The β-catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules☆
Introduction
Focal nodular hyperplasia (FNH), first described by Edmondson [1], is the second most common benign liver tumor, outnumbered only by hemangioma. FNH usually occurs in women 20–50 years old. A link between FNH and oral contraceptive use has been reported but is disputed [2]. Classical FNH is characterized by a central stellate fibrous region containing malformed vascular structures [3]. The solitary central artery with high flow and the absent portal vein give the lesions a characteristic radiological appearance [4] in more than 80% of FNH cases. However, some classical FNHs, mainly those smaller than 3 cm, have no central scar at pathological examination [5]. In all cases, the treatment of FNH is conservative because there is very low risk of complications such as bleeding, and malignant transformation has not yet been proven [6].
FNH typically occurs in normal or almost normal liver. The lesion is multinodular, composed of nearly normal hepatocytes arranged in 1–2-cell-thick plates. Bile ductules are usually found at the interface between hepatocytes and fibrous regions [7], [8]. It is thought that increased arterial flow hyperperfuses the local parenchyma, leading to secondary hepatocellular hyperplasia. FNH is therefore considered a hyperplastic response to increased blood flow, rather than a neoplastic process [3], [9], [10]. Various vascular abnormalities such as telangiectases, hereditary hemorrhagic telangiectasia, arteriovenous malformation and anomalous venous drainage may be present, especially in patients with multiple FNHs.
Clonal analysis demonstrated the reactive polyclonal nature of liver cells in FNH in 60–100% of cases, depending on the series [11], [12], [13], [14], [15]. Other studies analyzing chromosome gains and losses by comparative genomic hybridization, allelotyping, or karyotyping identified chromosome alterations indicating a clonal origin of the FNH nodules in 14–50% of cases [2], [15], [16]. However, genetic analysis of FNH did not demonstrate somatic gene mutations in CTNNB1, TP53, TCF1 or APC [15], [17], [18]. Recently, it was shown that two angiopoietin genes (ANGPT1 and ANGPT2) involved in vessel maturation have altered mRNA expression levels, with a consistently increased ANGPT1/ANGPT2 ratio in FNH [14], [15].
Focal nodular hyperplasia-like (FNH-like) nodules are lesions arising in cirrhotic liver that closely resemble FNH at both the morphological and radiological levels [19], [20]. It has been hypothesized that FNH-like nodules arise as a local hyperplastic response to vascular alterations [20], [21] known to occur in liver cirrhosis [3]. However, the exact pathogenesis of FNH-like nodules remains to be elucidated.
To better understand the pathophysiology of FNH, we searched for genes deregulated in FNH by conducting a combined cDNA and oligonucleotide transcriptomic analysis exploring expression of more than 15,000 different genes. In this experiment, transcriptome profiles of eight FNHs were compared to six non-tumor liver samples. After the analysis, selected genes belonging to the most strongly activated or inactivated pathways were validated using quantitative RT-PCR in a larger series of 70 benign liver tumors including FNH, hepatocellular adenomas (HCA), macroregenerative and dysplastic cirrhotic nodules and FNH-like lesions.
Section snippets
Patients and samples
A series of 11 FNHs, 15 HCAs, 6 normal liver tissues [including samples taken at a distance from HCAs (3), FNHs (1) and hemangiomas (2)], 8 cirrhotic nodules [including 3 high-grade dysplastic nodules (HGDN), 1 low-grade dysplastic nodules (LGDN) and 4 macroregenerative nodules (MRN)], 11 FNH-like nodules and 19 samples of random cirrhotic liver [including samples taken at a distance from hepatocellular carcinoma (8), FNH-like nodules (7) and dysplastic nodules (4)] were collected at the
Identification of overexpressed genes encoding proteins of the extracellular matrix
Analysis of the Affymetrix and cDNA microarray results revealed 240 and 284 genes that were, respectively, significantly up- and down-regulated in FNH compared to control non-tumor liver samples (Supplementary Table 1). We analyzed these sets of genes to identify biological pathways that were specifically altered. Using a gene ontology-based analysis, we identified several GO categories that were significantly over-represented in FNH (Supplementary Table 2). Among the up-regulated genes in FNH,
Discussion
In the present study, we carried out a transcriptomic analysis which revealed the molecular pathways altered in FNH. For the first time, activation of the β-catenin pathway was demonstrated in these tumors. Recently, β-catenin was identified as a master actor of hepatocyte proliferation, liver regeneration, hepatocyte metabolism, and liver development and as a master regulator of liver zonation [26], [30], [31], [32], [33], [34]. In normal hepatocytes, β-catenin and its known target genes, such
Acknowledgements
We thank Eric Chevet for critical reading of this manuscript. This work was supported by Inserm (Réseaux de recherche clinique et réseaux de recherche en santé des populations), the comité Dordogne de la Ligue contre le Cancer, the SNFGE and the program “Carte d’identité des tumeurs” by the ligue Nationale Contre le Cancer. S.R. was supported by a Ligue Nationale Contre le Cancer doctoral fellowship. JZR is supported by an interface contract between Inserm and Bordeaux Hospital.
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2022, Radiologic Clinics of North AmericaCitation Excerpt :More recently, Sagawa and colleagues reported a higher prevalence of HCC among patients with FALD, up to 9.8%.37 Given the multitude of liver lesions encountered in these patients and the increased risk of HCC, confident diagnosis of FNH-like lesions can be challenging because of overlap in imaging features of these lesions, including washout appearance after contrast administration.5 Stability, uniform homogenous arterial enhancement with central scar appearance and retention of contrast on the hepatobiliary phase are features suggestive of FNH-like lesions32 (Figs. 10 and 11).
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The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript.