Paediatric and Adult Hepatocellular Carcinoma: Comparison
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Hepatocellular carcinoma (HCC) is the most common primary liver cancer affecting adults and the second most common primary liver cancer affecting children. 

  • inherited cholestasis
  • hepatocellular carcinoma
  • ABCB11 gene
  • TJP2 gene
  • VPS33B gene

1. Introduction

Inherited cholestatic disorders refer to genetically determined conditions in which there is a defect in bile synthesis, secretion or flow. These conditions generally result in increased serum concentrations of the various components of bile, may manifest clinically as jaundice, pruritus, as well as fat and fat-soluble vitamin malabsorption, and can lead to significant liver injury. Certain inherited cholestatic disorders are associated with an increased risk of liver cancer in infancy and childhood. The exact mechanism by which cancer develops in patients with these disorders is unclear. However, their monogenic nature and the early onset of cancer in these disorders, typically in the absence of other known environmental factors, could shed light on how specific genes contribute to hepatocarcinogenesis. 
This entry will first provide a brief overview of the types of primary liver cancer affecting children and adults. Next, it will summarise the key similarities and differences between paediatric and adult HCC. Three genes implicated in rare cholestatic disorders will be discussed in relation to the development of HCC, focusing in particular on bile acid-induced damage (due to ATP-binding cassette subfamily B member 11, or ABCB11, changes), disruption of intercellular junction formation (due to tight junction protein 2, or TJP2, changes) and disruption of cell polarity (due to vacuolar protein sorting-associated protein 33B, or VPS33B, changes). TResearche full reviewrs focuses specifically on the  ABCB11, TJP2 and VPS33B genes due to the important and increasingly well-defined mechanisms by which variation in these genes leads to cholestasis and possibly HCC.

2. Primary Liver Cancer in Children and Adults

In adults, HCC accounts for approximately 75–90% of all liver cancers [1][2]. Major risk factors for HCC in adults include chronic viral hepatitis, alcohol-related liver disease and metabolic syndrome-associated liver disease [3][4]. The majority of HCCs occur in cirrhotic livers, although they may also occur in noncirrhotic livers. After HCC, the second most common type of liver cancer in adults is cholangiocarcinoma (CCA). Important risk factors for CCA include parasitic infection, primary sclerosing cholangitis, bile duct cysts and cholelithiasis [5]. A small subset of primary liver cancers exhibit features of both HCC and CCA and are referred to as combined hepatocellular-cholangiocarcinoma [6].
In children, hepatoblastoma is the most common type of liver cancer, although it accounts for just 1% of all paediatric cancers. Hepatoblastoma is associated with certain genetic syndromes such as Beckwith–Wiedemann syndrome, familial adenomatous polyposis and trisomy 18 [7][8]. Prematurity and low or very low birth weight have also been associated with hepatoblastoma [7][8] (Table 1). HCC is the second most common type of liver cancer in children and is the most common liver cancer diagnosed in children with inherited metabolic disorders [9]. Risk factors for HCC in children include genetically determined disorders such as progressive familial intrahepatic cholestasis (PFIC), hereditary tyrosinemia, glycogen storage disease (GSD), Alagille’s syndrome, as well as other conditions such as perinatally acquired hepatitis B virus (HBV) infection and congenital portosystemic shunts (Table 1). Some rare tumours show overlapping histological features between HCC and hepatoblastoma; these tumours, which typically affect older children and adolescents, were once termed ‘transitional liver cell tumours’ but are now by consensus termed ‘hepatocellular malignant neoplasms, not otherwise specified’ [10][11][12]. Fibrolamellar carcinoma (FLC) is another rare type of liver cancer that primarily affects adolescents and young adults without pre-existing chronic liver disease. Risk factors for its development have yet to be firmly established [13]. Though traditionally considered a variant of HCC, it has recently been suggested that FLC is likely to represent a distinct clinicopathologic entity [14]. CCA is also rare in children but has been described in the context of underlying liver [15][16] or immunological disease [17].
Table 1. Risk factors for hepatoblastoma and HCC in children [7][8][9][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39].
Type of Primary Liver Cancer Risk Factors (Not Exhaustive) References
Hepatoblastoma Genetic, overgrowth and/or cancer predisposition syndromes

Beckwith–Wiedemann syndrome

Familial adenomatous polyposis

Trisomy 18

Aicardi syndrome

Simpson–Golabi–Behmel syndrome

Other conditions

Prematurity

Low or very low birth weight		 [7][8]
HCC Possibly related to cirrhosis

Alagille’s syndrome

Hereditary tyrosinemia

GSD type 3

Alpha-1 antitrypsin deficiency

Transaldolase deficiency

Liver mitochondrial respiratory chain disorders

Wilson’s disease

Autoimmune liver disease

Biliary atresia

Possibly independent of cirrhosis

PFIC

GSD type 1

Citrin deficiency (including adult-onset citrullinemia type 2)

Congenital portosystemic shunts

Perinatally acquired HBV infection and hepatitis C virus (HCV) infection

Hepatic venous outflow tract obstruction

Note: Some conditions that can affect children (e.g., acute intermittent porphyria, hereditary haemochromatosis, chronic HCV infection, nonalcoholic fatty liver disease) may increase the risk of HCC later in life due to a longer latency period.		 [9][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]
Abbreviations: GSD, glycogen storage disease; PFIC, progressive familial intrahepatic cholestasis; HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma.
Other hepatic neoplasms include angiosarcoma of the liver and benign lesions such as hepatic adenoma and focal nodular hyperplasia.

3. Differences between Paediatric and Adult HCC

The cell of origin in paediatric and adult HCC has been subject to significant debate and study. It is possibly the hepatocyte, a specialised epithelial cell in the liver that performs myriad metabolic, synthetic, detoxification and secretory functions; however, the hepatic progenitor cell has also previously been suggested as a potential cell of origin [40][41]. Given the different risk factors associated with HCC development in children and in adults, it is worth considering at this stage whether paediatric HCC and adult HCC are, in fact, the same disease.
There are some general differences between paediatric and adult cancers. For instance, paediatric cancers generally tend to exhibit fewer genetic alterations compared to adult cancers [42]. Some of the proposed reasons for the lower mutational burden seen in paediatric cancers include their embryonal origin in many cases, perturbance of normal developmental pathways, and in the liver, the higher basal cellular growth rate in the paediatric liver [42][43]. Environmental carcinogens also seem to play a smaller role in paediatric cancers in general [42][44], although it must be acknowledged that there are certain well-established associations between environmental factors and childhood cancer—for instance, perinatally acquired HBV infection and the early development of HCC.
With respect to HCC, it is notable that response rates to chemotherapy are estimated to be approximately 20% in adults and 40% in children [45]. Different chemotherapeutic regimes and the higher frequency of medical comorbidities in adults should be taken into account when considering these different response rates in children and adults. At the same time, the significant difference in chemo-responsiveness may also be biologically determined and may suggest disparate mechanisms of HCC development.
Another difference between paediatric and adult HCC relates to the presence of underlying liver disease. While there are known risk factors for HCC in children, the majority of HCC cases are sporadic, occurring in the absence of pre-existing liver disease. In contrast, while HCC in adults can develop independently of cirrhosis, the majority of HCC cases occur in the setting of cirrhosis. Moreover, in the paediatric population, there is no clearly established difference in HCC risk between males and females [46]. This contrasts with the adult population, in which HCC occurs more frequently in men than in women [47].
Although large-scale studies to clarify the molecular and histopathological differences between paediatric and adult HCCs are inevitably limited by the rarity of paediatric HCC, there are some notable differences. For example, one group studying HBV-related HCC found a lower level of cyclin D1 expression and a higher frequency of loss of heterozygosity of chromosome 13q in paediatric tumours compared to adult tumours [48]. The significance of loss of heterozygosity of chromosome 13q may relate to loss of function of a tumour suppressor gene in this region, such as the retinoblastoma (RB) gene, the BRCA2 DNA repair associated (BRCA2) gene or another putative gene [49][50]. Another group reported diffuse expression of epithelial cell adhesion molecule (EpCAM) in 11 out of 12 (92%) paediatric HCCs compared to only focal EpCAM expression in 3 out of 20 (15%) adult HCCs [51]. It was suggested that the particular expression pattern of EpCAM in paediatric HCCs might reflect cell immaturity [51]. Although the exact implications of diffuse versus focal EpCAM expression are not certain, EpCAM has been described in the context of multiple cancers as a marker of cell ‘stemness’ [52][53].
While these differences are interesting (summarised in Table 2), there are also important parallels between paediatric and adult HCC. For instance, conventional paediatric HCC and adult HCC currently share diagnostic histological findings such as increased cell density, cytologic and nuclear atypia, frequent mitotic activity, loss of reticulin, increased arterialisation and expansion of the hepatocyte plate [54][55]. In addition, cellular pathways involved in growth, differentiation, apoptosis, angiogenesis and cell cycle control are frequently dysregulated in both paediatric and adult patients with HCC [43]. The genetic alterations present in paediatric and adult cancers are also highly heterogeneous [42]. For example, adult cancers show a high frequency of somatic mutations, and paediatric cancers may exhibit a higher frequency of germline changes, copy number alterations, structural chromosomal rearrangements such as chromoplexy, gene fusions and enhancer hijacking [42]. In a more clinical context, elevation of serum alpha-fetoprotein (AFP) levels may be seen in many but not all cases of paediatric and adult HCC [18][56][57][58], and many institutions use ultrasound imaging with monitoring of serum AFP levels as a screening or surveillance method for at-risk patients in both paediatric and adult populations. Finally, several genes that are associated with severe paediatric liver disease and/or early-onset HCC have also been implicated in adult HCC. 
Table 2. Summary of differences between paediatric and adult HCCs [3][4][18][33][42][43][44][45][48][51].
Paediatric Cancers Adult Cancers Reference
In General
Fewer genetic alterations More frequent genetic alterations [42]
Environmental factors play a smaller role Environmental factors play a greater role [42][44]
No clear difference in risk between males and females Risk is higher in males compared to females [46][47]
Focus on HCC
Majority of HCC cases are sporadic Majority of HCC cases occur in the setting of cirrhosis [33]
Risk factors include genetic cholestatic conditions (e.g., PFIC, Alagille’s syndrome), metabolic liver disease (e.g., hereditary tyrosinemia, GSD), perinatal HBV infection and congenital portosystemic shunts Major risk factors include chronic viral hepatitis, alcohol-related liver disease and metabolic syndrome-associated liver disease [3][4][18][33]
Higher response rates to chemotherapy Lower response rates to chemotherapy [45]
Lower level of cyclin D1 expression and higher frequency of loss of heterozygosity of chromosome 13q in HBV-related HCCs Higher level of cyclin D1 expression and lower frequency of loss of heterozygosity of chromosome 13q in HBV-related HCCs [48]
Diffuse EpCAM expression in the majority of cases in one study Focal EpCAM expression in some cases in one study [51]
Abbreviations: HCC, hepatocellular carcinoma; PFIC, progressive familial intrahepatic cholestasis; GSD, glycogen storage disease; HBV, hepatitis B virus; EpCAM, epithelial cell adhesion molecule.

References

  1. Dasgupta, P.; Henshaw, C.; Youlden, D.R.; Clark, P.J.; Aitken, J.F.; Baade, P.D. Global Trends in Incidence Rates of Primary Adult Liver Cancers: A Systematic Review and Meta-Analysis. Front. Oncol. 2020, 10, 171.
  2. Llovet, J.M.; Kelley, R.K.; Villanueva, A.; Singal, A.G.; Pikarsky, E.; Roayaie, S.; Lencioni, R.; Koike, K.; Zucman-Rossi, J.; Finn, R.S. Hepatocellular carcinoma. Nat. Rev. Dis. Primers 2021, 7, 6.
  3. Gomaa, A.I.; Khan, S.A.; Toledano, M.B.; Waked, I.; Taylor-Robinson, S.D. Hepatocellular carcinoma: Epidemiology, risk factors and pathogenesis. World J. Gastroenterol. 2008, 14, 4300–4308.
  4. Janevska, D.; Chaloska-Ivanova, V.; Janevski, V. Hepatocellular Carcinoma: Risk Factors, Diagnosis and Treatment. Open Access Maced. J. Med. Sci. 2015, 3, 732–736.
  5. Tyson, G.L.; El-Serag, H.B. Risk factors for cholangiocarcinoma. Hepatology 2011, 54, 173–184.
  6. Stavraka, C.; Rush, H.; Ross, P. Combined hepatocellular cholangiocarcinoma (cHCC-CC): An update of genetics, molecular biology, and therapeutic interventions. J. Hepatocell. Carcinoma 2019, 6, 11–21.
  7. Spector, L.G.; Birch, J. The epidemiology of hepatoblastoma. Pediatr. Blood Cancer 2012, 59, 776–779.
  8. Chen, H.; Guan, Q.; Guo, H.; Miao, L.; Zhuo, Z. The Genetic Changes of Hepatoblastoma. Front. Oncol. 2021, 11, 690641.
  9. Schady, D.A.; Roy, A.; Finegold, M.J. Liver tumors in children with metabolic disorders. Transl. Pediatr. 2015, 4, 290–303.
  10. Walther, A.; Tiao, G. Approach to pediatric hepatocellular carcinoma. Clin. Liver Dis. 2013, 2, 219–222.
  11. López-Terrada, D.; Alaggio, R.; de Dávila, M.T.; Czauderna, P.; Hiyama, E.; Katzenstein, H.; Leuschner, I.; Malogolowkin, M.; Meyers, R.; Ranganathan, S.; et al. Towards an international pediatric liver tumor consensus classification: Proceedings of the Los Angeles COG liver tumors symposium. Mod. Pathol. 2014, 27, 472–491.
  12. Prokurat, A.; Kluge, P.; Kościesza, 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, 510–518.
  13. Kassahun, W.T. Contemporary management of fibrolamellar hepatocellular carcinoma: Diagnosis, treatment, outcome, prognostic factors, and recent developments. World J. Surg. Oncol. 2016, 14, 151.
  14. Andersen, J.B. Fibrolamellar hepatocellular carcinoma: A rare but distinct type of liver cancer. Gastroenterology 2015, 148, 707–710.
  15. Deneau, M.; Adler, D.G.; Schwartz, J.J.; Hutson, W.; Sorensen, J.; Book, L.; Lowichik, A.; Guthery, S. Cholangiocarcinoma in a 17-year-old boy with primary sclerosing cholangitis and inflammatory bowel disease. J. Pediatr. Gastroenterol. Nutr. 2011, 52, 617–620.
  16. Yoon, H.J.; Jeon, T.Y.; Yoo, S.Y.; Kim, J.H.; Eo, H.; Lee, S.K.; Kim, J.S. Hepatic tumours in children with biliary atresia: Single-centre experience in 13 cases and review of the literature. Clin. Radiol. 2014, 69, e113–e119.
  17. Hayward, A.R.; Levy, J.; Facchetti, F.; Notarangelo, L.; Ochs, H.D.; Etzioni, A.; Bonnefoy, J.Y.; Cosyns, M.; Weinberg, A. Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM. J. Immunol. 1997, 158, 977–983.
  18. Khanna, R.; Verma, S.K. Pediatric hepatocellular carcinoma. World J. Gastroenterol. 2018, 24, 3980–3999.
  19. Ito, T.; Shiraki, K.; Sekoguchi, K.; Yamanaka, T.; Sugimoto, K.; Takase, K.; Tameda, Y.; Nakano, T. Hepatocellular carcinoma associated with adult-type citrullinemia. Dig. Dis. Sci. 2000, 45, 2203–2206.
  20. Wang, L.; Zhu, S.; Zhang, M.; Dong, Y.; Wang, F.S. A 6-Year-Old Child With Citrin Deficiency and Advanced Hepatocellular Carcinoma. Pediatrics 2019, 143, e20181931.
  21. Demo, E.; Frush, D.; Gottfried, M.; Koepke, J.; Boney, A.; Bali, D.; Chen, Y.T.; Kishnani, P.S. Glycogen storage disease type III-hepatocellular carcinoma a long-term complication? J. Hepatol. 2007, 46, 492–498.
  22. Jang, H.J.; Yang, H.R.; Ko, J.S.; Moon, J.S.; Chang, J.Y.; Seo, J.K. Development of Hepatocellular Carcinoma in Patients with Glycogen Storage Disease: A Single Center Retrospective Study. J. Korean Med. Sci. 2020, 35, e5.
  23. Kishnani, P.S.; Austin, S.L.; Abdenur, J.E.; Arn, P.; Bali, D.S.; Boney, A.; Chung, W.K.; Dagli, A.I.; Dale, D.; Koeberl, D.; et al. Diagnosis and management of glycogen storage disease type I: A practice guideline of the American College of Medical Genetics and Genomics. Genet. Med. 2014, 16, e1.
  24. Modin, L.; Arshad, A.; Wilkes, B.; Benselin, J.; Lloyd, C.; Irving, W.L.; Kelly, D.A. Epidemiology and natural history of hepatitis C virus infection among children and young people. J. Hepatol. 2019, 70, 371–378.
  25. Schindler, E.A.; Gilbert, M.A.; Piccoli, D.A.; Spinner, N.B.; Krantz, I.D.; Loomes, K.M. Alagille syndrome and risk for hepatocellular carcinoma: Need for increased surveillance in adults with mild liver phenotypes. Am. J. Med. Genet. A 2021, 185, 719–731.
  26. Valamparampil, J.J.; Shanmugam, N.; Vij, M.; Reddy, M.S.; Rela, M. Hepatocellular Carcinoma in Paediatric Patients with Alagille Syndrome: Case Series and Review of Literature. J. Gastrointest. Cancer 2020, 51, 1047–1052.
  27. Eriksson, S.; Carlson, J.; Velez, R. Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency. N. Engl. J. Med. 1986, 314, 736–739.
  28. Choe, E.J.; Choi, J.W.; Kang, M.; Lee, Y.K.; Jeon, H.H.; Park, B.K.; Won, S.Y.; Cho, Y.S.; Seo, J.H.; Lee, C.K.; et al. A population-based epidemiology of Wilson’s disease in South Korea between 2010 and 2016. Sci. Rep. 2020, 10, 14041.
  29. Lleo, A.; de Boer, Y.S.; Liberal, R.; Colombo, M. The risk of liver cancer in autoimmune liver diseases. Ther. Adv. Med. Oncol. 2019, 11, 1758835919861914.
  30. Hadžić, N.; Quaglia, A.; Portmann, B.; Paramalingam, S.; Heaton, N.D.; Rela, M.; Mieli-Vergani, G.; Davenport, M. Hepatocellular carcinoma in biliary atresia: King’s College Hospital experience. J. Pediatr. 2011, 159, 617–622.e1.
  31. Zhou, S.; Hertel, P.M.; Finegold, M.J.; Wang, L.; Kerkar, N.; Wang, J.; Wong, L.J.; Plon, S.E.; Sambrotta, M.; Foskett, P.; et al. Hepatocellular carcinoma associated with tight-junction protein 2 deficiency. Hepatology 2015, 62, 1914–1916.
  32. He, J.; Zhang, J.; Li, X.; Wang, H.; Feng, C.; Fang, F.; Shu, S. A Case Report: Can Citrin Deficiency Lead to Hepatocellular Carcinoma in Children? Front. Pediatr. 2019, 7, 371.
  33. Sergi, C.M. Carcinoma of the Liver in Children and Adolescents. In Liver Cancer; Sergi, C.M., Ed.; Exon Publications: Brisbane, Australia, 2021; Chapter 1. Available online: https://www.ncbi.nlm.nih.gov/books/NBK569801/ (accessed on 25 June 2022).
  34. Grammatikopoulos, T.; Hadzic, N.; Foskett, P.; Strautnieks, S.; Samyn, M.; Vara, R.; Dhawan, A.; Hertecant, J.; Al Jasmi, F.; Rahman, O.; et al. Liver Disease and Risk of Hepatocellular Carcinoma in Children With Mutations in TALDO1. Hepatol. Commun. 2022, 6, 473–479.
  35. Leduc, C.A.; Crouch, E.E.; Wilson, A.; Lefkowitch, J.; Wamelink, M.M.; Jakobs, C.; Salomons, G.S.; Sun, X.; Shen, Y.; Chung, W.K. Novel association of early onset hepatocellular carcinoma with transaldolase deficiency. JIMD Rep. 2014, 12, 121–127.
  36. Freisinger, P.; Fütterer, N.; Lankes, E.; Gempel, K.; Berger, T.M.; Spalinger, J.; Hoerbe, A.; Schwantes, C.; Lindner, M.; Santer, R.; et al. Hepatocerebral mitochondrial DNA depletion syndrome caused by deoxyguanosine kinase (DGUOK) mutations. Arch. Neurol. 2006, 63, 1129–1134.
  37. DiPaola, F.; Trout, A.T.; Walther, A.E.; Gupta, A.; Sheridan, R.; Campbell, K.M.; Tiao, G.; Bezerra, J.A.; Bove, K.E.; Patel, M.; et al. Congenital Portosystemic Shunts in Children: Associations, Complications, and Outcomes. Dig. Dis. Sci. 2020, 65, 1239–1251.
  38. Lissing, M.; Vassiliou, D.; Floderus, Y.; Harper, P.; Bottai, M.; Kotopouli, M.; Hagström, H.; Sardh, E.; Wahlin, S. Risk of primary liver cancer in acute hepatic porphyria patients: A matched cohort study of 1244 individuals. J. Intern. Med. 2022, 291, 824–836.
  39. Scheers, I.; Bachy, V.; Stephenne, X.; Sokal, E.M. Risk of hepatocellular carcinoma in liver mitochondrial respiratory chain disorders. J. Pediatr. 2005, 146, 414–417.
  40. Mu, X.; Español-Suñer, R.; Mederacke, I.; Affò, S.; Manco, R.; Sempoux, C.; Lemaigre, F.P.; Adili, A.; Yuan, D.; Weber, A.; et al. Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment. J. Clin. Investig. 2015, 125, 3891–3903.
  41. Tummala, K.S.; Brandt, M.; Teijeiro, A.; Graña, O.; Schwabe, R.F.; Perna, C.; Djouder, N. Hepatocellular Carcinomas Originate Predominantly from Hepatocytes and Benign Lesions from Hepatic Progenitor Cells. Cell Rep. 2017, 19, 584–600.
  42. Sweet-Cordero, E.A.; Biegel, J.A. The genomic landscape of pediatric cancers: Implications for diagnosis and treatment. Science 2019, 363, 1170–1175.
  43. Weeda, V.B.; Aronson, D.C.; Verheij, J.; Lamers, W.H. Is hepatocellular carcinoma the same disease in children and adults? Comparison of histology, molecular background, and treatment in pediatric and adult patients. Pediatr. Blood Cancer 2019, 66, e27475.
  44. Spector, L.G.; Pankratz, N.; Marcotte, E.L. Genetic and nongenetic risk factors for childhood cancer. Pediatr. Clin. N. Am. 2015, 62, 11–25.
  45. D’Souza, A.M.; Towbin, A.J.; Gupta, A.; Alonso, M.; Nathan, J.D.; Bondoc, A.; Tiao, G.; Geller, J.I. Clinical heterogeneity of pediatric hepatocellular carcinoma. Pediatr. Blood Cancer 2020, 67, e28307.
  46. Lau, C.S.; Mahendraraj, K.; Chamberlain, R.S. 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.
  47. Liu, P.; Xie, S.H.; Hu, S.; Cheng, X.; Gao, T.; Zhang, C.; Song, Z. Age-specific sex difference in the incidence of hepatocellular carcinoma in the United States. Oncotarget 2017, 8, 68131–68137.
  48. Kim, H.; Lee, M.J.; Kim, M.R.; Chung, I.P.; Kim, Y.M.; Lee, J.Y.; Jang, J.J. Expression of cyclin D1, cyclin E, cdk4 and loss of heterozygosity of 8p, 13q, 17p in hepatocellular carcinoma: Comparison study of childhood and adult hepatocellular carcinoma. Liver 2000, 20, 173–178.
  49. Wong, C.M.; Lee, J.M.; Lau, T.C.; Fan, S.T.; Ng, I.O. Clinicopathological significance of loss of heterozygosity on chromosome 13q in hepatocellular carcinoma. Clin. Cancer Res. 2002, 8, 2266–2272.
  50. Lin, Y.W.; Sheu, J.C.; Liu, L.Y.; Chen, C.H.; Lee, H.S.; Huang, G.T.; Wang, J.T.; Lee, P.H.; Lu, F.J. Loss of heterozygosity at chromosome 13q in hepatocellular carcinoma: Identification of three independent regions. Eur. J. Cancer 1999, 35, 1730–1734.
  51. 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, 671–682.
  52. Chan, A.W.; Tong, J.H.; Chan, S.L.; Lai, P.B.; To, K.F. Expression of stemness markers (CD133 and EpCAM) in prognostication of hepatocellular carcinoma. Histopathology 2014, 64, 935–950.
  53. Keller, L.; Werner, S.; Pantel, K. Biology and clinical relevance of EpCAM. Cell Stress 2019, 3, 165–180.
  54. Lachance, E.; Mandziuk, J.; Sergi, C.M.; Bateman, J.; Low, G. Radiologic-Pathologic Correlation of Liver Tumors. In Liver Cancer; Sergi, C.M., Ed.; Exon Publications: Brisbane, Australia, 2021; Chapter 5. Available online: https://www.ncbi.nlm.nih.gov/books/NBK569803/ (accessed on 25 June 2022).
  55. Chen, I.Y.; Agostini-Vulaj, D. Hepatocellular Carcinoma Overview. Available online: https://www.pathologyoutlines.com/topic/livertumorHCC.html (accessed on 24 June 2022).
  56. Zhang, J.; Chen, G.; Zhang, P.; Li, X.; Gan, D.; Cao, X.; Han, M.; Du, H.; Ye, Y. The threshold of alpha-fetoprotein (AFP) for the diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis. PLoS ONE 2020, 15, e0228857.
  57. Bialecki, E.S.; Di Bisceglie, A.M. Diagnosis of hepatocellular carcinoma. HPB 2005, 7, 26–34.
  58. Czauderna, P.; Mackinlay, G.; Perilongo, G.; Brown, J.; Shafford, E.; Aronson, D.; Pritchard, J.; Chapchap, P.; Keeling, J.; Plaschkes, J.; 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, 2798–2804.
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