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Page 2 of 7 Weeda et al. Hepatoma Res 2021;7:43 https://dx.doi.org/10.20517/2394-5079.2021.10

second most common primary pediatric liver cancer (http://seer.cancer.gov). In adults the incidence of
HCC is much higher making it the third worldwide cancer-related cause of death. HCC continues to pose a
significant therapeutic challenge. Despite overall progress in pediatric and adult oncology, the cure rates in
non-resectable HCC remain dismal, with 5-year overall survival ranges of 20%-30% in most multicenter
trials evaluating systemic treatment. The abundance of data from both basic research efforts and clinical
trials in adult HCC may be used to explore the most common aberrant molecular signaling pathways, to
stratify subtypes, and to guide research efforts to learn if these findings are present in pediatric HCC as well.
Stratification according to tumor subtype with accompanying molecular aberrance print may serve as a
guide for targeted systemic treatment in pediatric HCC.

ETIOLOGY AND CLASSIFICATION
Pediatric HCC may be divided into “de novo” HCC and HCC developing in a setting of underlying liver
[1]
disease .
De novo HCC (~70% of cases) may be subcategorized based on histology in three subtypes: conventional
type HCC, HCC with elements of hepatoblastoma, and fibrolamellar hepatocellular carcinoma.

Conventional type HCC is histologically similar to HCC in adult patients without cirrhosis. HCC with
elements of hepatoblastoma is by convention now termed hepatocellular neoplasm not otherwise specified
[2,3]
(HCN-NOS) and may respond differently to chemotherapy based on its biology . Fibrolamellar
hepatocellular carcinoma (FL-HCC) is usually a solitary tumor, often containing a central necrotizing scar,
[4]
and made up of lamellar stroma with polygonal tumor cells . It predominantly occurs in older children and
adolescents and comprises approximately 20% of all HCC in children . It was previously thought that FL-
[5]
HCC had a superior prognosis to conventional HCC; however, more recent reports disprove this .
[6,7]
Pediatric HCC associated with underlying disease (~30% of cases) may originate from a number of
conditions causing hepatocellular destruction. Amongst these are Alagille syndrome, alpha 1-antitrypsin
deficiency, ataxia telangiectasia, auto-immune hepatitis, Fanconi anemia, Gardner syndrome, familial
adenomatous polyposis, familial progressive intrahepatic cholestasis, hemochromatosis, liver mitochondrial
respiratory chain disease, primary sclerosing cholangitis, transaldolase deficiency, type 1 glycogen storage
disease, tyrosinemia, Wilson disease, and hepatitis B and C. The incidence of hepatitis B related pediatric
HCC - which was particularly high in low- and middle-income countries in Sub-Saharan Africa, Southeast
Asia, and South America - has declined significantly since the introduction of large-scale hepatitis B
vaccination programs .
[8]
[9]
Only a low percentage of pediatric HCC cases can be linked to cirrhosis . There are indications that fewer
genetic changes are needed for tumors to occur in the pediatric age group . Although the end stage
[10]
cirrhosis does not frequently occur in children, the process of repeated cycles of damage and repair resulting
consecutively in disturbed cell signaling, hyperplasia, dysplasia, and ultimately tumor formation is highly
similar to tumorigenesis in adult HCC patients .
[11]

MAJOR MOLECULAR ABERRANCES
In both pediatric and adult conventional HCC, actors in growth, development, and differentiation pathways
are frequently dysregulated [10,11] . Major aberrant molecular components in both pediatric and adult HCC are
WNT/CTNNB1 (Beta-catenin), EPHB2 (ephrin type B receptor 2), TGFB1 (transforming growth factor beta
1), and MTOR (mechanistic target of rapamycin) .
[12]