Background
Hepatoblastoma is the most common liver cancer in children, although it is relatively uncommon compared with other solid tumors in the pediatric age group. Over the past several years, pathologic variations of hepatoblastoma have been identified, and techniques for establishing the diagnosis of childhood hepatic tumors have improved. Surgical techniques and adjuvant chemotherapy have markedly improved the prognosis of children with hepatoblastoma. Complete surgical resection of the tumor at diagnosis, followed by adjuvant chemotherapy, is associated with 100% survival rates, but the outlook remains poor in children with residual disease after initial resection, even if they receive aggressive adjuvant therapy.
Considerable controversy has surrounded the discrepancy between US and international hepatoblastoma therapeutic protocols; surgery and staging are initially advised in the United States, whereas adjuvant therapy is strongly considered internationally. Significant data now support a role for preoperative neoadjuvant chemotherapy if the tumor is inoperable or if the tumor is unlikely to achieve gross total resection at initial diagnosis.[1] Early involvement of hepatologists and liver transplant teams is recommended if the tumor may not be completely resectable even with preoperative adjuvant chemotherapy. Liver transplantation is playing an increasing role in cases in which the tumor is deemed nonresectable after chemotherapy is administered or in "rescue" transplantation when initial surgery and chemotherapy are not successful.[2, 3]
Finally, reports state that aggressive surgical intervention may be warranted for isolated pulmonary metastases.[1, 4]
Pathophysiology
Hepatoblastomas originate from immature liver precursor cells and present morphologic features that mimic normal liver development. Hepatoblastomas are usually unifocal and affect the right lobe of the liver more often than the left lobe. Microvascular spread can extend beyond the apparently encapsulated tumor.
Grossly, the tumor is a tan bulging mass with a pseudocapsule. Cirrhosis is not associated with this tumor. Metastases affect the lungs and the porta hepatis; bone metastases are very rare. CNS involvement has been reported at diagnosis and during relapse. The identification of distinct subtypes and further molecular biological information derived regarding liver ontogenesis and growth regulation of hepatic tumors has recently helped pave the way for a more comprehensive classification system for this disease.
Loss of heterozygosity (LOH) of chromosome arm 11p markers occurs commonly in hepatoblastoma identified in association with Beckwith-Wiedemann syndrome (BWS) and hemihypertrophy. Isochromosome 8q is seen in mixed hepatoblastomas, and trisomy 20 is seen in pure epithelial hepatoblastomas (see Histologic Findings).
Patients with familial adenomatous polyposis (FAP), a syndrome of early-onset colonic polyps and adenocarcinoma, frequently develop hepatoblastomas. Germline mutations in the APC tumor suppressor gene occur in patients with FAP, and mutations in the APC tumor suppressor gene are frequently detected in the colonic polyps and adenocarcinomas associated with FAP. One study estimated that 1 in 20 hepatoblastomas is probably associated with FAP.[5] Interestingly, APC mutations, although common in patients with hepatoblastoma and FAP, are rare in patients with sporadic hepatoblastomas. Recently, Sanders and Furman reported 2 brothers with hepatoblastoma who had a significant family history of early onset colon cancer.[6] Testing of the younger brother revealed a deletion in exon 15 of the APC gene consistent with a diagnosis of FAP.
In a study of 29 tumors from children with sporadic hepatoblastoma, no germline APC mutations were found.[7] These authors conclude that routine APC screening does not need to be performed in these children without a family history of colorectal cancer or FAP.
Loss of function mutations in APC lead to intracellular accumulation of the protooncogene b-catenin, an effector of Wnt signal transduction. b-catenin mutations have been shown to be common in sporadic hepatoblastomas, occurring in as many as 67% of patients. Furthermore, a study in a mouse model of hepatoblastomas induced by toxin exposure detected mutations of the b-catenin protooncogene in 100% of the tumors analyzed (27 of 27).[8] This finding suggests that alterations in the Wnt signaling pathway likely contribute to the neoplastic process in this particular tumor.
Recent studies on other components of the Wnt signaling pathway have also demonstrated a likely role for constitutive activation of this pathway in the etiology of hepatoblastoma.[9, 10] Overexpression of human Dickkopf-1, a known antagonist of the Wnt pathway, has been found in hepatoblastoma. The authors postulate that this may be a direct negative feedback mechanism resulting from increased β-catenin commonly found in this tumor.[11]
A mutation in the axin gene, also a known antagonist of β-catenin accumulation, has been found in hepatoblastoma and may contribute to the etiology of the smaller percentage of hepatoblastomas in which β-catenin mutations have not been identified, thus implicating the constitutive activation of the Wnt pathway in a significant fraction of hepatoblastomas.[12, 13] Kuroda et al demonstrated a potential role for transcriptional targeting of tumors with strong β-catenin/T-cell factor activity with oncolytic herpes simplex virus vector.[14] The hedgehog (Hh) pathway has also been evaluated and has been found to be a potential therapeutic target for hepatoblastomas in which the Hh pathway is overexpressed or reactivated at an inappropriate time.[15]
Blocking the Hh pathway with the antagonist cyclonamine has shown a strong inhibitory effect on hepatoblastoma cell line proliferation. A high frequency of glioma-associated oncogene homolog 1 (GLI1) and patched homolog 1 (PTCH1) overexpression and Hh-interacting protein (HHIP) promoter methylation is noted in early childhood hepatoblastoma, which also supports a key role for Hh signalling activation in malignant transformation of embryonal liver cells.[16]
Wnt pathway activation appears to be more prevalent in embryonal and mixed subtypes of hepatoblastoma, whereas notch pathway activation is more prevalent with the more differentiated pure fetal hepatoblastoma tumors.[17] The relative activation of Hh, Wnt, and notched signaling pathways appears to be useful in stratification of different subtypes.
Increasing evidence suggests that hepatoblastoma is derived from a pluripotent stem cell.[18] This further supports the hypothesis that this tumor arises from a developmental error during hepatogenesis and supports the hypothesis that research particularly focused on these developmental processes governing liver maturation and growth may ultimately lead to more effective targeted therapy for this disease.
Epidemiology
Frequency
United States
Hepatoblastoma accounts for 79% of all liver tumors in children and almost two thirds of primary malignant liver tumors in the pediatric age group. Approximately 100 cases of hepatoblastoma are reported per year. The annual incidence of hepatoblastoma in infants younger than 1 year is 11.2 cases per million; in 1990-1995, the annual incidence in children overall was 1.5 cases per million, which is almost double the incidence from 1975-1979.
A significantly higher rate of hepatoblastomas is observed among low birth weight (LBW) and very low birth weight (VLBW) infants born prematurely.[19]
A Children’s Oncology Group (COG) protocol (AEP104C1) is currently investigating exogenous and endogenous causes for the increase in incidence and potential cause of premature births. The study is also exploring potential effectors independent of prematurity and LBW or VLBW. All children with hepatoblastoma diagnosed before age 6 years from 2000-2005 are eligible for retrospective analysis, and prospective analysis will be performed for children diagnosed between June 2005 and December 31, 2008. This is the largest, most comprehensive case-control study of hepatoblastoma performed thus far.
International
In Japan, efforts to improve vaccination rates have led to decreases in hepatocellular carcinoma (HCC) and, to a lesser degree, in hepatoblastoma. Carcinogen exposure in some developing countries is linked to hepatoblastoma and HCC.
Mortality/Morbidity
A large multicenter COG study included 182 children with hepatoblastoma diagnosed between August 1989 and December 1992.[20] Of these, 9 had stage I disease with favorable histology (FH), 43 had stage I with unfavorable histology (UH), 7 had stage II, 83 had stage III, and 40 had stage IV disease (see Staging).
All 9 patients with stage I and FH received treatment with low-dose doxorubicin and were alive and free of disease. Overall survival rates for all stages 5 years after treatment were 57-69%. The 5-year event-free survival (EFS) rates were 91% for patients with stage I with UH, 100% for stage II, 64% for stage III, and 25% for stage IV.
In general, patients who undergo complete resection of the tumor and adjuvant chemotherapy have a survival rate of 100%. Patients with favorable histology and low mitotic rate with complete resection may not require chemotherapy; for this reason, US protocols have advocated for formal staging and pathologic diagnosis prior to administering any adjuvant chemotherapy.
More recently, data from the International Childhood Liver Tumour Strategy Group (SIOPEL), which used preoperative adjuvant chemotherapy, demonstrated overall survival rates as high as 89% and event-free survival rates as high as 80%.[21] Australian investigators demonstrated that patients treated between 1984 and 2004 also had excellent outcomes, provided surgical margins were clear.[1] No correlation between α-fetoprotein (AFP) levels and outcome was reported in the study.
Other morbidity can result from precancerous medical conditions, operative complications, or toxic effects of chemotherapy. Short- and long-term sequelae and toxic effects of surgical management and chemotherapy are discussed below (see Surgical Care and Medical Care).
Race
White children are affected almost 5 times more frequently than black children. Black patients tend to have worse outcomes.
Sex
Males are typically affected more frequently than females; the male-to-female ratio is 1.7:1. Male-to-female ratios are somewhat higher in Europe (1.6-3.3:1) and Taiwan (2.9:1).
Age
Hepatoblastoma usually affects children younger than 3 years, and the median age at diagnosis is 1 year. Hepatoblastoma is very rarely diagnosed in adolescence and is exceedingly rare in adults. Occasionally, nests of hepatoblastoma cells are found in hepatocellular carcinoma lesions; this is more common in adults than in children. Older children and adults tend to have a worse prognosis.
Ang JP, Heath JA, Donath S, Khurana S, Auldist A. Treatment outcomes for hepatoblastoma: an institution's experience over two decades. Pediatr Surg Int. Feb 2007;23(2):103-9. [Medline].
Otte JB, Pritchard J, Aronson DC, et al. Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer. Jan 2004;42(1):74-83. [Medline].
Otte JB, de Ville de Goyet J, Reding R. Liver transplantation for hepatoblastoma: indications and contraindications in the modern era. Pediatr Transplant. Oct 2005;9(5):557-65. [Medline].
Czauderna P, Mackinlay G, Perilongo G, et al. Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol. Jun 15 2002;20(12):2798-804. [Medline].
Hirschman BA, Pollock BH, Tomlinson GE. The spectrum of APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. J Pediatr. Aug 2005;147(2):263-6. [Medline].
Sanders RP, Furman WL. Familial adenomatous polyposis in two brothers with hepatoblastoma: implications for diagnosis and screening. Pediatr Blood Cancer. Nov 2006;47(6):851-4. [Medline].
Harvey J, Clark S, Hyer W, Hadzic N, Tomlinson I, Hinds R. Germline APC mutations are not commonly seen in children with sporadic hepatoblastoma. J Pediatr Gastroenterol Nutr. Nov 2008;47(5):675-7. [Medline].
Anna CH, Sills RC, Foley JF, Stockton PS, Ton TV, Devereux TR. Beta-catenin mutations and protein accumulation in all hepatoblastomas examined from B6C3F1 mice treated with anthraquinone or oxazepam. Cancer Res. Jun 1 2000;60(11):2864-8. [Medline].
Koch A, Waha A, Hartmann W, et al. Elevated expression of Wnt antagonists is a common event in hepatoblastomas. Clin Cancer Res. Jun 15 2005;11(12):4295-304. [Medline].
Tan X, Apte U, Micsenyi A, et al. Epidermal growth factor receptor: a novel target of the Wnt/beta-catenin pathway in liver. Gastroenterology. Jul 2005;129(1):285-302. [Medline].
Wirths O, Waha A, Weggen S, et al. Overexpression of human Dickkopf-1, an antagonist of wingless/WNT signaling, in human hepatoblastomas and Wilms' tumors. Lab Invest. Mar 2003;83(3):429-34. [Medline].
Miao J, Kusafuka T, Udatsu Y, Okada A. Sequence variants of the Axin gene in hepatoblastoma. Hepatol Res. Feb 2003;25(2):174-179. [Medline].
Taniguchi K, Roberts LR, Aderca IN, et al. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene. Jul 18 2002;21(31):4863-71. [Medline].
Kuroda T, Rabkin SD, Martuza RL. Effective treatment of tumors with strong beta-catenin/T-cell factor activity by transcriptionally targeted oncolytic herpes simplex virus vector. Cancer Res. Oct 15 2006;66(20):10127-35. [Medline].
Arsic D, Beasley SW, Sullivan MJ. Switched-on Sonic hedgehog: a gene whose activity extends beyond fetal development - to oncogenesis. J Paediatr Child Health. Jun 2007;43(6):421-3. [Medline].
Eichenmuller M, Gruner I, Hagl B, et al. Blocking the hedgehog pathway inhibits hepatoblastoma growth. Hepatology. Feb 2009;49(2):482-90. [Medline].
Lopez-Terrada D, Gunaratne PH, Adesina AM, et al. Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors. Hum Pathol. Jun 2009;40(6):783-94. [Medline].
Ruck P, Xiao JC. Stem-like cells in hepatoblastoma. Med Pediatr Oncol. Nov 2002;39(5):504-7. [Medline].
Tanimura M, Matsui I, Abe J, et al. Increased risk of hepatoblastoma among immature children with a lower birth weight. Cancer Res. Jul 15 1998;58(14):3032-5. [Medline].
Ortega JA, Douglass EC, Feusner JH, et al. Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: A report from the Children's Cancer Group and the Pediatric Oncology Group. J Clin Oncol. Jul 2000;18(14):2665-75. [Medline].
Aronson DC, Schnater JM, Staalman CR, et al. Predictive value of the pretreatment extent of disease system in hepatoblastoma: results from the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study. J Clin Oncol. Feb 20 2005;23(6):1245-52. [Medline].
Feusner J, Plaschkes J. Hepatoblastoma and low birth weight: a trend or chance observation?. Med Pediatr Oncol. Nov 2002;39(5):508-9. [Medline].
Oue T, Kubota A, Okuyama H, et al. Hepatoblastoma in children of extremely low birth weight: a report from a single perinatal center. J Pediatr Surg. Jan 2003;38(1):134-7; discussion 134-7. [Medline].
Ucar C, Caliskan U, Toy H. Hepatoblastoma in a child with neurofibromatosis type I. Pediatr Blood Cancer. Nov 10 2005;[Medline].
Toxicology and Carcinogenesis Studies of Bromochloroacetic Acid (CAS No. 5589-96-8) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies). Natl Toxicol Program Tech Rep Ser. Feb 2009;1-270. [Medline].
Fuchs J, Rydzynski J, Von Schweinitz D, et al. Pretreatment prognostic factors and treatment results in children with hepatoblastoma: a report from the German Cooperative Pediatric Liver Tumor Study HB 94. Cancer. Jul 1 2002;95(1):172-82. [Medline].
Figarola MS, McQuiston SA, Wilson F, Powell R. Recurrent hepatoblastoma with localization by PET-CT. Pediatr Radiol. Dec 2005;35(12):1254-8. [Medline].
Rowland JM. Hepatoblastoma: assessment of criteria for histologic classification. Med Pediatr Oncol. Nov 2002;39(5):478-83. [Medline].
von Schweinitz D, Hecker H, Schmidt-von-Arndt G, Harms D. Prognostic factors and staging systems in childhood hepatoblastoma. Int J Cancer. Dec 19 1997;74(6):593-9. [Medline].
Douglass EC, Reynolds M, Finegold M, Cantor AB, Glicksman A. Cisplatin, vincristine, and fluorouracil therapy for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol. Jan 1993;11(1):96-9. [Medline].
Casanova M, Massimino M, Ferrari A, et al. Etoposide, cisplatin, epirubicin chemotherapy in the treatment of pediatric liver tumors. Pediatr Hematol Oncol. Apr-May 2005;22(3):189-98. [Medline].
[Best Evidence] Perilongo G, Maibach R, Shafford E, et al. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N Engl J Med. Oct 22 2009;361(17):1662-70. [Medline].
McCrudden KW, Hopkins B, Frischer J, et al. Anti-VEGF antibody in experimental hepatoblastoma: suppression of tumor growth and altered angiogenesis. J Pediatr Surg. Mar 2003;38(3):308-14; discussion 308-14. [Medline].
Warmann S, Gohring G, Teichmann B, Geerlings H, Fuchs J. MDR1 modulators improve the chemotherapy response of human hepatoblastoma to doxorubicin in vitro. J Pediatr Surg. Nov 2002;37(11):1579-84. [Medline].
Warmann S, Hunger M, Teichmann B, Flemming P, Gratz KF, Fuchs J. The role of the MDR1 gene in the development of multidrug resistance in human hepatoblastoma: clinical course and in vivo model. Cancer. Oct 15 2002;95(8):1795-801. [Medline].
Rana AN, Qidwai A, Pritchard J, Ashraf MS. Successful treatment of multifocal unresectable hepatoblastoma with chemotherapy only. Pediatr Hematol Oncol. Mar 2006;23(2):153-8. [Medline].
Widemann BC, Goodspeed W, Goodwin A, Fojo T, Balis FM, Fox E. Phase I trial and pharmacokinetic study of ixabepilone administered daily for 5 days in children and adolescents with refractory solid tumors. J Clin Oncol. Feb 1 2009;27(4):550-6. [Medline].
Levy CF, Oo KZ, Fireman F, et al. Reversible posterior leukoencephalopathy syndrome in a child treated with bevacizumab. Pediatr Blood Cancer. May 2009;52(5):669-71. [Medline].
Katzenstein HM, London WB, Douglass EC, et al. Treatment of unresectable and metastatic hepatoblastoma: a pediatric oncology group phase II study. J Clin Oncol. Aug 15 2002;20(16):3438-44. [Medline].
Katzenstein HM, Rigsby C, Shaw PH, Mitchell TL, Haut PR, Kletzel M. Novel therapeutic approaches in the treatment of children with hepatoblastoma. J Pediatr Hematol Oncol. Dec 2002;24(9):751-5. [Medline].
Fuchs J, Rydzynski J, Hecker H, et al. The influence of preoperative chemotherapy and surgical technique in the treatment of hepatoblastoma--a report from the German Cooperative Liver Tumour Studies HB 89 and HB 94. Eur J Pediatr Surg. Aug 2002;12(4):255-61. [Medline].
Finegold MJ. Chemotherapy for suspected hepatoblastoma without efforts at surgical resection is a bad practice. Med Pediatr Oncol. Nov 2002;39(5):484-6. [Medline].
Adesina AM, Lopez-Terrada D, Wong KK, et al. Gene expression profiling reveals signatures characterizing histologic subtypes of hepatoblastoma and global deregulation in cell growth and survival pathways. Hum Pathol. Jun 2009;40(6):843-53. [Medline].
Aihara R, Ohno T, Mochiki E, et al. Gastrointestinal stromal tumor of the lesser omentum in a young adult patient with a history of hepatoblastoma: Report of a case. Surg Today. 2009;39(4):349-52. [Medline].
Beaunoyer M, Vanatta JM, Ogihara M, et al. Outcomes of transplantation in children with primary hepatic malignancy. Pediatr Transplant. Sep 2007;11(6):655-60. [Medline].
Blaker H, Hofmann WJ, Rieker RJ, et al. Beta-catenin accumulation and mutation of the CTNNB1 gene in hepatoblastoma. Genes Chromosomes Cancer. Aug 1999;25(4):399-402. [Medline].
Borger JA, Barbosa JL, Lehan CA. Chemotherapy combined with surgery in successful treatment of hepatoblastoma. J Fla Med Assoc. Dec 1989;76(12):1023-6. [Medline].
Cairo S, Armengol C, De Reynies A, et al. Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell. Dec 9 2008;14(6):471-84. [Medline].
Cohen MM Jr. Beckwith-Wiedemann syndrome: historical, clinicopathological, and etiopathogenetic perspectives. Pediatr Dev Pathol. May-Jun 2005;8(3):287-304. [Medline].
Conran RM, Hitchcock CL, Waclawiw MA, Stocker JT, Ishak KG. Hepatoblastoma: the prognostic significance of histologic type. Pediatr Pathol. Mar-Apr 1992;12(2):167-83. [Medline].
[Guideline] Czauderna P, Otte JB, Aronson DC, et al. Guidelines for surgical treatment of hepatoblastoma in the modern era--recommendations from the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL). Eur J Cancer. May 2005;41(7):1031-6. [Medline].
Czauderna P, Zbrzezniak G, Narozanski W, Korzon M, Wyszomirska M, Stoba C. Preliminary experience with arterial chemoembolization for hepatoblastoma and hepatocellular carcinoma in children. Pediatr Blood Cancer. Jun 2006;46(7):825-8. [Medline].
D'Antiga L, Vallortigara F, Cillo U, et al. Features predicting unresectability in hepatoblastoma. Cancer. Sep 1 2007;110(5):1050-8. [Medline].
Ehrlich PF, Greenberg ML, Filler RM. Improved long-term survival with preoperative chemotherapy for hepatoblastoma. J Pediatr Surg. Jul 1997;32(7):999-1002; discussion 1002-3. [Medline].
Faraj W, Dar F, Marangoni G, et al. Liver transplantation for hepatoblastoma. Liver Transpl. Nov 2008;14(11):1614-9. [Medline].
Feusner J, Buckley J, Robison L, et al. Prematurity and hepatoblastoma: more than just an association?. J Pediatr. Oct 1998;133(4):585-6. [Medline].
Filler RM, Ehrlich PF, Greenberg ML, Babyn PS. Preoperative chemotherapy in hepatoblastoma. Surgery. Oct 1991;110(4):591-6; discussion 596-7. [Medline].
Finegold MJ. Chemotherapy for suspected hepatoblastoma without efforts at surgical resection is a bad practice. Med Pediatr Oncol. Nov 2002;39(5):484-6. [Medline].
Gutweiler JR, Yu DC, Kim HB, et al. Hepatoblastoma presenting with focal nodular hyperplasia after treatment of neuroblastoma. J Pediatr Surg. Dec 2008;43(12):2297-300. [Medline].
Herzog CE, Andrassy RJ, Eftekhari F. Childhood cancers: hepatoblastoma. Oncologist. 2000;5(6):445-53. [Medline].
Horton JD, Lee S, Brown SR, Bader J, Meier DE. Survival trends in children with hepatoblastoma. Pediatr Surg Int. May 2009;25(5):407-12. [Medline].
Kasahara M, Ueda M, Haga H, et al. Living-donor liver transplantation for hepatoblastoma. Am J Transplant. Sep 2005;5(9):2229-35. [Medline].
King SJ, Babyn PS, Greenberg ML, Phillips MJ, Filler RM. Value of CT in determining the resectability of hepatoblastoma before and after chemotherapy. AJR Am J Roentgenol. Apr 1993;160(4):793-8. [Medline].
Li FP, Thurber WA, Seddon J, Holmes GE. Hepatoblastoma in families with polyposis coli. JAMA. May 8 1987;257(18):2475-7. [Medline].
Lopez-Terrada D. Integrating the diagnosis of childhood malignancies. Adv Exp Med Biol. 2006;587:121-37. [Medline].
Mejia A, Langnas AN, Shaw BW, Torres C, Sudan DL. Living and deceased donor liver transplantation for unresectable hepatoblastoma at a single center. Clin Transplant. Dec 2005;19(6):721-5. [Medline].
Meyers RL, Katzenstein HM, Malogolowkin MH. Predictive value of staging systems in hepatoblastoma. J Clin Oncol. Feb 20 2007;25(6):737. [Medline].
Mody RJ, Pohlen JA, Malde S, Strouse PJ, Shulkin BL. FDG PET for the study of primary hepatic malignancies in children. Pediatr Blood Cancer. Jul 2006;47(1):51-5. [Medline].
Molmenti EP, Wilkinson K, Molmenti H, et al. Treatment of unresectable hepatoblastoma with liver transplantation in the pediatric population. Am J Transplant. Jul 2002;2(6):535-8. [Medline].
Otte JB, de Ville de Goyet J. The contribution of transplantation to the treatment of liver tumors in children. Semin Pediatr Surg. Nov 2005;14(4):233-8. [Medline].
Otte JB, de Ville de Goyet J, Reding R. Liver transplantation for hepatoblastoma: indications and contraindications in the modern era. Pediatr Transplant. Oct 2005;9(5):557-65. [Medline].
Pollock BH, Jenson HB, Leach CT, et al. Risk factors for pediatric human immunodeficiency virus-related malignancy. JAMA. May 14 2003;289(18):2393-9. [Medline].
Pritchard J, Brown J, Shafford E, et al. Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach--results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol. Nov 15 2000;18(22):3819-28. [Medline].
Quinn JJ, Altman AJ, Robinson HT, Cooke RW, Hight DW, Foster JH. Adriamycin and cisplatin for hepatoblastoma. Cancer. Oct 15 1985;56(8):1926-9. [Medline].
Raney B. Hepatoblastoma in children: a review. J Pediatr Hematol Oncol. Sep-Oct 1997;19(5):418-22. [Medline].
Ranganathan S, Tan X, Monga SP. beta-Catenin and met deregulation in childhood Hepatoblastomas. Pediatr Dev Pathol. Jul-Aug 2005;8(4):435-47. [Medline].
Reynolds M, Douglass EC, Finegold M, Cantor A, Glicksman A. Chemotherapy can convert unresectable hepatoblastoma. J Pediatr Surg. Aug 1992;27(8):1080-3; discussion 1083-4. [Medline].
Richter A, Grabhorn E, Schulz A, Schaefer HJ, Burdelski M, Ganschow R. Hepatoblastoma in a child with progressive familial intrahepatic cholestasis. Pediatr Transplant. Dec 2005;9(6):805-8. [Medline].
Ross JA, Gurney JG. Hepatoblastoma incidence in the United States from 1973 to 1992. Med Pediatr Oncol. Mar 1998;30(3):141-2. [Medline].
Sallam A, Paes B, Bourgeois J. Neonatal hepatoblastoma: two cases posing a diagnostic dilemma, with a review of the literature. Am J Perinatol. Nov 2005;22(8):413-9. [Medline].
Srinivasan P, McCall J, Pritchard J, et al. Orthotopic liver transplantation for unresectable hepatoblastoma. Transplantation. Sep 15 2002;74(5):652-5. [Medline].
[Guideline] Tan TY, Amor DJ. Tumour surveillance in Beckwith-Wiedemann syndrome and hemihyperplasia: a critical review of the evidence and suggested guidelines for local practice. J Paediatr Child Health. Sep 2006;42(9):486-90. [Medline].
Tomizawa M, Saisho H. Signaling pathway of insulin-like growth factor-II as a target of molecular therapy for hepatoblastoma. World J Gastroenterol. Oct 28 2006;12(40):6531-5. [Medline].
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. Oct 2005;44(2):177-84. [Medline].
Trobaugh-Lotrario AD, Tomlinson GE, Finegold MJ, Gore L, Feusner JH. Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors. Pediatr Blood Cancer. Mar 2009;52(3):328-34. [Medline].
Tsuchida Y, Ikeda H, Suzuki N, et al. A case of well-differentiated, fetal-type hepatoblastoma with very low serum alpha-fetoprotein. J Pediatr Surg. Dec 1999;34(12):1762-4. [Medline].
Vogl TJ, Scheller A, Jakob U, Zangos S, Ahmed M, Nabil M. Transarterial chemoembolization in the treatment of hepatoblastoma in children. Eur Radiol. Jun 2006;16(6):1393-6. [Medline].
Wang JD, Chang TK, Chen HC, et al. Pediatric liver tumors: initial presentation, image finding and outcome. Pediatr Int. Aug 2007;49(4):491-6. [Medline].
Warmann SW, Frank H, Heitmann H, et al. Bcl-2 Gene Silencing in Pediatric Epithelial Liver Tumors. J Surg Res. Jan 2008;144(1):43-48. [Medline].
Warmann SW, Heitmann H, Teichmann B, et al. Effects of P-glycoprotein modulation on the chemotherapy of xenotransplanted human hepatoblastoma. Pediatr Hematol Oncol. Jul-Aug 2005;22(5):373-86. [Medline].
Zimmermann A. The emerging family of hepatoblastoma tumours: from ontogenesis to oncogenesis. Eur J Cancer. Jul 2005;41(11):1503-14. [Medline].
Print
