Hepatocellular adenomas are benign tumors that can be difficult to diagnose. To refine their classification, we performed a comprehensive analysis of their genetic, pathological, and clinical features. A multicentric series of 96 liver tumors with a firm or possible diagnosis of hepatocellular adenoma was reviewed by liver pathologists. In all cases, the genes coding for hepatocyte nuclear factor 1␣ (HNF1␣) and ␤-catenin were sequenced. No tumors were mutated in both HNF1␣ and ␤-catenin enabling tumors to be classified into 3 groups, according to genotype. Tumors with HNF1␣ mutations formed the most important group of adenomas (44 cases). They were phenotypically characterized by marked steatosis (P < 10 ؊4 ), lack of cytological abnormalities (P < 10 ؊6 ), and no inflammatory infiltrates (P < 10 ؊4 ). In contrast, the group of tumors defined by ␤-catenin activation included 13 lesions with frequent cytological abnormalities and pseudo-glandular formation (P < 10 ؊5 ). The third group of tumors without mutation was divided into two subgroups based on the presence of inflammatory infiltrates. The subgroup of tumors consisting of 17 inflammatory lesions, resembled telangiectatic focal nodular hyperplasias, with frequent cytological abnormalities (P ‫؍‬ 10 ؊3 ), ductular reaction (P < 10 ؊2 ), and dystrophic vessels (P ‫؍‬ .02). In this classification, hepatocellular carcinoma associated with adenoma or borderline lesions between carcinoma and adenoma is found in 46% of the ␤-catenin-mutated tumors whereas they are never observed in inflammatory lesions and are rarely found in HNF1␣ mutated tumors (P ‫؍‬ .004). In conclusion, the molecular and pathological classification of hepatocellular adenomas permits the identification of strong genotype-phenotype correlations and suggests that adenomas with ␤-catenin activation have a higher risk of malignant transformation. (

Nonalcoholic fatty liver disease (NAFLD) has become a major public health issue. The goal of this study was to assess the clinical use of liver stiffness measurement (LSM) evaluated by supersonic shear imaging (SSI), FibroScan, and acoustic radiation force impulse (ARFI) in a cohort of NAFLD patients who underwent liver biopsy. A total of 291 NAFLD patients were prospectively enrolled from November 2011 to February 2015 at 2 French university hospitals. LSM was assessed by SSI, FibroScan (M probe), and ARFI within two weeks prior to liver biopsy. Calculations of the area under the receiver operating curve (AUROC) were performed and compared for the staging of liver fibrosis. AUROC for SSI, FibroScan, and ARFI were 0.86, 0.82, and 0.77 for diagnoses of F2; 0.89, 0.86, and 0.84 for F3; and 0.88, 0.87, and 0.84 for F4, respectively. SSI had a higher accuracy than ARFI for diagnoses of significant fibrosis ( F2) (P 5 0.004). Clinical factors related to obesity such as body mass index 30 kg/m 2 , waist circumference 102 cm or increased parietal wall thickness were associated with LSM failures when using SSI or FibroScan and with unreliable results when using ARFI. In univariate analysis, FibroScan values were slightly correlated with NAFLD activity score and steatosis (R 5 0.28 and 0.22, respectively), whereas SSI and ARFI were not; however, these components of NAFLD did not affect LSM results in multivariate analysis. The cutoff values for SSI and FibroScan for staging fibrosis with a sensitivity 90% were very close: 6.3/6.2 kPa for F2, 8.3/8.2 kPa for F3, and 10.5/9.5 kPa for F4. Conclusion: Although obesity is associated with an increase in LSM failure, the studied techniques and especially SSI provide high value for the diagnosis of liver fibrosis in NAFLD patients. (HEPATOLOGY 2016;63:1817-1827 SEE EDITORIAL ON PAGE 1762A s a result of the growing obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become a major public health issue. NAFLD currently represents the leading cause of chronic liver disease in Western countries and the second leading etiology among adults awaiting liver transplantation in the United States. (1-3) Liver-related morbidity and mortality in NAFLD patients are linked to the development of nonalcoholic steatohepatitis (NASH), which can progress to fibrosis and cirrhosis lesions. (4) NASH is also associated with an increased risk of hepatocellular carcinoma development and an increased risk of cardiovascular mortality and type 2 diabetes mellitus. (5) Liver biopsy is considered the gold Abbreviations: ARFI, acoustic radiation force impulse; AUROC, area under the receiver operating characteristics curve; BMI, body mass index; IQR, interquartile range; LSM, liver stiffness measurement; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD activity score; NASH, nonalcoholic steatohepatitis; SSI, supersonic shear imaging.

Inter-observer agreement on activity and fibrosis scores used in chronic viral hepatitis has only been studied under selected conditions. The aim of this study was to identify the sources of variability due to specimen characteristics and observers. This study included 254 liver specimens and 15 pathologists and used the Metavir score. In 44 specimens scored by 4 academic pathologists, agreement of Metavir score was good overall, but better for fibrosis ( ‫؍‬ 0.59) than for activity ( ‫؍‬ 0.43) and poor for lobular necrosis ( ‫؍‬ 0.15). The mean agreement was better for senior (0.60 ؎ 0.24) than junior pathologists (0.52 ؎ 0.30, P < .05). Mean intrabserver agreement was better than inter-observer agreement (0.77 ؎ 0.18 vs. 0.58 ؎ 0.26, P < .01). In 157 specimens scored by 2 expert pathologists (one senior, one junior), agreement of Metavir score was only good but greatly improved after consensus reading (fibrosis: ‫؍‬ 0.48 and 0.77, activity: ‫؍‬ 0.44 and 0.70, respectively, before and after consensus). Several causes of disagreement were identified: specimen length, fibrosis class number, observer bias, and putative causes related to Metavir score or specimen. In an intercenter evaluation involving 59 specimens, 1 expert and 10 nonacademic pathologists, agreement was very poor and did not improve over 5 years for activity ( ‫؍‬ 0.22-0.25) or fibrosis ( ‫؍‬ 0.13-0.18). In conclusion, the level of experience (specialization, duration, and location of practice) has more influence on agreement than the characteristics of the specimen (length, fibrosis class number, miscellaneous factors). Agreement can be improved by experienced pathologist or consensus reading. (HEPATOLOGY 2005;41:257-264.)