A practical approach to pediatric liver transplantation in hepatoblastoma and hepatocellular carcinoma

Abstract

Progressively, as chemotherapy has become more effective, more children with liver malignancies are amenable to liver transplantation, and indications have expanded from a limited range of cases (mostly hepatoblastoma) to a range of other unresectable malignant liver tumors; as a result, more children with hepatocellular carcinoma are also now proposed to transplantation, even and often outside the Milan criteria, for a cure. Recent series have highlighted that patient and graft survivals after transplantation for hepatoblastoma and hepatocellular carcinoma have improved in the last decade. Although consensus has not yet been reached about transplantation as a possible cure for other tumor types than hepatoblastoma and hepatocellular carcinoma, liver transplantation, generally speaking, has become an important pillar in the management of pediatric liver malignancies. Remaining limitations and inquiries relate to patient selection (in term of selection criteria considering the risk of recurrence), the role and usefulness of chemotherapy after transplantation, or the best immunosuppression strategy to both protect renal function and improve outcome. Although some prospective studies are on the way regarding these aspects, more studies are needed to explore this rapidly changing aspect of care.

Keywords

Pediatric liver transplantation / hepatoblastoma / hepatocellular carcinoma

References

[1] Vinayak R,Ranganathan S.Pediatric liver transplantation for hepatocellular cancer and rare liver malignancies: US multicenter and single-center experience (1981-2015).Liver Transpl2017;23:1577-88 PMCID:PMC5725660

[2] Registry ELT. Available from: http://www.eltr.org. [Last accessed on 14 Jul 2021]

[3] Stringer MD.The role of liver transplantation in the management of paediatric liver tumours.Ann R Coll Surg Engl2007;89:12-21 PMCID:PMC1963524

[4] Pham TA,Concepcion W,Bonham CA.Effect of liver transplant on long-term disease-free survival in children with hepatoblastoma and hepatocellular cancer.JAMA Surg2015;150:1150-8

[5] Tagge EP,Reyes J.Resection, including transplantation, for hepatoblastoma and hepatocellular carcinoma: Impact on survival.J Pediatr Surg1992;27:292-7 PMCID:PMC2977957

[6] Otte JB,Aronson DC.International Society of Pediatric Oncology (SIOP)Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience.Pediatr Blood Cancer2004;42:74-83

[7] Pimpalwar AP,Ramani P.Strategy for hepatoblastoma management: Transplant versus nontransplant surgery.J Pediatr Surg2002;37:240-5

[8] Hamilton EC,Nguyen DT,Heczey AA.Liver transplantation for primary hepatic malignancies of childhood: the UNOS experience.J Pediatr Surg2017:163-8

[9] Trobaugh-Lotrario AD,O'Neill AF.Unresectable hepatoblastoma: current perspectives.Hepat Med2017;9:1-6 PMCID:PMC5293365

[10] Molmenti E,Roden J.Liver transplantation for hepatoblastoma in the pediatric population.Transplant Proc2001;33:1749

[11] Cruz RJ Jr,Mazariegos G.Analysis of national and single-center incidence and survival after liver transplantation for hepatoblastoma: new trends and future opportunities.Surgery2013;153:150-9

[12] McAteer JP,Healey PJ.Surgical treatment of primary liver tumors in children: outcomes analysis of resection and transplantation in the SEER database.Pediatr Transplant2013;17:744-50

[13] Superina R.Results of liver transplantation in children with unresectable liver tumors.J Pediatr Surg1996;31:835-9

[14] Ng K.Pediatric liver tumors.Clin Liver Dis2018;22:753-72

[15] Kohorst MA,Matsumoto JM.Management of pediatric hepatocellular carcinoma: a multimodal approach.Pediatr Transplant2017;21:e13007

[16] Sindhi R,Bukowinski A.Liver transplantation for pediatric liver cancer.Cancers (Basel)2020;12:720 PMCID:PMC7140094

[17] Lake CM,Bondoc AJ.Surgical management of locally-advanced and metastatic hepatoblastoma.Semin Pediatr Surg2019;28:150856

[18] Baertschiger RM,Rougemont AL.Cure of multifocal panhepatic hepatoblastoma: is liver transplantation always necessary?.J Pediatr Surg2010;45:1030-6

[19] Freitas Paganoti G, Tannuri ACA, Dantas Marques AC, Torres RR, Mendes Gibelli NE, Tannuri U. Extensive hepatectomy as an alternative to liver transplant in advanced hepatoblastoma: a new protocol used in a pediatric liver transplantation center.Transplant Proc2019;51:1605-10

[20] Lautz TB,Tantemsapya N,Superina RA.Successful nontransplant resection of POST-TEXT III and IV hepatoblastoma.Cancer2011;117:1976-83

[21] Fahy AS,Gerstle JT.Multifocal hepatoblastoma: what is the risk of recurrent disease in the remnant liver?.J Pediatr Surg2019;54:1035-40

[22] Meyers RL,de Ville de Goyet J,Aronson DC.Hepatoblastoma state of the art: pre-treatment extent of disease, surgical resection guidelines and the role of liver transplantation.Curr Opin Pediatr2014;26:29-36

[23] Czauderna P,Roebuck DJ.International Childhood Liver Tumors Strategy Group (SIOPEL)Comments on surgical treatment of locally advanced hepatoblastoma.Cancer2012;118:4092-3; author reply 4094

[24] Uchida H,Sasaki K.Surgical treatment strategy for advanced hepatoblastoma: resection versus transplantation.Pediatr Blood Cancer2018;65:e27383

[25] Czauderna P,Hiyama E.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 Cancer2016;52:92-101 PMCID:PMC5141607

[26] Maibach R,Brugieres L.Prognostic stratification for children with hepatoblastoma: the SIOPEL experience.Eur J Cancer2012;48:1543-9

[27] Meyers RL,Hiyama E.Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration.Lancet Oncol2017;18:122-31 PMCID:PMC5650231

[28] Koh KN,Yoon HM.Recent improvement in survival outcomes and reappraisal of prognostic factors in hepatoblastoma.Cancer Med2021;10:3261-73 PMCID:PMC8124118

[29] Zsíros J,Shafford E.Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study.J Clin Oncol2010;28:2584-90

[30] Fonseca A,Shaikh F.Extreme hepatic resections for the treatment of advanced hepatoblastoma: are planned close margins an acceptable approach?.Pediatr Blood Cancer2018;65:e26820

[31] Fuchs J,Blumenstock G.POST-TEXT III and IV hepatoblastoma: extended hepatic resection avoids liver transplantation in selected cases.Ann Surg2017;266:318-23

[32] Aronson DC.Malignant tumors of the liver in children.Semin Pediatr Surg2016;25:265-75

[33] Otte JB,Reding R.Liver transplantation for hepatoblastoma: indications and contraindications in the modern era.Pediatr Transplant2005;9:557-65

[34] Perilongo G,Plaschkes J.SIOPEL trials using preoperative chemotherapy in hepatoblastoma.Lancet Oncol2000;1:94-100

[35] Brown J,Shafford E.Pretreatment prognostic factors for children with hepatoblastoma - results from the International Society of Paediatric Oncology (SIOP) Study SIOPEL 1.Eur J Cancer2000;36:1418-25

[36] Bucuvalas JC.Long-term outcomes after liver transplantation in children.Curr Opin Organ Transplant2008;13:247-51

[37] Perilongo G,Maibach R.International Society of Paediatric Oncology-SIOPEL 2Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology--SIOPEL 2.Eur J Cancer2004;40:411-21

[38] Aronson DC,Staalman CR.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 Oncol2005;23:1245-52

[39] Otte JB.The contribution of transplantation to the treatment of liver tumors in children.Semin Pediatr Surg2005;14:233-8

[40] Fuchs J,Ellerkamp V.Analysis of sternotomy as treatment option for the resection of bilateral pulmonary metastases in pediatric solid tumors.Surg Oncol2008;17:323-30

[41] Gupta AA,Ng V.Critical review of controversial issues in the management of advanced pediatric liver tumors.Pediatr Blood Cancer2011;56:1013-8

[42] Takahashi N,Hoshino K.Living donor liver re-transplantation for recurrent hepatoblastoma in the liver graft following complete eradication of peritoneal metastases under indocyanine green fluorescence imaging.Cancers (Basel)2019;11:730 PMCID:PMC6562613

[43] Kalicinski P,Broniszczak D.Non-resectable hepatic tumors in children - role of liver transplantation.Ann Transplant2008;13:37-41

[44] Namgoong JM,Hwang S,Park GC.Pediatric living donor liver transplantation with homograft replacement of retrohepatic inferior vena cava for advanced hepatoblastoma.Ann Hepatobiliary Pancreat Surg2019;23:178-82 PMCID:PMC6558128

[45] Hort A,Shun A.Use of a donor iliac vein graft for reconstruction of the inferior vena cava in liver transplantation for hepatoblastoma with caval extension.Pediatr Transplant2019;23:e13409

[46] Chardot C,Gilles A.Living-related liver transplantation and vena cava reconstruction after total hepatectomy including the vena cava for hepatoblastoma.Transplantation2002;73:90-2

[47] Hasegawa T,Ihara Y.Living-related liver transplantation with removal of inferior vena cava for unresectable hepatoblastoma.Pediatr Transplant2006;10:521-4

[48] Uchida H,Sasaki K.Benefit of early inflow exclusion during living donor liver transplantation for unresectable hepatoblastoma.J Pediatr Surg2016;51:1807-11

[49] Herden U,Lenhartz H,Fischer L.Excellent outcome following liver transplantation for hepatoblastoma using an extensive en bloc hepatectomy technique.Transplant Proc2019;51:1887-91

[50] Kueht M,Rana A,O'Mahony C.Effects of an early referral system on liver transplantation for hepatoblastoma at Texas Children's Hospital.Pediatr Transplant2016;20:515-22

[51] Venkatramani R,Sapra A.Effect of neoadjuvant chemotherapy on resectability of stage III and IV hepatoblastoma.Br J Surg2015;102:108-13

[52] Ruth ND,Sharif K,Lloyd C.Rejection is less common in children undergoing liver transplantation for hepatoblastoma.Pediatr Transplant2014;18:52-7

[53] Lee WS,Milford DV.Renal function following liver transplantation for unresectable hepatoblastoma.Pediatr Transplant2003;7:270-6

[54] Zavala R, Marzouki M, Beaunoyer M, Alvarez F. Glomerular filtration rate in liver transplant for unresectable hepatoblastoma.Pediatr Transplant2020;24:e13746

[55] Hendrickson RJ,Fischer R,Daniel J.Indications and efficacy of conversion from tacrolimus- to sirolimus-based immunosuppression in pediatric patients who underwent liver transplantation for unresectable hepatoblastoma.Pediatr Transplant2019;23:e13369

[56] Malek MM,Atri P.Review of outcomes of primary liver cancers in children: our institutional experience with resection and transplantation.Surgery2010;148:778-82; discussion 782

[57] Ramos-Gonzalez G,O'Neill AF.Long-term outcomes of liver transplantation for hepatoblastoma: a single-center 14-year experience.Pediatr Transplant2018;:e13250

[58] Suh MY,Gutweiler JR.Safety of minimal immunosuppression in liver transplantation for hepatoblastoma.J Pediatr Surg2008;43:1148-52

[59] Faraj W,Marangoni G.Liver transplantation for hepatoblastoma.Liver Transpl2008;14:1614-9

[60] Mejia A,Shaw BW,Sudan DL.Living and deceased donor liver transplantation for unresectable hepatoblastoma at a single center.Clin Transplant2005;19:721-5

[61] Al-oabandi W,Buckels J.Orthotopic liver transplantation for unresectable hepatoblastoma: a single center's experience.J Pediatr Surg1999;34:1261-4

[62] Sakamoto S,Mizuta K.Japanese Liver Transplantation SocietyNationwide survey of the outcomes of living donor liver transplantation for hepatoblastoma in Japan.Liver Transpl2014;20:333-46

[63] Tiao GM,Allen S.The current management of hepatoblastoma: a combination of chemotherapy, conventional resection, and liver transplantation.J Pediatr2005;146:204-11

[64] Ng K,Masand P.Fatal central nervous system post-transplant lymphoproliferative disease in a patient who underwent liver transplantation for hepatoblastoma.J Pediatr Gastroenterol Nutr2018;66:e21-3

[65] Austin MT,Feurer ID.Liver transplantation for childhood hepatic malignancy: a review of the United Network for Organ Sharing (UNOS) database.J Pediatr Surg2006;41:182-6

[66] Zsiros J,Brock P.Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study.Lancet Oncol2013;14:834-42 PMCID:PMC3730732

[67] Yang T,Vasudevan SA.Surgical management of hepatoblastoma and recent advances.Cancers (Basel)2019;11:1944 PMCID:PMC6966548

[68] Umeda K,Kawaguchi K.Prognostic and therapeutic factors influencing the clinical outcome of hepatoblastoma after liver transplantation: a single-institute experience.Pediatr Transplant2018;22:e13113

[69] Triana Junco P,Dore M.Prognostic Factors for Liver Transplantation in Unresectable Hepatoblastoma.Eur J Pediatr Surg2019;29:28-32

[70] Perilongo G,Shafford E.Liver Tumour Study Group of the International Society of Paediatric Oncology (SIOP)Hepatoblastoma presenting with lung metastases: Treatment results of the first cooperative, prospective study of the International Society of Paediatric Oncology on childhood liver tumors.Cancer2000;89:1845-53

[71] Otte JB.PLUTO first report.Pediatr Transplant2010;14:830-5

[72] Kosola S,Sairanen H,Jalanko H.High survival rates after liver transplantation for hepatoblastoma and hepatocellular carcinoma.Pediatr Transplant2010;14:646-50

[73] Browne M,Grant D.Survival after liver transplantation for hepatoblastoma: a 2-center experience.J Pediatr Surg2008;43:1973-81

[74] Khan AS,Vachharajani N.Liver Transplantation for malignant primary pediatric hepatic tumors.J Am Coll Surg2017;225:103-13

[75] Kim T,Kim KM.Pediatric liver transplantation for hepatoblastoma: a single center experience.Transplant Proc2012;44:523-5

[76] Kasahara M,Haga H.Living-donor liver transplantation for hepatoblastoma.Am J Transplant2005;5:2229-35

[77] Angelico R,Gazia C.How do synchronous lung metastases influence the surgical management of children with hepatoblastoma?.Cancers (Basel)2019;11:1693 PMCID:PMC6895839

[78] Srinivasan P,Pritchard J.Orthotopic liver transplantation for unresectable hepatoblastoma.Transplantation2002;74:652-5

[79] Isono K,Lee KJ.Pretransplant trends in α-fetoprotein levels as a predictor of recurrence after living donor liver transplantation for unresectable hepatoblastoma: a single-institution experience.Pediatr Transplant2018;22:e13221

[80] Lauferman L,Aredes D.Prognostic factors for event-free survival in liver transplantation for hepatoblastoma: a single-center experience.Pediatr Transplant2019;23:e13581

[81] Czauderna P,Perilongo G.Liver Tumors Study Group of the International Society of Pediatric OncologyHepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group.J Clin Oncol2002;20:2798-804

[82] D'Souza AM,Gupta A.Clinical heterogeneity of pediatric hepatocellular carcinoma.Pediatr Blood Cancer2020;67:e28307

[83] Mazzaferro V,Miceli R.Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis.Lancet Oncol2009;10:35-43

[84] Schmid I.Pediatric hepatocellular carcinoma: challenges and solutions.J Hepatocell Carcinoma2017;4:15-21 PMCID:PMC5248979

[85] Sugawara Y.Living-donor liver transplantation for patients with hepatocellular carcinoma in Japan: current situations and challenge.Hepatobiliary Pancreat Dis Int2020;19:1-2

[86] Ville de Goyet J, Meyers RL, Tiao GM, Morland B. Beyond the Milan criteria for liver transplantation in children with hepatic tumours.Lancet Gastroenterol Hepatol2017;2:456-62

[87] Triana P,Romo MM.Hepatocellular carcinoma: referral to a transplantation unit.Eur J Pediatr Surg2017;27:16-9

[88] Ismail H,Kaliciński P.Liver transplantation in children with hepatocellular carcinoma. Do Milan criteria apply to pediatric patients?.Pediatr Transplant2009;13:682-92

[89] Ziogas IA,Matsuoka LK.Surgical management of pediatric hepatocellular carcinoma: an analysis of the National Cancer Database.J Pediatr Surg2021;56:772-7

[90] Reyes JD,Dvorchik I.Liver transplantation and chemotherapy for hepatoblastoma and hepatocellular cancer in childhood and adolescence.J Pediatr2000;136:795-804

[91] Kelly D,Brown RM.Hepatocellular carcinoma in children.Clin Liver Dis2015;19:433-47

[92] Ziogas IA,Zhao Z.Population-based analysis of hepatocellular carcinoma in children: identifying optimal surgical treatment.J Am Coll Surg2020;230:1035-44.e3

[93] Baumann U,Duvoux C.European Liver and Intestine Transplant AssociationSurvival of children after liver transplantation for hepatocellular carcinoma.Liver Transpl2018;24:246-55

[94] Ozçay F,Bilezikçi B,Karakayali H.Effect of living donor liver transplantation on outcome of children with inherited liver disease and hepatocellular carcinoma.Clin Transplant2006;20:776-82

[95] Llovet JM,Mazzaferro V.SHARP Investigators Study GroupSorafenib in advanced hepatocellular carcinoma.N Engl J Med2008;359:378-90

[96] Liang W,Ling X.Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma: a meta-analysis.Liver Transpl2012;18:1226-36

[97] Katz SC,Liau KH.Operative blood loss independently predicts recurrence and survival after resection of hepatocellular carcinoma.Ann Surg2009;249:617-23

[98] Nishizaki T,Kanematsu T,Sugimachi K.Surgical manipulation of VX2 carcinoma in the rabbit liver evokes enhancement of metastasis.J Surg Res1990;49:92-7

[99] Beaunoyer M,Ogihara M.Outcomes of transplantation in children with primary hepatic malignancy.Pediatr Transplant2007;11:655-60

[100] Ravaioli M,Neri F.Liver transplantation for hepatic tumors: a systematic review.World J Gastroenterol2014;20:5345-52 PMCID:PMC4017049

[101] Geissler EK,Zülke C.Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label phase 3 trial.Transplantation2016;100:116-25 PMCID:PMC4683033

[102] Koneru B,Busuttil RW.Liver transplantation for hepatoblastoma. The American experience.Ann Surg1991;213:118-21 PMCID:PMC1358382

[103] Cillo U,Bassanello M.Liver transplantation for the management of hepatoblastoma.Transplant Proc2003;35:2983-5

[104] Casas-Melley AT,Consolini D.Successful liver transplant for unresectable hepatoblastoma.J Pediatr Surg2007;42:184-7

[105] Héry G,Habes D.Initial liver transplantation for unresectable hepatoblastoma after chemotherapy.Pediatr Blood Cancer2011;57:1270-5

[106] Barrena S,Miguel M.High-risk hepatoblastoma: results in a pediatric liver transplantation center.Eur J Pediatr Surg2011;21:18-20

[107] Kirnap M,Ozcay F,Ozdemir BH.Pediatric liver transplant for hepatoblastoma: a single-center experience.Exp Clin Transplant2017;15:50-2

[108] Ezekian B,Schroder PM.Improved contemporary outcomes of liver transplantation for pediatric hepatoblastoma and hepatocellular carcinoma.Pediatr Transplant2018;22:e13305

[109] Okur MH,Cimşit B.Liver transplant in children with hepatoblastoma.Exp Clin Transplant2019;17:644-7

[110] Feng J,Wei L.Assessment of survival of pediatric patients with hepatoblastoma who received chemotherapy following liver transplant or liver resection.JAMA Netw Open2019;2:e1912676 PMCID:PMC6784752

[111] Arikan C,Nart D.Hepatocellular carcinoma in children and effect of living-donor liver transplantation on outcome.Pediatr Transplant2006;10:42-7

[112] Sevmis S,Ozçay F.Liver transplantation for hepatocellular carcinoma in children.Pediatr Transplant2008;12:52-6

[113] Romano F,Bravi M.Favorable outcome of primary liver transplantation in children with cirrhosis and hepatocellular carcinoma.Pediatr Transplant2011;15:573-9

[114] Weiss KE,Rangaswami AA.Transarterial chemoembolization in children to treat unresectable hepatocellular carcinoma.Pediatr Transplant2018;22:e13187