hepatocellular adenoma ( hca ) is an uncommon benign liver tumor , constituting 2% of all liver neoplasms.1 it is known to occur mainly in women with a history of oral contraceptive use.2 although a rare occurrence , hepatocellular carcinoma ( hcc ) can arise from hca.3 recent studies have revealed that -catenin mutation is the leading cause for the malignant transformation of hca to hcc.46 here we report three cases of -catenin activated hca . a 46-year - old man showed a hepatic mass found during a routine check - up . his past history was unremarkable and he had no history of alcohol or drug abuse . laboratory findings were all within normal ranges , including aspartate aminotransferase , alanine aminotransferase , -glutamyltransferase , lactate dehydrogenase , total bilirubin , and total protein . hepatitis b surface antigen and antihepatitis c virus antibody were negative , but anti - hbs antibody was positive . serum levels of -fetoprotein and protein - induced by vitamin k absence or antagonist ii were normal . liver dynamic computed tomography ( ct ) showed an arterial enhancing 6-cm sized lesion without washout in portal and delayed phase . gadobenate dimeglumine ( gd - bopta ) enhanced magnetic resonance imaging ( mri ) showed slight hyposignal intensity in t1-weighted image , and arterial enhancement without washout on portal phase . in 3-hour delayed hepatobiliary phase , the lesion was hypointense . in t2-weighted image , however , there was a focal washout area within the enhancing mass , which may suggest hcc ( fig . right lobectomy was performed and the specimen revealed a multilobular mass measuring 75 cm with a nodule - in - nodule pattern ( fig . microscopically , the mass showed a well - defined border with an expanding growth pattern ( fig . the outer nodules , the major part of the tumor , were composed of hepatocyte - like cells with mild nuclear atypia ( fig . the tumor cells were arranged in trabecular cords of one- or two - cell thickness . there were several abnormal vessels with mono - nuclear infiltrates ( fig . 2c ) . in contrast , the inner nodule showed an acinar pattern and prominent cellular atypia with stromal invasion ( fig . the tumor cells of the outer and inner nodules showed positivity for serum amyloid protein a ( saa ) ( fig . 2e ) , diffuse strong cytoplasmic expression of glutamine synthetase ( gs ) ( fig . in contrast , the expression of heat shock protein 70 ( hsp-70 ) was found in only the inner nodule ( fig . the nonneoplastic liver showed mild macrovesicular steatosis . taken together , the inner nodule was discerned to be a malignant transformation of hca . the patient has been followed up regularly for 6 years with no evidence of metastasis or recurrence after operation . a 23-year - old woman presented with a huge hepatic mass . her past medical history was unremarkable and she had no history of oral contraceptive use . the mass showed arterial enhancement and washout on portal and delay phase . on mri , the mass showed slight low signal intensity in t1-weighted image and gross fat component in dual - echo t1-weighted image . on t2-weighted image , the lesion showed slight high signal intensity , and t2 hyperintense , delayed enhancing central scar . with gadolinium - ethoxybenzyl - diethylenetriamine penta - acetic acid ( gd - eob - dtpa ) injection , the mass showed arterial enhancement , subsequent slight washout , and hypointensity on hepatobiliary phase ( fig . microscopically , the tumor was composed of hepatocyte - like cells with abundant and eosinophilic granular cytoplasm . most tumor cells showed a bland - looking appearance , but focal areas exhibited an acinar pattern and nuclear pleomorphism ( fig . the patient has been followed up for 3 years with no evidence of recurrence or metastasis of the tumor . a 36-year - old man presented with an incidental hepatic mass . the mass was slightly hyperintense in t2-weighted image with several poorly defined bright foci , and isointense in t1-weighted image , and arterial enhancement and slight washout on late dynamic phase . on mri , no gross fat or hemorrhage was noted in the tumor ( fig . macroscopically , the specimen comprised a huge mass , measuring 10 cm in size , with a cut surface showing a dark - green color and focal areas of congestion ( fig . microscopically , the nuclei of tumor cells were slightly larger than those of the nontumor hepatocytes . moderate mononuclear inflammatory cell infiltrates were found around abnormally shaped blood vessels . in the cytoplasm of the tumor cells , dark - brown colored granular pigment was observed ( fig . 6b ) , mimicking dubin - johnson - like pigment . additionally , diffuse immunoexpression of saa ( fig . the patient has been followed up for a period of 3 years with no evidence of local recurrence or metastasis after operation . a 46-year - old man showed a hepatic mass found during a routine check - up . his past history was unremarkable and he had no history of alcohol or drug abuse . laboratory findings were all within normal ranges , including aspartate aminotransferase , alanine aminotransferase , -glutamyltransferase , lactate dehydrogenase , total bilirubin , and total protein . hepatitis b surface antigen and antihepatitis c virus antibody were negative , but anti - hbs antibody was positive . serum levels of -fetoprotein and protein - induced by vitamin k absence or antagonist ii were normal . liver dynamic computed tomography ( ct ) showed an arterial enhancing 6-cm sized lesion without washout in portal and delayed phase . gadobenate dimeglumine ( gd - bopta ) enhanced magnetic resonance imaging ( mri ) showed slight hyposignal intensity in t1-weighted image , and arterial enhancement without washout on portal phase . in 3-hour delayed hepatobiliary phase , the lesion was hypointense . in t2-weighted image , however , there was a focal washout area within the enhancing mass , which may suggest hcc ( fig . right lobectomy was performed and the specimen revealed a multilobular mass measuring 75 cm with a nodule - in - nodule pattern ( fig . microscopically , the mass showed a well - defined border with an expanding growth pattern ( fig . the outer nodules , the major part of the tumor , were composed of hepatocyte - like cells with mild nuclear atypia ( fig . the tumor cells were arranged in trabecular cords of one- or two - cell thickness . there were several abnormal vessels with mono - nuclear infiltrates ( fig . 2c ) . in contrast , the inner nodule showed an acinar pattern and prominent cellular atypia with stromal invasion ( fig . the tumor cells of the outer and inner nodules showed positivity for serum amyloid protein a ( saa ) ( fig . 2e ) , diffuse strong cytoplasmic expression of glutamine synthetase ( gs ) ( fig . in contrast , the expression of heat shock protein 70 ( hsp-70 ) was found in only the inner nodule ( fig . the nonneoplastic liver showed mild macrovesicular steatosis . taken together , the inner nodule was discerned to be a malignant transformation of hca . the patient has been followed up regularly for 6 years with no evidence of metastasis or recurrence after operation . her past medical history was unremarkable and she had no history of oral contraceptive use . the mass showed arterial enhancement and washout on portal and delay phase . on mri , the mass showed slight low signal intensity in t1-weighted image and gross fat component in dual - echo t1-weighted image . on t2-weighted image , the lesion showed slight high signal intensity , and t2 hyperintense , delayed enhancing central scar . with gadolinium - ethoxybenzyl - diethylenetriamine penta - acetic acid ( gd - eob - dtpa ) injection , the mass showed arterial enhancement , subsequent slight washout , and hypointensity on hepatobiliary phase ( fig . microscopically , the tumor was composed of hepatocyte - like cells with abundant and eosinophilic granular cytoplasm . most tumor cells showed a bland - looking appearance , but focal areas exhibited an acinar pattern and nuclear pleomorphism ( fig . the patient has been followed up for 3 years with no evidence of recurrence or metastasis of the tumor . a 36-year - old man presented with an incidental hepatic mass . his past history was unremarkable and laboratory findings were normal . the mass was slightly hyperintense in t2-weighted image with several poorly defined bright foci , and isointense in t1-weighted image , and arterial enhancement and slight washout on late dynamic phase . the mass was hypointense at hepatobiliary phase image . on mri , no gross fat or hemorrhage macroscopically , the specimen comprised a huge mass , measuring 10 cm in size , with a cut surface showing a dark - green color and focal areas of congestion ( fig . microscopically , the nuclei of tumor cells were slightly larger than those of the nontumor hepatocytes . moderate mononuclear inflammatory cell infiltrates were found around abnormally shaped blood vessels . in the cytoplasm of the tumor cells , dark - brown colored granular pigment was observed ( fig . 6b ) , mimicking dubin - johnson - like pigment . additionally , diffuse immunoexpression of saa ( fig . the patient has been followed up for a period of 3 years with no evidence of local recurrence or metastasis after operation . hca is a rare benign tumor that usually develops in noncirrhotic liver , and is more frequently found in women than in men.7 the use of oral contraceptives is widely accepted as contributing to the development of hca , and the natural history of hcas is closely correlated with the dose and duration of oral contraceptive used.2 an increased risk of hca is also associated with anabolic androgens , metabolic disorders , and vascular diseases.8,9 recent reports from eastern countries , however , suggest that hcas exhibit significant epidemiological differences between eastern and western patients . in eastern countries , hcas have been reported mainly in males , and the degree of association with the use of oral contraceptives is much lower than that in western populations . a review of 206 asian patients reported a male preponderance of 59.7% ( 123/206 ) and only 13.2% ( 11/83 ) of female patients had a history of using oral contraceptives.10 based on genotype - phenotype features , hcas can be sub - categorized as follows : 1 ) hca with mutations in hepatocyte nuclear factor 1 ( hnf1 ) ; 2 ) hca with mutations in the -catenin gene ; 3 ) hca with inflammatory features ; and 4 ) hca , not otherwise specified.4,6 mutations in hnf1 , observed in approximately 35% of cases of hca , are considered the least likely to involve malignant transformation . the presence of activating mutation in -catenin , however , has been identified in about 10% of all hca cases , and is highly correlated with malignant transformation.4,5 inflammatory hcas are characterized as displaying mononuclear infiltrates and immunohistochemically positivity for saa and crp . about one tenth of these hcas have been reported to comprise mutations in the -catenin gene.6 all cases of the present report were considered to be indicative of -catenin activated hca ; the first and the third cases were demonstrative of hca with inflammatory features . the first case showed features of malignant transformation with a nodule - in - nodule pattern and stromal invasion . in the others , worrisome features suggesting hcc were present , but there was no definite evidence of malignant transformation . all patients have shown no disease recurrence or metastasis for at least 3 years after treatment . distinguishing hca from well - differentiated hcc is very important for the treatment of the patients , but it is difficult and sometimes impossible to attain , even in resected specimens . histological features suggestive of hcc include liver cell plates of more than three cells thick , increased cellularity with high nuclear / cytoplasm ratio , and stromal invasion of tumor cells.11 immunohistochemically , application of identification of glypi - can-3 expression is recommended to detect well - differentiated hcc . however , its usefulness is limited because it has been reported to be negative in one third of hccs.12 therefore , it is more helpful to apply a combination of hcc markers including glypican-3 , hsp-70 , and gs to distinguish well differentiated hcc from hca.13 identification of -catenin gene mutation is also important as -catenin activation in hca is associated with risk of malignant potential , and it shows an aberrant nuclear and cytoplasmic expression of -catenin and a diffuse , strong expression of gs.5 therefore , combined application of identification of -catenin and gs expression may be more effective in distinguishing -catenin activated hca from other subtypes of hca . interestingly , dubin - johnson - like pigment was observed in the third case of the present study . the pigment showed larger and darker granules than lipofuscin , and was positive for fontana - masson stain . recent study has indicated that dubin - johnson pigment is actually derived from lipofuscin , atypical bile pigments , or porphyrins , and may arise as the result of a defect in biliary excretion.14 in the literature , among seven series , eight cases of pigmented hca have been reported , and one of those was diagnosed as hcc.1517