Hepatoblastoma is a malignant embryonal liver tumor that occurs almost exclusively in infants and very young children.
Hepatoblastoma is composed of epithelial and mesenchymal elements in varying proportions and at various stages of differentiation. The epithelial element recapitulates the stages of hepatocyte development from the primitive blastema through embryonal hepatocytes to fetal hepatocytes. The blastemal or undifferentiated cells have been postulated to represent neoplastic hepatocyte progenitor cells.
Epidemiology
world-wide incidence of 0.5-1.5 cases per million children
60 and 85% of all hepatic tumors in children
most common type of pediatric liver tumor
Synopsis
bilobar involvement is seen in 20-30%
multicentric involvement in 15%
elevated serum alpha-fetoprotein (AFP) levels
distant metastases usually occur very late in advanced disease stages
- rare placental localization in fetal forms (9724342)
Subtypes
Approximately 56% of tumors are of the epithelial type, which is subclassified further as pure fetal (31%), embryonal (19%), macrotrabecular (3%), and small-cell undifferentiated (anaplastic; 3%).
Approximately 44% of tumors contain both mixed epithelial and mesenchymal components. Mesenchymal elements may consist of osteoid, cartilage, or other spindle cells.
epithelial hepatoblastoma (56%)
- well differentiated fetal hepatoblastoma (31%)
- embryonal and fetal hepatoblastoma (19%)
- macrotrabecular pattern (3%)
- focal or diffuse small undifferentiated cells in hepatoblastoma (3%) (11753992)
mixed epithelial and mesenchymal hepatoblastoma (44%)
- without teratoid features
- with teratoid features
In completely resected tumors a pure fetal appearance confers a better prognosis, whereas a small cell undifferentiated or anaplasia is associated with a poor prognosis.
Variants
placental involvement in congenital hepatoblastoma (9724342)
Immunochemistry (2443437)
epithelial membrane antigen + (EMA)
cytokeratin +
alpha-fetoprotein +
+/- alpha 1-antitrypsin +
+/- ferritin +
+/- vimentin +
Predispostion - Association
chromosomal anomalies
- Down syndrome
- trisomy 18 (9267879, 9025831)
- partial trisomy 9p syndrome (15588861)
11p15 region deregulation
- Beckwith-Wiedemann syndrome (BWS)
- BWS-associated hepatoblastoma (16010495, 14692643)
- +/- opsoclonus-myoclonus
- hemihypertrophy
APC germline mutations
- familial adenomatous polyposis coli (FAP) (2848134)
- Gardner syndrome
- Goldenhar syndrome (oculoauriculovertebral dysplasia, absence of portal vein)
- Schinzel-Geidion syndrome
miscellaneous malformations
- heterotopic lung tissue
- horseshoe kidney
- persistent ductus arteriosus
- renal dysplasia
- right-sided diaphragmatic hernia
- umbilical hernia
- inguinal hernia
- absence of left adrenal gland
- bilateral talipes
- cleft palate
- macroglossia, dysplasia of ear lobes
- malrotation of colon
- meckel diverticulum
- pectum excavatum
- intrathoracic kidney
- single coronary artery
- duplicated ureters
other tumors
- synchronous Wilms tumor
metabolic diseases
- heterozygous alpha-antitrypsin deficiency
- type 1a glycogen storage disease
- cystothionuria
infections
- HIV infection
- HBV infection
consequences
- sexual precocity
- osteoporosis
- hypoglycemia
- Budd-Chiari syndrome
toxics and drugs
- maternal use of clomiphene and pergonal
- oral contraceptive
- alcohol embryopathy
miscellaneous conditions
- fetal hydrops
- very low birth weight
Cytogenetics (15981236)
abnormal karyotypes (50%)
numerical aberrations (36%)
- trisomies or gains
- trisomy 1q, tetrasomy 1q (10565309, 11150606)
- trisomy 2, gains of 2q (11150606, 9351578)
- trisomy 8
- trisomy 14, tetrasomy 14 (10565309)
- trisomy 19 (10565309)
- trisomy 20 (11150606, 9351578)
- deletions
structural anomalies
- translocations
- t(3;5)(p25;q31) (1377019)
- t(10;22) in undifferentiated small cell hepatoblastoma (1384017)
- t(22;22)(q11;q13) in undifferentiated small cell hepatoblastoma (12010372)
- t(7;8;11) (11943350)
- t(2;11) (11943350)
add(4)(q35) (15588850)
add(5)(q31) (10812168)
dup(4)(q12q26)
| Gains | 1q | 2p | 2q | 7q | 8p | 8q | 12p | 12q | 17 | 20 | 22q |
| % | 60% | 70% | - | - | - | - | - | - | 40% | 30% | - |
| Genes involved | - | - | - | - | - | PLAG1 | - | - | - | - | - |
| Losses | Chr.4 | Chr.11 | |||||||||
| % | 20% | 20% |
Amplified regions
8q11.2-q13 (14695992)
Molecular biology
11p15.15 imprinted genes deregulation
- LOH at 11p15 (7923113)
- high frequency of inactivation of the imprinted H19 gene in sporadic hepatoblastoma (10404060)
- loss of imprinting at 11p15.5 locus (7728748)
WNT signaling pathway deregulation
- beta-catenin accumulation (10398436)
- beta-catenin (CTNNB1) activating mutations (10398436)
- AXIN2 somatic inactivating mutations
TP53 mutations (2.5%) (8721685)
- anaplastic hepatoblastoma (8721685)
amplification and overexpression of the IGF2 regulator PLAG1 at 8q11.2-q13 (14695992)
Allelotyping
Transcriptional profiling (12935928)
Case records
Case 12619: Small hepatoblastoma
References
Tomlinson GE, Douglass EC, Pollock BH, Finegold MJ, Schneider NR. Cytogenetic evaluation of a large series of hepatoblastomas: numerical abnormalities with recurring aberrations involving 1q12-q21. Genes Chromosomes Cancer. 2005 Oct;44(2):177-84. PMID: 15981236
Haas JE, Feusner JH, Finegold MJ. Small cell undifferentiated histology in hepatoblastoma may be unfavorable. Cancer. 2001 Dec 15;92(12):3130-4. PMID: 11753992
Hu J, Wills M, Baker BA, Perlman EJ. Comparative genomic hybridization analysis of hepatoblastomas. Genes Chromosomes Cancer. 2000 Feb;27(2):196-201. PMID: 10612809
Weinberg AG, Finegold MJ. Primary hepatic tumors of childhood. Hum Pathol. 1983 Jun;14(6):512-37. PMID: 6303939
Lack EE, Neave C, Vawter GF. Hepatoblastoma. A clinical and pathologic study of 54 cases. Am J Surg Pathol. 1982 Dec;6(8):693-705. PMID: 6301295
Gonzalez-Crussi F, Upton MP, Maurer HS. Hepatoblastoma. Attempt at characterization of histologic subtypes. Am J Surg Pathol. 1982 Oct;6(7):599-612. PMID: 6295193