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
 hepatocellular adenoma ( hca ) is an uncommon benign hepatic tumor , and the use of oral contraceptives is known to contribute to the development of hca . 
 recently , a genotype and phenotype classification system for hca was suggested , and malignant transformation to hepatocellular carcinoma ( hcc ) was shown to be strongly associated with activating mutations in -catenin . 
 here , we report three cases of hca in korean patients : 7-cm , inflammatory and -catenin - activated hca with hcc transformation in a 46-year - old man ; 13-cm , -catenin - activated hca with cytological atypia in a 23-year - old woman ; and 10-cm , pigmented , inflammatory and -catenin - activated hca in a 36-year - old man . 
 all cases exhibited the nuclear expression of -catenin and diffuse cytoplasmic expression of glutamine synthetase upon immunohistochemical staining . 
 all tumors were completely resected , and the patients were followed for 3 to 6 years with no evidence of local recurrence or metastasis . 
INTRODUCTION
CASE REPORTS
1. Case 1
2. Case 2
3. Case 3
DISCUSSION