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Solid Tumour Section
Mini Review
Liver: Hepatoblastoma
Marja Steenman
INSERM U533, Faculté de Médecine, 1 rue Gaston Veil - BP 53508, 44035 Nantes Cedex 1, France (MS)
Published in Atlas Database: November 2001
Online updated version : http://AtlasGeneticsOncology.org/Tumors/HepatoblastID5089.html
DOI: 10.4267/2042/37822
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Epidemiology
Classification
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.
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
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.
Clinics and pathology
Etiology
Most cases of hepatoblastoma are sporadic, but
sometimes it is found to be associated with BeckwithWiedemann syndrome (BWS) or familial adenomatous
polyposis coli (FAP).
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(1)
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Liver: Hepatoblastoma
Steenman M
Parkin DM, Stiller CA, Draper GJ, Bieber CA. The international
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Cytogenetics
Cytogenetics Morphological
KiechleSchwarz M, Scherer G, Kovacs G. Cytogenetic and
molecular studies on six sporadic hepatoblastomas. Cancer
Genet Cytogenet. 1989;41:Abst p286.
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.
Koufos A, Grundy P, Morgan K, Aleck KA, Hadro T, Lampkin
BC, Kalbakji A, Cavenee WK. Familial Wiedemann-Beckwith
syndrome and a second Wilms tumor locus both map to
11p15.5. Am J Hum Genet. 1989 May;44(5):711-9
Ping AJ, Reeve AE, Law DJ, Young MR, Boehnke M, Feinberg
AP. Genetic linkage of Beckwith-Wiedemann syndrome to
11p15. Am J Hum Genet. 1989 May;44(5):720-3
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Genes involved and proteins
Byrne JA, Simms LA, Little MH, Algar EM, Smith PJ. Three
non-overlapping regions of chromosome arm 11p allele loss
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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.
Kar S, Jaffe R, Carr BI. Mutation at codon 249 of p53 gene in a
human hepatoblastoma. Hepatology. 1993 Sep;18(3):566-9
Saxena R, Leake JL, Shafford EA, Davenport M, Mowat AP,
Pritchard J, Mieli-Vergani G, Howard ER, Spitz L, Malone M.
Chemotherapy effects on hepatoblastoma. A histological study.
Am J Surg Pathol. 1993 Dec;17(12):1266-71
Albrecht S, von Schweinitz D, Waha A, Kraus JA, von Deimling
A, Pietsch T. Loss of maternal alleles on chromosome arm 11p
in hepatoblastoma. Cancer Res. 1994 Oct 1;54(19):5041-4
Montagna M, Menin C, Chieco-Bianchi L, D'Andrea E.
Occasional loss of constitutive heterozygosity at 11p15.5 and
imprinting relaxation of the IGFII maternal allele in
hepatoblastoma. J Cancer Res Clin Oncol. 1994;120(12):732-6
Li X, Adam G, Cui H, Sandstedt B, Ohlsson R, Ekström TJ.
Expression, promoter usage and parental imprinting status of
insulin-like growth factor II (IGF2) in human hepatoblastoma:
uncoupling of IGF2 and H19 imprinting. Oncogene. 1995 Jul
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Oda H, Nakatsuru Y, Imai Y, Sugimura H, Ishikawa T. A
mutational hot spot in the p53 gene is associated with
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Rainier S, Dobry CJ, Feinberg AP. Loss of imprinting in
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von Schweinitz D, Hecker H, Harms D, Bode U, Weinel P,
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Atlas Genet Cytogenet Oncol Haematol. 2002; 6(1)
This article should be referenced as such:
Steenman M. Liver: Hepatoblastoma. Atlas Genet Cytogenet
Oncol Haematol. 2002; 6(1):50-52.
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