using the DNA methylation data reproducibly showed that HCAs with morphological atypia are much more similar to nonmalignant samples than to malignant samples. Finally, atypical HCAs showed no relevant copy number variations (CNV). ConclusionIn our series, mutational, DNA methylation, as well as CNV analyses, supported a relationship of atypical HCAs with nonatypical 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.

KW - epigenetic

KW - hepatocellular adenoma

KW - hepatocellular carcinoma

KW - liver

KW - methylation analysis

KW - next generation sequencing

KW - MALIGNANT POTENTIAL PROPOSAL

KW - CLASSIFICATION

KW - CARCINOMA

KW - NEOPLASM

U2 - 10.1111/his.14858

DO - 10.1111/his.14858

M3 - Journal article

C2 - 36583256

VL - 82

SP - 722

EP - 730

JO - Histopathology

JF - Histopathology

SN - 0309-0167

IS - 5

ER -