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Pediatric Hepatocellular Carcinoma

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Abstract

Purpose

Pediatric hepatocellular carcinoma is rarely seen in childhood. It constitutes approximately 1% of childhood solid organ malignancies. Pediatric hepatocellular carcinoma is the second most common malignant liver tumor after hepatoblastoma in children. In this review, we aimed to review the diagnosis and treatment of pediatric hepatocellular carcinoma in the light of the latest literature.

Methods

We reviewed the literature in terms of the diagnosis and treatment of pediatric hepatocellular carcinoma.

Results

Hepatocellular carcinoma (HCC) and hepatoblastoma constitute 0.5–1.5% of all childhood malignant tumors. HCC is responsible for 27% of all liver tumors and 4% of all pediatric liver transplantations. While 99.6% of HCC is seen in adults, only 0.4% of it is seen in pediatric patients. Etiological predisposition and biological behavior are different from adults. In a child with cirrhosis or liver disease, HCC should be suspected in the presence of a high level of AFP and an abnormal nodule on ultrasonography. Hepatoblastoma should be considered first in the differential diagnosis.

Conclusion

Treatment of pediatric HCC is challenging. Complete surgical resection is essential for the cure. To this end, different neoadjuvant chemotherapy protocols have been designed to convert non-resectable tumors into resectable tumors. For tumors that cannot be resected, liver transplantation for each patient with childhood HCC should be decided individually.

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Abbreviations

HCC:

Hepatocellular carcinoma

SEER:

Surveillance, Epidemiology, and End Result

AFP:

Alpha-fetoprotein

HCN-NOS:

Hepatocellular neoplasm not otherwise specified

NTBC:

[2-(2-nitro-4-trifluoromethybenzoyl)-1,3cyclohexanedion]

GSD:

Glycogen storage diseases

PFIC:

Progressive familial intrahepatic cholestasis

BSEP:

Bile salt export pump

TJP2:

Tight junction protein 2

AIH:

Autoimmune hepatitis

WD:

Wilson disease

CT:

Tomography

MR:

Magnetic resonance

APASL:

Asian Pacific Association for the Study of the Liver

EFS:

Event-free survival

OS:

Overall survival

SIOPEL:

International Society of Pediatric Oncology Liver Tumor Study

GPOH:

German Society for Pediatric Oncology and Hematology

NASPGHAN:

North America Society for Pediatric Gastroenterology, Hepatology and Nutrition

UNOS:

United Network for Organ Sharing

References

  1. Angelico R, Grimaldi C, Saffioti MC, Castellano A, Spada M. Hepatocellular carcinoma in children: hepatic resection and liver transplantation. Transl Gastroenterol Hepatol. 2018;3:59. Published 2018 Sep 10. https://doi.org/10.21037/tgh.2018.09.05.

    Article  Google Scholar 

  2. Schmid I, von Schweinitz D. Pediatric hepatocellular carcinoma: challenges and solutions. J Hepatocell Carcinoma. 2017;4:15–21. Published 2017 Jan 16. https://doi.org/10.2147/JHC.S94008.

    Article  Google Scholar 

  3. Khanna R, Verma SK. Pediatric hepatocellular carcinoma. World J Gastroenterol. 2018;24(35):3980–99. https://doi.org/10.3748/wjg.v24.i35.3980.

    Article  Google Scholar 

  4. Meyers RL. Tumors of the liver in children. Surg Oncol. 2007;16(3):195–203. https://doi.org/10.1016/j.suronc.2007.07.002.

    Article  Google Scholar 

  5. 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. https://doi.org/10.1016/j.jpedsurg.2013.09.050.

    Article  Google Scholar 

  6. Buendia MA. Genetic alterations in hepatoblastoma and hepatocellular carcinoma: common and distinctive aspects. Med Pediatr Oncol. 2002;39(5):530–5. https://doi.org/10.1002/mpo.10180.

    Article  Google Scholar 

  7. Kelly D, Sharif K, Brown RM, Morland B. Hepatocellular carcinoma in children. Clin Liver Dis. 2015;19(2):433–47. https://doi.org/10.1016/j.cld.2015.01.010.

    Article  Google Scholar 

  8. Hadzic N, Finegold MJ. Liver neoplasia in children. Clin Liver Dis. 2011;15(2):443-x. https://doi.org/10.1016/j.cld.2011.03.011.

    Article  Google Scholar 

  9. McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis. 2015;19(2):223–38. https://doi.org/10.1016/j.cld.2015.01.001.

    Article  Google Scholar 

  10. Katzenstein HM, Krailo MD, Malogolowkin MH, Ortega JA, Liu-Mares W, Douglass EC, et al. Hepatocellular carcinoma in children and adolescents: results from the Pediatric Oncology Group and the Children’s Cancer Group intergroup study. J Clin Oncol. 2002;20(12):2789–97. https://doi.org/10.1200/JCO.2002.06.155.

    Article  Google Scholar 

  11. 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;2015:670728–10. https://doi.org/10.1155/2015/670728.

    Article  Google Scholar 

  12. Weeda VB, Murawski M, McCabe AJ, 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. https://doi.org/10.1016/j.ejca.2013.04.012.

    Article  CAS  Google Scholar 

  13. Czauderna P, Mackinlay G, Perilongo G, Brown J, Shafford E, Aronson D, et al. Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol. 2002;20(12):2798–804. https://doi.org/10.1200/JCO.2002.06.102.

    Article  CAS  Google Scholar 

  14. Chan KL, Fan ST, Tam PK, Chiang AK, Chan GC, Ha SY. Paediatric hepatoblastoma and hepatocellular carcinoma: retrospective study. Hong Kong Med J. 2002;8(1):13–7.

    CAS  Google Scholar 

  15. Zeybek AC, Kiykim E, Soyucen E, et al. Hereditary tyrosinemia type 1 in Turkey: twenty year single-center experience. Pediatr Int. 2015;57(2):281–9. https://doi.org/10.1111/ped.12503.

    Article  CAS  Google Scholar 

  16. Mayorandan S, Meyer U, Gokcay G, et al. Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice. Orphanet J Rare Dis. 2014;9:107. Published 2014 Aug 1. https://doi.org/10.1186/s13023-014-0107-7.

    Article  Google Scholar 

  17. Larochelle J, Alvarez F, Bussières JF, Chevalier I, Dallaire L, Dubois J, et al. Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec. Mol Genet Metab. 2012;107(1–2):49–54. https://doi.org/10.1016/j.ymgme.2012.05.022.

    Article  CAS  Google Scholar 

  18. Kishnani PS, Austin SL, Arn P, Bali DS, Boney A, Case LE, et al. Glycogen storage disease type III diagnosis and management guidelines [published correction appears in Genet Med. 2010 Sep;12(9):566]. Genet Med. 2010;12(7):446–63. https://doi.org/10.1097/GIM.0b013e3181e655b6.

    Article  CAS  Google Scholar 

  19. Demo E, Frush D, Gottfried M, Koepke J, Boney A, Bali D, et al. Glycogen storage disease type III-hepatocellular carcinoma a long-term complication? J Hepatol. 2007;46(3):492–8. https://doi.org/10.1016/j.jhep.2006.09.022.

    Article  CAS  Google Scholar 

  20. 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. https://doi.org/10.1111/j.1399-3046.2011.01528.x.

    Article  CAS  Google Scholar 

  21. Ismail H, Broniszczak D, Kaliciński 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. https://doi.org/10.1111/j.1399-3046.2009.01062.x.

    Article  CAS  Google Scholar 

  22. Pawlikowska L, Strautnieks S, Jankowska I, Czubkowski P, Emerick K, Antoniou A, et al. Differences in presentation and progression between severe FIC1 and BSEP deficiencies. J Hepatol. 2010;53(1):170–8. https://doi.org/10.1016/j.jhep.2010.01.034.

    Article  Google Scholar 

  23. Vij M, Shanmugam NP, Reddy MS, Govil S, Rela M. Hepatocarcinogenesis in multidrug-resistant P-glycoprotein 3 deficiency. Pediatr Transplant. 2017;21(3). https://doi.org/10.1111/petr.12889.

  24. Sambrotta M, Strautnieks S, Papouli E, et al. Mutations in TJP2 cause progressive cholestatic liver disease. Nat Genet. 2014;46(4):326–8. https://doi.org/10.1038/ng.2918.

    Article  CAS  Google Scholar 

  25. Kamath BM, Baker A, Houwen R, Todorova L, Kerkar N. Systematic review: the epidemiology, natural history, and burden of Alagille syndrome. J Pediatr Gastroenterol Nutr. 2018;67(2):148–56. https://doi.org/10.1097/MPG.0000000000001958.

    Article  Google Scholar 

  26. Bernard O, Franchi-Abella S, Branchereau S, Pariente D, Gauthier F, Jacquemin E. Congenital portosystemic shunts in children: recognition, evaluation, and management. Semin Liver Dis. 2012;32(4):273–87. https://doi.org/10.1055/s-0032-1329896.

    Article  CAS  Google Scholar 

  27. Tansel A, Katz LH, El-Serag HB, et al. Incidence and determinants of hepatocellular carcinoma in autoimmune hepatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2017;15(8):1207–1217.e4. https://doi.org/10.1016/j.cgh.2017.02.006.

    Article  Google Scholar 

  28. Pfeiffenberger J, Mogler C, Gotthardt DN, Schulze-Bergkamen H, Litwin T, Reuner U, et al. Hepatobiliary malignancies in Wilson disease. Liver Int. 2015;35(5):1615–22. https://doi.org/10.1111/liv.12727.

    Article  Google Scholar 

  29. Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67(1):358–80. https://doi.org/10.1002/hep.29086.

    Article  Google Scholar 

  30. Sevmis S, Karakayali H, Ozçay F, et al. Liver transplantation for hepatocellular carcinoma in children. Pediatr Transplant. 2008;12(1):52–6. https://doi.org/10.1111/j.1399-3046.2007.00777.x.

    Article  Google Scholar 

  31. Arikan C, Kilic M, Nart D, Ozgenc F, Ozkan T, Tokat Y, et al. Hepatocellular carcinoma in children and effect of living-donor liver transplantation on outcome. Pediatr Transplant. 2006;10(1):42–7. https://doi.org/10.1111/j.1399-3046.2005.00395.x.

    Article  CAS  Google Scholar 

  32. Roberts LR, Sirlin CB, Zaiem F, Almasri J, Prokop LJ, Heimbach JK, et al. Imaging for the diagnosis of hepatocellular carcinoma: a systematic review and meta-analysis. Hepatology. 2018;67(1):401–21. https://doi.org/10.1002/hep.29487.

    Article  Google Scholar 

  33. McAteer JP, Goldin AB, Healey PJ, Gow KW. Hepatocellular carcinoma in children: epidemiology and the impact of regional lymphadenectomy on surgical outcomes. J Pediatr Surg. 2013;48(11):2194–201. https://doi.org/10.1016/j.jpedsurg.2013.05.007.

    Article  Google Scholar 

  34. Mavros MN, Mayo SC, Hyder O, Pawlik TM. A systematic review: treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma. J Am Coll Surg. 2012;215(6):820–30. https://doi.org/10.1016/j.jamcollsurg.2012.08.001.

    Article  Google Scholar 

  35. Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int. 2017;11(4):317–70. https://doi.org/10.1007/s12072-017-9799-9.

    Article  Google Scholar 

  36. 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. https://doi.org/10.1200/JCO.2014.60.2250.

    Article  CAS  Google Scholar 

  37. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66(24):11851–8. https://doi.org/10.1158/0008-5472.CAN-06-1377.

    Article  CAS  Google Scholar 

  38. Peck-Radosavljevic M, Greten TF, Lammer J, Rosmorduc O, Sangro B, Santoro A, et al. Consensus on the current use of sorafenib for the treatment of hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2010;22(4):391–8. https://doi.org/10.1097/MEG.0b013e328333df23.

    Article  CAS  Google Scholar 

  39. Schmid I, Häberle B, Albert MH, Corbacioglu S, Fröhlich B, Graf N, et al. Sorafenib and cisplatin/doxorubicin (PLADO) in pediatric hepatocellular carcinoma. Pediatr Blood Cancer. 2012;58(4):539–44. https://doi.org/10.1002/pbc.23295.

    Article  Google Scholar 

  40. Ince V, Akbulut S, Otan E, et al. Liver transplantation for hepatocellular carcinoma: malatya experience and proposals for expanded criteria [published online ahead of print, 2020 Jun 5] [published correction appears in J Gastrointest Cancer. 2020 Jul 8;]. J Gastrointest Cancer. 2020. https://doi.org/10.1007/s12029-020-00424-w.

  41. Squires RH, Ng V, Romero R, Ekong U, Hardikar W, Emre S, et al. Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Hepatology. 2014;60(1):362–98. https://doi.org/10.1002/hep.27191.

    Article  Google Scholar 

  42. Guiteau JJ, Cotton RT, Karpen SJ, O'Mahony CA, Goss JA. Pediatric liver transplantation for primary malignant liver tumors with a focus on hepatic epithelioid hemangioendothelioma: the UNOS experience. Pediatr Transplant. 2010;14(3):326–31. https://doi.org/10.1111/j.1399-3046.2009.01266.x.

    Article  Google Scholar 

  43. Vinayak R, Cruz RJ Jr, Ranganathan S, Mohanka R, Mazariegos G, Soltys K, et al. Pediatric liver transplantation for hepatocellular cancer and rare liver malignancies: US multicenter and single-center experience (1981-2015). Liver Transpl. 2017;23(12):1577–88. https://doi.org/10.1002/lt.24847.

    Article  Google Scholar 

  44. Baumann U, Adam R, Duvoux C, Mikolajczyk R, Karam V, D'Antiga L, et al. Survival of children after liver transplantation for hepatocellular carcinoma. Liver Transpl. 2018;24(2):246–55. https://doi.org/10.1002/lt.24994.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Faculty of Medicine, Inonu University, 244280, Malatya, Turkey

    Fatma İlknur Varol

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Varol, F.İ. Pediatric Hepatocellular Carcinoma. J Gastrointest Canc 51, 1169–1175 (2020). https://doi.org/10.1007/s12029-020-00494-w

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