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Objectives: Sonic hedgehog hepatocellular adenoma (shHCA) is a new hepatocellular adenoma (HCA) subgroup characterized by high risk of hemorrhage. ShHCA account for below 10% of all HCA cases and are often associated with female gender, obesity, and non-alcoholic steatohepatitis. No specific MRI characteristics have been described to date. The objective of this study was to assess the value of using MRI to identify shHCA, and correlate MRI findings with histology., Methods: We retrospectively collected MRI scans of 29 patients with shHCA from our center and from different liver referral centers to include 35 lesions. Diagnosis of shHCA was assessed by immunohistochemical overexpression of argininosuccinate synthase 1 or prostaglandin D2 synthase, then confirmed by molecular analysis of sonic hedgehog pathway activation and/or by proteomic analysis., Results: In 46% (n = 16/35) of shHCA cases, we detected intralesional fluid-filled cavities defined on MR images as fluid-like foci markedly hyperintense on T2-weighted sequences, and hypointense on T1-weighted sequences, with or without delayed enhancement. Pathologically, these cavities were observed in 54% of cases as vacuoles filled with blood at different stages of degradation. Hemorrhage and/or necrosis were detected among 71% of cases by MRI analysis (n = 25/35) versus 82% pathologically. Seventeen percent of shHCA cases (n = 6/35) were completely homogeneous via MRI and pathological analysis. No MRI criteria was found in favor of focal nodular hyperplasia, HNF1A-mutated HCA, or typical inflammatory HCA., Conclusion: We reveal the presence of intralesional fluid-filled cavities among 46% of our shHCA cases that represent a new MRI finding possibly helpful for shHCA diagnosis., Clinical Relevance Statement: This multicenter study is the first clinical study about the radiological aspect of this new hepatocellular adenoma subgroup. This highlights a strong correlation between MRI and histological analysis, with a specific pattern emerging for diagnosis., Key Points: • Sonic hedgehog hepatocellular adenoma is a new hepatocellular adenoma subgroup associated with high risk of hemorrhage, but imaging features of this subgroup remain unknown. • Analysis of MR images and correlation with pathology revealed intralesional fluid-filled cavities and necrotic-hemorrhagic changes. • Intralesional fluid-filled cavities have not yet been described in other adenoma subtypes and represent a new MRI finding for sonic hedgehog hepatocellular adenoma., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Objective: Our aim was to determine independent risk factors of clinical bleeding of hepatocellular adenoma (HCA) to define a better management strategy., Summary Background Data: HCA is a rare benign liver tumor with severe complications: malignant transformation that is rare (5%-8%) and more often, hemorrhage (20%-27%). To date, only size > 5 cm and histological subtype (possibly sonic hedgehog) are associated with bleeding, but these criteria are not clearly established., Methods: We retrospectively collected data from a cohort of 268 patients with HCA managed in our tertiary center, from 1984 to 2020 and focused on clinical bleeding. Hemorrhage was considered severe when it required intensive care and moderate when bleeding symptoms required a hospitalization. We included 261 patients, of whom 130 (49.8%) had multiple HCAs or liver adenomatosis. All surgical specimen and liver biopsy were reviewed by an experienced liver pathologist and reclassified in the light of the current immunohistochemistry. Mean duration of follow-up was 93.3 months (range 1-363). We analyzed type, frequency, consequences of bleeding, and risk factors among clinical data and HCA characteristics., Results: Eighty-three HCA (31.8%) were hemorrhagic. There were 4 pregnant women with 1 newborn death. One patient died before treatment. Surgery was performed in 78 (94.0%) patients. Mortality was nil and severe complications occurred in 11.5%. Multivariate analysis identified size (OR 1.02 [1.01-1.02], P < 0.001), shHCA (OR 21.02 [5.05-87.52], P < 0.001), b-catenin mutation on exon 7/8 (OR 6.47 [1.78-23.55], P = 0.0046), chronic alcohol consumption (OR 9.16 [2.47-34.01], P < 0.001) as independent risk factors of clinical bleeding., Conclusions: This series, focused on the hemorrhagic risk of HCA, shows that size, but rather more molecular subtype is determinant in the natural history of HCA., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To assess the value of hepatospecific MR contrast agent uptake on hepatobiliary phase (HBP) images to detect marked activation of the β-catenin pathway in hepatocellular adenomas (HCAs)., Methods: This multicentric retrospective IRB-approved study included all patients with a pathologically proven HCA who underwent gadobenate dimeglumine-enhanced liver MRI with HBP. Tumor signal intensity on HBP was first assessed visually, and lesions were classified into three distinct groups-hypointense, isointense, or hyperintense-according to the relative signal intensity to liver. Uptake was then quantified using the lesion-to-liver contrast enhancement ratio (LLCER). Finally, the accuracy of HBP analysis in depicting marked β-catenin activation in HCA was evaluated., Results: A total of 124 HCAs were analyzed including 12 with marked β-catenin activation (HCA B+). Visual analysis classified 94/124 (76%), 12/124 (10%), and 18/124 (14%) HCAs as being hypointense, isointense, and hyperintense on HBP, respectively. Of these, 1/94 (1%), 3/12 (25%), and 8/18 (44%) were HCA B+, respectively (p < 0.001). The LLCER of HCA B+ was higher than that of HCA without marked β-catenin activation in the entire cohort (means 4.9 ± 11.8% vs. - 19.8 ± 11.4%, respectively, p < 0.001). A positive LLCER, i.e., LLCER ≥ 0%, had 75% (95% CI 43-95%) sensitivity and 97% (95% CI 92-99%) specificity, with a LR+ of 28 (95% CI 8.8-89.6) for the diagnosis of HCA B+., Conclusions: Hepatospecific contrast uptake on hepatobiliary phase is strongly associated with marked activation of the β-catenin pathway in hepatocellular adenoma, and its use might improve hepatocellular adenoma subtyping on MRI., Key Points: • Tumor uptake on hepatobiliary phase in both the visual and quantitative analyses had a specificity higher than 90% for the detection of marked β-catenin activation in hepatocellular adenoma. • However, the sensitivity of visual analysis alone is inferior to that of LLCER quantification on HBP due to the high number of HCAs with signal hyperintensity on HBP, especially those developed on underlying liver steatosis.

Objective: A new computer tool is proposed to distinguish between focal nodular hyperplasia (FNH) and an inflammatory hepatocellular adenoma (I-HCA) using contrast-enhanced ultrasound (CEUS). The new method was compared with the usual qualitative analysis., Methods: The proposed tool embeds an "optical flow" algorithm, designed to mimic the human visual perception of object transport in image series, to quantitatively analyse apparent microbubble transport parameters visible on CEUS. Qualitative (visual) and quantitative (computer-assisted) CEUS data were compared in a cohort of adult patients with either FNH or I-HCA based on pathological and radiological results. For quantitative analysis, several computer-assisted classification models were tested and subjected to cross-validation. The accuracies, area under the receiver-operating characteristic curve (AUROC), sensitivity and specificity, positive predictive values (PPVs), negative predictive values (NPVs), false predictive rate (FPRs) and false negative rate (FNRs) were recorded., Results: Forty-six patients with FNH (n = 29) or I-HCA (n = 17) with 47 tumours (one patient with 2 I-HCA) were analysed. The qualitative diagnostic parameters were accuracy = 93.6%, AUROC = 0.94, sensitivity = 94.4%, specificity = 93.1%, PPV = 89.5%, NPV = 96.4%, FPR = 6.9% and FNR = 5.6%. The quantitative diagnostic parameters were accuracy = 95.9%, AUROC = 0.97, sensitivity = 93.4%, specificity = 97.6%, PPV = 95.3%, NPV = 96.7%, FPR = 2.4% and FNR = 6.6%., Conclusions: Microbubble transport patterns evident on CEUS are valuable diagnostic indicators. Machine-learning algorithms analysing such data facilitate the diagnosis of FNH and I-HCA tumours., Key Points: • Distinguishing between focal nodular hyperplasia and an inflammatory hepatocellular adenoma using dynamic contrast-enhanced ultrasound is sometimes difficult. • Microbubble transport patterns evident on contrast-enhanced sonography are valuable diagnostic indicators. • Machine-learning algorithms analysing microbubble transport patterns facilitate the diagnosis of FNH and I-HCA.

Three liver nodules were fortuitously discovered in a 30-year-old obese woman during a gynecological workup and resected. Two nodules (6 and 1.5 cm) with histological characteristics of inflammatory hepatocellular adenoma (HCA) were C reactive protein positive with normal expression of glutamine synthetase. The third 6 cm nodule had all the characteristics of an Unclassified HCA with an overexpression of Argininosuccinate Synthase 1 (ASS1) in the tumor compared to the non-tumoral liver. The non-tumoral liver was highly steatotic. Upon MRI review, two HCAs were identified as inflammatory HCAs based on specific criteria. The third HCA was different from the other two with the presence of peculiar intratumoral fluid cavities. This first report on the association between unclassified HCA expressing ASS1 and inflammatory HCA reinforces the concept that common factors are implicated in HCA subtypes genesis. ASS1 is an interesting immuno-marker to identify among unclassified HCA a subgroup with a high risk of bleeding. ASS1 overexpression decreases sharply the number of "true" unclassified HCA., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background and Aims: Stopping oral contraceptives following nodule detection usually prevents further hepatocellular growth (HCA); rare cases of growth have been reported after surgery. The aim of the study was to review our resected HCA cases and their outcomes and more specifically, growth., Methods: We retrieved all HCA cases that required a second intervention and HCA growth cases of none resected HCA after resection of one or several HCAs., Results: Out of the 210 resected classified HCA cases, a second resection was performed in 5 cases, 4 of which were in women with HNF1alpha-inactivated adenomatosis (H-adenomatosis) and had a favorable outcome. The fifth case was the occurrence of an inflammatory HCA, 3 years after resection of a previous one. Of the 65 resected HNF1-inactivated HCAs (H-HCAs), the nodules that remained continued to increase very slowly in 3 adenomatosis cases. After surgery, the liver became dysmorphic years later in one case, and the nodules grew but not significantly in another case. After the diagnosis of adenomatosis, progressive growth leads to surgery 12 years later in the last case., Conclusion: These results confirm that, in rare H-adenomatosis, size of nodules may increase very slowly, probably in part through coalescence of micro H-HCAs and leading occasionally to a second resection., (Copyright © 2018. Published by Elsevier Masson SAS.)

Objective: MRI is crucial for the classification of hepatocellular adenomas (HCA) into subtypes. Our objective was to review and increase MRI criteria for subtype classification and define the limits., Methods: Pathological and radiological data of 116 HCAs were retrospectively analyzed to investigate MRI features of HCA pathological subtypes. Risk for complication was also evaluated with regard to subtype and tumor size., Results: 38/43 (88%) HNF1α-mutated HCAs (H-HCAs) were discriminated by (i) fatty component (homogeneous or heterogeneous) and (ii) hypovascular pattern, with a sensitivity of 88% and a specificity of 97%. 51/58 (88%) inflammatory HCAs (IHCAs) displayed features of sinusoidal dilatation (SD) including three different patterns (global SD, atoll sign, and a new "crescent sign" corresponding to a partial peripheral rim, hyperintense on T2W and/or arterial phase with persistent delayed enhancement). Sensitivity was 88% and specificity 100%. However, some HCA remained unclassifiable by MRI: HCA remodeled by necrotic/hemorrhagic changes covering > 50% of the lesion, H-HCAs without steatosis, IHCAs without SD, β-catenin-mutated and unclassified HCAs. Regarding malignant transformation (5/116) and bleeding (24/116), none was observed when the HCA diameter was smaller than 5.2 cm and 4.2 cm, respectively., Conclusion: Based on the largest series evaluated until now, we identified several non-described MRI features and propose new highly sensitive and specific MRI criteria. With the addition of these new features, 88% of the two main HCA subtypes could be identified., Key Points: • HNF1α-mutated hepatocellular adenomas (H-HCA) are characterized by the presence of fat and hypovascular pattern in MRI. • Inflammatory hepatocellular adenomas (I-HCA) are characterized by different patterns translating sinusoidal dilatation including the newly described crescent sign. • No MRI specific pattern was identified for β-catenin-mutated HCA (b-HCA).

Hepatocellular adenomas (HCA) are rare benign hepatocellular tumors occurring mainly in women taking oral contraceptives with 2 major complications: severe bleeding and malignant transformation that can be avoided if nodules exceeding 5 cm are resected. This simple attitude has been challenged in the recent years with HCA in men, in young adolescent, in aged persons, and complications in hepatocellular adenomas below 5 cm. The discovery of specific mutations leading to specific phenotypes has modified the clinical spectrum of the disease. The phenotypic immune classification of HCA based on the molecular classification is being widely used in liver referral centers. The aim of this snapshot is to briefly present for each subtype the clinical, pathological, immuno-pathological criteria as well as the risk of complications and guidelines for treatment and management., (Copyright © 2018. Published by Elsevier Masson SAS.)

Background and Aims: It is rare but not uncommon to discover micro/small HNF1α-inactivated hepatocellular adenoma (H-HCA) outside the context of resected H-HCA. We aimed to review our cases of micro/small H-HCA discovered by chance on different kinds of liver resected specimens., Methods: We retrieved cases of micro/small H-HCA discovered by chance on resected specimens outside the context of H-HCA. All these nodules were liver fatty acid binding protein (LFABP)-negative contrasting with normal positivity in the surrounding non-tumoural liver, ruling out the possibility of focal steatosis or other subtypes of micro-HCAs., Results: We identified 19 micro/small H-HCA cases. In 16 cases they were discovered in patients who underwent surgery for benign nodules including one haemangioma, six focal nodular hyperplasia, seven inflammatory HCA (including one with b-catenin activation), one HCA, whose subtype could not be identified because of massive necrosis/hemorrhage, and one hepatocellular carcinoma. In two additional cases, patients followed up for a melanoma underwent liver surgery to remove micro nodules possibly related to a metastatic process. Finally in one case a micro nodule was seen and resected during a cholecystectomy., Conclusion: Taken together, H-HCAs are more frequent than we initially supposed as micro and small HCAs cannot all be detected by routine ultrasound. Despite no information on the potential growth of these micro/small H-HCAs, there is no argument to stop oral contraceptives or to ask for a specific regular surveillance. The association of different subtypes of HCAs with focal nodular hyperplasia suggests they share or have common etiological factors., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hepatocellular adenomas are rare benign nodules developed mainly in women taking oral contraceptives. They are solitary or multiple. Their size is highly variable. There is no consensus in the literature for their management except that once their size exceeds 5 cm nodules are taken out to prevent 2 major complications: bleeding and malignant transformation. There are exceptions particularly in men where it is recommended to remove smaller nodules. Since the beginning of this century, major scientific contributions have unveiled the heterogeneity of the disease. HCA are composed of four major subtypes. HNF1A (coding for hepatocyte nuclear factor 1a) inactivating mutations (H-HCA); inflammatory adenomas (IHCA); the β-catenin-mutated HCAs (β-HCA) and unclassified HCA (UHCA) occurring in 30-40%, 40-50%, 10-15% and 10% of all HCA, respectively. Half of β-HCAs are also inflammatory (β-IHCA). Importantly, β-catenin mutations are associated with a high risk of malignant transformation. HCA subtypes can be identified on liver tissue, including biopsies using specific immunomarkers with a good correspondence with molecular data. Recent data has shown that TERT promoter mutation was a late event in the malignant transformation of β-HCA, β-IHCA. Furthermore, in addition to β-catenin exon 3 mutations, other mutations do exist (exon 7 and 8) with a lower risk of malignant transformation. With these new scientific informations, we have the tools to better know the natural history of the different subtypes, in terms of growth, disappearance, bleeding, malignant transformation and to investigate HCA in diseased livers (vascular diseases, alcoholic cirrhosis). A better knowledge of HCA should lead to a more rational management of HCA. This can be done only if the different subspecialties, including hepatologists, liver pathologists, radiologists and surgeons work altogether in close relationship with molecular biologists. It is a long way to go., (Copyright © 2014. Published by Elsevier Masson SAS.)

Hepatocellular adenomas (HCAs) are heterogeneous group of benign tumors; three pathomolecular subtypes have been identified so far: hepatocyte nuclear factor 1 α-inactivated HCA (H-HCA) (35-40%), inflammatory HCA (I-HCA) (>50%), β-catenin activated HCA (10%). Ten percent of I-HCA are also β-catenin activated. We report a rare case of three histologically confirmed steatotic HCAs of three different phenotypes: I-HCA, β-catenin activated I-HCA, and H-HCA in a 36-year-old woman. This observation outlines that in the same patient, HCA may be of different subtypes. The predisposition to develop different HCA hypothetically caused by a "benign tumorigenic field effect" may result, even rarely, in different genotypes/phenotypes such as H-HCA and I-HCA. Moreover, we illustrate the very high specificity of MR for subtyping HCA., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

In 1985, adenomatosis, a term coined to mean ten or more nodules, was considered as a specific entity different from hepatocellular adenoma (HCA) whether single or multiple. In the 2000s the term has lost its individuality. The great contribution of the classification was to clearly demonstrate that in all hepatocellular subtypes and in particular etiologies such as glycogenosis and male hormone administration, HCA could be solitary, multiple (<10) or multiple (>10: adenomatosis). Management of hepatocellular adenomatosis may not be different from solitary or multiple HCA. To keep its specificity in terms of management and prognosis compared to solitary or multiple HCA, it is necessary to indicate the number of nodules including the combination of three parameters: size, location and subtypes. When the classical armentarium to treat nodules is not possible or too risky, embolization or liver transplantation remains the only therapeutic options., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)