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Liver: Hepatoblastoma

Written2001-11Marja Steenman
INSERM U533, Faculté de Médecine, 1 rue Gaston Veil - BP 53508, 44035 NANTES CEDEX 1, France

(Note : for Links provided by Atlas : click)


ICD-Morpho 8970/3 Hepatoblastoma
Atlas_Id 5089
Phylum Digestive organs: Liver::Hepatoblastoma
WHO/OMS Classification Digestive organs


    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

    Etiology 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).
    Epidemiology 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.
    Clinics 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.
    Pathology 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.


    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

    Note 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

    Loss of maternal alleles on chromosome arm 11p in hepatoblastoma.
    Albrecht S, von Schweinitz D, Waha A, Kraus JA, von Deimling A, Pietsch T
    Cancer research. 1994 ; 54 (19) : 5041-5044.
    PMID 7923113
    Pretreatment prognostic factors for children with hepatoblastoma-- results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1.
    Brown J, Perilongo G, Shafford E, Keeling J, Pritchard J, Brock P, Dicks-Mireaux C, Phillips A, Vos A, Plaschkes J
    European journal of cancer (Oxford, England : 1990). 2000 ; 36 (11) : 1418-1425.
    PMID 10899656
    Three non-overlapping regions of chromosome arm 11p allele loss identified in infantile tumors of adrenal and liver.
    Byrne JA, Simms LA, Little MH, Algar EM, Smith PJ
    Genes, chromosomes & cancer. 1993 ; 8 (2) : 104-111.
    PMID 7504513
    Liver tumors in children in the particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey--1974.
    Exelby PR, Filler RM, Grosfeld JL
    Journal of pediatric surgery. 1975 ; 10 (3) : 329-337.
    PMID 49416
    Childhood cancers: hepatoblastoma.
    Herzog CE, Andrassy RJ, Eftekhari F
    The oncologist. 2000 ; 5 (6) : 445-453.
    PMID 11110595
    Somatic mutations of beta-catenin play a crucial role in the tumorigenesis of sporadic hepatoblastoma.
    Jeng YM, Wu MZ, Mao TL, Chang MH, Hsu HC
    Cancer letters. 2000 ; 152 (1) : 45-51.
    PMID 10754205
    Mutation at codon 249 of p53 gene in a human hepatoblastoma.
    Kar S, Jaffe R, Carr BI
    Hepatology (Baltimore, Md.). 1993 ; 18 (3) : 566-569.
    PMID 8395458
    Cytogenetic and molecular studies on six sporadic hepatoblastomas.
    KiechleSchwarz M, Scherer G, Kovacs G
    Cancer Genet Cytogenet. 1989 ; 41 : page 286.
    Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene.
    Koch A, Denkhaus D, Albrecht S, Leuschner I, von Schweinitz D, Pietsch T
    Cancer research. 1999 ; 59 (2) : 269-273.
    PMID 9927029
    Familial Wiedemann-Beckwith syndrome and a second Wilms tumor locus both map to 11p15.5.
    Koufos A, Grundy P, Morgan K, Aleck KA, Hadro T, Lampkin BC, Kalbakji A, Cavenee WK
    American journal of human genetics. 1989 ; 44 (5) : 711-719.
    PMID 2539717
    Loss of heterozygosity in three embryonal tumours suggests a common pathogenetic mechanism.
    Koufos A, Hansen MF, Copeland NG, Jenkins NA, Lampkin BC, Cavenee WK
    Nature. 1985 ; 316 (6026) : 330-334.
    PMID 2991766
    Loss of heterozygosity on chromosome 1 in human hepatoblastoma.
    Kraus JA, Albrecht S, Wiestler OD, von Schweinitz D, Pietsch T
    International journal of cancer. Journal international du cancer. 1996 ; 67 (4) : 467-471.
    PMID 8759602
    Expression, promoter usage and parental imprinting status of insulin-like growth factor II (IGF2) in human hepatoblastoma: uncoupling of IGF2 and H19 imprinting.
    Li X, Adam G, Cui H, Sandstedt B, Ohlsson R, Ekström TJ
    Oncogene. 1995 ; 11 (2) : 221-229.
    PMID 7624139
    Cytogenetic characterization of childhood hepatoblastoma.
    Ma SK, Cheung AN, Choy C, Chan GC, Ha SY, Ching LM, Wan TS, Chan LC
    Cancer genetics and cytogenetics. 2000 ; 119 (1) : 32-36.
    PMID 10812168
    Occasional loss of constitutive heterozygosity at 11p15.5 and imprinting relaxation of the IGFII maternal allele in hepatoblastoma.
    Montagna M, Menin C, Chieco-Bianchi L, D'Andrea E
    Journal of cancer research and clinical oncology. 1994 ; 120 (12) : 732-736.
    PMID 7798299
    Somatic mutations of the APC gene in sporadic hepatoblastomas.
    Oda H, Imai Y, Nakatsuru Y, Hata J, Ishikawa T
    Cancer research. 1996 ; 56 (14) : 3320-3323.
    PMID 8764128
    A mutational hot spot in the p53 gene is associated with hepatoblastomas.
    Oda H, Nakatsuru Y, Imai Y, Sugimura H, Ishikawa T
    International journal of cancer. Journal international du cancer. 1995 ; 60 (6) : 786-790.
    PMID 7896446
    Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group.
    Ortega JA, Krailo MD, Haas JE, King DR, Ablin AR, Quinn JJ, Feusner J, Campbell JR, Lloyd DA, Cherlow J
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1991 ; 9 (12) : 2167-2176.
    PMID 1720452
    Parkin DM, Kramarova E, Draper GJ
    International incidence of childhood cancer, vol..
    The international incidence of childhood cancer.
    Parkin DM, Stiller CA, Draper GJ, Bieber CA
    International journal of cancer. Journal international du cancer. 1988 ; 42 (4) : 511-520.
    PMID 3170025
    Genetic linkage of Beckwith-Wiedemann syndrome to 11p15.
    Ping AJ, Reeve AE, Law DJ, Young MR, Boehnke M, Feinberg AP
    American journal of human genetics. 1989 ; 44 (5) : 720-723.
    PMID 2565083
    Loss of imprinting in hepatoblastoma.
    Rainier S, Dobry CJ, Feinberg AP
    Cancer research. 1995 ; 55 (9) : 1836-1838.
    PMID 7728748
    Chemotherapy effects on hepatoblastoma. A histological study.
    Saxena R, Leake JL, Shafford EA, Davenport M, Mowat AP, Pritchard J, Mieli-Vergani G, Howard ER, Spitz L, Malone M
    The American journal of surgical pathology. 1993 ; 17 (12) : 1266-1271.
    PMID 8238734
    The first recurring chromosome translocation in hepatoblastoma: der(4)t(1;4)(q12;q34).
    Schneider NR, Cooley LD, Finegold MJ, Douglass EC, Tomlinson GE
    Genes, chromosomes & cancer. 1997 ; 19 (4) : 291-294.
    PMID 9258666
    Comparative genomic hybridization analysis of hepatoblastomas: additional evidence for a genetic link with Wilms tumor and rhabdomyosarcoma.
    Steenman M, Tomlinson G, Westerveld A, Mannens M
    Cytogenetics and cell genetics. 1999 ; 86 (2) : 157-161.
    PMID 10545709
    Significance of extra copies of chromosome 20 and the long arm of chromosome 2 in hepatoblastoma.
    Swarts S, Wisecarver J, Bridge JA
    Cancer genetics and cytogenetics. 1996 ; 91 (1) : 65-67.
    PMID 8908169
    Timing 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, Buckley JD, Quinn JJ, Feusner JH, Krailo MD, King DR, Hammond GD, Ortega JA
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1997 ; 15 (3) : 1190-1197.
    PMID 9060563
    Characterization of genomic alterations in hepatoblastomas. A role for gains on chromosomes 8q and 20 as predictors of poor outcome.
    Weber RG, Pietsch T, von Schweinitz D, Lichter P
    The American journal of pathology. 2000 ; 157 (2) : 571-578.
    PMID 10934159
    Activation of beta-catenin in epithelial and mesenchymal hepatoblastomas.
    Wei Y, Fabre M, Branchereau S, Gauthier F, Perilongo G, Buendia MA
    Oncogene. 2000 ; 19 (4) : 498-504.
    PMID 10698519
    Trisomy 1q, 2, and 20 in a case of hepatoblastoma: possible significance of 2q35-q37 and 1q12-q21 rearrangements.
    Yeh YA, Rao PH, Cigna CT, Middlesworth W, Lefkowitch JH, Murty VV
    Cancer genetics and cytogenetics. 2000 ; 123 (2) : 140-143.
    PMID 11150606
    Complete 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, Hecker H, Harms D, Bode U, Weinel P, Bürger D, Erttmann R, Mildenberger H
    Journal of pediatric surgery. 1995 ; 30 (6) : 845-852.
    PMID 7545228


    This paper should be referenced as such :
    Steenman, M
    Liver: Hepatoblastoma
    Atlas Genet Cytogenet Oncol Haematol. 2002;6(1):53-55.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :

    Other genes implicated (Data extracted from papers in the Atlas) [ 17 ]


    External links

    arrayMap Topo ( C22) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
    Other databaseICGC Data Portal - [LIHC-US] Liver Hepatocellular carcinoma - TCGA, US
    Disease databaseLiver: Hepatoblastoma
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed

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