1: J Hepatol. 2008 Jan;48(1):163-70. Epub 2007 Oct 30.

Molecular pathogenesis of focal nodular hyperplasia and hepatocellular adenoma.

Rebouissou S, Bioulac-Sage P, Zucman-Rossi J.

Inserm, U674, Génomique fonctionnelle des tumeurs solides, Génétique des tumeurs hépatiques, Paris, France.

Focal nodular hyperplasia (FNH) and hepatocellular adenomas (HCAs) are benign
tumors that occur in otherwise normal liver parenchyma. FNH is considered to be the result of a hyperplastic response to increased blood flow secondary to vascular malformations. Most FNH are polyclonal and to date, the molecular pathway and mechanisms that are altered in FNH have yet to be elucidated. In contrast, HCAs are consistently monoclonal tumors, which have been divided up
into three subtypes of tumors depending on the molecular alteration detected in the tumors: HNF1alpha inactivation, beta-catenin activation and/or an acute inflammatory response in the tumor. These molecular features are closely related to clinical and pathological characteristics, and one of the most critical correlations is the higher risk of malignant transformation for beta-catenin
activated HCA cases. Moreover, various risk factors, such as oral contraception and obesity, are associated with HCA occurrence and may collaborate with constitutional genetic predisposition related to HNF1alpha or CYP1B1 germline mutations. Altogether, the recent identification of different molecular pathways that contribute to tumor development has significantly increased our knowledge of benign hepatocellular tumorigenesis. These findings may modify our clinical practice, particularly in the diagnosis and follow-up of HCA patients.

2: Ned Tijdschr Geneeskd. 2007 Jun 16;151(24):1321-4.

Hepatocellular adenoma, a tumour particularly seen in mostly young women

Teeuwen PH, Ruers TJ, Wobbes T.

Universitair Medisch Centrum St Radboud, afd. Heelkunde, onderafd. Chirurgische Oncologie, Postbus 9101, 6500 HB Nijmegen.

A 37-year-old woman was examined because of temporary diarrhoea. On CT scan, there was an abnormality of the liver. MRI showed a tumour that was suspicious for adenoma. Biopsy confirmed the diagnosis of hepatocellular adenoma. The patient then discontinued the use of oral contraceptives. The tumour regressed and was resected after two years. A 22-year-old woman presented with abdominal pain. A tumour was found in the upper right quadrant of the abdomen. In the laboratory, liver function tests were abnormal. Ultrasound and a CT scan of the liver showed an adenoma. After withdrawal of oral contraceptives, abdominal complaints lessened, but no regression of the tumour was detected. Surgical resection was uncomplicated. Hepatocellular adenoma is a rare, benign tumour of the liver, most often seen in young healthy women. Its incidence is rising due to the prolonged use of oral contraceptives. Not rarely, benign liver tumours are incidental findings on echography. If symptomatic, the presentation usually consists of vague abdominal complaints. Spontaneous rupture and malignant degeneration have been reported for adenoma. A reliable diagnosis is mandatory for the decision whether to apply surgery or continue observation. Radiological investigations play a key role in the detection and diagnosis of hepatocellular adenoma. Due to the risk of bleeding and malignant degeneration, elective surgical resection is indicated in symptomatic adenomas, asymptomatic adenomas larger than 5 cm in diameter, and smaller adenomas without regression after discontinuation of oral contraceptives.

3: Hepatology. 2007 Sep;46(3):740-8.

Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry.

Bioulac-Sage P, Rebouissou S, Thomas C, Blanc JF, Saric J, Sa Cunha A, Rullier A, Cubel G, Couchy G, Imbeaud S, Balabaud C, Zucman-Rossi J.

Department of Pathology, CHU Bordeaux, France.

Hepatocellular adenomas (HCA) with activated beta-catenin present a high risk of malignant transformation. To permit robust routine diagnosis to allow for HCA subtype classification, we searched new useful markers. We analyzed the expression of candidate genes by quantitative reverse transcription polymerase chain reaction QRT-PCR followed by immunohistochemistry to validate their specificity and sensitivity according to hepatocyte nuclear factor 1 alpha(HNF1alpha) and beta-catenin mutations as well as inflammatory phenotype. Quantitative RT-PCR showed that FABP1 (liver fatty acid binding protein) and UGT2B7 were downregulated in HNF1alpha-inactivated HCA (P <or= 0.0002); GLUL (glutamine synthetase) and GPR49 overexpression were associated with beta-catenin-activating mutations (P <or= 0.0005), and SAA2 (serum amyloid A2) and CRP (C-reactive protein) were upregulated in inflammatory HCA (P = 0.0001).
Immunohistochemistry validation confirmed that the absence of liver-fatty acid binding protein (L-FABP) expression rightly indicated HNF1alpha mutation (100% sensitivity and specificity), the combination of glutamine synthetase overexpression and nuclear beta-catenin staining were excellent predictors of beta-catenin-activating mutation (85% sensitivity, 100% specificity), and SAA hepatocytic staining was ideal to classify inflammatory HCA (91% sensitivity and specificity). Finally, a series of 93 HCA was unambiguously classified using our 4 validated immunohistochemical markers. Importantly, new associations were revealed for inflammatory HCA defined by SAA staining with frequent hemorrhages (P = 0.003), telangiectatic phenotype (P < 0.001), high body mass index, and alcohol intake (P <or= 0.04). Previously described associations were confirmed
and in particular the significant association between beta-catenin-activated HCA and hepatocellular carcinomas (HCC) at diagnosis or during follow-up (P < 10(-5)). CONCLUSION: We refined HCA classification and its phenotypic correlations, providing a routine test to classify hepatocellular adenomas using simple and robust immunohistochemistry.

4: World J Gastroenterol. 2007 May 21;13(19):2649-54.

Genotype phenotype classification of hepatocellular adenoma.

Bioulac-Sage P, Blanc JF, Rebouissou S, Balabaud C, Zucman-Rossi J.

Studies that compare tumor genotype with phenotype have provided the basis of a new histological/molecular classification of hepatocellular adenomas. Based on two molecular criteria (presence of a TCF1/HNF1 alpha or beta-catenin mutation), and an additional histological criterion (presence or absence of an inflammatory infiltrate), subgroups of hepatocellular adenoma can be defined and distinguished from focal nodular hyperplasia. Analysis of 96 hepatocellular adenomas performed by a French collaborative network showed that they can be divided into four broad
subgroups: the first one is defined by the presence of mutations in TCF1 gene inactivating the hepatocyte nuclear factor 1 (HNF1 alpha); the second by the presence of beta-catenin activating mutations; the category without mutations of HNF1 alpha or beta-catenin is further divided into 2 subgroups depending on the presence or absence of inflammation. Therefore, the approach to the diagnosis of problematic benign hepatocytic nodules may be entering a new era directed by new
molecular information. It is hoped that immunohistological tools will improve significantly diagnosis of liver biopsy in our ability to distinguish hepatocellular adenoma from focal nodular hyperplasia (FNH), and to delineate clinically meaningful entities within each group to define the best clinical
management. The optimal care of patients with a liver nodule will benefit from the recent knowledge coming from molecular biology and the combined expertise of hepatologists, pathologists, radiologists, and surgeons.

5: J Hepatol. 2007 Mar;46(3):521-7. Epub 2007 Jan 2.

Pathological diagnosis of liver cell adenoma and focal nodular hyperplasia: Bordeaux update.

Bioulac-Sage P, Balabaud C, Bedossa P, Scoazec JY, Chiche L, Dhillon AP, Ferrell L, Paradis V, Roskams T, Vilgrain V, Wanless IR, Zucman-Rossi J; Laennec and Elves groups.

Hôpital St André, Service d'Hépatologie Gastroentérologie, CHU Bordeaux, 1 Rue Jean Burguet, Bordeaux cedex, France. charles.balabaud@chu-bordeaux.fr

....Some lesions have histologic features of both adenoma and FNH. These variant lesions have often been classified as the telangiectatic type of FNH [1,18]. These tumours are often multiple. Clinical and molecular evidence indicates that telangiectatic ‘‘FNH’’ should be reclassified as adenomas..

Hepatocellular adenomas without mutations of HNF1a or b-catenin genes:
The remaining broad group (approximately 40%) of HCAs lack HNF1a or b-catenin mutations and represent a heterogeneous group. One subset defined by the presence of inflammatory infiltrates [22] corresponds, at least partly, to the newly characterized entity (previously called telangiectatic FNH), a variant of hepatocellular adenoma often designated as inflammatory
adenoma and/or telangiectatic adenoma [25] depending upon the importance of inflammatory infiltrates and/or sinusoidal dilatation. We believe this subset of tumours is HCA [22] rather than FNH for two reasons. First, the lesions display macroscopic appearances of HCA that include typical gross features of soft large tumours with a significant risk of haemorrhage instead of the nodular and fibrous appearance of typical FNH. Secondly, these lesions also have molecular characteristics of HCA, which include monoclonality and Ang1/Ang2 mRNA ratio in the range found in HCA of the usual type [21,23].....

....until now, the presence of ductules (CK7 positive and usually CK19 negative) in hepatocytic nodules has prevented the diagnosis of adenoma for a lesion otherwise closely similar to classical HCA. One important lesson learned from molecular studies is that the presence of ductules does not preclude the diagnosis of HCA particularly when associated with sinusoidal dilatation (the so-called telangiectasia in telangiectactic FNH). These ductules can be dystrophic and differ from those observed in FNH. The cytokeratin 7 positive cells should not be wrongly interpreted as progenitor cells [26], since these cells may also be present in FNH [27]. Thus, a better correlation
of histologic and molecular properties of these lesions is needed.

6: Br J Surg. 2006 Dec;93(12):1495-502.

Case-orientated approach to the management of hepatocellular adenoma.

van der Windt DJ, Kok NF, Hussain SM, Zondervan PE, Alwayn IP, de Man RA, IJzermans JN.

Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands.

BACKGROUND: Treatment of suspected hepatocellular adenoma (HA) remains controversial. The aim of this study was to evaluate the management of HA at a time when magnetic resonance imaging (MRI) and computed tomography (CT) are highly sensitive methods for diagnosing HA. METHODS: Between January 2000 and January 2005, data from 48 consecutive women with HA (median age 36 years) were prospectively collected. The protocol for diagnostic work-up consisted of multiphasic MRI or CT. Management was observation if the tumour was smaller than 5 cm and surgical intervention if it was 5 cm or larger. RESULTS: The median follow-up was 24 (range 3-73) months. Sixteen (33 per cent) patients had invasive procedures because of tumour size 5 cm or larger, malignant characteristics or haemorrhage. The remaining 32 patients (67 per cent) were observed; haemorrhage and malignant degeneration did not occur and none of the lesions showed
enlargement after withdrawal of oral contraceptives. Multiple HAs were found in 32 (67 per cent) patients; liver steatosis was significantly more common in these patients than in those with a solitary lesion (59 versus 19 per cent; P = 0.008). CONCLUSION: Observation of adenomas smaller than 5 cm is justified because of improved radiological reliability. Resection should be reserved for patients with malignant tumour characteristics or with single lesions 5 cm or larger.

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Abstracts: Telangiectatic Focal Nodular Hyperplasia of the liver

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1: Pediatr Dev Pathol. 2005 Sep-Oct;8(5):581-6.
Telangiectatic focal nodular hyperplasia of the liver in the perinatal period: case report.

Okamura N, Nakadate H, Ishida K, Nakahara S, Isobe Y, Ohbu M, Okayasu I.

Cyto-histopathology, Graduate School of Medical Science, Kitasato University, 1-15-1 Kitasato Sagamihara, Kanagawa 228-8555, Japan.

We report a case of congenital telangiectatic focal nodular hyperplasia, a rare variant form of the disease. The patient was a 2-month-old boy whose parents noticed abdominal distention about 2 weeks after birth, and ultrasonogram revealed a large mass in the liver. He underwent right lobectomy, and gross findings showed an ill-defined mass without any central scar. Histologic findings demonstrated proliferating hepatocytes without atypia arranged in cords of 1- or 2-cell thickness with marked sinusoidal dilatation and extramedullary hematopoiesis. In addition, a significantly increased Ki-67 labeling index in the tumor compared with non-tumor liver cells, and cytogenetic analysis of 23 G-banded metaphase preparations revealed 3 abnormal karyotypes, suggesting hyperplastic or neoplastic features. To the best of our knowledge, the present case is only the third documented case of congenital telangiectatic focal nodular hyperplasia.

2: Gastroenterology. 2005 May;128(5):1211-8.
Clinical, morphologic, and molecular features defining so-called telangiectatic focal nodular hyperplasias of the liver.

Bioulac-Sage P, Rebouissou S, Sa Cunha A, Jeannot E, Lepreux S, Blanc JF, Blanché H, Le Bail B, Saric J, Laurent-Puig P, Balabaud C, Zucman-Rossi J.

Department of Pathology, Centre Hospitalier Universitaire de Bordeaux, France.

BACKGROUND & AIMS: Telangiectatic focal nodular hyperplasia (TFNH) of the liver is generally believed to belong to the focal nodular hyperplasia (FNH) family. The aim of this study was to use molecular markers, in addition to morphologic features, to better characterize TFNH. METHODS: Thirteen patients with TFNH were compared with 28 patients with FNH and 17 patients with hepatocellular adenoma. Full clinical and morphologic data were analyzed. Molecular markers included determination of clonality by examining the active X chromosome, genome-wide allelotyping, a search for hepatocyte nuclear factor 1alpha (HNF1alpha) mutations, and determination of ANGPT1/ANGPT2 transcript levels. RESULTS: No clinical differences were evident between patients with TFNH and adenoma; in particular, bleeding was observed in 77% and 53% of the cases, respectively. Patients with TFNH were more likely to experience nodule recurrence and the presence of multiple nodules than those with either FNH or adenoma. All TFNH and adenoma samples that were available for analysis were monoclonal, in contrast to 40% of the FNH samples. Chromosome losses confirmed monoclonality and were significantly less frequent in TFNH and FNH (22% and 26%) than in adenoma (53%). HNF1alpha mutations were found exclusively in half of the adenomas. ANGPT2 was overexpressed in TFNH and down-regulated in adenoma (P < .01) and FNH (P < .0005). CONCLUSIONS: TFNHs are monoclonal lesions frequently subject to bleeding that are similar to adenomas not carrying HNF1alpha mutations and require a similar type of treatment. However, morphologic and molecular data support the hypothesis that TFNH is a separate entity.

3: Gastroenterology. 2004 May;126(5):1323-9.
Telangiectatic focal nodular hyperplasia: a variant of hepatocellular adenoma.

Paradis V, Benzekri A, Dargère D, Bièche I, Laurendeau I, Vilgrain V, Belghiti J, Vidaud M, Degott C, Bedossa P.

Service d'Anatomie Pathologique, Hôpital Beaujon, Clichy, France. vparadis@teaser.fr

BACKGROUND & AIMS: "Telangiectatic focal nodular hyperplasia" designate atypical lesions considered as variants of focal nodular hyperplasia (FNH). However, because "telangiectatic FNH" share several morphologic patterns with hepatocellular adenomas, classification of such lesions deserve further clarification. Therefore, the aim of the present study was to reconsider the classification of telangiectatic FNH with the help of a molecular approach. METHODS: Ten telangiectatic FNH, 6 typical FNH, and 6 hepatocellular adenomas were studied. DNA, RNA, and protein from each lesion were extracted. Clonality was assessed by the study of the X chromosome inactivation pattern (HUMARA assay). Angiopoietin (ANGPT-1 and ANGPT-2) mRNA, genes the expression of which is typically modified in FNH, were quantified by a real-time RT-PCR procedure. Protein profiles were analyzed by SELDI-TOF PROTEINCHIP (Cyphergen Biosystem, Inc., Fremont, CA) technology. RESULTS: Although all informative cases of FNH (5 of 6) and hepatocellular adenomas (6 of 6) were polyclonal and monoclonal, respectively, clonal analysis showed a nonrandom pattern of X chromosome inactivation consistent with a monoclonal lesion in 6 of 8 cases of telangiectatic FNH. The mean value of the ANGPT-1/ANGPT-2 mRNA ratio was 21.4 in FNH, 2.6 in adenomas, and 2.1 in telangiectatic FNH (P <or = 0.001 in telangiectatic FNH vs. FNH). SELDI-TOF PROTEINCHIP profiling and hierarchical clustering analysis showed that all except 1 telangiectatic FNH clustered within the group of hepatocellular adenomas. CONCLUSIONS: These results show that telangiectatic FNH display a molecular pattern closer to that of hepatocellular adenomas than to FNH and suggest that these lesions should instead be referred to as "telangiectatic hepatocellular adenomas."