Hepatic Adenomas: Analysis of Sex Steroid Receptor Status and the Wnt Signaling Pathway

Abstract

Hepatic adenomas are strongly linked to excess hormonal exposure, but little else is known about their pathogenesis. The Wnt signaling pathway, which is activated in both hepatocellular carcinomas and hepatoblastomas, has not been studied in hepatic adenomas. Fifteen hepatic adenomas were studied by immunohistochemistry for estrogen, progesterone, and androgen receptors (ER, PR, AR, respectively) and correlated with the results of immunostaining for β-catenin. Direct sequencing was performed to look for mutations in key genes involved in the Wnt signaling pathway: Exon 3 of β-catenin encompassing the glycogen synthase kinase 3β (GSK-3β) phosphorylation region and the mutational cluster region of the adenomatosis polyposis coli protein (APC). Analysis for loss of heterozygosity (LOH) at chromosome 5q was also performed. Immunostaining for both ER and PR was present in 11/15 (73%) adenomas, and staining with one hormone receptor was positively associated with staining for the other receptor. AR positivity was present in 3/15 cases. Nuclear accumulation of β-catenin was present in 7/15 (46%) of adenomas, indicating activation of the Wnt signaling pathway. However, no β-catenin mutations, no APC mutations in the mutational cluster region, and no 5q LOH were detected. Two APC polymorphisms of unknown significance were seen. No clear association between β-catenin nuclear accumulation and hormone receptor positivity was discerned. Activation of the Wnt signaling pathway appears to be important in a subset of hepatic adenomas but does not result from common β-catenin or APC mutations and does not appear to be directly linked to hormonal receptor status.