To compare the added values of hepatobiliary phase (HBP) MRI and contrast-enhanced ultrasound (CEUS) in addition to inconclusive extracellular gadolinium-based contrast-enhanced MRI (CE-MRI) to characterize benign hepatocellular tumors (BHT).

Pathology InternationalVolume 65, Issue 6 p. 338-338 Letter to the Editor Bile duct adenoma should not be designated as a reactive process Anaïs Pujals, Anaïs Pujals Assistance Publique-Hôpitaux de Paris, Department of Pathology, Groupe Hospitalier Henri Mondor, Créteil, France Faculté de Médecine de Créteil, Université Paris-Est Créteil, Inserm U955, Créteil, France Equipe 9, Institut Mondor de Recherche Biomédicale, Créteil, FranceSearch for more papers by this authorElie Serge Zafrani, Elie Serge Zafrani Assistance Publique-Hôpitaux de Paris, Department of Pathology, Groupe Hospitalier Henri Mondor, Créteil, France Faculté de Médecine de Créteil, Université Paris-Est Créteil, Inserm U955, Créteil, FranceSearch for more papers by this authorJulien Calderaro, Julien Calderaro Assistance Publique-Hôpitaux de Paris, Department of Pathology, Groupe Hospitalier Henri Mondor, Créteil, France Faculté de Médecine de Créteil, Université Paris-Est Créteil, Inserm U955, Créteil, France Equipe 18, Institut Mondor de Recherche Biomédicale, Créteil, FranceSearch for more papers by this author Anaïs Pujals, Anaïs Pujals Assistance Publique-Hôpitaux de Paris, Department of Pathology, Groupe Hospitalier Henri Mondor, Créteil, France Faculté de Médecine de Créteil, Université Paris-Est Créteil, Inserm U955, Créteil, France Equipe 9, Institut Mondor de Recherche Biomédicale, Créteil, FranceSearch for more papers by this authorElie Serge Zafrani, Elie Serge Zafrani Assistance Publique-Hôpitaux de Paris, Department of Pathology, Groupe Hospitalier Henri Mondor, Créteil, France Faculté de Médecine de Créteil, Université Paris-Est Créteil, Inserm U955, Créteil, FranceSearch for more papers by this authorJulien Calderaro, Julien Calderaro Assistance Publique-Hôpitaux de Paris, Department of Pathology, Groupe Hospitalier Henri Mondor, Créteil, France Faculté de Médecine de Créteil, Université Paris-Est Créteil, Inserm U955, Créteil, France Equipe 18, Institut Mondor de Recherche Biomédicale, Créteil, FranceSearch for more papers by this author First published: 02 March 2015 https://doi.org/10.1111/pin.12273Citations: 3Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1Aishima S, Tanaka Y, Kubo Y, Shirabe K, Maehara Y, Oda Y. Bile duct adenoma and von Meyenburg complex-like duct arising in hepatitis and cirrhosis: Pathogenesis and histological characteristics. Pathol Int 2014; 64: 551– 559. 2Pujals A, Amaddeo G, Castain C et al. BRAF V600E mutations in bile duct adenomas. Hepatology 2015; 61: 403– 405. 3Allaire GS, Rabin L, Ishak KG, Sesterhenn IA. Bile duct adenoma. A study of 152 cases. Am J Surg Pathol 1988; 12: 708– 715. 4Bhathal PS, Hughes NR, Goodman ZD. The so-called bile duct adenoma is a peribiliary gland hamartoma. The so-called bile duct adenoma is a peribiliary gland hamartoma. Am J Surg Pathol 1996; 20: 858– 864. 5Hasebe T, Sakamoto M, Mukai K et al. Cholangiocarcinoma arising in bile duct adenoma with focal area of bile duct hamartoma. Virchows Arch 1995; 426: 209– 213. 6Pinho AC, Melo RB, Oliveira M et al. Adenoma-carcinoma sequence in intrahepatic cholangiocarcinoma. Int J Surg Case Rep 2012; 3: 131– 133. Citing Literature Volume65, Issue6June 2015Pages 338-338 ReferencesRelatedInformation

Hepatocellular adenoma is considered to occur exclusively in non-fibrotic livers. It is a heterogeneous entity and a molecular classification is now widely accepted. The most frequent hepatocellular adenoma subtype, namely inflammatory adenoma, harbor somatic activating mutations of genes involved in the interleukin-6 pathway that lead to high C-reactive protein and serum amyloid A expression. The aim of our study was to investigate a series of benign hepatocellular neoplasms developed on cirrhotic livers and characterized by an unequivocal histological diagnosis. We performed a clinical, pathological, and molecular study of 10 benign hepatocellular neoplasms developed in three patients with cirrhosis. Markers allowing hepatocellular adenoma classification were assessed by quantitative real-time PCR and immunohistochemistry. Samples were sequenced for CTNNB1, HNF1A, IL6ST, GNAS, STAT3, and TERT (promoter) mutations. A control series of 32 classical macronodules developed in cirrhosis related to various etiologies was screened by immunohistochemistry and gene sequencing. The three patients had cirrhosis related to metabolic syndrome and/or alcohol intake; two had a single tumor, while the third developed more than 30 lesions. Microscopic examination showed well-differentiated neoplasms sharing features with inflammatory adenoma including inflammatory infiltrates, sinusoidal dilatation, and dystrophic vessels. Sequencing revealed classical hotspot somatic mutations (IL6ST, n=8; STAT3, n=1; and GNAS, n=1) known to be responsible for IL-6/JAK/STAT pathway activation. Two classical high-grade macronodules demonstrated high serum amyloid A and/or C-reactive protein expression, without gene mutations. Altogether, our findings support the existence of rare inflammatory adenoma developed in cirrhosis.

Aims: Bile duct adenomas (BDA) and bile duct hamartomas (BDH) are benign bile duct lesions considered neoplastic or secondary to ductal plate malformation, respectively. We have reported previously a high prevalence of BRAF V600E mutations detected by allele-specific polymerase chain reaction assay in BDA, and suggested that BDA may be precursors to a subset of intrahepatic cholangiocarcinomas harbouring V600E mutations. The aim of the present study was to assess the existence of BRAF V600E mutations, using immunohistochemical methods, in additional BDA as well as in BDH.Methods and results: Fifteen BDA and 35 BDH were retrieved from the archives of the pathology departments of two French university hospitals. All cases were reviewed by two pathologists specialized in liver diseases. BRAF V600E mutational status was investigated by immunohistochemistry. Mutated BRAF mutant protein was detected in 53% of the BDA and in none of the cases of BDH.Conclusion: Our findings suggest that BDA and BDH are different processes, and that BDA represent true benign neoplasms. They also support the hypothesis that mutated BDA might precede the development of the subset of intrahepatic cholangiocarcinomas harbouring BRAF V600E mutations.

Le cavernome portal fait suite à une occlusion chronique de la veine porte. Les conséquences à long terme sont peu connues. L'objectif de cette étude était de rapporter les étiologies des cavernomes portaux et leur évolution naturelle en excluant ceux secondaires à une hépatopathie.Une étude rétrospective monocentrique a été menée à partir de la base de données du service de radiologie du CHU de Clermont-Ferrand de 2000 à 2011. Les patients pour lesquels l'imagerie a mis en évidence un cavernome portal ont été recherchés et ceux qui avaient une hépatopathie quelle qu'en soit la cause ou un syndrome de Budd-Chiari ont été exclus.Trente-deux observations (18 femmes et 14 hommes) ont été ainsi retenues. L'âge moyen au diagnostic était de 54,2 ans avec un suivi moyen de 5,4 ans. La découverte d'un cavernome était fortuite dans 8 cas. Une étiologie était retrouvée dans 24 cas : il s'agissait d'une pathologie hématologique dans 15 cas (10 syndromes myéloprolifératifs, 2 syndrome des antiphospholipides, 1 thalassémie majeure, 1 hyperhomocystéinémie, 1 mutation hétérozygote du facteur II), d'une pathologie générale dans 2 cas (maladie cœliaque et néoplasie pancréatique) et d'une inflammation locale dans 7 cas. Un aspect dysmorphique du foie était noté sur l'imagerie dans 11 cas sur 32. La biopsie hépatique effectuée dans 4 cas était normale. Seize patients ont développé des varices œsophagiennes, 4 patients ont eu une ascite, 3 patients avaient une compression biliaire asymptomatique par le cavernome portal et le patient dont le suivi était le plus long (15 ans) a fait une encéphalopathie.Le pronostic des cavernomes portaux, en dehors de celui de la pathologie sous-jacente éventuelle, est essentiellement lié à la survenue de varices œsophagiennes dont la recherche et le traitement sont essentiels dans le suivi de ces malades.Portal cavernoma follows a chronic occlusion of the portal vein. The long-term consequences of portal cavernoma are not well known. The objective of this study was to report the aetiology of the portal cavernoma and its natural course after excluding liver diseases causes.A single centre retrospective study based on the data collected from the radiology department of the Clermont-Ferrand hospital was conducted from 2000 to 2011. All the patients for whom an imagery found a portal cavernoma have been looked for excluding the patients having a liver disease whatever the aetiology and the Budd-Chiari syndrome.Thirty-two cases (18 women and 14 men) were selected. The mean age at diagnosis was 54.2 years and the mean follow-up period was 5.4 years. The discovery of a portal cavernoma was incidental for 8 cases. An aetiology was found for 24 cases: it was an haematological aetiology in 15 cases (10 myeloproliferative syndromes, 2 antiphospholid syndromes, 1 thalassemia major, 1 hyperhomocysteinemia, 1 prothrombin gene mutation), a general aetiology in 2 cases (1 coeliac disease, 1 pancreatic neoplasia), and a local inflammation in 7 cases. A dysmorphic aspect of the liver was noticed on medical imaging for 11 out of the 32 cases. A liver biopsy was performed in 4 patients and was normal for all of them. Sixteen patients developed oesophageal varices, 4 patients developed ascites, 3 developed asymptomatic biliary compression by the portal cavernoma, and the patient who had been followed for the longest time (15 years) developed an encephalopathy.In addition to its underlying etiology, the prognosis of portal is mainly related to the occurrence of oesophageal varices that may develop during the follow-up of the patients.

958 EXTRAHEPATIC MALIGNANCIES AFTER LIVER TRANSPLANTATION FOR PRIMARY SCLEROSING CHOLANGITIS – A LONG-TERM FOLLOW-UP OBSERVATIONAL STUDY OF A LARGE, MULTICENTER COHORT T. Horn, N. Pannicke, A. Dechene, D. Gotthardt, G. Kirchner, K. Herzer, H. Lenzen, H. Barg-Hock, M. Sterneck, U. Spengler, M.P. Manns, C.P. Strassburg, C. Schramm, T.J. Weismuller, German PSC Study Group. Gastroenterology, Hepatology und Endokrinology, Hannover Medical School, Hannover, 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Department of Medicine, University Hospital of Heidelberg, Heidelberg, Department of Internal Medicine I, University Hospital of Regensburg, Regensburg, General, Visceral and Transplantation Surgery, University Hospital of Essen, Essen, General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Department of Internal Medicine 1, University of Bonn, Bonn, Germany E-mail: tobias.weismueller@gmx.de

POSTERSpregnancy.LS was measured by Fibroscan either using the M or XL probe.Besides basic gynecological data, BMI and transaminases were obtained.Results: LS could be measured in all 103 women using the M probe except one case where the XL probe was required for reliable interquartile range.17 women (16.5%) had a pathological LS higher than 8 kPa, four of them higher than 12.5 kPa which is regarded as cut-off value for F4 fibrosis.All women with increased LS were in the third trimester starting with week 31 while all women within the second trimester had normal LS <6 kPa.LS correlated slightly with duration of pregnancy (P < 0.05), but not with gain of weight or BMI.Primary biliary or hepatic causes of increased LS were excluded by blood tests and ultrasound.No abnormal liver function tests were observed in this study population except one HELLP syndrome with elevated LS.Increased LS completely normalized after delivery in the three patients studied.Further studies on narcotized German landrace pigs suggest that not an elevated intraabdominal pressure alone but an impaired hepatic venous outflow seems to cause the increased LS during pregnancy.Conclusion: LS is significantly increased in >20% of pregnant women in the third trimester probably due to hemodynamic reasons.Increased LS generally normalizes after delivery.Our data suggest that LS could be an important non-invasive predictor of hepatic complications during pregnancy.

Connaître les éléments diagnostiques caractéristiques de l’hyperplasie nodulaire focale en imagerie. Connaître la stratégie diagnostique de l’hyperplasie nodulaire focale. Connaître les éléments sémiologiques fondamentaux anatomopathologiques. Connaître les atypies en imagerie et en anatomopathologie de l’HNF. L’IRM est l’examen fondamental permettant la caractérisation formelle de l’hyperplasie nodulaire focale dans sa forme typique. L’échographie de contraste, par l’identification d’une cinétique de rehaussement central, centrifuge peut permettre une distinction entre hyperplasie nodulaire focale et adénome. Les éléments anatomopathologiques caractéristiques de l’hyperplasie nodulaire focale sont la présence de bandes fibreuses inflammatoires contenant des structures vasculaires dystrophiques, associée à une prolifération cholangiolaire délimitant plus ou moins complètement des nodules d’hépatocytes normaux. Le diagnostic de l’hyperplasie nodulaire focale typique repose sur les données de l’IRM, permettant d’identifier une lésion homogène, en faible hypersignal T2, avec une zone stellaire centrale en hypersignal T2, une cinétique de rehaussement précoce, homogène, et le rehaussement tardif d’une zone stellaire centrale et l’absence de capsule péri-lésionnelle. La présence en échographie de contraste d’un rehaussement précoce intense, généralement alimenté par une artère centrale et progressant de façon centrifuge est un élément diagnostique important. L’aspect macroscopique est évocateur lorsqu’il montre un nodule hépatocytaire bien délimité du reste du parnchyme mais non encapsulé, fait lui-même de nodules confluents et centré par un élément fibreux étoile. Le diagnostic histopathologique formel repose sur l’association d’éléments caractéristiques que sont les bandes fibreuses contenant des vaisseaux à parois dystrophiques et délimitant plus ou moins complètement des nodules d’hépatocytes réguliers, la présence d’une inflammation mononucléée et d’une prolifération. Certaines atypies histopathologiques telles qu’une stéatose marquée, la rareté des bandes fibreuses ou de l’infiltrat inflammatoire, ou encore des atypies cyto-nucléaires peuvent poser un problème de diagnostic différentiel avec d’autres lésions hépatocytaires, en particulier les adénomes voire les carcinomes hépatocellulaires.

A 26-year-old woman was admitted to our institution for cyclic neutropenia and hepatitis B viral infection. Clinical examination revealed hair and cutaneous hypopigmentation and bilateral nystagmus. Leukocyte and neutrophil counts were 1700 and 500/ L, respectively. Platelet count was 185,000/ L. Liver tests showed minimal elevation of alanine aminotransferase and slightly prolonged prothrombin time. Serum aspartate aminotransferase, alkaline phosphatase, -glutamyl transpeptidase, bilirubin, immunoglobulins, and albumin were within normal ranges. The patient was positive for serum hepatitis B surface antigen, and there was no evidence for hepatitis C, hepatitis D, herpes, or cytomegalovirus infection. Percutaneous liver biopsy showed moderately active chronic hepatitis with bridging fibrosis and numerous ground-glass hepatocytes. One striking finding was the presence of small aggregates of macrophages, mainly portal, containing in their cytoplasm a granular material (Fig. A) that was stained by periodic acid-Schiff with (Fig. B) and without diastase pretreatment and by Fontana’s technique (Fig. C). These granules were strongly autofluorescent under ultraviolet light, were not refringent under polarized light, and corresponded to ceroid lipofuscin (Fig. D). Such lipofuscin-type granules resemble those observed in Dubin-Johnson syndrome but, in this latter condition, they are localized in the cytoplasm of the hepatocytes, mainly around terminal hepatic veins, and not in the cytoplasm of the macrophages. The fluorescent hepatocellular inclusions noted in porphyria cutanea tarda, and corresponding to uroporphyrin accumulation, are different because they are needleshaped and refringent under polarized light. Accumulation of ceroid lipofuscin within macrophages in a patient with hair and cutaneous hypopigmentation, nystagmus, and cyclic neutropenia is consistent with the disease described in 1959 by Hermansky and Abbreviation: HPS, Hermansky-Pudlak syndrome. Address reprint requests to: Elie Serge Zafrani, Service d’Anatomie et de Cytologie Pathologiques, Département de Pathologie, Groupe Hospitalier Albert ChenevierHenri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94 010 Créteil cedex, France. E-mail: elie-serge.zafrani@hmn.aphp.fr; fax: 33 1 49 81 27 33. Copyright © 2009 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.23080 Potential conflict of interest: Nothing to report.

Background: Liver is exposed to bacterial components related to intestinal permeability.NOD1, a bacterial receptor, appears to regulate the crosstalk between innate and adaptive immunity and the functions of polymorphonuclear neutrophils (PMN) in intestinal diseases.No data are available concerning the role of NOD1 in PMN related liver diseases.Aim: To explore the regulatory role of NOD1 in the PMN-induced liver injury.Methods: Livers taken from Nod1 +/ + and Nod1 -/ -mice challenged with CCl 4 were examined; main functions of PMN isolated from Nod1 +/ + and Nod1 -/ -mice were studied.Migration tests were performed in Boyden chambers using chemoattractants.Phagocytosis capacity was tested using the Phagotest ® ; we studied the main inflammatory pathways in PMN and CD11b expression on PMN surface by FACS analysis.Results: We observed that NOD1 was expressed in hepatocytes and PMN at mRNA and protein levels.In PMN-mediated injury models in mice, we showed that: After CCl 4 exposure, livers of Nod1 -/ -mice disclosed more than 50% lower PMN infiltration within necrotic areas compared to Nod1 +/ + .A lower PMN infiltration was also observed in Nod1 -/ -mice using a thioglycolate-mediated peritonitis model; The lack of difference in the liver expression of mRNA chemokines between Nod1 -/ -and control mice.There were no constitutional defects in blood formula or in granuloblasts isolated from bone marrow in Nod1 -/ -mice.Taken together these results suggested an impaired PMN recruitment.Then, in ex-vivo studies, we focused on PMN functions: PMN isolated from Nod1 -/ - mice displayed a 90% decrease in migration capacity compared to the Nod1 +/ + PMN; FK565, a potent ligand of NOD1, increased significantly human PMN migration; Phagocytosis capacity of Nod1 -/ -neutrophils was decreased by more than 50% compared to Nod1 +/ + .In terms of mechanistic insights: upon FK565 and fMLP stimulation, p38, JNK and NFkB activations were altered in Nod1 -/ -PMN; expression of CD11b on the Nod1 -/ -PMN surface was significantly decreased compared to Nod1 +/ + .Conclusions: NOD1 is involved in the ability of PMN to migrate in the liver.In terms of mechanisms, the defect of NOD1 leads to altered functional activities of PMN.NOD1 may be an interesting target to regulate PMN-related liver injury.

Oval cells participate in liver regeneration when hepatocyte replication is impaired. These precursor cells proliferate in periportal regions and organize in ductules. They are surrounded by a basement membrane, the degradation of which by matrix metalloproteinases (MMP) might trigger their terminal differentiation into hepatocytes. We studied the expression of MMP-2 and MMP-9 and that of one of their tissue inhibitors (TIMP-1) in a model of hepatic regeneration from precursor cells. Regeneration was induced by treating rats with 2-acetylaminofluorene followed by partial hepatectomy. MMP-2 and MMP-9 hepatic expression paralleled oval cell number with a peak at day 9-14 after hepatectomy. They were mainly detected in oval cells. TIMP-1 mRNA and oncostatin M receptor mRNA, a major regulator of TIMP-1 synthesis, markedly increased from day 1 after surgery until day 9 and then declined; they were mainly detected in interlobular bile duct cells and oval cells until day 14. In agreement with the in vivo data, the WB-F344 liver precursor cell line expressed MMP-2 and MMP-9, as well as TIMP-1 and oncostatin M receptor. These data suggest that (a) early increased TIMP-1 synthesis by biliary and oval cells favors basement membrane deposition around proliferating ductular structures through MMP inhibition, (b) delayed increased MMP expression, concomitant to decreased TIMP-1 synthesis, leads to basement membrane degradation, preceding oval cell differentiation, (c) the oncostatin M pathway might play a major role in increased TIMP-1 synthesis.

Thar~xday, I 2 April nontransgenic control mice, before and after Triton WRI 339 treatment.Plasmatic TG concentrations were lower in transgenic mice than in the non-transgenic littermates.Moreover, there was a 30% reduction in hepatic TG and ApoB secretion after Triton treatment in transgenic mice relative to the controls, suggesting a default in the VLDL secretion mechanism.SREBPlc is an essential activator of fatty acid synthesis in the liver, through transactivation of the fatty acid synthase (FAS) gene.We observed a mild increase of SREBPlc and FAS expression in HCV-transgenic mice developing liver steatosis when compared to non-transgenic controls.In parallel, we noticed an increase in Insig2 expression, a potent inhibitor of SREBP I c nuclear translocation.ER-stress is another potent mechanism that induces TG synthesis through SREBPlc activation.We tested the level of expression for two markers of ER-stress in the liver and were able to demonstrate that, in our transgenic model, steatosis was not induced through such a mechanism.In conclusion, our results suggest that TG that accumulate in lipid droplets in HCV-transgenic hepatocytes are not synthesized as a result of ER-stress but more likely originate from a default in VLDL secretion.The lipid metabolism of full-length polyprotein transgenic mice is currently under extensive investigation.

04D. Molecular and cellular biology (d) Liver regeneration and experimental oncology