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Precision Molecular Pathology of Neoplastic Pediatric Diseases pp 281–329Cite as

Liver and Pancreas

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Part of the book series: Molecular Pathology Library ((MPLB))

Abstract

Hepatoblastoma (HB) is the most common malignant liver tumor of childhood. It is an embryonal tumor that has varied morphology, leading to its subclassification based on the histologic subtypes seen within the tumor. Molecular studies to date have consistently shown varying CTNNB1 (β-catenin) mutations or deletions in HB, and almost 90% of the tumors have some defect in the Wnt pathway. Varying partner pathways include the Notch pathway, EGFR pathway, YAP (HIPPO kinase pathway), c-myc, and possibly c-met and others that continue to be identified using more advanced molecular techniques. The author has tried to integrate this unique aspect of HB in which the morphology, the immunophenotype, and molecular events appear to go hand in hand. The chapter also looks at known prognostic markers as well as novel defects that seem to drive tumorigenesis in these patients.

Hepatocellular carcinoma (HCC) is the most common pediatric liver tumor in older children and adolescents. Rare instances of pediatric HCC occur in a background of normal liver, and activation of the Wnt/β-catenin pathway has been implicated in many of these pediatric tumors. Older children may develop the fibrolamellar variant of HCC that is unique in that it has a specific recently described translocation (DNAJB1-PRKACA). This chapter looks into the advances made in HCC in general, but with the hope of focusing more on the unique group of pediatric HCC tumors.

Pancreatoblastoma is an uncommon primitive tumor of childhood that shares in common with hepatoblastomas the presence of CTNNB1 mutations. The hallmark of the histologic diagnosis is the presence of squamous morular areas in a background of primitive tumor cells that may show acinic and neuroendocrine differentiation. While originally it was considered to represent the pediatric analog of the solid-pseudopapillary tumor due to its shared β-catenin staining, more recent data suggests that the adult counterpart may actually be an acinic cell carcinoma of the pancreas. The current chapter explores the scant molecular studies of these tumors.

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References

  1. Ross JA, Gurney JG. Hepatoblastoma incidence in the United States from 1973 to 1992. Med Pediatr Oncol. 1998;30(3):141–2.

    Article  CAS  PubMed  Google Scholar 

  2. Czauderna P, Haeberle B, Hiyama E, Rangaswami A, Krailo M, Maibach R, et al. The Children’s Hepatic tumors International Collaboration (CHIC): novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model. Eur J Cancer. 2016;52:92–101.

    Article  PubMed  Google Scholar 

  3. Spector LG, Feusner JH, Ross JA. Hepatoblastoma and low birth weight. Pediatr Blood Cancer. 2004;43(6):706.

    Article  PubMed  Google Scholar 

  4. Turcotte LM, Georgieff MK, Ross JA, Feusner JH, Tomlinson GE, Malogolowkin MH, et al. Neonatal medical exposures and characteristics of low birth weight hepatoblastoma cases: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2014;61(11):2018–23.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ikeda H, Matsuyama S, Tanimura M. Association between hepatoblastoma and very low birth weight: a trend or a chance? J Pediatr. 1997;130(4):557–60.

    Article  CAS  PubMed  Google Scholar 

  6. Ikeda H, Hachitanda Y, Tanimura M, Maruyama K, Koizumi T, Tsuchida Y. Development of unfavorable hepatoblastoma in children of very low birth weight: results of a surgical and pathologic review. Cancer. 1998;82(9):1789–96.

    Article  CAS  PubMed  Google Scholar 

  7. Trobaugh-Lotrario AD, Chaiyachati BH, Meyers RL, Haberle B, Tomlinson GE, Katzenstein HM, et al. Outcomes for patients with congenital hepatoblastoma. Pediatr Blood Cancer. 2013;60(11):1817–25.

    Article  PubMed  Google Scholar 

  8. Meyers RL, Maibach R, Hiyama E, Haberle B, Krailo M, Rangaswami A, et al. Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children’s hepatic tumors international collaboration. Lancet Oncol. 2017;18(1):122–31.

    Google Scholar 

  9. Meyers RL, Tiao G, de Ville de Goyet J, Superina R, Aronson DC. Hepatoblastoma state of the art: pre-treatment extent of disease, surgical resection guidelines and the role of liver transplantation. Curr Opin Pediatr. 2014;26(1):29–36.

    Article  CAS  PubMed  Google Scholar 

  10. Czauderna P, Lopez-Terrada D, Hiyama E, Haberle B, Malogolowkin MH, Meyers RL. Hepatoblastoma state of the art: pathology, genetics, risk stratification, and chemotherapy. Curr Opin Pediatr. 2014;26(1):19–28.

    Article  CAS  PubMed  Google Scholar 

  11. 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. 2002;24(9):751–5.

    Article  PubMed  Google Scholar 

  12. Malogolowkin MH, Katzenstein HM, Meyers RL, Krailo MD, Rowland JM, Haas J, et al. Complete surgical resection is curative for children with hepatoblastoma with pure fetal histology: a report from the Children’s oncology group. J Clin Oncol. 2011;29(24):3301–6.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Czauderna P, Otte JB, Aronson DC, Gauthier F, Mackinlay G, Roebuck D, 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. 2005;41(7):1031–6.

    Article  PubMed  Google Scholar 

  14. Perilongo G, Shafford E, Plaschkes J, Liver Tumour Study Group of the International Society of Paediatric Oncology. SIOPEL trials using preoperative chemotherapy in hepatoblastoma. Lancet Oncol. 2000;1:94–100.

    Article  CAS  PubMed  Google Scholar 

  15. Cruz RJ Jr, Ranganathan S, Mazariegos G, Soltys K, Nayyar N, Sun Q, et al. Analysis of national and single-center incidence and survival after liver transplantation for hepatoblastoma: new trends and future opportunities. Surgery. 2013;153(2):150–9.

    Article  PubMed  Google Scholar 

  16. Zsiros J, Maibach R, Shafford E, Brugieres L, Brock P, Czauderna P, et al. Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study. J Clin Oncol. 2010;28(15):2584–90.

    Article  CAS  PubMed  Google Scholar 

  17. Lopez-Terrada D, Alaggio R, de Davila MT, Czauderna P, Hiyama E, Katzenstein H, et al. Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium. Mod Pathol. 2014;27(3):472–91.

    Article  PubMed  Google Scholar 

  18. De Ioris M, Brugieres L, Zimmermann A, Keeling J, Brock P, Maibach R, et al. Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience. Eur J Cancer. 2008;44(4):545–50.

    Article  CAS  PubMed  Google Scholar 

  19. Tsuchida Y, Ikeda H, Suzuki N, Takahashi A, Kuroiwa M, Sakai M, et al. A case of well-differentiated, fetal-type hepatoblastoma with very low serum alpha-fetoprotein. J Pediatr Surg. 1999;34(12):1762–4.

    Article  CAS  PubMed  Google Scholar 

  20. Maibach R, Roebuck D, Brugieres L, Capra M, Brock P, Dall’Igna P, et al. Prognostic stratification for children with hepatoblastoma: the SIOPEL experience. Eur J Cancer. 2012;48(10):1543–9.

    Article  PubMed  Google Scholar 

  21. Sumazin P, Chen Y, Trevino LR, Sarabia SF, Hampton OA, Patel K, et al. Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups. Hepatology. 2016;65(1):104–21.

    Article  CAS  PubMed  Google Scholar 

  22. Trobaugh-Lotrario AD, Venkatramani R, Feusner JH. Hepatoblastoma in children with Beckwith-Wiedemann syndrome: does it warrant different treatment? J Pediatr Hematol Oncol. 2014;36(5):369–73.

    Article  PubMed  Google Scholar 

  23. Kosaki R, Takenouchi T, Takeda N, Kagami M, Nakabayashi K, Hata K, et al. Somatic CTNNB1 mutation in hepatoblastoma from a patient with Simpson-Golabi-Behmel syndrome and germline GPC3 mutation. Am J Med Genet A. 2014;164A(4):993–7.

    Article  CAS  PubMed  Google Scholar 

  24. Venkatramani R, Spector LG, Georgieff M, Tomlinson G, Krailo M, Malogolowkin M, et al. Congenital abnormalities and hepatoblastoma: a report from the Children’s Oncology Group (COG) and the Utah Population Database (UPDB). Am J Med Genet A. 2014;164A(9):2250–5.

    Article  PubMed  Google Scholar 

  25. Zhou S, Ranganathan S, Venkatramani R, Gomulia E, Wang L. Teratoid hepatoblastoma with abundant cholangioblastic component in a child with full trisomy 13. Pediatr Dev Pathol. 2013;16(6):438–41.

    Article  PubMed  Google Scholar 

  26. Bachmann N, Crazzolara R, Bohne F, Kotzot D, Maurer K, Enklaar T, et al. Novel deletion in 11p15.5 imprinting center region 1 in a patient with Beckwith-Wiedemann syndrome provides insight into distal enhancer regulation and tumorigenesis. Pediatr Blood Cancer. 2017;64(3): Epub 2016.

    Google Scholar 

  27. Gaston V, Le Bouc Y, Soupre V, Burglen L, Donadieu J, Oro H, et al. Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2001;9(6):409–18.

    Article  CAS  PubMed  Google Scholar 

  28. Maas SM, Vansenne F, Kadouch DJ, Ibrahim A, Bliek J, Hopman S, et al. Phenotype, cancer risk, and surveillance in Beckwith-Wiedemann syndrome depending on molecular genetic subgroups. Am J Med Genet A. 2016;170(9):2248–60.

    Article  CAS  PubMed  Google Scholar 

  29. Azzi S, Rossignol S, Steunou V, Sas T, Thibaud N, Danton F, et al. Multilocus methylation analysis in a large cohort of 11p15-related foetal growth disorders (Russell Silver and Beckwith Wiedemann syndromes) reveals simultaneous loss of methylation at paternal and maternal imprinted loci. Hum Mol Genet. 2009;18(24):4724–33.

    Article  CAS  PubMed  Google Scholar 

  30. Bastaki F, Saif F, Al Ali MT, Hamzeh AR. Molecular and clinical characterization of a nonsense CDKN1C mutation in an Emirati patient with Beckwith-Wiedemann syndrome. Saudi Med J. 2016;37(2):215–6.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Fukuzawa R, Hata J, Hayashi Y, Ikeda H, Reeve AE. Beckwith-Wiedemann syndrome-associated hepatoblastoma: wnt signal activation occurs later in tumorigenesis in patients with 11p15.5 uniparental disomy. Pediatr Dev Pathol. 2003;6(4):299–306.

    Article  CAS  PubMed  Google Scholar 

  32. Gomes MV, Gomes CC, Pinto W Jr, Ramos ES. Methylation pattern at the KvDMR in a child with Beckwith-Wiedemann syndrome conceived by ICSI. Am J Med Genet A. 2007;143A(6):625–9.

    Article  CAS  PubMed  Google Scholar 

  33. Neri G, Marini R, Cappa M, Borrelli P, Opitz JM. Simpson-Golabi-Behmel syndrome: an X-linked encephalo-tropho-schisis syndrome. Am J Med Genet. 1988;30(1–2):287–99.

    Article  CAS  PubMed  Google Scholar 

  34. Xuan JY, Besner A, Ireland M, Hughes-Benzie RM, MacKenzie AE. Mapping of Simpson-Golabi-Behmel syndrome to Xq25-q27. Hum Mol Genet. 1994;3(1):133–7.

    Article  CAS  PubMed  Google Scholar 

  35. Cottereau E, Mortemousque I, Moizard MP, Burglen L, Lacombe D, Gilbert-Dussardier B, et al. Phenotypic spectrum of Simpson-Golabi-Behmel syndrome in a series of 42 cases with a mutation in GPC3 and review of the literature. Am J Med Genet C Semin Med Genet. 2013;163C(2):92–105.

    Article  CAS  PubMed  Google Scholar 

  36. Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen EY, Huber R, et al. Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat Genet. 1996;12(3):241–7.

    Article  CAS  PubMed  Google Scholar 

  37. Lindsay S, Ireland M, O’Brien O, Clayton-Smith J, Hurst JA, Mann J, et al. Large scale deletions in the GPC3 gene may account for a minority of cases of Simpson-Golabi-Behmel syndrome. J Med Genet. 1997;34(6):480–3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. DeBaun MR, Ess J, Saunders S. Simpson Golabi Behmel syndrome: progress toward understanding the molecular basis for overgrowth, malformation, and cancer predisposition. Mol Genet Metab. 2001;72(4):279–86.

    Article  CAS  PubMed  Google Scholar 

  39. Thomas D, Pritchard J, Davidson R, McKiernan P, Grundy RG, de Ville de Goyet J. Familial hepatoblastoma and APC gene mutations: renewed call for molecular research. Eur J Cancer. 2003;39(15):2200–4.

    Article  CAS  PubMed  Google Scholar 

  40. Kurahashi H, Takami K, Oue T, Kusafuka T, Okada A, Tawa A, et al. Biallelic inactivation of the APC gene in hepatoblastoma. Cancer Res. 1995;55(21):5007–11.

    PubMed  CAS  Google Scholar 

  41. Giardiello FM, Petersen GM, Brensinger JD, Luce MC, Cayouette MC, Bacon J, et al. Hepatoblastoma and APC gene mutation in familial adenomatous polyposis. Gut. 1996;39(6):867–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Blaker H, Hofmann WJ, Rieker RJ, Penzel R, Graf M, Otto HF. Beta-catenin accumulation and mutation of the CTNNB1 gene in hepatoblastoma. Genes Chromosomes Cancer. 1999;25(4):399–402.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  44. 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. 2008;47(5):675–7.

    Article  CAS  PubMed  Google Scholar 

  45. Inukai T, Furuuchi K, Sugita K, Uno K, Ooi A, Sasaki F, et al. Nuclear accumulation of beta-catenin without an additional somatic mutation in coding region of the APC gene in hepatoblastoma from a familial adenomatous polyposis patient. Oncol Rep. 2004;11(1):121–6.

    PubMed  CAS  Google Scholar 

  46. Weinberg AG, Finegold MJ. Primary hepatic-tumors of childhood. Hum Pathol. 1983;14(6):512–37.

    Article  CAS  PubMed  Google Scholar 

  47. Lopez-Terrada D, Gunaratne PH, Adesina AM, Pulliam J, Hoang DM, Nguyen Y, et al. Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors. Hum Pathol. 2009;40(6):783–94.

    Article  CAS  PubMed  Google Scholar 

  48. Zimmermann A. Hepatoblastoma with cholangioblastic features (‘cholangioblastic hepatoblastoma’) and other liver tumors with bimodal differentiation in young patients. Med Pediatr Oncol. 2002;39(5):487–91.

    Article  PubMed  Google Scholar 

  49. Sainati L, Leszl A, Stella M, Montaldi A, Perilongo G, Rugge M, et al. Cytogenetic analysis of hepatoblastoma: hypothesis of cytogenetic evolution in such tumors and results of a multicentric study. Cancer Genet Cytogenet. 1998;104(1):39–44.

    Article  CAS  PubMed  Google Scholar 

  50. Schneider NR, Cooley LD, Finegold MJ, Douglass EC, Tomlinson GE. The first recurring chromosome translocation in hepatoblastoma: der(4)t(1;4)(q12;q34). Genes Chromosomes Cancer. 1997;19(4):291–4.

    Article  CAS  PubMed  Google Scholar 

  51. Yeh YA, Rao PH, Cigna CT, Middlesworth W, Lefkowitch JH, Murty VV. Trisomy 1q, 2, and 20 in a case of hepatoblastoma: possible significance of 2q35-q37 and 1q12-q21 rearrangements. Cancer Genet Cytogenet. 2000;123(2):140–3.

    Article  CAS  PubMed  Google Scholar 

  52. Tomlinson GE. Cytogenetics of hepatoblastoma. Front Biosci (Elite Ed). 2012;4:1287–92.

    Article  Google Scholar 

  53. Swarts S, Wisecarver J, Bridge JA. Significance of extra copies of chromosome 20 and the long arm of chromosome 2 in hepatoblastoma. Cancer Genet Cytogenet. 1996;91(1):65–7.

    Article  CAS  PubMed  Google Scholar 

  54. 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(2):571–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Kraus JA, Albrecht S, Wiestler OD, von Schweinitz D, Pietsch T. Loss of heterozygosity on chromosome 1 in human hepatoblastoma. Int J Cancer. 1996;67(4):467–71.

    Article  CAS  PubMed  Google Scholar 

  56. Rugge M, Sonego F, Pollice L, Perilongo G, Guido M, Basso G, et al. Hepatoblastoma: DNA nuclear content, proliferative indices, and pathology. Liver. 1998;18(2):128–33.

    Article  CAS  PubMed  Google Scholar 

  57. Chopra A, Iyer VK, Agarwala S, Mathur SR, Aron M, Gupta SD, et al. Apoptotic protein expression, glycogen content, DNA ploidy and cell proliferation in hepatoblastoma subtyping and their role in prognostication. Pediatr Surg Int. 2010;26(12):1173–8.

    Article  PubMed  Google Scholar 

  58. Terracciano LM, Bernasconi B, Ruck P, Stallmach T, Briner J, Sauter G, et al. Comparative genomic hybridization analysis of hepatoblastoma reveals high frequency of X-chromosome gains and similarities between epithelial and stromal components. Hum Pathol. 2003;34(9):864–71.

    Article  CAS  PubMed  Google Scholar 

  59. Albrecht S, Hartmann W, Houshdaran F, Koch A, Gartner B, Prawitt D, et al. Allelic loss but absence of mutations in the polyspecific transporter gene BWR1A on 11p15.5 in hepatoblastoma. Int J Cancer. 2004;111(4):627–32.

    Article  CAS  PubMed  Google Scholar 

  60. Hartmann W, Waha A, Koch A, Goodyer CG, Albrecht S, von Schweinitz D, et al. p57(KIP2) is not mutated in hepatoblastoma but shows increased transcriptional activity in a comparative analysis of the three imprinted genes p57(KIP2), IGF2, and H19. Am J Pathol. 2000;157(4):1393–403.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Adesina AM, Nguyen Y, Guanaratne P, Pulliam J, Lopez-Terrada D, Margolin J, et al. FOXG1 is overexpressed in hepatoblastoma. Hum Pathol. 2007;38(3):400–9.

    Article  CAS  PubMed  Google Scholar 

  62. Suzuki M, Kato M, Yuyan C, Takita J, Sanada M, Nannya Y, et al. Whole-genome profiling of chromosomal aberrations in hepatoblastoma using high-density single-nucleotide polymorphism genotyping microarrays. Cancer Sci. 2008;99(3):564–70.

    Article  CAS  PubMed  Google Scholar 

  63. Buendia MA. Genetic alterations in hepatoblastoma and hepatocellular carcinoma: common and distinctive aspects. Med Pediatr Oncol. 2002;39(5):530–5.

    Article  PubMed  Google Scholar 

  64. Cairo S, Armengol C, Buendia MA. Activation of Wnt and Myc signaling in hepatoblastoma. Front Biosci (Elite Ed). 2012;4:480–6.

    Article  Google Scholar 

  65. Armengol C, Cairo S, Fabre M, Buendia MA. Wnt signaling and hepatocarcinogenesis: the hepatoblastoma model. Int J Biochem Cell Biol. 2011;43(2):265–70.

    Article  CAS  PubMed  Google Scholar 

  66. Zaret KS, Grompe M. Generation and regeneration of cells of the liver and pancreas. Science. 2008;322(5907):1490–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Zaret KS. Genetic programming of liver and pancreas progenitors: lessons for stem-cell differentiation. Nat Rev Genet. 2008;9(5):329–40.

    Article  CAS  PubMed  Google Scholar 

  68. Lade A, Ranganathan S, Luo J, Monga SP. Calpain induces N-terminal truncation of beta-catenin in normal murine liver development: diagnostic implications in hepatoblastomas. J Biol Chem. 2012;287(27):22789–98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Alison MR, Islam S, Lim S. Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly. J Pathol. 2009;217(2):282–98.

    Article  CAS  PubMed  Google Scholar 

  70. Yang J, Mowry LE, Nejak-Bowen KN, Okabe H, Diegel CR, Lang RA, et al. Beta-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation! Hepatology. 2014;60(3):964–76.

    Article  PubMed  CAS  Google Scholar 

  71. Monga SP. Beta-catenin signaling and roles in liver homeostasis, injury, and tumorigenesis. Gastroenterology. 2015;148(7):1294–310.

    Article  PubMed  CAS  Google Scholar 

  72. Ranganathan S, Tan X, Monga SP. Beta-catenin and met deregulation in childhood hepatoblastomas. Pediatr Dev Pathol. 2005;8(4):435–47.

    Article  CAS  PubMed  Google Scholar 

  73. Thompson MD, Monga SP. WNT/beta-catenin signaling in liver health and disease. Hepatology. 2007;45(5):1298–305.

    Article  CAS  PubMed  Google Scholar 

  74. Wei Y, Fabre M, Branchereau S, Gauthier F, Perilongo G, Buendia MA. Activation of beta-catenin in epithelial and mesenchymal hepatoblastomas. Oncogene. 2000;19(4):498–504.

    Article  CAS  PubMed  Google Scholar 

  75. 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(2):269–73.

    PubMed  CAS  Google Scholar 

  76. Takayasu H, Horie H, Hiyama E, Matsunaga T, Hayashi Y, Watanabe Y, et al. Frequent deletions and mutations of the beta-catenin gene are associated with overexpression of cyclin D1 and fibronectin and poorly differentiated histology in childhood hepatoblastoma. Clin Cancer Res. 2001;7(4):901–8.

    PubMed  CAS  Google Scholar 

  77. Koch A, Weber N, Waha A, Hartmann W, Denkhaus D, Behrens J, et al. Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastomas. J Pathol. 2004;204(5):546–54.

    Article  CAS  PubMed  Google Scholar 

  78. Cairo S, Armengol C, De Reynies A, Wei Y, Thomas E, Renard CA, et al. Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell. 2008;14(6):471–84.

    Article  CAS  PubMed  Google Scholar 

  79. Purcell R, Childs M, Maibach R, Miles C, Turner C, Zimmermann A, et al. HGF/c-Met related activation of beta-catenin in hepatoblastoma. J Exp Clin Cancer Res. 2011;30:96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Sylvester KG, Colnot S. Hippo/YAP, beta-catenin, and the cancer cell: a “menage a trois” in hepatoblastoma. Gastroenterology. 2014;147(3):562–5.

    Article  PubMed  Google Scholar 

  81. Tao J, Calvisi DF, Ranganathan S, Cigliano A, Zhou L, Singh S, et al. Activation of beta-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice. Gastroenterology. 2014;147(3):690–701.

    Article  PubMed  CAS  Google Scholar 

  82. Luo JH, Ren B, Keryanov S, Tseng GC, Rao UN, Monga SP, et al. Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas. Hepatology. 2006;44(4):1012–24.

    Article  PubMed  CAS  Google Scholar 

  83. Ranganathan S, Ningappa M, Ashokkumar C, Higgs BW, Min J, Sun Q, et al. Loss of EGFR-ASAP1 signaling in metastatic and unresectable hepatoblastoma. Sci Rep. 2016;6:38347.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Eichenmuller M, Trippel F, Kreuder M, Beck A, Schwarzmayr T, Haberle B, et al. The genomic landscape of hepatoblastoma and their progenies with HCC-like features. J Hepatol. 2014;61(6):1312–20.

    Article  CAS  PubMed  Google Scholar 

  85. Comerford SA, Hinnant EA, Chen Y, Bansal H, Klapproth S, Rakheja D, et al. Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant beta-catenin. JCI Insight. 2016;1(16):e88549.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Jia D, Dong R, Jing Y, Xu D, Wang Q, Chen L, et al. Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex. Hepatology. 2014;60(5):1686–96.

    Article  CAS  PubMed  Google Scholar 

  87. Li H, Wolfe A, Septer S, Edwards G, Zhong X, Abdulkarim AB, et al. Deregulation of Hippo kinase signalling in human hepatic malignancies. Liver Int. 2012;32(1):38–47.

    Article  CAS  PubMed  Google Scholar 

  88. Wang H, Lu J, Edmunds LR, Kulkarni S, Dolezal J, Tao J, et al. Coordinated activities of multiple myc-dependent and myc-independent biosynthetic pathways in hepatoblastoma. J Biol Chem. 2016;291(51):26241–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Cui X, Liu B, Zheng S, Dong K, Dong R. Genome-wide analysis of DNA methylation in hepatoblastoma tissues. Oncol Lett. 2016;12(2):1529–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Honda S, Arai Y, Haruta M, Sasaki F, Ohira M, Yamaoka H, et al. Loss of imprinting of IGF2 correlates with hypermethylation of the H19 differentially methylated region in hepatoblastoma. Br J Cancer. 2008;99(11):1891–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Honda S, Haruta M, Sugawara W, Sasaki F, Ohira M, Matsunaga T, et al. The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients. Int J Cancer. 2008;123(5):1117–25.

    Article  CAS  PubMed  Google Scholar 

  92. Honda S, Minato M, Suzuki H, Fujiyoshi M, Miyagi H, Haruta M, et al. Clinical prognostic value of DNA methylation in hepatoblastoma: four novel tumor suppressor candidates. Cancer Sci. 2016;107(6):812–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Godeke J, Luxenburger E, Trippel F, Becker K, Haberle B, Muller-Hocker J, et al. Low expression of N-myc downstream-regulated gene 2 (NDRG2) correlates with poor prognosis in hepatoblastoma. Hepatol Int. 2016;10(2):370–6.

    Article  PubMed  Google Scholar 

  94. Cairo S, Wang Y, de Reynies A, Duroure K, Dahan J, Redon MJ, et al. Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer. Proc Natl Acad Sci U S A. 2010;107(47):20471–6.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Gnemmi V, Leteurtre E, Sudour-Bonnange H, Devisme L, Guettier C, Buob D, et al. SALL4 is a marker of the embryonal subtype of hepatoblastoma. Histopathology. 2013;63(3):425–8.

    Article  PubMed  Google Scholar 

  96. Zhou S, Venkatramani R, Gomulia E, Shillingford N, Wang L. The diagnostic and prognostic value of SALL4 in hepatoblastoma. Histopathology. 2016;69(5):822–30.

    Article  PubMed  Google Scholar 

  97. Hiyama E, Yamaoka H, Matsunaga T, Hayashi Y, Ando H, Suita S, et al. High expression of telomerase is an independent prognostic indicator of poor outcome in hepatoblastoma. Br J Cancer. 2004;91(5):972–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Haas JE, Feusner JH, Finegold MJ. Small cell undifferentiated histology in hepatoblastoma may be unfavorable. Cancer. 2001;92(12):3130–4.

    Article  CAS  PubMed  Google Scholar 

  99. 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. 2009;52(3):328–34.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 1999;59(1):74–9.

    PubMed  CAS  Google Scholar 

  101. Biegel JA, Kalpana G, Knudsen ES, Packer RJ, Roberts CW, Thiele CJ, et al. The role of INI1 and the SWI/SNF complex in the development of rhabdoid tumors: meeting summary from the workshop on childhood atypical teratoid/rhabdoid tumors. Cancer Res. 2002;62(1):323–8.

    PubMed  CAS  Google Scholar 

  102. Rikhi RR, Spady KK, Hoffman RI, Bateman MS, Bateman M, Howard LE. Hepatoblastoma: a need for cell lines and tissue banks to develop targeted drug therapies. Front Pediatr. 2016;4:22.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Prokurat A, Kluge P, Kosciesza A, Perek D, Kappeler A, Zimmermann A. Transitional liver cell tumors (TLCT) in older children and adolescents: a novel group of aggressive hepatic tumors expressing beta-catenin. Med Pediatr Oncol. 2002;39(5):510–8.

    Article  PubMed  Google Scholar 

  104. Allan BJ, Wang B, Davis JS, Parikh PP, Perez EA, Neville HL, et al. A review of 218 pediatric cases of hepatocellular carcinoma. J Pediatr Surg. 2014;49(1):166–71.

    Article  PubMed  Google Scholar 

  105. Finegold MJ, Bennington JL. Pathology of neoplasia in children and adolescents, vol. xviii. Philadelphia: Saunders; 1986. p. 481.

    Google Scholar 

  106. Finegold MJ. Tumors of the liver. Semin Liver Dis. 1994;14(3):270–81.

    Article  CAS  PubMed  Google Scholar 

  107. Finegold MJ, Egler RA, Goss JA, Guillerman RP, Karpen SJ, Krishnamurthy R, et al. Liver tumors: pediatric population. Liver Transpl. 2008;14(11):1545–56.

    Article  PubMed  Google Scholar 

  108. Lau CS, Mahendraraj K, Chamberlain RS. Hepatocellular carcinoma in the pediatric population: a population based clinical outcomes study involving 257 patients from the surveillance, epidemiology, and end result (SEER) database (1973–2011). HPB Surg. 2015;2015:670728.

    PubMed  PubMed Central  Google Scholar 

  109. Schady DA, Roy A, Finegold MJ. Liver tumors in children with metabolic disorders. Transl Pediatr. 2015;4(4):290–303.

    PubMed  PubMed Central  Google Scholar 

  110. Suchy FJ, Sokol RJ, Balistreri WF. Liver disease in children, vol. xvii. 3rd ed. Cambridge: Cambridge University Press; 2007. p. 1030.

    Book  Google Scholar 

  111. Yu SB, Kim HY, Eo H, Won JK, Jung SE, Park KW, et al. Clinical characteristics and prognosis of pediatric hepatocellular carcinoma. World J Surg. 2006;30(1):43–50.

    Article  PubMed  Google Scholar 

  112. Murawski M, Weeda VB, Maibach R, Morland B, Roebuck DJ, Zimmerman A, et al. Hepatocellular carcinoma in children: does modified platinum- and doxorubicin-based chemotherapy increase tumor resectability and change outcome? Lessons learned from the SIOPEL 2 and 3 studies. J Clin Oncol. 2016;34(10):1050–6.

    Article  CAS  PubMed  Google Scholar 

  113. Otte JB, Pritchard J, Aronson DC, Brown J, Czauderna P, Maibach R, 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. 2004;42(1):74–83.

    Article  CAS  PubMed  Google Scholar 

  114. Ismail H, Broniszczak D, Kalicinski P, Markiewicz-Kijewska M, Teisseyre J, Stefanowicz M, et al. Liver transplantation in children with hepatocellular carcinoma. Do Milan criteria apply to pediatric patients? Pediatr Transplant. 2009;13(6):682–92.

    Article  CAS  PubMed  Google Scholar 

  115. Goh GB, Chang PE, Tan CK. Changing epidemiology of hepatocellular carcinoma in Asia. Best Pract Res Clin Gastroenterol. 2015;29(6):919–28.

    Article  PubMed  Google Scholar 

  116. El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology. 2014;60(5):1767–75.

    Article  PubMed  Google Scholar 

  117. El-Serag HB. Epidemiology of hepatocellular carcinoma in USA. Hepatol Res. 2007;37(Suppl 2):S88–94.

    Article  PubMed  Google Scholar 

  118. Knisely AS, Strautnieks SS, Meier Y, Stieger B, Byrne JA, Portmann BC, et al. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology. 2006;44(2):478–86.

    Article  CAS  PubMed  Google Scholar 

  119. Vij M, Safwan M, Shanmugam NP, Rela M. Liver pathology in severe multidrug resistant 3 protein deficiency: a series of 10 pediatric cases. Ann Diagn Pathol. 2015;19(5):277–82.

    Article  PubMed  Google Scholar 

  120. Zhou S, Hertel PM, Finegold MJ, Wang L, Kerkar N, Wang J, et al. Hepatocellular carcinoma associated with tight-junction protein 2 deficiency. Hepatology. 2015;62(6):1914–6.

    Article  PubMed  Google Scholar 

  121. Gruner BA, DeNapoli TS, Andrews W, Tomlinson G, Bowman L, Weitman SD. Hepatocellular carcinoma in children associated with Gardner syndrome or familial adenomatous polyposis. J Pediatr Hematol Oncol. 1998;20(3):274–8.

    Article  CAS  PubMed  Google Scholar 

  122. Nault JC, Couchy G, Balabaud C, Morcrette G, Caruso S, Blanc JF, et al. Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation. Gastroenterology. 2017;152(4):880–94.

    Google Scholar 

  123. Pilati C, Letouze E, Nault JC, Imbeaud S, Boulai A, Calderaro J, et al. Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation. Cancer Cell. 2014;25(4):428–41.

    Article  CAS  PubMed  Google Scholar 

  124. Hadzic N, Quaglia A, Portmann B, Paramalingam S, Heaton ND, Rela M, et al. Hepatocellular carcinoma in biliary atresia: King’s college hospital experience. J Pediatr. 2011;159(4):617–22 e1.

    Article  PubMed  Google Scholar 

  125. Romano F, Stroppa P, Bravi M, Casotti V, Lucianetti A, Guizzetti M, et al. Favorable outcome of primary liver transplantation in children with cirrhosis and hepatocellular carcinoma. Pediatr Transplant. 2011;15(6):573–9.

    PubMed  CAS  Google Scholar 

  126. Nam SW, Park JY, Ramasamy A, Shevade S, Islam A, Long PM, et al. Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling. Hepatology. 2005;42(4):809–18.

    Article  CAS  PubMed  Google Scholar 

  127. Nguyen TB, Roncalli M, Di Tommaso L, Kakar S. Combined use of heat-shock protein 70 and glutamine synthetase is useful in the distinction of typical hepatocellular adenoma from atypical hepatocellular neoplasms and well-differentiated hepatocellular carcinoma. Mod Pathol. 2016;29(3):283–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Theise ND, Curado MP, Franceschi S, et al. In: Bosman FT, et al., editors. Hepatocellular carcinoma. Lyon: IARC; 2010.

    Google Scholar 

  129. Singhi AD, Jain D, Kakar S, Wu TT, Yeh MM, Torbenson M. Reticulin loss in benign fatty liver: an important diagnostic pitfall when considering a diagnosis of hepatocellular carcinoma. Am J Surg Pathol. 2012;36(5):710–5.

    Article  PubMed  Google Scholar 

  130. Shafizadeh N, Ferrell LD, Kakar S. Utility and limitations of glypican-3 expression for the diagnosis of hepatocellular carcinoma at both ends of the differentiation spectrum. Mod Pathol. 2008;21(8):1011–8.

    Article  CAS  PubMed  Google Scholar 

  131. Ando S, Shibahara J, Hayashi A, Fukayama M. Beta-catenin alteration is rare in hepatocellular carcinoma with steatohepatitic features: immunohistochemical and mutational study. Virchows Arch. 2015;467(5):535–42.

    Article  CAS  PubMed  Google Scholar 

  132. Endo K, Ueda T, Ueyama J, Ohta T, Terada T. Immunoreactive E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin proteins in hepatocellular carcinoma: relationships with tumor grade, clinicopathologic parameters, and patients’ survival. Hum Pathol. 2000;31(5):558–65.

    Article  CAS  PubMed  Google Scholar 

  133. Mao TL, Chu JS, Jeng YM, Lai PL, Hsu HC. Expression of mutant nuclear beta-catenin correlates with non-invasive hepatocellular carcinoma, absence of portal vein spread, and good prognosis. J Pathol. 2001;193(1):95–101.

    Article  CAS  PubMed  Google Scholar 

  134. Wong CM, Fan ST, Ng IO. Beta-catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer. 2001;92(1):136–45.

    Article  CAS  PubMed  Google Scholar 

  135. Jakubovic BD, Jothy S. Glypican-3: from the mutations of Simpson-Golabi-Behmel genetic syndrome to a tumor marker for hepatocellular carcinoma. Exp Mol Pathol. 2007;82(2):184–9.

    Article  CAS  PubMed  Google Scholar 

  136. Nguyen T, Phillips D, Jain D, Torbenson M, Wu TT, Yeh MM, et al. Comparison of 5 immunohistochemical markers of hepatocellular differentiation for the diagnosis of hepatocellular carcinoma. Arch Pathol Lab Med. 2015;139(8):1028–34.

    Article  CAS  PubMed  Google Scholar 

  137. Geramizadeh B, Seirfar N. Diagnostic value of arginase-1 and glypican-3 in differential diagnosis of hepatocellular carcinoma, cholangiocarcinoma and metastatic carcinoma of liver. Hepat Mon. 2015;15(7):e30336.

    PubMed  PubMed Central  Google Scholar 

  138. Jain D. Tissue diagnosis of hepatocellular carcinoma. J Clin Exp Hepatol. 2014;4(Suppl 3):S67–73.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Krings G, Ramachandran R, Jain D, Wu TT, Yeh MM, Torbenson M, et al. Immunohistochemical pitfalls and the importance of glypican 3 and arginase in the diagnosis of scirrhous hepatocellular carcinoma. Mod Pathol. 2013;26(6):782–91.

    Article  CAS  PubMed  Google Scholar 

  140. Zhang L, Liu H, Sun L, Li N, Ding H, Zheng J. Glypican-3 as a potential differential diagnosis marker for hepatocellular carcinoma: a tissue microarray-based study. Acta Histochem. 2012;114(6):547–52.

    Article  CAS  PubMed  Google Scholar 

  141. Chan AW, Tong JH, Chan SL, Lai PB, To KF. Expression of stemness markers (CD133 and EpCAM) in prognostication of hepatocellular carcinoma. Histopathology. 2014;64(7):935–50.

    Article  PubMed  Google Scholar 

  142. Terris B, Cavard C, Perret C. EpCAM, a new marker for cancer stem cells in hepatocellular carcinoma. J Hepatol. 2010;52(2):280–1.

    Article  CAS  PubMed  Google Scholar 

  143. Yamashita T, Forgues M, Wang W, Kim JW, Ye Q, Jia H, et al. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res. 2008;68(5):1451–61.

    Article  CAS  PubMed  Google Scholar 

  144. Zen Y, Vara R, Portmann B, Hadzic N. Childhood hepatocellular carcinoma: a clinicopathological study of 12 cases with special reference to EpCAM. Histopathology. 2014;64(5):671–82.

    Article  PubMed  Google Scholar 

  145. Zeng SS, Yamashita T, Kondo M, Nio K, Hayashi T, Hara Y, et al. The transcription factor SALL4 regulates stemness of EpCAM-positive hepatocellular carcinoma. J Hepatol. 2014;60(1):127–34.

    Article  CAS  PubMed  Google Scholar 

  146. Yakaboski E, Jares A, Ma Y. Stem cell gene SALL4 in aggressive hepatocellular carcinoma: a cancer stem cell-specific target? Hepatology. 2014;60(1):419–21.

    Article  PubMed  CAS  Google Scholar 

  147. Yong KJ, Gao C, Lim JS, Yan B, Yang H, Dimitrov T, et al. Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. N Engl J Med. 2013;368(24):2266–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Rao UN, Gollin SM, Beaves S, Cieply K, Nalesnik M, Michalopoulos GK. Comparative genomic hybridization of hepatocellular carcinoma: correlation with fluorescence in situ hybridization in paraffin-embedded tissue. Mol Diagn. 2001;6(1):27–37.

    Article  CAS  PubMed  Google Scholar 

  149. Tan L, Meier T, Kuhlmann M, Xie F, Baier C, Zhu Z, et al. Distinct set of chromosomal aberrations in childhood hepatocellular carcinoma is correlated to hepatitis B virus infection. Cancer Genet. 2016;209(3):87–96.

    Article  CAS  PubMed  Google Scholar 

  150. Nagai H, Pineau P, Tiollais P, Buendia MA, Dejean A. Comprehensive allelotyping of human hepatocellular carcinoma. Oncogene. 1997;14(24):2927–33.

    Article  CAS  PubMed  Google Scholar 

  151. Ki Kim S, Ueda Y, Hatano E, Kakiuchi N, Takeda H, Goto T, et al. TERT promoter mutations and chromosome 8p loss are characteristic of nonalcoholic fatty liver disease-related hepatocellular carcinoma. Int J Cancer. 2016;139(11):2512–8.

    Article  CAS  PubMed  Google Scholar 

  152. Nault JC, Calderaro J, Di Tomaso L, Balabaud C, Zafrani ES, Bioulac-Sage P, et al. TERT promoter mutation is an early somatic genetic alteration in the malignant transformation of cirrhotic nodules in hepatocellular carcinoma. Hepatology. 2014;60:262a–3a.

    Article  CAS  Google Scholar 

  153. Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, et al. High frequency of telomerase reverse transcriptase (tert) promoter somatic mutations in hepatocellular carcinoma and pre-neoplastic lesions. Hepatology. 2013;58:1057a-a.

    Google Scholar 

  154. Nault JC, Zucman-Rossi J. TERT promoter mutations in primary liver tumors. Clin Res Hepatol Gas. 2016;40(1):9–14.

    Article  CAS  Google Scholar 

  155. Lee SE, Chang SH, Kim WY, Lim SD, Kim WS, Hwang TS, et al. Frequent somatic TERT promoter mutations and CTNNB1 mutations in hepatocellular carcinoma. Oncotarget. 2016;7(43):69267–75.

    PubMed  PubMed Central  Google Scholar 

  156. Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, et al. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene. 2002;21(31):4863–71.

    Article  CAS  PubMed  Google Scholar 

  157. Nejak-Bowen KN, Monga SP. Beta-catenin signaling, liver regeneration and hepatocellular cancer: sorting the good from the bad. Semin Cancer Biol. 2011;21(1):44–58.

    Article  CAS  PubMed  Google Scholar 

  158. Giakoustidis A, Giakoustidis D, Mudan S, Sklavos A, Williams R. Molecular signalling in hepatocellular carcinoma: role of and crosstalk among WNT/ss-catenin, Sonic Hedgehog, Notch and Dickkopf-1. Can J Gastroenterol Hepatol. 2015;29(4):209–17.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Wands JR, Kim M. WNT/beta-catenin signaling and hepatocellular carcinoma. Hepatology. 2014;60(2):452–4.

    Article  CAS  PubMed  Google Scholar 

  160. Cieply B, Zeng G, Proverbs-Singh T, Geller DA, Monga SP. Unique phenotype of hepatocellular cancers with exon-3 mutations in beta-catenin gene. Hepatology. 2009;49(3):821–31.

    Article  PubMed  CAS  Google Scholar 

  161. Park JY, Park WS, Nam SW, Kim SY, Lee SH, Yoo NJ, et al. Mutations of beta-catenin and AXIN I genes are a late event in human hepatocellular carcinogenesis. Liver Int. 2005;25(1):70–6.

    Article  CAS  PubMed  Google Scholar 

  162. Kakar S, Grenert JP, Paradis V, Pote N, Jakate S, Ferrell LD. Hepatocellular carcinoma arising in adenoma: similar immunohistochemical and cytogenetic features in adenoma and hepatocellular carcinoma portions of the tumor. Mod Pathol. 2014;27(11):1499–509.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Pilati C, Nault JC, Letouze E, Imbeaud S, Mallet M, Boulai A, et al. Integrative genomic profiling of hepatocellular adenomas identify mutational processes involved in malignant transformation. Hepatology. 2013;58:262a-a.

    Google Scholar 

  164. You J, Yang H, Lai Y, Simon L, Au J, Burkart AL. ARID2, p110alpha, p53, and beta-catenin protein expression in hepatocellular carcinoma and clinicopathologic implications. Hum Pathol. 2015;46(7):1068–77.

    Article  PubMed  Google Scholar 

  165. Levy L, Renard CA, Wei Y, Buendia MA. Genetic alterations and oncogenic pathways in hepatocellular carcinoma. Ann N Y Acad Sci. 2002;963:21–36.

    Article  CAS  PubMed  Google Scholar 

  166. Pinyol R, Nault JC, Quetglas IM, Zucman-Rossi J, Llovet JM. Molecular profiling of liver tumors: classification and clinical translation for decision making. Semin Liver Dis. 2014;34(4):363–75.

    Article  CAS  PubMed  Google Scholar 

  167. Zhang M, Zhang C, Zhang L, Yang Q, Zhou S, Wen Q, et al. Nrf2 is a potential prognostic marker and promotes proliferation and invasion in human hepatocellular carcinoma. BMC Cancer. 2015;15:531.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Chen J, Yu Y, Ji T, Ma R, Chen M, Li G, et al. Clinical implication of Keap1 and phosphorylated Nrf2 expression in hepatocellular carcinoma. Cancer Med. 2016;5(10):2678–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016;63(1):173–84.

    Article  CAS  PubMed  Google Scholar 

  170. Shi L, Wu L, Chen Z, Yang J, Chen X, Yu F, et al. MiR-141 activates Nrf2-dependent antioxidant pathway via down-regulating the expression of Keap1 conferring the resistance of hepatocellular carcinoma cells to 5-fluorouracil. Cell Physiol Biochem. 2015;35(6):2333–48.

    Article  CAS  PubMed  Google Scholar 

  171. Vilarinho S, Erson-Omay EZ, Harmanci AS, Morotti R, Carrion-Grant G, Baranoski J, et al. Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations. J Hepatol. 2014;61(5):1178–83.

    Article  CAS  PubMed  Google Scholar 

  172. Schoedel KE, Tyner VZ, Kim TH, Michalopoulos GK, Mars WM. HGF, MET, and matrix-related proteases in hepatocellular carcinoma, fibrolamellar variant, cirrhotic and normal liver. Mod Pathol. 2003;16(1):14–21.

    Article  PubMed  Google Scholar 

  173. Nalesnik MA, Michalopoulos GK. Growth factor pathways in development and progression of hepatocellular carcinoma. Front Biosci (Schol Ed). 2012;4:1487–515.

    Article  Google Scholar 

  174. Luedde T, Schwabe RF. NF-kappaB in the liver–linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2011;8(2):108–18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Lu B, Guo H, Zhao J, Wang C, Wu G, Pang M, et al. Increased expression of iASPP, regulated by hepatitis B virus X protein-mediated NF-kappaB activation, in hepatocellular carcinoma. Gastroenterology. 2010;139(6):2183–94 e5.

    Article  CAS  PubMed  Google Scholar 

  176. Ding J, Huang S, Wang Y, Tian Q, Zha R, Shi H, et al. Genome-wide screening reveals that miR-195 targets the TNF-alpha/NF-kappaB pathway by down-regulating IkappaB kinase alpha and TAB3 in hepatocellular carcinoma. Hepatology. 2013;58(2):654–66.

    Article  CAS  PubMed  Google Scholar 

  177. Hsu HC, Jeng YM, Mao TL, Chu JS, Lai PL, Peng SY. Beta-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. Am J Pathol. 2000;157(3):763–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Becker D, Sfakianakis I, Krupp M, Staib F, Gerhold-Ay A, Victor A, et al. Genetic signatures shared in embryonic liver development and liver cancer define prognostically relevant subgroups in HCC. Mol Cancer. 2012;11:55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Becker D, Sfakianakis I, Krupp M, Staib F, Victor A, Blettner M, et al. Genetic signatures shared in embryonic liver development and liver cancer define prognostically relevant subgroups in Hcc. Hepatology. 2010;52(4):947a-a.

    Google Scholar 

  180. Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009;69(18):7385–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Lachenmayer A, Alsinet C, Savic R, Cabellos L, Toffanin S, Hoshida Y, et al. Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clin Cancer Res. 2012;18(18):4997–5007.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Nault JC, De Reynies A, Villanueva A, Calderaro J, Rebouissou S, Couchy G, et al. A hepatocellular carcinoma 5-gene score associated with survival of patients after liver resection. Gastroenterology. 2013;145(1):176–87.

    Article  CAS  PubMed  Google Scholar 

  183. Eggert T, McGlynn KA, Duffy A, Manns MP, Greten TF, Altekruse SF. Epidemiology of fibrolamellar hepatocellular carcinoma in the USA, 2000-10. Gut. 2013;62(11):1667–8.

    Article  PubMed  Google Scholar 

  184. Weeda VB, Murawski M, McCabe AJ, Maibach R, Brugieres L, Roebuck D, et al. Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma–results and treatment recommendations from the childhood liver tumour strategy group (SIOPEL) experience. Eur J Cancer. 2013;49(12):2698–704.

    Article  CAS  PubMed  Google Scholar 

  185. Njei B. Fibrolamellar hepatocellular carcinoma versus conventional hepatocellular carcinoma: better 5-year survival or artifactual result of research methodology? Gut. 2014;63(9):1374–5.

    Article  PubMed  Google Scholar 

  186. Atienza LG, Berger J, Mei X, Shah MB, Daily MF, Grigorian A, et al. Liver transplantation for fibrolamellar hepatocellular carcinoma: a national perspective. J Surg Oncol. 2016;115(3):319–23.

    Article  PubMed  Google Scholar 

  187. Lack EE, Neave C, Vawter GF. Hepatocellular carcinoma. Review of 32 cases in childhood and adolescence. Cancer. 1983;52(8):1510–5.

    Article  CAS  PubMed  Google Scholar 

  188. Saxena R, Albores-Saavedra J, Bioulac-Sage P, et al. In: Bosman FT, et al., editors. Diagnostic algorithms for tumours of the liver. 4th ed. Lyon: IARC; 2010. p. 2010.

    Google Scholar 

  189. Ranganathan S, Hicks J The liver, gallbladder and biliary tree. In Hussain AN, Stocker JT, Dehner LP, ed. Pediatric Pathology, 4th ed. Wolters Kluwer; 2016, 729–44.

    Google Scholar 

  190. Torbenson M. Fibrolamellar carcinoma: 2012 update. Scientifica (Cairo). 2012;2012:743790.

    Google Scholar 

  191. Abdul-Al HM, Wang G, Makhlouf HR, Goodman ZD. Fibrolamellar hepatocellular carcinoma: an immunohistochemical comparison with conventional hepatocellular carcinoma. Int J Surg Pathol. 2010;18(5):313–8.

    Article  PubMed  Google Scholar 

  192. Zhou S, Parham DM, Yung E, Pattengale P, Wang L. Quantification of glypican 3, beta-catenin and claudin-1 protein expression in hepatoblastoma and paediatric hepatocellular carcinoma by colour deconvolution. Histopathology. 2015;67(6):905–13.

    Article  PubMed  Google Scholar 

  193. Honeyman JN, Simon EP, Robine N, Chiaroni-Clarke R, Darcy DG, Lim II, et al. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science. 2014;343(6174):1010–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Graham RP, Jin L, Knutson DL, Kloft-Nelson SM, Greipp PT, Waldburger N, et al. DNAJB1-PRKACA is specific for fibrolamellar carcinoma. Mod Pathol. 2015;28(6):822–9.

    Article  CAS  PubMed  Google Scholar 

  195. Oikawa T, Wauthier E, Dinh TA, Selitsky SR, Reyna-Neyra A, Carpino G, et al. Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells. Nat Commun. 2015;6:8070.

    Article  PubMed  CAS  Google Scholar 

  196. Cornella H, Alsinet C, Sayols S, Zhang Z, Hao K, Cabellos L, et al. Unique genomic profile of fibrolamellar hepatocellular carcinoma. Gastroenterology. 2015;148(4):806–18 e10.

    Article  CAS  PubMed  Google Scholar 

  197. Buckley AF, Burgart LJ, Kakar S. Epidermal growth factor receptor expression and gene copy number in fibrolamellar hepatocellular carcinoma. Hum Pathol. 2006;37(4):410–4.

    Article  CAS  PubMed  Google Scholar 

  198. Riehle KJ, Yeh MM, Yu JJ, Kenerson HL, Harris WP, Park JO, et al. mTORC1 and FGFR1 signaling in fibrolamellar hepatocellular carcinoma. Mod Pathol. 2015;28(1):103–10.

    Article  CAS  PubMed  Google Scholar 

  199. Horie A, Yano Y, Kotoo Y, Miwa A. Morphogenesis of pancreatoblastoma, infantile carcinoma of the pancreas: report of two cases. Cancer. 1977;39(1):247–54.

    Article  CAS  PubMed  Google Scholar 

  200. Morohoshi T, Held G, Kloppel G. Exocrine pancreatic tumours and their histological classification. A study based on 167 autopsy and 97 surgical cases. Histopathology. 1983;7(5):645–61.

    Article  CAS  PubMed  Google Scholar 

  201. Buchino JJ, Castello FM, Nagaraj HS. Pancreatoblastoma. A histochemical and ultrastructural analysis. Cancer. 1984;53(4):963–9.

    Article  CAS  PubMed  Google Scholar 

  202. Kawamoto K, Matsuo T, Jubashi T, Ikeda T, Tomita S. Primary pancreatic carcinoma in childhood. Pancreatoblastoma. Acta Pathol Jpn. 1985;35(1):137–43.

    PubMed  CAS  Google Scholar 

  203. Mierau GW, Orsini EN Jr. Diagnosis of human tumors. Case 2: pancreatoblastoma mimicking fibrolamellar hepatocarcinoma. Ultrastruct Pathol. 1983;5(4):281–4.

    Article  CAS  PubMed  Google Scholar 

  204. Chisholm KM, Hsu CH, Kim MJ, Rangaswami A, Gray Hazard FK. Congenital pancreatoblastoma: report of an atypical case and review of the literature. J Pediatr Hematol Oncol. 2012;34(4):310–5.

    Article  PubMed  Google Scholar 

  205. Kerr NJ, Fukuzawa R, Reeve AE, Sullivan MJ. Beckwith-Wiedemann syndrome, pancreatoblastoma, and the wnt signaling pathway. Am J Pathol. 2002;160(4):1541–2.

    Article  PubMed  Google Scholar 

  206. Koh TH, Cooper JE, Newman CL, Walker TM, Kiely EM, Hoffmann EB. Pancreatoblastoma in a neonate with Wiedemann-Beckwith syndrome. Eur J Pediatr. 1986;145(5):435–8.

    Article  CAS  PubMed  Google Scholar 

  207. Sorrentino S, Conte M, Nozza P, Granata C, Capra V, Avanzini S, et al. Simultaneous occurrence of pancreatoblastoma and neuroblastoma in a newborn with beckwith-wiedemann syndrome. J Pediatr Hematol Oncol. 2010;32(5):e207–9.

    Article  PubMed  Google Scholar 

  208. Hoorens A, Gebhard F, Kraft K, Lemoine NR, Kloppel G. Pancreatoblastoma in an adult: its separation from acinar cell carcinoma. Virchows Arch. 1994;424(5):485–90.

    Article  CAS  PubMed  Google Scholar 

  209. Levey JM, Banner BF. Adult pancreatoblastoma: a case report and review of the literature. Am J Gastroenterol. 1996;91(9):1841–4.

    PubMed  CAS  Google Scholar 

  210. Klimstra DS, Wenig BM, Adair CF, Heffess CS. Pancreatoblastoma. A clinicopathologic study and review of the literature. Am J Surg Pathol. 1995;19(12):1371–89.

    Article  CAS  PubMed  Google Scholar 

  211. Roebuck DJ, Yuen MK, Wong YC, Shing MK, Lee CW, Li CK. Imaging features of pancreatoblastoma. Pediatr Radiol. 2001;31(7):501–6.

    Article  CAS  PubMed  Google Scholar 

  212. Chung EM, Travis MD, Conran RM. Pancreatic tumors in children: radiologic-pathologic correlation. Radiographics. 2006;26(4):1211–38.

    Article  PubMed  Google Scholar 

  213. Klimstra DS. Nonductal neoplasms of the pancreas. Mod Pathol. 2007;20(Suppl 1):S94–112.

    Article  PubMed  Google Scholar 

  214. Nishimata S, Kato K, Tanaka M, Ijiri R, Toyoda Y, Kigasawa H, et al. Expression pattern of keratin subclasses in pancreatoblastoma with special emphasis on squamoid corpuscles. Pathol Int. 2005;55(6):297–302.

    Article  CAS  PubMed  Google Scholar 

  215. Morohoshi T, Kanda M, Horie A, Chott A, Dreyer T, Kloppel G, et al. Immunocytochemical markers of uncommon pancreatic tumors. Acinar cell carcinoma, pancreatoblastoma, and solid cystic (papillary-cystic) tumor. Cancer. 1987;59(4):739–47.

    Article  CAS  PubMed  Google Scholar 

  216. Cingolani N, Shaco-Levy R, Farruggio A, Klimstra DS, Rosai J. Alpha-fetoprotein production by pancreatic tumors exhibiting acinar cell differentiation: study of five cases, one arising in a mediastinal teratoma. Hum Pathol. 2000;31(8):938–44.

    Article  CAS  PubMed  Google Scholar 

  217. Kissane JM. Pancreatoblastoma and solid and cystic papillary tumor: two tumors related to pancreatic ontogeny. Semin Diagn Pathol. 1994;11(2):152–64.

    PubMed  CAS  Google Scholar 

  218. Hua C, Shu XK, Lei C. Pancreatoblastoma: a histochemical and immunohistochemical analysis. J Clin Pathol. 1996;49(11):952–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Klimstra DS, Adsay V. Acinar neoplasms of the pancreas-A summary of 25 years of research. Semin Diagn Pathol. 2016;33(5):307–18.

    Article  PubMed  Google Scholar 

  220. Kletter GB, Sweetser DA, Wallace SF, Sawin RS, Rutledge JC, Geyer JR. Adrenocorticotropin-secreting pancreatoblastoma. J Pediatr Endocrinol Metab. 2007;20(5):639–42.

    Article  PubMed  Google Scholar 

  221. Morohoshi T, Sagawa F, Mitsuya T. Pancreatoblastoma with marked elevation of serum alpha-fetoprotein. An autopsy case report with immunocytochemical study. Virchows Arch A Pathol Anat Histopathol. 1990;416(3):265–70.

    Article  CAS  PubMed  Google Scholar 

  222. Abraham SC, Wu TT, Hruban RH, Lee JH, Yeo CJ, Conlon K, et al. Genetic and immunohistochemical analysis of pancreatic acinar cell carcinoma: frequent allelic loss on chromosome 11p and alterations in the APC/beta-catenin pathway. Am J Pathol. 2002;160(3):953–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  223. Cao D, Maitra A, Saavedra JA, Klimstra DS, Adsay NV, Hruban RH. Expression of novel markers of pancreatic ductal adenocarcinoma in pancreatic nonductal neoplasms: additional evidence of different genetic pathways. Mod Pathol. 2005;18(6):752–61.

    Article  CAS  PubMed  Google Scholar 

  224. Tanaka Y, Kato K, Notohara K, Nakatani Y, Miyake T, Ijiri R, et al. Significance of aberrant (cytoplasmic/nuclear) expression of beta-catenin in pancreatoblastoma. J Pathol. 2003;199(2):185–90.

    Article  CAS  PubMed  Google Scholar 

  225. Wood LD, Klimstra DS. Pathology and genetics of pancreatic neoplasms with acinar differentiation. Semin Diagn Pathol. 2014;31(6):491–7.

    Article  PubMed  PubMed Central  Google Scholar 

  226. Comper F, Antonello D, Beghelli S, Gobbo S, Montagna L, Pederzoli P, et al. Expression pattern of claudins 5 and 7 distinguishes solid-pseudopapillary from pancreatoblastoma, acinar cell and endocrine tumors of the pancreas. Am J Surg Pathol. 2009;33(5):768–74.

    Article  PubMed  Google Scholar 

  227. Abraham SC, Wu TT, Klimstra DS, Finn LS, Lee JH, Yeo CJ, et al. Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas : frequent alterations in the APC/beta-catenin pathway and chromosome 11p. Am J Pathol. 2001;159(5):1619–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  228. Hackeng WM, Hruban RH, Offerhaus GJ, Brosens LA. Surgical and molecular pathology of pancreatic neoplasms. Diagn Pathol. 2016;11(1):47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  229. Jiao Y, Yonescu R, Offerhaus GJ, Klimstra DS, Maitra A, Eshleman JR, et al. Whole-exome sequencing of pancreatic neoplasms with acinar differentiation. J Pathol. 2014;232(4):428–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  230. Wong IH, Chan J, Wong J, Tam PK. Ubiquitous aberrant RASSF1A promoter methylation in childhood neoplasia. Clin Cancer Res. 2004;10(3):994–1002.

    Article  CAS  PubMed  Google Scholar 

  231. Kerr NJ, Chun YH, Yun K, Heathcott RW, Reeve AE, Sullivan MJ. Pancreatoblastoma is associated with chromosome 11p loss of heterozygosity and IGF2 overexpression. Med Pediatr Oncol. 2002;39(1):52–4.

    Article  PubMed  Google Scholar 

  232. Haag MM, Sutcliffe MJ, Dumont DP, McFarland JA, Favara BE, Chamizo W. Cytogenetic findings in rare pediatric tumors: report of a case of interdigitating reticulum cell sarcoma and a case of pancreatoblastoma. Cancer Genet Cytogenet. 1995;84(2):158.

    Article  Google Scholar 

  233. Wiley J, Posekany K, Riley R, Holbrook T, Silverman J, Joshi V, et al. Cytogenetic and flow cytometric analysis of a pancreatoblastoma. Cancer Genet Cytogenet. 1995;79(2):115–8.

    Article  CAS  PubMed  Google Scholar 

  234. Defachelles AS, Martin De Lassalle E, Boutard P, Nelken B, Schneider P, Patte C. Pancreatoblastoma in childhood: clinical course and therapeutic management of seven patients. Med Pediatr Oncol. 2001;37(1):47–52.

    Article  CAS  PubMed  Google Scholar 

  235. Jaksic T, Yaman M, Thorner P, Wesson DK, Filler RM, Shandling B. A 20-year review of pediatric pancreatic tumors. J Pediatr Surg. 1992;27(10):1315–7.

    Article  CAS  PubMed  Google Scholar 

  236. Ohike N, Morohoshi T. Exocrine pancreatic neoplasms of nonductal origin: acinar cell carcinoma, pancreatoblastoma, and solid-pseudopapillary neoplasm. Surg Pathol Clin. 2011;4(2):579–88.

    Article  PubMed  Google Scholar 

  237. Perez EA, Gutierrez JC, Koniaris LG, Neville HL, Thompson WR, Sola JE. Malignant pancreatic tumors: incidence and outcome in 58 pediatric patients. J Pediatr Surg. 2009;44(1):197–203.

    Article  PubMed  Google Scholar 

  238. Vannier JP, Flamant F, Hemet J, Caillaud JM, Gruner M, Bachy B, et al. Pancreatoblastoma: response to chemotherapy. Med Pediatr Oncol. 1991;19(3):187–91.

    Article  CAS  PubMed  Google Scholar 

  239. Dall’igna P, Cecchetto G, Bisogno G, Conte M, Chiesa PL, D’Angelo P, et al. Pancreatic tumors in children and adolescents: the Italian TREP project experience. Pediatr Blood Cancer. 2010;54(5):675–80.

    PubMed  Google Scholar 

  240. Bien E, Godzinski J, Dall’igna P, Defachelles AS, Stachowicz-Stencel T, Orbach D, et al. Pancreatoblastoma: a report from the European cooperative study group for paediatric rare tumours (EXPeRT). Eur J Cancer. 2011;47(15):2347–52.

    Article  PubMed  Google Scholar 

  241. Ellerkamp V, Warmann SW, Vorwerk P, Leuschner I, Fuchs J. Exocrine pancreatic tumors in childhood in Germany. Pediatr Blood Cancer. 2012;58(3):366–71.

    Article  PubMed  Google Scholar 

  242. Shorter NA, Glick RD, Klimstra DS, Brennan MF, Laquaglia MP. Malignant pancreatic tumors in childhood and adolescence: the Memorial Sloan-Kettering experience, 1967 to present. J Pediatr Surg. 2002;37(6):887–92.

    Article  PubMed  Google Scholar 

  243. Sheng L, Weixia Z, Longhai Y, Jinming Y. Clinical and biologic analysis of pancreatoblastoma. Pancreas. 2005;30(1):87–90.

    PubMed  Google Scholar 

  244. Glick RD, Pashankar FD, Pappo A, Laquaglia MP. Management of pancreatoblastoma in children and young adults. J Pediatr Hematol Oncol. 2012;34(Suppl 2):S47–50.

    Article  CAS  PubMed  Google Scholar 

  245. Girlanda R, Pozzi A, Matsumoto CS, Fishbein TM. Multi-visceral transplantation in a 21-year-old man with prior pancreatoblastoma. Int J Organ Transplant Med. 2016;7(3):193–6.

    PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA

    Sarangarajan Ranganathan MD

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  1. Department of Pathology, University of Utah/ARUP Laboratories, Salt Lake City, Utah, USA

    Larissa V. Furtado

  2. Department of Pathology, University of Chicago, Chicago, Illinois, USA

    Aliya N. Husain

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Ranganathan, S. (2018). Liver and Pancreas. In: Furtado, L., Husain, A. (eds) Precision Molecular Pathology of Neoplastic Pediatric Diseases . Molecular Pathology Library. Springer, Cham. https://doi.org/10.1007/978-3-319-89626-7_14

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