hepatocellular carcinoma ( hcc ) is a rare tumour in young adults . in older patients , common predisposing conditions include cirrhosis in general , and in particular chronic liver disease associated with persistent hepatitis b and c infection .
however , young patients who develop hcc are less likely to have associated chronic liver disease ( 33% ) compared to adults ( 7090% ) . in children , inborn errors of metabolism , such as alpha-1-antitrypsin deficiency , hereditary tyrosinaemia , gaucher 's disease , congenital biliary atresia , urea cycle defects , and familial cholestatic syndrome caused by a bile salt export pump deficiency , may be the underlying cause .
prognosis in the presence of metastatic disease is poor , although it may be somewhat better in children and younger adults compared to older adults , with long - term survival of 1020% compared to less than 5% , respectively .
we describe a case of advanced hcc in a young patient arising in a non - cirrhotic liver , which was thought to be causally associated with a congenital cholestasis syndrome .
the patient was first admitted to the hospital as an infant when he was 2 weeks old . the reason was weakness and jaundice .
bilirubin was elevated to 500 mol / l , of which only one third was conjugated .
a diagnosis of abo haemolytic disease of the newborn was suspected , but intensive phototherapy and exchange transfusion had only limited effect .
a liver biopsy performed at the age of 2 months showed severe pan- and multiacinar canalicular cholestasis with numerous bile thrombi and cholestatic rosettes .
liver cells were swollen with marked feathery degeneration and there was widespread giant cell transformation .
there were scattered apoptotic hepatocytes but only minimal accompanying inflammation . in addition , there was focal extramedullary haematopoiesis .
portal bile ducts were present in normal numbers , and there was no morphological evidence of extrahepatic large duct obstruction .
a biliary scintigraphy confirmed cholestasis , showing no drainage of bile into the central hepatic bile ducts or the duodenum , and the extrahepatic bile ducts were normal at endoscopy .
bilirubin slowly normalised during the following year , while alkaline phosphatases stayed elevated at 1,0001,500 u / l for several years , indicating a mild , long - term cholestasis ( fig .
the patient developed recurrent , intermittent swollen legs and periorbital oedema , and had episodes of stomach pain and fatigue .
repeated liver biopsies at the age of 3 and 6 years showed only minimal , non - specific portal inflammation without evidence of cholestasis or fibrosis .
a diagnosis of aagenaes syndrome was suspected ; however , no typical genetic alterations were found , and the patients condition improved spontaneously and alkaline phosphatases normalised as he reached adolescence . at the age of 17 years
a ct scan demonstrated a 150  100 mm necrotic tumour in the right liver lobe with multiple hepatic satellite nodules , multiple metastases to the lungs , a tumour embolus in the right atrium and extensive thromboses involving the inferior vena cava , hepatic vein and portal vein .
serum -foetoprotein ( fp ) was markedly raised at 296,000 u / ml ( normal < 14 u / ml ) , while hcg was normal . no clinical or biochemical evidence of cirrhosis was found and hepatitis virus titres were negative .
a biopsy from the large liver mass showed a malignant tumour composed of hepatocyte - like cells , organised in a trabecular pattern .
immunohistochemical staining revealed a typical phenotype , including tumour cell positivity for hep - par1 , glypican-3 and fp .
taken at the same time from a lung metastasis revealed infiltrating hcc , subsequently confirmed by immunohistochemistry .
a biopsy from the non - tumorous liver showed reactive tissue without evidence of cirrhosis .
the patient 's oncological treatment is summarised in figure 2 together with fp values and the results of tumour evaluation by ct - scans . at the time of first treatment
his poor condition ( who performance status ( ps ) 3 ) precluded combination chemotherapy and single - drug cisplatin was therefore offered .
prior to the second treatment cycle , his condition had improved ( ps 2 ) , allowing the administration of five series of combination chemotherapy , which contained gemcitabine , docetaxel and cisplatin .
toxicity included diarrhoea and neutropenia ctc grade i , together with vomiting , anorexia , anaemia and alopecia ( grade ii ) .
a further improvement in the patient 's clinical condition was observed during this treatment , and its effect was confirmed by a major , partial response on the corresponding ct scans ( fig .
the response defined by ct was preceded by a rapidly dropping fp . after a pause in chemotherapy , ct scans showed progression , accompanied by a continuous rise in fp . at the first progression , sorafenib at standard dose was offered .
toxicity was dose limiting and consisted of neutropenia grade ii , diarrhoea , vomiting , rash and pruritus grade iii , requiring a 4-week treatment break .
sorafenib was then administered at a reduced dose for 2 weeks and later escalated with acceptable toxicity . at the 2nd objective progression
the patient was offered chemotherapy with gemcitabine and oxaliplatin , but no apparent effect was observed .
, the patient had remained in excellent general condition ( ps 01 ) . at the 3rd progression , experimental treatment with erlotinib plus bevacizumab
however , bevacizumab was never administered because of deterioration in the patient 's general condition .
he continued on best supportive care and lived for a further 3 months , totalling 13 months of survival after initiation of chemotherapy .
in this rare case , the development of hcc was associated with a history of neonatal and childhood cholestasis with elevated bilirubin and alcalic phosphatases , and intermittent episodes of periorbital oedema and oedema in the legs , stomach pain and fatigue .
these symptoms resemble those of the rare aagenaes syndrome , also called lymphoedema cholestasis syndrome .
the heritance of this disorder is mainly autosomal recessive ; however , dominant inheritance has also been proposed .
a key symptom is transient jaundice with increased conjugated bilirubin that becomes evident soon after birth with recurrent episodes throughout life .
oedema in the legs due to hypoplasia of the lymphatic vessels begins around school age and may progress . globally , more than 80 cases have been described .
there has been only one previous case diagnosed in denmark , apart from the current case , in which the diagnosis was strongly suspected .
patients with aagenaes syndrome have an approximately 25% risk of developing liver cirrhosis , mainly in early childhood .
one previous patient who had frequent episodes of cholestasis died at the age of 50 years with cirrhosis and hcc ( professor aagens , personal communication 2012 ) . in the current case ,
the diagnosis of aagenaes syndrome could not be clearly established , in part because of the lack of permanent signs of lymphoedema and absence of typical genetic alterations .
although not specific , the histological picture was consistent with various forms of congenital neonatal cholestasis syndrome , including aagenaes syndrome .
the choice of systemic treatment in juvenile hcc is difficult , since no phase iii studies of adolescent patients with advanced hcc have been performed .
an aggressive approach , including liver tumour resection or liver transplantation and metastasectomy when feasible , is often advocated .
in contrast to adult patients with hcc , in whom the tyrosine - kinase inhibitor sorafenib is the only approved drug today , pediatric and juvenile patients are often treated with chemotherapy with much higher response rates .
for example , cisplatin and doxorubicin or cisplatin/5-fluorouracil / vincristine produced responses in approximately 50% of treated patients .
molecular differences in tumorigenesis and in the underlying liver diseases may account for this difference in effect , comparing children and adults .
interpretation of treatment reports is , however , hampered since children with hepatoblastoma , a tumour type which is more chemosensitive than hcc , were included .
early studies , e.g. with doxorubicin , showed only modest response rates with significant toxicity , without any clear survival benefits .
more recently , phase ii - studies of newer drugs showed response rates around 20% with acceptable toxicity , for example when using gemcitabine / oxaliplatin , in one study combined with the anti - angiogenetic antibody bevacizumab .
an asian study of 371 patients randomised to either oxaliplatin + 5-fluorouracil / leucovorin or doxorubicin was insignificant at the preplanned final survival analysis ( p = 0.0695 ) , but significant at a follow - up analysis ( p = 0.0425 ) .
a randomised phase ii study of 96 patients treated by either sorafenib / doxorubicin or doxorubicin showed a clear advantage for the two - drug combination ( median time to progression 6.4 vs. 2.8 months , p = 0.02 ) and also the median overall survival was significantly improved ( 13.7 vs. 6.5 months , p = 0.006 ) .
results of a phase iii - study of this combination are pending . response to chemotherapy is apparently more frequently seen in patients with hcc in nonalcoholic cirrhosis , in the absence of cirrhosis , or in patients with rare variants of hcc , and complete responders have even been reported in patients with metastatic disease .
the effect of sorafenib has only been studied in adult patients , most of whom had hcc associated with cirrhosis , or with hepatitis b or c virus infection .
sorafenib is a per oral tyrosine kinase inhibitor with activity against multiple growth factors , especially angiogenic growth factors .
two randomised phase iii - studies showed modest median survival benefits of 2.8 and 2.3 months , respectively , the hazard ratio of sorafenib versus placebo being approximately 0.69 [ 12 , 13 ] .
objective response rates reported were less than 5% , but rare major responders have been documented even in the setting of metastatic hcc .
the effect of sorafenib in children and young patients is unknown , although a recent phase i study showed that the treatment is feasible .
the current case illustrates that early development of hcc may be associated with congenital cholestasis , even in the absence of cirrhosis .
it confirms that chemotherapy , although experimental , is feasible and tolerable in juvenile advanced hcc arising in a non - cirrhotic liver and can provide a major objective response and a meaningful palliation for individual patients .
 this case describes the clinical course and treatment of a 17-year - old male patient with advanced hepatocellular carcinoma ( hcc ) arising in a non - cirrhotic liver . 
 the disease was thought to be caused by a congenital cholestatic syndrome associated with intermittent oedema in childhood , resembling the rare aagenaes syndrome . 
 treatment choices in advanced hcc arising in adolescence are discussed . 
Introduction
Case
Discussion
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