hepatocellular carcinoma ( hcc ) is the most common primary malignant tumor of the liver and the second leading cause of cancer - related death in the world .
almost 80% of hcc cases are associated with cirrhosis due to chronic hepatitis b or c virus infection .
however , hccs that are very large in size and mass mostly develop in non - cirrhotic livers .
surgical resection is the only potentially curative treatment for patients with adequate liver functional reserve .
we present the case of a patient with an extensive hcc , who clinically presented with thoracic pain due to an extrahepatic metastasis .
a 33-year - old male presented to an ambulant orthopedic surgeon with left thoracic pain for six months . the patient s history offered no trauma , no alcoholism or smoking as well as no drug abuse or intake of steroid hormones . clinical examination revealed selective pressure pain over the fifth rib near the left mammilla .
a gadoxetic acid - enhanced mri was performed and revealed a giant inhomogeneous tumor originating from the left liver lobe with compression of surrounding organs ( fig .
liver biopsy revealed a hepatocellular adenoma ( hca ) with conspicuous cytoplasmic yellow - brown granular pigments ( fig .
tumor cells showed nuclear -catenin expression and overexpression of glutamine synthetase , leading to the diagnosis of hca with -catenin activation .
although in biopsy tissue transition to hcc was not evident , progression to hcc was suspected due to the big tumor size .
furthermore , a single - photon emission computed tomography ( spect ) showed suspect tumor in the left fifth rib ( fig .
1b ) , and a ct - guided puncture revealed hcc metastasis , verifying the suspicion of malignant progression .
a moderate increase of transaminases with alanine aminotransferase ( alt ) of 0.92  katal / l ( normal : 0.220.77 ) and aspartate aminotransferase ( ast ) of 1.0  katal / l ( normal : < 0.59 ) was assessed by blood sample .
the tumor markers alpha - fetoprotein ( afp ) , cancer embryonic antigen ( cea ) and carbohydrate antigen 19 - 9 ( ca19 - 9 ) were all within normal limits , whereas carbohydrate antigen 125 ( ca125 ) was moderately increased with 24.8  u / ml ( normal : < 20 ) .
preoperative ct volumetric measurement revealed a right liver lobe volume of 1367 cubic centimeter by using the summation - of - area method.fig .
1(a ) gadoxetic acid - enhanced mri axial t2-weighted showed large inhomogeneous abdominal mass and continuation with the parenchyma of left hepatic lobe ( arrows ) .
( b ) single - photon emission computed tomography ( spect ) showed metastasis of fifth left rib ( arrow).fig .
1 ( a ) gadoxetic acid - enhanced mri axial t2-weighted showed large inhomogeneous abdominal mass and continuation with the parenchyma of left hepatic lobe ( arrows ) .
( b ) single - photon emission computed tomography ( spect ) showed metastasis of fifth left rib ( arrow ) .
the huge tumor did not invade surrounding organs and hepatic cirrhosis or peritoneal metastasis was not observed ( fig .
after cholecystectomy and complete mobilization of the left liver , the left portal vein and left hepatic artery were ligated and divided .
liver transection of left liver including segment i and partial segment iv was performed by using endo gia 60-mm vascular with tri - staple technology ( covidien , mansfield , massachusetts , usa ) , whereas larger vessels and biliary tracts were overstitched ( fig .
the resection surface was sealed with fibrin sealant patch ( tachosil , takeda , osaka , japan ) to avoid bleeding .
the intraoperative course was uneventful , the tumor capsule was not disrupted and there was no need of blood transfusion .
the giant tumor mass was found to be 34    24    24  cm in size and 7.2  kg in weight .
macroscopic examination showed a multinodular and multicoloured tumor with yellow - green as well as dark pigmented areas ( fig .
histological evaluation revealed a well - differentiated hcc with trabecular growth pattern , invasion of portal vein branches and tumor - free resection margins .
tumor cells of the macroscopically dark coloured areas in histology contained brown cytoplasmic pigments ( data not shown ) , just as observed in the cells of the hca .
as a two - stage surgical procedure , partial en bloc resection of the left fifth rib was performed 4 weeks after hepatectomy .
the defect of the thoracic wall was repaired by using peri - guard repair patch ( synovis life technologies , saint paul , minnesota , usa ) , a biological tissue prepared from bovine pericardium . in summary , this case was classified as a pt3a pn0 pm1 stage iv , according to the 7th edition of the uicc tnm staging system for hcc.fig .
( b ) image of intraoperative situs after left hemihepatectomy showed prominent feeding vessel originating from the left gastric artery ( arrow).fig .
3(a , b ) multinodular and multicoloured appearance of the tumor with yellow - green areas , caused by bile production , and dark pigmented areas .
( c ) yellow - green appearance of the bone metastasis due to bile deposition.fig .
4upper line : ( a ) hepatocellular adenoma with cytoplasmic granular pigments , ( b ) nuclear -catenin expression , ( c ) conserved reticulin fiber meshwork and ( d ) very low proliferative activity .
lower line : ( e ) hepatocellular carcinoma with trabecular growth pattern , low nuclear atypia and bile plugs ( arrows ) , ( f ) showing regular membraneous -catenin expression , ( g ) fiber - destructive growth and ( h ) medium proliferative activity .
a , e : hematoxylin & eosin ; b , f : -catenin immunohistochemistry ; c , g : gomori silver staining ; d , h : ki67 immunohistochemistry.fig .
( b ) image of intraoperative situs after left hemihepatectomy showed prominent feeding vessel originating from the left gastric artery ( arrow ) .
( a , b ) multinodular and multicoloured appearance of the tumor with yellow - green areas , caused by bile production , and dark pigmented areas .
( c ) yellow - green appearance of the bone metastasis due to bile deposition .
upper line : ( a ) hepatocellular adenoma with cytoplasmic granular pigments , ( b ) nuclear -catenin expression , ( c ) conserved reticulin fiber meshwork and ( d ) very low proliferative activity .
lower line : ( e ) hepatocellular carcinoma with trabecular growth pattern , low nuclear atypia and bile plugs ( arrows ) , ( f ) showing regular membraneous -catenin expression , ( g ) fiber - destructive growth and ( h ) medium proliferative activity .
a , e : hematoxylin & eosin ; b , f : -catenin immunohistochemistry ; c , g : gomori silver staining ; d , h : ki67 immunohistochemistry .
the post - operative period was uneventful and the patient was discharged home one week after the second operation .
a follow - up surveillance according to the recent guidelines of the european association for the study of the liver ( easl ) was initiated .
a 33-year - old male presented to an ambulant orthopedic surgeon with left thoracic pain for six months . the patient s history offered no trauma , no alcoholism or smoking as well as no drug abuse or intake of steroid hormones . clinical examination revealed selective pressure pain over the fifth rib near the left mammilla .
a gadoxetic acid - enhanced mri was performed and revealed a giant inhomogeneous tumor originating from the left liver lobe with compression of surrounding organs ( fig .
liver biopsy revealed a hepatocellular adenoma ( hca ) with conspicuous cytoplasmic yellow - brown granular pigments ( fig .
tumor cells showed nuclear -catenin expression and overexpression of glutamine synthetase , leading to the diagnosis of hca with -catenin activation .
although in biopsy tissue transition to hcc was not evident , progression to hcc was suspected due to the big tumor size .
furthermore , a single - photon emission computed tomography ( spect ) showed suspect tumor in the left fifth rib ( fig .
1b ) , and a ct - guided puncture revealed hcc metastasis , verifying the suspicion of malignant progression .
a moderate increase of transaminases with alanine aminotransferase ( alt ) of 0.92  katal / l ( normal : 0.220.77 ) and aspartate aminotransferase ( ast ) of 1.0  katal / l ( normal : < 0.59 ) was assessed by blood sample .
the tumor markers alpha - fetoprotein ( afp ) , cancer embryonic antigen ( cea ) and carbohydrate antigen 19 - 9 ( ca19 - 9 ) were all within normal limits , whereas carbohydrate antigen 125 ( ca125 ) was moderately increased with 24.8  u / ml ( normal : < 20 ) .
preoperative ct volumetric measurement revealed a right liver lobe volume of 1367 cubic centimeter by using the summation - of - area method.fig .
1(a ) gadoxetic acid - enhanced mri axial t2-weighted showed large inhomogeneous abdominal mass and continuation with the parenchyma of left hepatic lobe ( arrows ) .
( b ) single - photon emission computed tomography ( spect ) showed metastasis of fifth left rib ( arrow).fig .
1 ( a ) gadoxetic acid - enhanced mri axial t2-weighted showed large inhomogeneous abdominal mass and continuation with the parenchyma of left hepatic lobe ( arrows ) .
( b ) single - photon emission computed tomography ( spect ) showed metastasis of fifth left rib ( arrow ) .
the huge tumor did not invade surrounding organs and hepatic cirrhosis or peritoneal metastasis was not observed ( fig .
after cholecystectomy and complete mobilization of the left liver , the left portal vein and left hepatic artery were ligated and divided .
liver transection of left liver including segment i and partial segment iv was performed by using endo gia 60-mm vascular with tri - staple technology ( covidien , mansfield , massachusetts , usa ) , whereas larger vessels and biliary tracts were overstitched ( fig .
the resection surface was sealed with fibrin sealant patch ( tachosil , takeda , osaka , japan ) to avoid bleeding .
the intraoperative course was uneventful , the tumor capsule was not disrupted and there was no need of blood transfusion .
the giant tumor mass was found to be 34    24    24  cm in size and 7.2  kg in weight .
macroscopic examination showed a multinodular and multicoloured tumor with yellow - green as well as dark pigmented areas ( fig .
histological evaluation revealed a well - differentiated hcc with trabecular growth pattern , invasion of portal vein branches and tumor - free resection margins .
tumor cells of the macroscopically dark coloured areas in histology contained brown cytoplasmic pigments ( data not shown ) , just as observed in the cells of the hca .
as a two - stage surgical procedure , partial en bloc resection of the left fifth rib was performed 4 weeks after hepatectomy .
the defect of the thoracic wall was repaired by using peri - guard repair patch ( synovis life technologies , saint paul , minnesota , usa ) , a biological tissue prepared from bovine pericardium . in summary , this case was classified as a pt3a pn0 pm1 stage iv , according to the 7th edition of the uicc tnm staging system for hcc.fig .
( b ) image of intraoperative situs after left hemihepatectomy showed prominent feeding vessel originating from the left gastric artery ( arrow).fig .
3(a , b ) multinodular and multicoloured appearance of the tumor with yellow - green areas , caused by bile production , and dark pigmented areas .
( c ) yellow - green appearance of the bone metastasis due to bile deposition.fig .
4upper line : ( a ) hepatocellular adenoma with cytoplasmic granular pigments , ( b ) nuclear -catenin expression , ( c ) conserved reticulin fiber meshwork and ( d ) very low proliferative activity .
lower line : ( e ) hepatocellular carcinoma with trabecular growth pattern , low nuclear atypia and bile plugs ( arrows ) , ( f ) showing regular membraneous -catenin expression , ( g ) fiber - destructive growth and ( h ) medium proliferative activity .
a , e : hematoxylin & eosin ; b , f : -catenin immunohistochemistry ; c , g : gomori silver staining ; d , h : ki67 immunohistochemistry.fig .
4 ( a ) in situ appearance of the hepatocellular carcinoma mass . ( b )
image of intraoperative situs after left hemihepatectomy showed prominent feeding vessel originating from the left gastric artery ( arrow ) .
( a , b ) multinodular and multicoloured appearance of the tumor with yellow - green areas , caused by bile production , and dark pigmented areas .
( c ) yellow - green appearance of the bone metastasis due to bile deposition .
upper line : ( a ) hepatocellular adenoma with cytoplasmic granular pigments , ( b ) nuclear -catenin expression , ( c ) conserved reticulin fiber meshwork and ( d ) very low proliferative activity .
lower line : ( e ) hepatocellular carcinoma with trabecular growth pattern , low nuclear atypia and bile plugs ( arrows ) , ( f ) showing regular membraneous -catenin expression , ( g ) fiber - destructive growth and ( h ) medium proliferative activity .
a , e : hematoxylin & eosin ; b , f : -catenin immunohistochemistry ; c , g : gomori silver staining ; d , h : ki67 immunohistochemistry .
the post - operative period was uneventful and the patient was discharged home one week after the second operation .
a follow - up surveillance according to the recent guidelines of the european association for the study of the liver ( easl ) was initiated .
giant hepatocellular carcinomas have a diameter over 10  cm , whereas a diameter over 20  cm is extremely rare .
interestingly , very large hccs mostly develop in non - cirrhotic livers . at time of diagnosis
an extrahepatic spread occurs in only about 515% of patients and mainly in advanced - stage primary tumors over 5  cm .
the most common sites of hcc metastases are lung ( 49% ) , abdominal organs ( 24% ) and bone ( 1316% ) .
skeletal metastases appear as expansive soft tissue masses with bone destruction and mainly involved sites are the vertebrae , pelvis , ribs , skull , humerus and sternum . in the presented case the progression from a hca with -catenin activation to hcc
was documented . molecular characterization of hcas has been practiced for few years now , resulting in an improved risk stratification of the heterogenous entity of hcas .
these -catenin activated hcas are often associated with male sex and administration of androgenic hormones and have an increased risk of malignant transformation . in this case
it is suggested that these pigments constitute lipofuscin deposits and several reports indicate an increased risk of malignancy in pigmented hcas , .
the pigments were also found in the hcc cells , but , unexpectedly , the nuclear -catenin activation of the hca was not preserved in the hcc cells .
however , pigmentation of hcas besides molecular characterization could serve as additional hint in evaluation of malignant potential of hcas .
currently , surgical resection is the only curative treatment with the best long - term survival .
preoperative liver function as a key parameter and the skill and experience of the surgeon significantly affect the success of resection in complicated hcc .
recurrence is the major challenge , as it occurs in approximately 70% of patients within 5 years after hepatic resection .
predictive factors of recurrence are disruption of tumor capsule , daughter nodules , positive surgical resection margins and blood transfusion . according to the literature
, we recommend a therapy specific to the patient on a case - by - case basis . to our knowledge , this is the first case report of a two - staged surgical resection of a giant hcc with skeletal metastasis in a young adult .
bone metastasis of a hepatocellular carcinoma ( hcc ) is a very rare cause of thoracic pain .
hepatocelluar adenomas ( hca ) with an activating mutation of -catenin , which occurs in up to 15% of cases , have a high risk of malignant transformation . molecular characterization and morphological feature of pigmentation are useful tools for risk assessment of hcas and
hepatobiliary surgery with metastasis resection is the only curative treatment and can be safe and effective even in patients with giant hccs , as our case report shows .
written informed consent was obtained from the patient for publication of this case report and accompanying images .
a copy of the written consent is available for review by the editor - in - chief of this journal on request .
sebastian lnse : study concept , data collection , literature research and writing the manuscript .
 highlightshepatocellular carcinoma ( hcc ) is an extremely rare finding in young adult.giant hccs are larger than 10  cm in diameter and mostly develop in non - cirrhotic livers.pigmented hepatocellular adenoma ( hca ) with beta - catenin activation have an increased risk for malignant transformation.surgical resection is the only curative treatment with best long - term outcome.molecular classification of hcas is a useful tool for risk assessment of malignant transformation . 