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Primary liver cancer arises either from hepatocytic or biliary lineage cells, giving rise to hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICCA). Combined hepatocellular- cholangiocarcinomas (cHCC-CCA) exhibit equivocal or mixed features of both, causing diagnostic uncertainty and difficulty in determining proper management. Here, we perform a comprehensive deep learning-based phenotyping of multiple cohorts of patients. We show that deep learning can reproduce the diagnosis of HCC vs. CCA with a high performance. We analyze a series of 405 cHCC-CCA patients and demonstrate that the model can reclassify the tumors as HCC or ICCA, and that the predictions are consistent with clinical outcomes, genetic alterations and in situ spatial gene expression profiling. This type of approach could improve treatment decisions and ultimately clinical outcome for patients with rare and biphenotypic cancers such as cHCC-CCA., (© 2023. The Author(s).)

Background: Hepatocellular 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., Methods: We 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., Results: Subtyping of the five HCAs with atypical features revealed two β-catenin mutated HCA (b-HCA), two β-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)., Conclusion: In 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., (© 2022 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Background & Aims: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer (PLC) associated with a poor prognosis. Given the challenges in its identification and its clinical implications, biomarkers are critically needed. We aimed to investigate the diagnostic and prognostic value of the immunohistochemical expression of Nestin, a progenitor cell marker, in a large multicentric series of PLCs., Methods: We collected 461 cHCC-CCA samples from 32 different clinical centers. Control cases included 368 hepatocellular carcinomas (HCCs) and 221 intrahepatic cholangiocarcinomas (iCCAs). Nestin immunohistochemistry was performed on whole tumor sections. Diagnostic and prognostic performances of Nestin expression were determined using receiver-operating characteristic curves and Cox regression modeling., Results: Nestin was able to distinguish cHCC-CCA from HCC with AUCs of 0.85 and 0.86 on surgical and biopsy samples, respectively. Performance was lower for the distinction of cHCC-CCA from iCCA (AUCs of 0.59 and 0.60). Nestin, however, showed a high prognostic value, allowing identification of the subset of cHCC-CCA ("Nestin High", >30% neoplastic cells with positive staining) associated with the worst clinical outcome (shorter disease-free and overall survival) after surgical resection and liver transplantation, as well as when assessment was performed on biopsies., Conclusion: We show in different clinical settings that Nestin has diagnostic value and that it is a useful biomarker to identify the subset of cHCC-CCA associated with the worst clinical outcome. Nestin immunohistochemistry may be used to refine risk stratification and improve treatment allocation for patients with this highly aggressive malignancy., Lay Summary: There are different types of primary liver cancers (i.e. cancers that originate in the liver). Accurately identifying a specific subtype of primary liver cancer (and determining its associated prognosis) is important as it can have a major impact on treatment allocation. Herein, we show that a protein called Nestin could be used to refine risk stratification and improve treatment allocation for patients with combined hepatocellular carcinoma, a rare but highly aggressive subtype of primary liver cancer., Competing Interests: Conflict of interest JC consults for Crosscope, KB is Crosscope Chief Technology Officer, JS is Crosscope Chief Executive Officer. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

MiR-22 is mostly considered as a hepatic tumor-suppressor microRNA based on in vitro analyses. Yet, whether miR-22 exerts a tumor-suppressive function in the liver has not been investigated in vivo. Herein, in silico analyses of miR-22 expression were performed in hepatocellular carcinomas from human patient cohorts and different mouse models. Diethylnitrosamine-induced hepatocellular carcinomas were then investigated in lean and diet-induced obese miR-22-deficient mice. The proteome of liver tissues from miR-22-deficient mice prior to hepatocellular carcinoma development was further analyzed to uncover miR-22 regulated factors that impact hepatocarcinogenesis with miR-22 deficiency. MiR-22 downregulation was consistently observed in hepatocellular carcinomas from all human cohorts and mouse models investigated. The time of appearance of the first tumors was decreased and the number of tumoral foci induced by diethylnitrosamine was significantly increased by miR-22-deficiency in vivo, two features which were further drastically exacerbated with diet-induced obesity. At the molecular level, we provide evidence that the loss of miR-22 significantly affects the energetic metabolism and mitochondrial functions of hepatocytes, and the expression of tumor-promoting factors such as thrombospondin-1. Our study demonstrates that miR-22 acts as a hepatic tumor suppressor in vivo by restraining pro-carcinogenic metabolic deregulations through pleiotropic mechanisms and the overexpression of relevant oncogenes.

In the last two decades there has been significant progress in research on and diagnosis of hepatocellular adenoma (HCA), resulting in the establishment of a molecular and immunohistological HCA classification. This review aims to fine-tune the current expertise in order to enhance the histopathological diagnostic possibilities, by refining issues that are already known, addressing diagnostic difficulties, and identifying still unknown aspects of HCA. We discuss novel methods to identify HCA subtypes, in particular the sonic hedgehog HCAs and the interpretation of glutamine synthetase patterns for the recognition of β-catenin-mutated HCAs. The major complications of HCAs, i.e. bleeding and malignant transformation, are considered, including the dilemmas of atypical and borderline lesions. HCAs in different clinical and geographical settings, e.g. pregnancy, cirrhosis and non-western countries, are also discussed. The natural history of the different HCA subtypes in relation to age, sex and risk factors is a feature that is still insufficiently investigated. This is also true for the risks of clinical bleeding and malignant transformation in association with HCA subtypes. As HCA is a relatively rare tumour, a multicentre and multidisciplinary approach across geographical boundaries will be the appropriate method to establish prospective programmes with which to identify, classify and manage HCAs, focusing on several aspects, e.g. aetiology, underlying liver disease, complications, regression, and growth. Updating what we know and identifying and addressing what we do not know matters for optimal patient management., (© 2021 John Wiley & Sons Ltd.)

Objective: Hepatocellular carcinoma (HCC) development occurs with non-alcoholic fatty liver disease (NAFLD) in the absence of cirrhosis and with an increasing incidence due to the obesity pandemic. Mutations of tumour suppressor (TS) genes and oncogenes (ONC) have been widely characterised in HCC. However, mounting evidence indicates that non-genomic alterations of TS/ONC occur early with NAFLD, thereby potentially promoting hepatocarcinogenesis in an inflammatory/fibrotic context. The aim of this study was to identify and characterise these alterations., Design: The proteome of steatotic liver tissues from mice spontaneously developing HCC was analysed. Alterations of TSs/ONCs were further investigated in various mouse models of NAFLD/HCC and in human samples. The inflammatory, fibrogenic and oncogenic functions of S100A11 were assessed through in vivo, in vitro and ex-vivo analyses., Results: A whole set of TSs/ONCs, respectively, downregulated or upregulated was uncovered in mice and human with NAFLD. Alterations of these TSs/ONCs were preserved or even exacerbated in HCC. Among them, overexpression of S100A11 was associated with high-grade HCC and poor prognosis. S100A11 downregulation in vivo significantly restrains the development of inflammation and fibrosis in mice fed a choline/methionine-deficient diet. Finally, in vitro and ex-vivo analyses revealed that S100A11 is a marker of hepatocyte de-differentiation, secreted by cancer cells, and promoting cell proliferation and migration., Conclusion: Cellular stress associated with NAFLD triggers non-genomic alterations of a whole network of TSs/ONCs fostering hepatocarcinogenesis. Among those, overexpression of the oncogenic factor S100A11 promotes inflammation/fibrosis in vivo and is significantly associated with high-grade HCC with poor prognosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver carcinoma showing variable degrees of differentiation toward hepatocellular and cholangiocellular carcinoma. Its great heterogeneity in term of morphology, immunophenotype, molecular, radiological and clinical features represents a challenge still to overcome. The multidisciplinary 2018 International Consensus on the nomenclature of cHCC-CCA allowed to define key issues of this entity. Here we review the historical controversies of cHCC-CCA, resume the key elements of the 2018 consensus, now incorporated in the 2019 WHO classification, and propose a short survival guide to help surgical pathologists facing cHCC-CCA in their routine workup., (Copyright © 2019. Published by Elsevier Inc.)

Primary liver carcinomas with both hepatocytic and cholangiocytic differentiation have been referred to as "combined (or mixed) hepatocellular-cholangiocarcinoma." These tumors, although described over 100 years ago, have attracted greater attention recently because of interest in possible stem cell origin and perhaps because of greater frequency and clinical recognition. Currently, because of a lack of common terminology in the literature, effective treatment and predictable outcome data have been challenging to accrue. This article represents a consensus document from an international community of pathologists, radiologists, and clinicians who have studied and reported on these tumors and recommends a working terminology for diagnostic and research approaches for further study and evaluation., Conclusion: It is recommended that diagnosis is based on routine histopathology with hematoxylin and eosin (H&E); immunostains are supportive, but not essential for diagnosis. (Hepatology 2018;68:113-126)., (© 2018 by the American Association for the Study of Liver Diseases.)

Hepatocellular nodules have been recognized in vascular liver diseases for a long time and mostly described and studied in the imaging literature. Some confusions in their identification and overlap in their definitions exist, especially in this specific clinical context. Pathology descriptions report the development of nodular regenerative hyperplasia, large regenerative nodule, and focal nodular hyperplasia, as adaptive responses of the liver parenchyma to the modified blood flow. True neoplastic hepatocellular nodules such as hepatocellular adenoma and hepatocellular carcinoma can also appear, mainly in Budd-Chiari syndrome, and have to be correctly diagnosed. This is more difficult for the radiologist in these diseased livers, leading more frequently to perform liver biopsies. We describe the histology of each type of well-differentiated hepatocellular nodules and provide some clues for their differential diagnosis. A review of the literature gives an historical perspective of the problem and enlightens the frequency and the subtypes of hepatocellular nodules found in the most common vascular liver diseases.

Benign focal liver lesions are a heterogeneous group of tumors of different cellular origin. They might develop from mesenchymal cells, hepatocytes or cholangiocytes. They are more often detected due to the increasing number of imaging investigations and the excellent performance of the new ultrasound machines. The imaging findings have to be interpreted while bearing the patient's clinical context in mind. The aim of this review is to discuss the three most frequent benign focal hepatic lesions : hemangioma, focal nodular hyperplasia and hepatocellular adenoma., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

In 1984, a 24-year-old woman underwent a right hepatectomy after a 17-cm nodule, diagnosed as a hepatocellular adenoma with some atypia. The resection was incomplete. Follow-up was interrupted. In 1996, a computed tomographic scan revealed a large multifocal hepatocellular carcinoma confirmed on biopsies. The patient died the same year. We reviewed these nodules using immunohistochemistry and gene sequencing. C-reactive protein was overexpressed in the tumor resected in 1984. Glutamine synthetase was heterogeneous in the tumor, with a few tumor nuclei expressing β-catenin. Glypican and heat shock protein 70 were negative. In this β-catenin-activated inflammatory hepatocellular adenoma, S45 β-catenin-activating mutation was detected on fixed tissue, embedded in paraffin without TERT promoter mutation. An identical CTNNB1 mutation was identified in the 1996 liver tumor together with a TERT promoter mutation showing that this hepatocellular carcinoma results from the malignant transformation of the initial β-catenin inflammatory adenoma., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are two distinct forms of primary liver carcinoma recognizable at the microscope by their architectural and cytological characteristics, as well as specific immunohistochemical profiles. This straightforward concept however, is increasing imperiled by the recognition of primary liver carcinomas that do not subscribe to a dichotomous paradigm of differentiation, and instead demonstrate biphenotypic differentiation, stem/progenitor cell like features or other variant patterns of differentiation. Appropriate nomenclature, diagnostic criteria, prognostic significance and optimal therapeutic approach for these variant tumors are not completely defined, not leasyt because they are not always identified correctly and when they are, lack of uniform terminology hinders collection of adequate number of cases to facilitate their study. Similar to hepatocellular carcinoma and in contrast with intrahepatic cholangiocarcinoma, primary liver tumors showing biphenotypic differentiation, stem/progenitor cell features or variant differentiation occur mainly, but not always, on a background of chronic liver disease. They are particularly frequent after neo-adjuvant therapy. Whether they represent trans-differentiation of malignant cells, or whether they derive from a stem/progenitor cell that gives rise to divergent differentiation remains yet another area of uncertainty., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background & Aims: A broad range of hepatocellular nodules has been reported in hepatic vascular disorders. It is not clear whether hepatocellular adenoma (HCA) in this context share the same characteristics as conventional HCA. The aim of this study was to carry out a retrospective multicenter survey of hepatocellular nodules associated with hepatic vascular disorders., Methods: Forty-five cases were reviewed, including 32 Budd-Chiari syndrome (BCS). Benign nodules were subtyped using the HCA immunohistochemical panel., Results: Nodules with a HCA morphology were observed in 11 cases. Six originated in BCS: two were liver fatty acid binding protein (LFABP) negative (one with malignant transformation); two expressed glutamine synthetase (GS) and nuclear b-catenin, two expressed C reactive protein (CRP). Among three cases with portal vein agenesis, one nodule was LFABP negative, two expressed GS and nuclear b-catenin, both with malignant transformation. In a Fallot tetralogy case, there were multiple LFABP negative nodules with borderline features and in a hepatoportal sclerosis case, the nodule looked like an inflammatory HCA. Two additional cases had nodules expressing CRP, without typical characteristics of inflammatory HCA., Conclusion: HCA of different immunohistochemical phenotype can develop in hepatic vascular disorders; they may have a different behavior compared to conventional HCA and be more at risk of malignant transformation., (Copyright © 2015. Published by Elsevier B.V.)

We describe the case of a 54 years old woman, with hepatitis B, in whom the diagnosis of a 6 cm hepatocellular carcinoma (HCC) in the left liver was made in 2001. Alpha-foeto-protein (AFP) was 63 ng/mL (NI < 10 ng/mL). After work-up including liver and tumor biopsy confirming HCC and only fibrosis in the nontumoral liver, left hepatectomy was performed. Final pathology showed a well differentiated HCC with tumoral portal vein thrombosis. Unfortunately, lung and mediastinal adenopathies were detected by CT scan 17 months later. Mediastinal nodes were punctured by endosonographic ultrasound, confirming HCC. The patient started treatment with Lanreotide 30 mg twice a month (Somatuline PR, Ipsen). Three months later, CT showed decrease in size of the mediastinal nodes and complete disappearance of the lung nodes. This objective response lasted for 42 months. The treatment was without any significant side effect. Retrospectively, immunohistochemistry was performed to detect somatostatine receptors (sstr) 2. Both the primary tumor and the node showed intense membranous and cytoplasmic staining for sstr2. In 2006, AFP rose and CT showed the appearance of a new mediastinal node. At that time, octreoscan was performed and showed uptake in the new node, although insufficient for metabolic radiotherapy. This case suggests that, although a number of randomized controlled trials did not show a benefit of somatostatin analogues in the treatment of advanced HCC, a subset of patients could benefit from treatment provided their tumor expresses sstr2, on which the existing drugs are efficient.

The authors present an interesting case of a 60-year-old man who underwent right hepatectomy for a diagnosis of hepatocellular carcinoma (HCC) on a background of noncirrhotic chronic hepatitis C. Pathologic examination confirmed the presence of HCC near the porta hepatis, which invaded the right portal vein branch. In addition, a well-demarcated 13.5 × 7.8 × 4.0 cm yellow and firm area upstream of the HCC was noted. This yellow area corresponded to a tumoral ductular proliferation, which cytologically was extremely bland, but invaded portal tracts and the adjacent liver parenchyma. This tumoral proliferation mimicked ductular reaction, except that it had more anastomosing structures and was associated with abundant hyalinized fibrotic stroma. Cytologically, the tumor cells had round to oval nuclei with fine chromatin, indistinct nucleoli, and scant cytoplasm. They exhibited immunohistochemical features of hepatic progenitor cells, i.e., expressing CK7, CK19, and N-CAM; and their malignancy was supported by the p53 and Ki67 immunoreactivity. The authors concluded that the patient had cholangiolocellular carcinoma with an aggressive hepatocellular carcinoma component. Cholangiolocellular carcinoma has been reported to be associated with chronic hepatitis C viral infection and to derive from hepatic progenitor cells, which explains why hepatocellular carcinoma and/or cholangiocarcinoma component may be present., (© Thieme Medical Publishers.)

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death, and its incidence is increasing worldwide. Due to the known risk factors (mainly hepatitis B and C viruses), we believe there is a rationale for a chemopreventive approach to treat HCC. Here, based on described in vitro data, we evaluated the preventive effects of lanreotide, a somatostatin analog, on the induction of early carcinogenic events. We monitored preneoplastic foci induced by a two-stage initiation/promotion model of hepatocarcinogenesis in male Wistar rats, using diethylnitrosamine and 2-acetylaminofluorene. Lanreotide was given starting the day after the first diethylnitrosamine injection. By quantitative morphometry, we showed that lanreotide significantly decreases the size of induced preneoplastic foci. Analysis of proliferation and apoptosis assessed by immunohistochemistry, showed decreased proliferation and increased cell death in rats treated with lanreotide. As these events were associated with a significant decreased expression of the cell cycle regulator cyclin D1 and an increased expression of the cyclin-dependent kinase inhibitor p27(kip1) compared to the non-treated group, it is tempting to speculate that these factors are involved in the favorable effect of lanreotide. In conclusion, lanreotide significantly decreases early carcinogenic transformation in a two-step rat model. As lanreotide has a low toxicity profile, we believe it would be interesting to evaluate its effect in chemoprevention of HCC.

Background/aims: Surgical resection is a standard treatment of hepatocellular carcinoma, but liver cirrhosis is known to be associated to a high tumor recurrence rate., Methodology: A retrospective study of 55 consecutive patients (37 males, 18 females) suffering from hepatocellular carcinoma having undergone surgical resection. Hepatocellular carcinoma developed in 29 patients with normal liver (group A) and in 26 patients with chronic liver disease (CLD) (group B). Patients were significantly older and at high-risk in Group B., Results: Radical liver resection was achieved in 98% (100% in group A; 96% in group B). Overall 2-month mortality was 2% (0% in group A; 4% in group B). The 5-year overall and disease-free survival was respectively 55% and 35%. However, the 5-year overall and disease-free survival was significantly better in Group A (71% and 59%) compared to Group B (37% and 6%) (p < 0.001), respectively. Multivariate statistical analysis demonstrated that age > 50 years, poor tumor differentiation and presence of satellite nodules were significant independent adverse predictive factors of overall and disease-free survival., Conclusions: Resection of HCC is safe and effective with satisfactory overall and disease-free survival rates, except when underlying chronic liver disease and poor tumor differentiation are present.