Premium
Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry
Author(s) -
BioulacSage Paulette,
Rebouissou Sandra,
Thomas Cristel,
Blanc JeanFrédéric,
Saric Jean,
Sa Cunha Antonio,
Rullier Anne,
Cubel Gaëlle,
Couchy Gabrielle,
Imbeaud Sandrine,
Balabaud Charles,
ZucmanRossi Jessica
Publication year - 2007
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21743
Subject(s) - immunohistochemistry , microbiology and biotechnology , biology , immunology
Hepatocellular adenomas (HCA) with activated β‐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 (HNF1α) and β‐catenin mutations as well as inflammatory phenotype. Quantitative RT‐PCR showed that FABP1 (liver fatty acid binding protein) and UGT2B7 were downregulated in HNF1α‐inactivated HCA ( P ≤ 0.0002); GLUL (glutamine synthetase) and GPR49 overexpression were associated with β‐catenin–activating mutations ( P ≤ 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 HNF1α mutation (100% sensitivity and specificity), the combination of glutamine synthetase overexpression and nuclear β‐catenin staining were excellent predictors of β‐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 ≤ 0.04). Previously described associations were confirmed and in particular the significant association between β‐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. (H EPATOLOGY 2007.)