Liver: Hepatoblastoma

Classification

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.

Cytogenetics

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

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

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.

J Pediatr Surg.1975;10:329-337

Loss of heterozygosity in three embryonal tumours suggests a common pathogenetic mechanism.

Koufos A, Hansen M, Copeland N, Jenkins N, Lampkin B, Cavenee W.

Nature.1985;316:330-334

The international incidence of childhood cancer.

Parkin DM, Stiller CA, Draper GJ, Bieber CA.

Int J Cancer.1988;42:511-520

Cytogenetic and molecular studies on six sporadic hepatoblastomas.

Kiechle-Schwarz M, Scherer G, Kovacs G.

Cancer Genet Cytogenet.1989;41:286

Familial Wiedemann-Beckwith syndrome and a second Wilms tumor locus both map to 11p15.5.

Koufos A, Grundy P, Morgan K, Aleck K, Hadro T, Lampkin B, Kalbakji A, Cavenee W.

Am J Hum Genet.1989;44:711-719

Genetic linkage of Beckwith-Wiedemann syndrome to 11p15.

Ping A, Reeve A, Law D, Young M, Boehnke M, Feinberg A.

Am J Hum Genet.1989;44:720-723

Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group.

DA, Cherlow J, .

J Clin Oncol.1991;9:2167-2176

Three non-overlapping regions of chromosome arm 11p allele loss identified in infantile tumors of adrenal and liver.

Byrne J, Simms L, Little M, Algar E, Smith P.

Genes Chromosom Cancer.1993;8:104-111

Mutation at codon 249 of the p53 gene in a human hepatoblastoma.

Kar S, Jaffe R, Carr B.

Hepatology.1993;18:566-569

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, .

Am J Surg Pathol.1993;17:1266-1271

Loss of maternal alleles on chromosome arm 11p in hepatoblastoma.

Albrecht S, von Schweinitz D, Waha A, Kraus J, von Deissling A, Pietsch T.

Cancer Res.1994;54:5041-5044

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.

J Cancer Res Clin Oncol.1994;120:732-736

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, Ekstrom T.

Oncogene.1995;11:221-229

A mutational hotspot in the p53 gene is associated with hepatoblastomas.

Oda H, Nakatsuru Y, Imai Y, Sugimura H, Ishikawa T.

Int J Cancer.1995;60:786-790

Loss of imprinting in hepatoblastoma.

Rainier S, Dobry C, Feinberg A.

Cancer Res.1995;55:1836-1838

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, Burger D, Erttmann R, Mildenberger H.

J Pediatr Surg.1995;30:845-852

Loss of heterozygosity on chromosome 1 in human hepatoblastoma.

Kraus J, Albrecht S, Wiestler O, von Schweinitz D, Pietsch T.

Int J Cancer.1996;67:467-471

Somatic mutations of the APC gene in sporadic hepatoblastomas.

Oda H, Imai Y, Nakatsuru Y, Hata J, Ishikawa T.

Cancer Res.1996;56:3320-3323

Significance of extra copies of chromosome 20 and the long arm of chromosome 2 in hepatoblastoma.

Swarts S, Wisecarver J, Bridge J.

Cancer Genet Cytogenet.1996;91:65-67

The first recurring chromosome translocation in hepatoblastoma: der(4)t(1;4)(q12;q34).

Schneider N, Cooley L, Finegold M, Douglass E, Tomlinson G.

Genes Chromosom Cancer.1997;19:291-294

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.

J Clin Oncol.1997;15:1190-1197

Parkin DM, Kramarova E, Draper GJ.

International incidence of childhood cancer, vol. II. IARC Scientific publications. 1998.

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 Res.1999;59:269-273

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.

Cytogenet Cell Genet.1999;86:157-161

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.

Eur J Cancer.2000;36:1418-1425

Childhood cancers: hepatoblastoma.

Herzog CE, Andrassy RJ, Eftekhari F.

Oncologist.2000;5:445-453

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 Lett.2000;152:45-51

Cytogenetic characterization of childhood hepatoblastoma.

Ma SK, Cheung AN, Choy C, Chan GC, Ha SY, Ching LM, Wan TS, Chan LC.

Cancer Genet Cytogenet.2000;119:32-36

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.

Am J Pathol.2000;157:571-578

Activation of beta-catenin in epithelial and mesenchymal hepatoblastomas.

Wei Y, Fabre M, Branchereau S, Gauthier F, Perilongo G, Buendia MA.

Oncogene.2000;19:498-504

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 Genet Cytogenet.2000;123:140-143

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Contributor(s)

Written	11-2001	Marja Steenman
		INSERM U533, Faculté de Médecine, 1 rue Gaston Veil - BP 53508, 44035 NANTES CEDEX 1, France

Citation

This paper should be referenced as such :

Steenman M . Liver: Hepatoblastoma. Atlas Genet Cytogenet Oncol Haematol. November 2001 . URL : http://AtlasGeneticsOncology.org/Tumors/HepatoblastID5089.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Thu Apr 17 14:14:34 2008

For comments and suggestions or contributions, please contact us