Liver: Hepatoblastoma

2001-11-01   Marja Steenman 

1.INSERM U533, Faculté de Médecine, 1 rue Gaston Veil - BP 53508, 44035 NANTES CEDEX 1, France



There used to be multiple classification systems to distinguish between the different stages of hepatoblastoma development, making it difficult to compare results obtained by different study groups. In 1999 it was agreed that all groups would use the criteria of the SIOPEL group (SIOP = International Society of Paediatric Oncology). This group used (pre-treatment) intrahepatic tumor extension (PRETEXT) to classify the tumors. In this system the liver is divided into four sectors and the stages are based on the tumor extension within these four sectors:
  • Stage I: tumor in one sector, three adjoining sectors free;
  • Stage II: tumor involves two sectors, two adjoining sectors free;
  • Stage III: tumor involves two or three sectors, one sector or two non-adjoining sectors free;
  • Stage IV: tumor in all four sectors, no free sector.

    Additional information is noted as follows:

  • Hepatic vein (V): presence of hepatic vein involvement;
  • Portal vein (P): presence of portal vein involvement;
  • Extrahepatic (E): presence of extrahepatic direct spread, limited to enlargement of the hilar lymph nodes;
  • Metastases (M): presence of distant metastases.
  • Clinics and Pathology


    Most cases of hepatoblastoma are sporadic, but sometimes it is found to be associated with Beckwith-Wiedemann syndrome (BWS) or familial adenomatous polyposis coli (FAP).


    Hepatoblastoma occurs with a world-wide incidence of 0.5-1.5 cases per million children. It accounts for between 60 and 85% of all hepatic tumors in children and therefore it represents the most common type of pediatric liver tumor.


    Because of missing clinical symptoms during early growth, patients often present with locally extended tumors. The right lobe is involved three times more commonly than the left. Bilobar involvement is seen in 20-30% of the cases, multicentric involvement in 15%. Distant metastases usually occur very late in advanced disease stages. Often these patients have elevated serum alpha-fetoprotein (AFP) levels. Although there is no clear correlation between AFP and outcome, AFP level is a sensitive marker of disease. Furthermore, there is a correlation between AFP and extent of disease, and the rate of decline in AFP with treatment is prognostic.


    Histologically, HB can be classified into two major types: epithelial (56% of the cases) and mixed epithelial/mesenchymal (44% of the cases). The presence of mesenchymal elements has been associated with an improved prognosis in patients with advanced disease. The epithelial type can be further subdivided into 4 subtypes: pure fetal (31%), embryonal (19%), macrotrabecular (3%) and small cell undifferentiated (3%). In completely resected tumors a pure fetal histology confers a better prognosis, whereas a small cell undifferentiated histology is associated with a poor prognosis.


    Cytogenetics morphological

    Although cytogenetic analyses of HBs have been far from numerous, certain characteristics can be deduced from the literature. The most recurrent cytogenetic abnormalities are the presence of extra copies of chromosomes 2q and 20. Four cases have been reported with a t(1;4)(q12;q34) resulting in partial trisomy 1q and partial monosomy 4q. Chromosome breaks occur frequently at 1q12-q21 and 2q35-q37. In order to obtain a global overview of chromosomal losses and gains, two comparative genomic hybridization studies were performed on a total of 50 HBs. The results showed frequent gains of chromosomes 1, 2, 7, 8, 17, 20 and 22q, and loss of 4q.

    Genes Involved and Proteins


    Genes that play a causative role in the development of HB should be sought in the region associated with BWS (11p15.5). In addition, the FAP-genes APC and b-catenin represent good candidate genes for the onset of these tumors.
  • BWS, with which HB has been associated, has been linked to chromosome 11p15.5. In molecular analyses of sporadic HBs loss of heterozygosity (LOH) of this region has been found (33% of the cases in the largest series). This LOH has been shown to be uniquely of maternal origin, indicating a role for genomic imprinting in the disease. Indeed, loss of imprinting of insulin-like growth factor 2 (IGF2, located on 11p15.5) was found in a few cases. Loss of imprinting of the closely related H19 gene was found in one case but not in others.
  • Since HB also occurs with increased frequency in FAP patients, the APC gene has been the focus of some studies. Indeed, this gene shows a high frequency of loss of function mutations in sporadic HBs (69%). The APC gene has been implicated in the wingless/WNT developmental pathway, and another gene, b-catenin, that also plays a role in this pathway, has been shown to undergo activating mutations in a substantial amount of HBs.
  • In addition, mutations of p53 and LOH of chromosome 1 have been found.
  • Bibliography

    Pubmed IDLast YearTitleAuthors
    79231131994Loss of maternal alleles on chromosome arm 11p in hepatoblastoma.Albrecht S et al
    108996562000Pretreatment prognostic factors for children with hepatoblastoma-- results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1.Brown J et al
    75045131993Three non-overlapping regions of chromosome arm 11p allele loss identified in infantile tumors of adrenal and liver.Byrne JA et al
    494161975Liver tumors in children in the particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey--1974.Exelby PR et al
    111105952000Childhood cancers: hepatoblastoma.Herzog CE et al
    107542052000Somatic mutations of beta-catenin play a crucial role in the tumorigenesis of sporadic hepatoblastoma.Jeng YM et al
    83954581993Mutation at codon 249 of p53 gene in a human hepatoblastoma.Kar S et al
    99270291999Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene.Koch A et al
    25397171989Familial Wiedemann-Beckwith syndrome and a second Wilms tumor locus both map to 11p15.5.Koufos A et al
    29917661985Loss of heterozygosity in three embryonal tumours suggests a common pathogenetic mechanism.Koufos A et al
    87596021996Loss of heterozygosity on chromosome 1 in human hepatoblastoma.Kraus JA et al
    76241391995Expression, promoter usage and parental imprinting status of insulin-like growth factor II (IGF2) in human hepatoblastoma: uncoupling of IGF2 and H19 imprinting.Li X et al
    108121682000Cytogenetic characterization of childhood hepatoblastoma.Ma SK et al
    77982991994Occasional loss of constitutive heterozygosity at 11p15.5 and imprinting relaxation of the IGFII maternal allele in hepatoblastoma.Montagna M et al
    87641281996Somatic mutations of the APC gene in sporadic hepatoblastomas.Oda H et al
    78964461995A mutational hot spot in the p53 gene is associated with hepatoblastomas.Oda H et al
    17204521991Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group.Ortega JA et al
    31700251988The international incidence of childhood cancer.Parkin DM et al
    25650831989Genetic linkage of Beckwith-Wiedemann syndrome to 11p15.Ping AJ et al
    77287481995Loss of imprinting in hepatoblastoma.Rainier S et al
    82387341993Chemotherapy effects on hepatoblastoma. A histological study.Saxena R et al
    92586661997The first recurring chromosome translocation in hepatoblastoma: der(4)t(1;4)(q12;q34).Schneider NR et al
    105457091999Comparative genomic hybridization analysis of hepatoblastomas: additional evidence for a genetic link with Wilms tumor and rhabdomyosarcoma.Steenman M et al
    89081691996Significance of extra copies of chromosome 20 and the long arm of chromosome 2 in hepatoblastoma.Swarts S et al
    90605631997Timing and magnitude of decline in alpha-fetoprotein levels in treated children with unresectable or metastatic hepatoblastoma are predictors of outcome: a report from the Children's Cancer Group.Van Tornout JM et al
    109341592000Characterization of genomic alterations in hepatoblastomas. A role for gains on chromosomes 8q and 20 as predictors of poor outcome.Weber RG et al
    106985192000Activation of beta-catenin in epithelial and mesenchymal hepatoblastomas.Wei Y et al
    111506062000Trisomy 1q, 2, and 20 in a case of hepatoblastoma: possible significance of 2q35-q37 and 1q12-q21 rearrangements.Yeh YA et al
    75452281995Complete resection before development of drug resistance is essential for survival from advanced hepatoblastoma--a report from the German Cooperative Pediatric Liver Tumor Study HB-89.von Schweinitz D et al

    External Links


    Marja Steenman

    Liver: Hepatoblastoma

    Atlas Genet Cytogenet Oncol Haematol. 2001-11-01

    Online version: