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Definition: 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

An increased incidence of hepatoblastoma (from 0.4 to 1.0 per million between 1971 and 1983) has been observed at a Children’s Tumour Registry in Manchester, United Kingdom.

The US National Cancer Institute Surveillance, Epidemiology, and End Result (SEER) program includes approximately 14% of the population; it revealed an average annual increase of 5.2% in the incidence of hepatoblastoma from 1973 to 1992.3 This change might be explained by hepatoblastoma occurring in surviving premature infants.

Hepatoblastomas in Japan accounted for 58% of all malignancies in children who weighed less than 1000 g at birth.4 Further analysis of the Japanese Children’s Cancer Registry data revealed that 15 (5%) of 303 hepatoblastomas between 1985 to 1995 occurred in infants with history of prematurity and weight less than 1500 g at birth. This rate was greater than 10 times that for all live births.

The relative risk for hepatoblastoma for children who weighed less than 1000 g at birth was 15.64 compared with 2.53 for those 1000 g to 1499 g and 1.21 for 2000 g to 2499 g.

Of 77 children with hepatoblastoma in the German registry, 3 (4%) were premature infants who required parenteral nutrition, a treatment that has been lifesaving for many small premature infants but has been reported to lead to cirrhosis in many survivors. It has not previously been associated with hepatoblastoma. The histologic features of hepatoblastoma following prematurity are indistinguishable from other hepatoblastomas.

The Children’s Cancer Group has evaluated environmental or drug exposure. Seventyfive sets of parents of children with hepatoblastoma were compared with those of age-matched controls. Before and during pregnancy, there was a significant excess of maternal exposure to metals used in welding and soldering, lubricating oils, and protective greases.6 Paternal exposure to metals was also greater. At 23 weeks, a congenital hepatoblastoma was found in a stillborn fetus whose mother was an artist exposed to volatile hydrocarbons.

Clinical features

The presenting symptom of virtually all liver tumors in children is abdominal swelling secondary to hepatomegaly. When confronted with this symptom, it is useful to consider the age at which liver tumors tend to occur.

Exceptions are frequent, but age can serve as a guide when the presenting symptoms lack specificity. In the Pediatric Oncology Group series from 1986 to 2002,1 66% of hepatoblastomas were manifest by the second year, and 11% before 6 months of age.

Approximately 50% of those in infants were congenital, given their size when discovered by 2 to 3 months of age; 6% of hepatoblastomas occurred after age 5 years. Hepatocellular carcinomas have been observed as early as 6 months. Seven examples of mixed hepatoblastomas and hepatocellular carcinomas have been observed at a mean age of 8.5 years; perinatally acquired hepatitis B virus was responsible in 3 instances.

Yolk sac tumors are more common in early childhood, but they also occur rarely in older adults. Systemic malignancies and metastatic disease must be considered at all ages because hepatomegaly due to megakaryoblastic leukemia, Langerhans cell histiocytosis, and neuroblastoma are important sources of confusion with hepatoblastoma in infancy, as are intra-abdominal desmoplastic small round cell tumors later in childhood.

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#)

Macroscopy

The evaluation of margins for total or partial hepatectomy specimens depends on the method and extent of resection. It is recommended that the surgeon be consulted to determine the critical foci within the margins that require microscopic evaluation.

The transection margin of a partial hepatectomy may be large, rendering it impractical for complete examination. In this setting, grossly positive margins should be microscopically confirmed and documented.

If the margins are grossly free of tumor, judicious sampling of the cut surface in the region closest to the nearest identified tumor nodule is indicated. In selected cases, adequate random sampling of the cut surface may be sufficient. If the neoplasm is found near the surgical margin, the distance from the margin should be reported.

For multiple tumors, the distance from the nearest tumor should be reported.

Microscopy and 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%)
  • hepatoblastoma, epithelial type, purely fetal pattern (mitotically inactive)
  • hepatoblastoma, epithelial type, purely fetal pattern (mitotically active)
• embryonal and fetal hepatoblastoma (19%)
• hepatoblastoma, epithelial type, macrotrabecular pattern (3%)
• focal or diffuse small undifferentiated cells in hepatoblastoma (3%) (#11753992#)
  • undifferentiated small cell hepatoblastoma (#1384017#)

 mixed epithelial and mesenchymal hepatoblastoma (44%)

• hepatoblastoma, mixed epithelial and mesenchymal type, without teratoid features
• hepatoblastoma, mixed epithelial and mesenchymal type, with teratoid features
• hepatoblastoma, rhabdoid type
• hepatoblastoma, other subtype

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.

There is no relationship between the age of the child and predominant cell type in hepatoblastoma.

Of all cases at all ages, 85% to 90% contain both fetal and embryonal derivatives in variable proportions; 20% have stromal derivatives. Because these histologic types tend to be randomly intermingled, both fine-needle aspiration and biopsies may capture a nonrepresentative sample of tumor.

 epithelial fetal hepatoblastoma

Distinguishing well-differentiated (mitotically inactive) fetal hepatocytic tumor cells from normal liver in an infant can be difficult. The fetal tumor cells are larger than normal fetal hepatocytes and have a higher nuclear cytoplasmic ratio. The nuclei are regular and round with little discernible mitotic activity (<2 mitoses per 10 high-power [X40 objective] fields) in the well-differentiated variety.

Fetal tumor cells grow in cords, as in normal liver, or nests or nodules. Clusters of normoblasts (extramedullary hematopoiesis) are commonly seen, as in fetal liver. The cytoplasm of the fetal tumor cells varies from eosinophilic to clear, depending on the amount of glycogen content. Fetal tumor cells may also contain abundant lipid, producing vacuolization. In well-differentiated fetal hepatoblastoma, bile secretion may be observed.

Well-differentiated (mitotically inactive) fetal histology was superior to embryonal differentiation in long-term survival; therefore, the COG study is treating stage I well-differentiated fetal hepatoblastoma (with low mitotic rate) with surgery alone.

 epithelial fetal and embryonal hepatoblastoma

The embryonal cellular component of hepatoblastoma is less well-differentiated than its fetal hepatocytic counterpart, with cells that are small and have a high nuclear cytoplasmic ratio with ovoid nuclei and that may assume a tubular or rosette-like configuration. Purely embryonal tumors are almost never encountered and invariably show some fetal areas.

 macrotrabecular

A macrotrabecular pattern of hepatoblastoma growth is one in which fetal or embryonal cells numbered 20 or more within a cord or cluster, as opposed to the usual 2- to 6-cellthick cords or plates.

 anaplastic hepatoblastoma and undifferentiated hepatoblastoma

An urgent research need is to identify more effective medical therapy for both small cell undifferentiated hepatoblastoma and rhabdoid hepatoblastoma, the most aggressive forms of this malignancy.

When first distinguished from embryonal epithelium, small undifferentiated cells in hepatoblastoma were noted to resemble neuroblastoma, to have a low mitotic rate, and were called "anaplastic", consistent with the dictionary definition, characterized by imperfect development.

Since “anaplastic” was redefined by Faria et al20 for Wilms tumor as nuclear enlargement to 3 times those of typical tumor cells, hyperchromasia and atypical mitoses, the small cell undifferentiated component no longer is designated as anaplastic.

Beckwith-type anaplasia does occur rarely in hepatoblastoma, and its significance is unknown. The small cells have been considererd a putative hepatic progenitor cells on the basis of immunohistochemical and electron microscopic studies.

When present in a significant fraction of the hepatoblastoma (75%), or as the sole cell type, the small cell type is typically found in infants younger than 1 year; they have a poor prognosis, with poor response to current therapy.

The prognostic significance of smaller proportions of the small cell undifferentiated type is still undetermined.

 rhabdoid hebatoblastoma

Rhabdoid cells have the characteristic eccentric pink cytoplasmic inclusions (periodic acid-Schiff/diastase positive, vimentin or cytokeratin positive) with vesicular nuclei and fibrillar inclusion bodies by electron microscopy.

They may be associated with the small cell component in otherwise typical hepatoblastomas or as the exclusive cell type, in which case they occur in infancy and are associated with a poor prognosis.

 mixed hepatoblastoma (epithelial and mesenchymatous hepatoblastoma)

Often, mixed hepatoblastomas contain epithelial membrane antigen (EMA)-positive nests of squamous epithelium. The osteoid component of mixed hepatoblastomas is found to be a matrix of collagen surrounding cells expressing EMA and having ultrastructural features of epithelium rather than osteoblasts.

Hepatoblastomas may contain other stromal derivatives, including cartilage and rhabdomyoblasts. There is no prognostic significance to the presence of mixed histologic features.

 multinucleated tumor giant cells

Multinucleated tumor giant cells are found in rare hepatoblastomas, sometimes associated with HCG production and clinical virilization.

 teratoid hepatoblastoma

Teratoid hepatoblastoma was initially depicted as having intestinal, neural, and melanocytic elements. These are distinguished from true teratomas, which can also occur in the livers of children, on the basis of organoid differentiation and even greater diversity of tissue elements in the teratomas.

 post-chemotherapy hepatoblastoma

Postchemotherapy resection specimens often show eradication of the embryonal cells and more prevalent osteoid-like foci.

Heifetz et al. reported that vascular invasion, amount of mesenchyme, persistence of embryonal epithelium, extent of tumor necrosis, and mitotic activity of the epithelial component have predictive value in this type of specimen.

This has yet to be confirmed, but the items should be documented, as should the presence of any small undifferentiated cells, which are known to negatively affect prognosis but may have been missed in the initial biopsies of stage III and IV lesions.

 lymph nodes

Histologic examination of a regional lymphadenectomy specimen usually involves examination of 3 or more lymph nodes. The regional lymph nodes of the hepatic region include the hilar, hepatoduodenal ligament, and caval lymph nodes. Nodal involvement of the inferior phrenic lymph nodes or other lymph nodes distal to the hilar, hepatoduodenal ligament, and caval lymph nodes are considered as distant metastasis.

Histological grade

 Favorable grade

• epithelial, purely fetal hepatoblastoma, mitotically inactive with 2 or fewer mitoses in 10, X40 objective

 Less favorable grade

• others type except unfavorable, below.
• May be more favorable if stage I (usually treated with multimodality therapy).

 Unfavorable grade

• small cell undifferentiated hepatoblastoma, predominant or sole histopathologic subtype, at any stage or therapy
• rhabdoid hepatoblastoma, predominant or sole histopathologic subtype, at any stage or therapy

Tumors with favorable histopathologic features are purely fetal, well-differentiated lesions defined as mitotically inactive with a minimal mitotic rate of 2 or fewer mitoses per 10, X40 objective fields. These tumors are also stage I and are usually treated with surgery alone.

Tumors with unfavorable histopathologic features have either undifferentiated small cell or rhabdoid subtypes or both.

When present in a significant fraction of the hepatoblastoma (75%) or as the sole cell type, the small cell, undifferentiated subtype is typically found in infants younger than 1 year with poor prognosis regardless of stage or therapy. When this subtype is present in lesser proportions, the prognostic implications remain undetermined.

When the rhabdoid cell type is the exclusive histopathology, it is also found typically in infants with poor prognosis.

Less favorable histopathologies include all other tumor subtypes not mentioned above, although they may be associated with favorable prognosis if stage I, and are usually treated with multimodal therapy.

Staging

Staging in the United States combines imaging with surgical judgment about resectability.

Computed tomography and magnetic resonance imaging are used exclusively in the SIOPEL (Societé Internationale D’Oncologie Pediatrique Liver Tumor Study Group) protocol to determine the location and extent of hepatic involvement of hepatoblastoma preoperatively; tumors sparing the left medial and right anterior sectors are primarily resected.

Dissemination of hepatic malignancies occurs within portal veins and follows the expected ready access of infiltration into hepatic veins, with frequent lung involvement.

Further spread to the brain may occur. Hilar lymph node metastases are relatively infrequent, but capsular rupture of subcapsular masses either before or during surgery can upstage an otherwise resectable malignancy.

The Children’s Oncology Group staging system is recommended for hepatoblastomas.

Stage I (favorable histologic type) tumors are completely resected and have typical histologic features of a purely fetal well-differentiated histologic pattern (minimal mitotic index of 2 mitoses per 10 high-power [X40 objective] fields).

Stage I (other histologic type) tumors are completely resected, with a histologic picture other than purely fetal, well-differentiated pattern.

Stage II tumors are grossly resected with evidence of microscopic residual tumor. Such tumors are rare, and patients with this stage have not fared differently from those with stage I tumors in previous protocols. Resected tumors with preoperative (intraoperative) rupture are classified stage II.

Stage III (unresectable) tumors are those that are considered by the attending surgeon not to be resectable without undue risk to the patient. These include partially resected tumors with measurable tumor left behind. They do not include grossly resected tumors with microscopic disease at the margins or resected tumors with preoperative/intraoperative rupture. Lymph node involvement is considered stage III disease and may require evaluation with second laparotomy after initial 4 courses of chemotherapy.

Stage IV tumors are those that present with measurable metastatic disease to the lungs or other organ. Nodal involvement of the inferior phrenic lymph nodes or other lymph nodes distal to the hilar, hepatoduodenal ligament, or caval lymph nodes are considered as distant metastases.

Resectability is the key prognostic feature for all liver malignancies, with the possible exception of rhabdomyosarcoma (see separate College of American Pathologists protocol for rhabdomyosarcoma).

Unfortunately 67% of hepatoblastomas were not amenable to primary surgery (48% stage III and 19% stage IV) in the 16 years of Pediatric Oncology Group/Children’s Oncology Group accessions.

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

 malformative syndromes

• Goldenhar syndrome (oculoauriculovertebral dysplasia, absence of portal vein)
• Schinzel-Geidion syndrome
• Beckwith-Wiedemann syndrome
• Beckwith-Wiedemann syndrome with opsoclonus, myoclonus
• Budd-Chiari syndrome

 genetic diseases

• Prader-Willi syndrome
• Aicardi syndrome
• Sotos syndrome (#19914434#)
• Li-Fraumeni syndrome (TP53 germline mutation)

 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
• Absence of left adrenal gland
• bilateral talipes
• duplicated ureters
• dysplasia of ear lobes
• cleft palate
• fetal hydrops
• hemihypertrophy
• heterotopic lung tissue
• horseshoe kidney
• inguinal hernia
• intrathoracic kidney
• macroglossia
• Meckel diverticulum
• persistent ductus arteriosus
• renal dysplasia
• right-sided diaphragmatic hernia
• single coronary artery
• umbilical hernia

 other tumors

• synchronous Wilms tumor

 metabolic diseases

• heterozygous alpha-antitrypsin deficiency
• type 1a glycogen storage disease
• cystothionuria
• Cystathioninuria
• Glycogen storage disease types Ia, III, and IV
• Hypoglycemia
• Heterozygous alpha1-antitrypsin deficiency
• Isosexual precocity
• Prematurity
• Total parenteral nutrition
• Very low birth weight

 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

 Environmental / Other

• Alcohol embryopathy
• Human immunodeficiency virus or hepatitis B virus infection
• Maternal clomiphene citrate or Pergonal
• Oral contraceptive, mother
• Oral contraceptive, patient
• Osteoporosis
• Synchronous Wilms tumor

 miscellaneous conditions

• fetal hydrops
• very low birth weight

Cytogenetics (#15981236#)

Karyotyping of hepatoblastomas has revealed a recurrent pattern of chromosomal abnormalities. The most common karyotypic changes are extra copies of entire chromosomes (trisomies), sometimes in conjunction with other complex structural changes and often in association with double-minute chromosomes.

Trisomies of chromosomes 2 and 20 have each been reported most commonly,8,9 and each of these trisomies has been reported as a sole karyotypic event, suggesting that they may represent an early stage of tumor evolution.

Trisomy of chromosome 20 and duplication of the long arm of chromosome 20 have been also observed in rhabdomyosarcoma, suggesting a link between these 2 embryonal tumors, both of which are associated also with losses at the Beckwith-Wiedemann syndrome locus.

Trisomy of chromosome 8 is also common; other trisomies are seen with lesser frequency. Occasional losses of entire chromosomes are seen, and these, too, are not random.

The clinical significance of trisomies is at present unknown, although a recent study using comparative genomic hybridization has suggested that chromosomal gains at chromosome 8 and 20 may be associated with an adverse prognosis.

A unique translocation has been reported in undifferentiated small cell hepatoblastoma, a variant associated with a poor prognosis, although this cytogenetic variant has not been reported in other cases.

 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
  • 1q12-21 rearrangements (18%) (#15981236#)
    • t(1;1) (#11943350#)
    • t(1;4)(q12;q34) (#9258666#, #10812168#, #15981236#) (6%)

• • 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)

CGH (#10934159#, #10612809#)

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

Numerous recent studies have documented molecular genetic abnormalities in hepatoblastomas and other hepatic tumors. Several genetic changes are shared with other embryonal tumors, such as loss of heterozygosity at chromosome 11p15, also described in rhabdomyosarcomas and Wilms tumors.

Acquired mutations of the APC gene and the ß-catenin gene, both members of the Wnt signaling pathway, have also been reported in hepatoblastoma.

The high frequency of ß-catenin mutations in hepatoblastomas and the increased incidence of hepatoblastomas in familial adenomatous polyposis families suggest the important role of an overactivation of wingless/Wnt pathway in the pathogenesis of hepatoblastoma.

 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#)

APC (APC-associated hepatoblastoma)

 Germline APC mutations are not commonly seen in children with sporadic hepatoblastoma. (#18955873#)

 APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. (#16126064#)

Anomalies of methylation

 MT1G hypermethylation is a potential prognostic marker for hepatoblastoma. (#20032811#)

Allelotyping

 11p15 LOH (#7923113#)

Transcriptional profiling (#12935928#)

siRNA

 Altered microRNA Expression Patterns in Hepatoblastoma Patients. (#19701500#)

Case records

 Case 12619: Small hepatoblastoma

Books

 Finegold MJ. Hepatic tumors in childhood. In: Russo P, Ruchelli ED, Piccoli D, eds. Pathology of Pediatric Gastrointestinal and Liver Disease. New York, NY: Springer-Verlag; 2004:300-346.

References

Cytogenetics and CGH

 Cytogenetic and array comparative genomic hybridization analysis of a series of hepatoblastomas. Stejskalová E, Malis J, Snajdauf J, Pýcha K, Urbánková H, Bajciová V, Starý J, Kodet R, Jarosová M. Cancer Genet Cytogenet. 2009 Oct 15;194(2):82-7. PMID: #19781440#

 Cytogenetic evaluation of a large series of hepatoblastomas: numerical abnormalities with recurring aberrations involving 1q12-q21. Tomlinson GE, Douglass EC, Pollock BH, Finegold MJ, Schneider NR. Genes Chromosomes Cancer. 2005 Oct;44(2):177-84. PMID: #15981236#

 Cytogenetic findings in two new cases of hepatoblastoma. Ali W, Savasan S, Rabah R, Mohamed AN. Cancer Genet Cytogenet. 2002 Mar;133(2):179-82.PMID: #11943350#

 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#

 Fletcher JA, Kozakewich HP, Pavelka K et al. Consistent cytogenetic aberrations in hepatoblastoma: a common pathway of genetic alterations in embryonal liver and skeletal muscle malignancies? Genes Chromosomes Cancer. 1991;3:37-43.

 Steenman M, Tomlinson G, Westerveld A, Mannens M. Comparative genomic hybridization analysis of hepatoblastomas: additional evidence for a genetic link with Wilms tumor and rhabdomyosarcoma. Cytogenet Cell Genet. 1999;86:157-161.

 Weber RG, Pietsch T, von Schweinitz D, Lichter P. Characterization of genomic alterations in hepatoblastomas: a role for gains on chromosomes 8q and 20 as predictors of poor outcome. Am J Pathol. 2000;157:571-578.

gene mutations

 Germline APC mutations are not commonly seen in children with sporadic hepatoblastoma. Harvey J, Clark S, Hyer W, Hadzic N, Tomlinson I, Hinds R. J Pediatr Gastroenterol Nutr. 2008 Nov;47(5):675-7. PMID: #18955873#

 The spectrum of APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. Hirschman BA, Pollock BH, Tomlinson GE. J Pediatr. 2005 Aug;147(2):263-6. PMID: #16126064#

 Jeng YM, Wu MZ, Mao TL, Chang MH, Hsu HC. Somatic mutations of beta-catenin play a crucial role in the tumorigenesis of sporadic hepatoblastoma. Cancer Lett. 2000;152:45-51.

 Koch A, Denkhaus D, Albrecht S, Leuschner I, von Schweinitz D, Pietsch T. Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene. Cancer Res. 1999;59:269-273.

DNA methylation

 MT1G hypermethylation: a potential prognostic marker for hepatoblastoma. Sakamoto LH, de Camargo B, Cajaiba M, Soares FA, Vettore AL. Pediatr Res. 2009 Dec 21. PMID: #20032811#

Expression profiling

 Signature genes for both hepatoblastoma and hepatocellular carcinoma. Chen F, Li S, Castranova V. Eur J Gastroenterol Hepatol. 2009 Oct;21(10):1220-2. PMID: #19749507#

miRNA

 Altered microRNA Expression Patterns in Hepatoblastoma Patients. Magrelli A, Azzalin G, Salvatore M, Viganotti M, Tosto F, Colombo T, Devito R, Di Masi A, Antoccia A, Lorenzetti S, Maranghi F, Mantovani A, Tanzarella C, Macino G, Taruscio D. Transl Oncol. 2009 Aug 18;2(3):157-63. PMID: #19701500#

Microscopical subtypes

 Small cell undifferentiated histology in hepatoblastoma may be unfavorable. Haas JE, Feusner JH, Finegold MJ. Cancer. 2001 Dec 15;92(12):3130-4. PMID: #11753992#

 Undifferentiated small cell hepatoblastoma with a unique chromosomal translocation: a case report. Hansen K, Bagtas J, Mark HF, Homans A, Singer DB. Pediatr Pathol. 1992;12:457-462.

 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#

Surgery

 Schnater JM, Aronson DC, Plaschkes J et al. Surgical view of the treatment of patients with hepatoblastoma: results from the first prospective trial of the International Society of Pediatric Oncology Liver Tumor Study Group. Cancer. 2002;94:1111-1120.