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

 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#)
  • undifferentiated small cell hepatoblastoma (#1384017#)

 mixed epithelial and mesenchymal hepatoblastoma (44%)

• without teratoid features
• with teratoid features

In completely resected tumors a pure fetal histology confers a better prognosis, whereas a small cell undifferentiated histology is associated with a poor prognosis.

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) +/- opsoclonus-myoclonus
• hemihypertrophy

 APC germline mutations

• familial adenomatous polyposis coli (FAP) (#2848134#)
• Gardner syndrome

 malformative syndromes

• Goldenhar syndrome (oculoauriculovertebral dysplasia, absence of portal vein)
• Schinzel-Geidion syndrome

 genetic diseases

• Prader-Willi syndrome
• Aicardi 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
  • del(1)(p22) (#15588850#)
  • del(3)(q11.2;q13.2)(#12034532#)
  • del(12)(p12) (#15588850#)
  • del(17p): del(17)(p12) (#7530489#)

 structural anomalies

• translocations
  • unbalanced translocations involving 1q12-21 (18%)
    • t(1;1) (#11943350#)

 add(4)(q35) (#15588850#)
 add(5)(q31) (#10812168#)
 dup(4)(q12q26)

CGH (#10934159#, #10612809#)

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

 11p15 LOH (#7923113#)

Transcriptional profiling (#12935928#)

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#