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Background: Recent studies provide evidence that hepatocellular  adenomas  (HCAs) frequently take up gadoxetic acid (Gd-EOB) during the hepatobiliary phase (HBP). The purpose of our study was to investigate how to differentiate between Gd-EOB-enhancing HCAs and focal nodular hyperplasias (FNHs). We therefore retrospectively included 40 HCAs classified as HBP Gd-EOB-enhancing lesions from a sample of 100 histopathologically proven HCAs in 65 patients. These enhancing HCAs were matched retrospectively with 28 FNH lesions (standard of reference: surgical resection). Two readers (experienced abdominal radiologists blinded to clinical data) reviewed the images evaluating morphologic features and subjectively scoring Gd-EOB uptake (25-50%, 50-75% and 75-100%) for each lesion. Quantitative lesion-to-liver enhancement was measured in arterial, portal venous (PV), transitional and HBP. Additionally, multivariate regression analyses were performed., Results: Subjective scoring of intralesional Gd-EOB uptake showed the highest discriminatory accuracies (AUC: 0.848 (R#1); 0.920 (R#2)-p < 0.001) with significantly higher uptake scores assigned to FNHs (Cut-off: 75%-100%). Typical lobulation and presence of a central scar in FNH achieved an accuracy of 0.750 or higher in at least one reader (lobulation-AUC: 0.809 (R#1); 0.736 (R#2); central scar-AUC: 0.595 (R#1); 0.784 (R#2)). The multivariate regression emphasized the discriminatory power of the Gd-EOB scoring (p = 0.001/OR:22.15 (R#1) and p < 0.001/OR:99.12 (R#2). The lesion-to-liver ratio differed significantly between FNH and HCA in the PV phase and HBP (PV: 132.9 (FNH) and 110.2 (HCA), p = 0.048 and HBP: 110.3 (FNH) and 39.2 (HCA), p < 0.001)), while the difference was not significant in arterial and transitional contrast phases (p > 0.05)., Conclusion: Even in HBP-enhancing HCA, characterization of Gd-EOB uptake was found to provide the strongest discriminatory power in differentiating HCA from FNH. Furthermore, a lobulated appearance and a central scar are more frequently seen in FNH than in HCA.

Purpose: This study was conducted in order to evaluate if iso- or hyperintensity of HCAs on HBP is systematically related to a high uptake of hepatospecific contrast agent, using a quantitative approach., Methods: This bicentric retrospective study included all patients with histologically confirmed and subtyped HCA from 2009 to 2017 who underwent MRI with HBP after Gd-BOPTA injection and who showed iso- or hyperintensity on HBP. The signal intensity of tumors on pre- and postcontrast images and the presence of hepatic steatosis were noted. Contrast uptake on HBP was quantified using the liver-to-lesion contrast enhancement ratio (LLCER) and compared between HCA subtypes (Wilcoxon signed-rank test). Categorical variables were compared using chi-square tests., Results: Twenty-four HCAs showed iso- or hyperintensity on HBP, specifically 17 inflammatory (IHCAs) and 7 β-catenin HCAs (BHCAs). Eighteen HCAs (75%) (17 IHCAs and 1 BHCAs) had a LLCER < 0% (median - 13.6%, group 1), of which 94% were hyperintense on precontrast T1-W images, with background hepatic steatosis. Six HCAs (25%) had LLCER ≥ 0% (median 2.9%, group 2), and all were BHCAs. A LLCER ≥ 1.6% was associated with the diagnosis of BHCA with a sensitivity of 86% and a specificity of 100%., Conclusion: In conclusion, iso- or hyperintensity of hepatocellular adenomas on HBP does not necessarily correspond to an increased hepatospecific contrast-agent uptake. In IHCA, tumor hyperintensity on precontrast images and the underlying steatosis likely explain such iso- or hyperintensity, which do show reduced HBP contrast-agent uptake. On the other hand, marked contrast uptake can be observed, especially in BHCA., Key Points: • Iso- or hyperintensity on HBP does not necessarily reflect a high uptake of hepatospecific contrast agent. • Discrepancies between qualitative signal intensity and quantitative hepatospecific contrast uptake can be explained in IHCA by a combination of tumor hyperintensity on precontrast images and underlying hepatic steatosis. • In BHCA, iso- or hyperintensity on HBP does actually correspond to a greater contrast uptake than that of the liver, demonstrated by an increased lesion-to-liver contrast enhancement ratio (LLCER).

Aims: To examine copper deposition in focal nodular hyperplasia (FNH) and inflammatory hepatocellular adenoma (IHA) and to determine if it can play a role in their differentiation., Methods: 28 FNHs and 19 IHAs from surgical resections showing typical morphological and immunohistochemical features were stained with rhodanine to evaluate for copper deposition. Histological features such as nodularity, fibrous bands, ductular proliferation, steatosis, ballooned hepatocytes and lymphocytic inflammation were also scored., Results: Copper deposition was detected in 96% (27/28) of FNHs and 37% (7/19) of IHAs, P<0.001. In all cases, copper was seen within the hepatocytes only around the pseudo-portal tracts or areas of fibrosis. Copper deposition in IHA was significantly associated with presence of lymphocytic inflammation (P=0.04) but not associated with features like nodularity, fibrous bands, ductular proliferation, ballooned hepatocytes and steatosis (P>0.05, for all). In FNH, the presence and degree of copper deposition was not significantly associated with any histological features (P>0.05, for all)., Conclusions: Copper deposition occurs more frequently in FNH (96%) than IHA (37%), P<0.001. However, the presence of copper alone cannot be used as a feature to differentiate between FNH and IHA., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Hepatocellular carcinoma (HCC) can be difficult to distinguish from its mimics, including metastatic tumor, benign hepatocellular lesion, and high-grade dysplastic nodule, especially when limited biopsy material is available. Hence, the judicious use of immunohistochemical stains is necessary to establish a correct diagnosis. This article describes advantages and disadvantages of immunohistochemical markers that are most commonly used to distinguish between these lesions. Diagnostic workup of malignant liver mass (HCC and its histologic variants vs metastatic tumor) as well as well-differentiated hepatocellular lesion (well-differentiated HCC vs focal nodular hyperplasia vs hepatocellular adenoma) is also discussed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

1,3-Dichloropropene (1,3-D) is a soil fumigant used primarily for preplanting control of parasitic nematodes. In a previous chronic dietary exposure study, 1,3-D induced an increased incidence of hepatocellular adenomas in male rats at a dose of 25 mg/kg/day. Although the mechanism for tumor induction in the rat liver by 1,3-D has not been specifically elucidated, available data suggested that the observed liver tumorigenesis was through a nongenotoxic mode of action at the tumor promotion stage. Fischer 344 rats containing preneoplastic lesions were treated (via gavage) with 25 mg/kg/day 1,3-D or 80 mg/kg/day phenobarbital (PB) for 30 days and 60 days, or for 30 days followed by a 30-day recovery period (no compound exposure). Following treatment, placental form glutathione S-transferase (GSTP) positive and GSTP-negative liver focal lesions were quantitated as to size and number. 1,3-D treatment had no effect on GSTP-positive foci number or relative size but significantly increased the number, labeling index, and relative size of GSTP-negative focal lesions (identified by H and E staining) after 30 and 60 days of treatment. Following the 30-day recovery period, the number, labeling index, and relative size of the GSTP-negative lesions in 1,3-D-treated animals returned to control levels. As expected, PB treatment produced an increase in number and relative size of the GSTP-positive lesions. The results of this study are consistent with 1,3-D inducing liver carcinogenesis through a nongenotoxic mode of action by functioning as a tumor promoter specifically through induction of a non-GSTP staining focal hepatocyte population., (© The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology.All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: The nuclear Pregnane X Receptor (PXR, NR1I2) plays a pivotal role in xenobiotic metabolism. Here, we sought to characterize a new PXR isoform (hereafter called small PXR or sPXR) stemming from alternative transcription starting sites downstream of a CpG Island located near exon 3 of the human PXR gene., Methods: Quantitative RT-PCR, western blot, methylation-specific PCR, luciferase reporter assays, electro-mobility shift assays, and stable sPXR overexpression were used to examine sPXR expression and function in hepatocellular cell lines, healthy human liver (n=99), hepatocellular adenomas (HCA, n=91) and hepatocellular carcinoma samples (HCC, n=213)., Results: Liver sPXR mRNA expression varied importantly among individuals and encodes a 37kDa nuclear protein consisting of the ligand-binding domain of PXR that behaves as a dominant-negative of PXR transactivation properties. In vitro methylation of the sPXR upstream promoter abolished its activity, while the demethylation agent 5-aza-2-deoxycytidine increased sPXR mRNA expression in several cell lines. Finally, we observed that sPXR mRNA expression displayed significant differences related to HCA or HCC biology., Conclusions: This novel PXR isoform, displaying a dominant-negative activity and regulated by DNA methylation, is associated with outcomes of patients with HCC treated by resection, suggesting that it represents a key modulator of PXR., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

A molecular and pathological classification system for hepatocellular adenomas (HCAs) was recently introduced in Europe, resulting in four major identified subgroups. Asian countries have a considerably lower incidence of HCA as well as a different etiology. We aimed to characterize HCAs in a Chinese population based on this new classification system. A series of 30 patients with HCA were analyzed based on the phenotypic classification system using immunohistochemical analysis. Investigated antigens included liver-fatty acid binding protein (L-FABP), glutamine synthetase (GS), β-catenin, serum amyloid A (SAA), and C-reactive protein (CRP). Of the 30 cases (20 female) included in this study, only one had a history of oral contraceptive use. We identified 9 (30%) hepatocyte nuclear factor (HNF)-1α-inactivated HCAs, 3 (10%) β-catenin-activated HCAs, 11 (36.7%) inflammatory HCAs, and 7 (23.3%) unclassified HCAs. In the inflammatory HCA group, 2 cases demonstrated concurrent β-catenin-activation. Homogeneous steatosis (6/9) and microadenomas (2/9) were more frequently observed in HNF1α-inactivated HCAs. A body mass index (BMI) of greater than 25 (5/11), alcohol use (4/11), and steatosis in background liver (3/11) were more frequent in inflammatory HCAs. β-catenin-activated HCAs were larger than those of other subgroups. Despite obvious differences in etiology and gender proportion compared with Western countries, the clinical and pathological characteristics of HCA subgroups in China are similar to those in Europe. The phenotypic classification system could be reliably applied to Chinese patients as a meaningful tool for HCA management.

Background: Hepatic lesions often present diagnostic connundrums with conventional MR techniques. Hepatobiliary phase contrast-enhanced imaging with gadoxetic acid can aid in the characterization of such lesions. However, quantitative measures describing late-phase enhancement must be assessed relative to their accuracy of hepatic lesion classification., Purpose: To compare quantitative parameters in gadoxetic acid contrast-enhanced dynamic and hepatobiliary phase imaging versus apparent diffusion coefficients in hepatic lesion characterization., Material and Methods: 57 patients with focal hepatic lesions on gadoxetic acid MR were included. Lesion enhancement at standard post-contrast time points and in the hepatobiliary phase (HB; 15 and 25 minutes post-contrast) was assessed via calculation of contrast (CR) and enhancement ratios (ER). Apparent diffusion coefficient (ADC) values were also obtained. Values for these parameters were compared among lesions and ROC analyses performed., Results: HB enhancement was greatest with FNH and adenomas. HB ER parameters but not HB CR could distinguish HCC from benign entities (0.9 ER ROC AUC versus 0.5 CR ROC AUC). There was no statistically significant difference found between the 15 and 25 minutes HB time points in detection of any lesion (p>0.4). ADC values were statistically significantly higher with hemangiomas (p<0.05) without greater accuracy in lesion detection relative to HB phase parameters., Conclusion: Hepatobiliary phase gadoxetic acid contrast-enhanced MR characterizes focal hepatic lesions more accurately than ADC and conventional dynamic post-contrast time point enhancement parameters. ER values are generally superior to CR. No discernible benefit of 25 minute versus 15 minute delayed imaging is demonstrated.

Interactions between epigenome and the environment in biology and in disease are of fundamental importance. The incidence of hepatocellular adenomas in flatfish exceeds 20% in some environments forming a unique opportunity to study environmental tumorigenesis of general relevance to cancer in humans. We report the novel finding of marked DNA methylation and metabolite concentration changes in histopathologically normal tissue distal to tumors in fish liver. A multi-"omics" discovery approach led to targeted and quantitative gene transcription analyses and metabolite analyses of hepatocellular adenomas and histologically normal liver tissue in the same fish. We discovered a remarkable and consistent global DNA hypomethylation, modification of DNA methylation and gene transcription, and disruption of one-carbon metabolism in distal tissue compared to livers of non-tumor-bearing fish. The mechanism of this disruption is linked not to depletion of S-adenosylmethionine, as is often a feature of mammalian tumors, but to a decrease in choline and elevated S-adenosylhomocysteine, a potent inhibitor of DNA methyltransferase. This novel feature of normal-appearing tissue of tumor-bearing fish helps to understand the unprecedentedly high incidence of tumors in fish sampled from the field and adds weight to the controversial epigenetic progenitor model of tumorigenesis. With further studies, the modifications may offer opportunities as biomarkers of exposure to environmental factors influencing disease.

Biallelic inactivating mutations of the transcription factor 1 gene (TCF1), encoding hepatocyte nuclear factor 1alpha (HNF1alpha) were identified in 50% of hepatocellular adenomas (HCA) phenotypically characterized by a striking steatosis. To understand the molecular basis of this aberrant lipid storage, we performed a microarray transcriptome analysis validated by quantitative reverse transcription-PCR, Western blotting, and lipid profiling. In mutated HCA, we showed a repression of gluconeogenesis coordinated with an activation of glycolysis, citrate shuttle, and fatty acid synthesis predicting elevated rates of lipogenesis. Moreover, the strong down-regulation of liver fatty acid-binding protein suggests that impaired fatty acid trafficking may also contribute to the fatty phenotype. In addition, transcriptional profile analysis of the observed deregulated genes in non-HNF1alpha-mutated HCA as well as in non-tumor livers allowed us to define a specific signature of the HNF1alpha-mutated HCA. In these tumors, lipid composition was dramatically modified according to the transcriptional deregulations identified in the fatty acid synthetic pathway. Surprisingly, lipogenesis activation did not operate through sterol regulatory element-binding protein-1 (SREBP-1) and carbohydrate-response element-binding protein (ChREBP) that were repressed. We conclude that steatosis in HNF1alpha-mutated HCA results mainly from an aberrant promotion of lipogenesis that is linked to HNF1alpha inactivation and that is independent of both SREBP-1 and ChREBP activation. Finally, our findings have potential clinical implications since lipogenesis can be efficiently inhibited by targeted therapies.

The purpose of this review was to summarise what is known about the benign hepatic tumors, especially the role that free radicals play in the etiology and in the complications of these neoplasms. Nowadays benign liver tumors are considered as common entities. With the technical developments of radiology their diagnosis has become much easier, but still it is the major difficulty for the doctor to handle. There are different types of benign hepatic neoplasms: liver cyst, hemangioma, hepatocellular adenoma, focal nodular hyperplasia and there are also some rare tumor types. The relationship between hepatocellular adenoma and the use of oral contraceptives is well known. The oral contraceptives reduce the antioxidant capacity of the blood, this could be an explanation for the generation of these neoplasms. Benign liver tumors are also associated to thrombotic reactions. These neoplasms may require surgical treatment, so the oxidative stress is one of the main prognostic factors of the patients' survival.

The purpose of this study was to investigate the natural history of adenomatous hyperplasia (AH) in liver cirrhosis, which is suspected of being a precancerous condition of hepatocellular carcinoma (HCC). Sixteen patients with 19 histologically proven AH nodules were followed-up over time with ultrasonographic (US) examinations performed every 3-4 months. The biopsy was repeated whenever the volume of the lesion increased, its US pattern changed, or there was a change in the alpha-fetoprotein values. Thirteen out of 19 AH (68.4%) evolved toward HCC after 8-31 months (mean 14.2 months). Malignant transformation was proved in 7/18 AH within 1 year of its initial detection, in 12/15 AH within 2 years, and in 13/14 AH within 4 years. Six AH remained unchanged in size and US pattern for 9-70 months (mean 29.5 months). Long term follow-up of AH confirms that this lesion is a precursor of HCC.