As per the SEER database conducted over a period of 1973 to 1997 in United States, pediatric HCC constituted 0.3% of all pediatric malignancies and 31% of all primary hepatic malignancies. The overall age-adjusted incidence rate of pediatric HCC was estimated to be 0.41 (0.24-0.65) per 1000000. The rates were slightly higher for males than females (0.45 vs 0.37 per 1000000). Of these, 12.9% were among children below 5 years of age and 34% were between 15 to 19 years of age. Incidence is highest (0.8 per million) among adolescents. This is in contrast to hepatoblastoma where a majority (91.3%) of cases belong to under-5 year age group[5]. In most of the studies, males outnumbered females with a factor ranging from 1.27 to 2.45[6-8,12-18].

Epidemiological studies from the East have shown higher incidence of pediatric HCC as compared to West and this is primarily related to the high prevalence of perinatally acquired HBV infection. In certain areas it was reported as the commonest childhood liver malignancy[6,7]. There is bimodal age distribution of cases with first peak at around 1 year of age, then a decline to trough at 4 years and a second peak at around 12 to 15 years of age[6]. Male preponderance is more marked in the East with a male to female ratio of 2.1-13.3:1[6,7,12]. A South-African study has found a gender ratio-difference of 2.5 between Hepatitis-B surface antigen (HBsAg) positive vs negative cases of pediatric HCC[7].

As per SEER database, whites and non-Hispanics comprise 72% and 82% of pediatric HCC, respectively[8]. Hence, the racial differences are not as pronounced as in adults with HCC.

Epidemiological data from 2003 has shown that there is a declining trend in pediatric HCC from 1973 to 1997. This is in contrast to almost double the number of cases of hepatoblastoma[5]. In a subsequent analysis by SEER published in 2013, the overall incidence of pediatric HCC has been estimated to be 0.59 per million per year with a relatively stable incidence over last 4 decades (0.62 in 1970s, 0.43 in 1980s, 0.59 in 1990s and 0.62 in 2000s per million per year)[8]. Contrastingly, data from East has shown an 85% reduction in the incidence of pediatric HCC 20-years following introduction of HBV immunization[32].

There has been a dramatic change in the incidence of HBV related HCC in pediatric age-group following introduction of mass immunization against HBV in the Asia-Pacific region. Chang et al[33] showed that following universal HBV vaccination, the average annual incidence of HCC in children 6-14 years of age declined from 0.70 to 0.36 over a decade. This translated in a corresponding (50%) reduction in mortality due to pediatric HCC in the same age group. Study by Taiwan Childhood Hepatoma Study Group further showed that the vaccination program also resulted in reducing boy-girl incidence ratio for the disease from 4.5 in 1981-1984 to 1.9 in 1990-1996. There was a dramatic reduction in incidence of disease in boys (relative risk 0.72) over this time period. However, for girls there was no decrease in the incidence and with increasing age a rising incidence was observed[34]. Subsequent analysis by the same group of workers showed that vaccination resulted in almost 70% reduction in the risk of developing HCC adjusted to age and gender. Moreover, in the vaccination cohort, the risk of developing HCC was found to be related to incomplete vaccination (odd’s ratio, OR = 4.32), prenatal maternal HBsAg seropositivity (OR = 29.5), prenatal HBeAg seropositivity [with administration of HBV immunoglobulin (OR = 5.13) and without it (OR = 9.43)][32].

Hepatitis-B infection is the commonest cause of HCC in adults who live in regions with high endemicity like Southeast Asia and sub-Saharan Africa. HBV constitutes 65% of HCC cases in adults from China and Far East as compared to < 20% from United States. Chronic carriers of HBV have upto 30-fold increased risk of development of HCC[11]. Pediatric HCC in the setting of HBV infection usually develops with perinatally acquired infection and is more common in males with genotype B[31,35]. Gender disparity is universal for all types of HCC and is related to the protection against the tumor by estrogen via a complex pathway involving hepatocyte nuclear factor-4[36]. Family studies from Far-East have confirmed that early infection with HBV, particularly through HBsAg positive mother, leads to persistent chronic infection in children, subsequently leading to development of chronic hepatitis, post-necrotic cirrhosis and HCC[36,37]. Majority of tumors are multi-centric, although cirrhosis may be absent in 26%-53% of cases[12,38] (Figures 3 and 4). Pediatric HCC secondary to HBV differs from non-HBV cases with regard to male predominance (68%-93% vs 50%), older age of presentation (14.5 years vs 10.9 years), presence of cirrhosis (56% vs 23%) and portal vein invasion (56% vs 23%), but there is no difference with respect to tumor size, number of lesions or metastases[6-8,12-16,30]. Thus, HBV related HCC represents more aggressive and advance disease, and complements its adult counterpart. An old study from Taiwan on HBV related pediatric HCC showed that the presence of cirrhosis is more common in younger children below 9 years of age (95% vs 58%). Hepatitis-B early antigen (HBeAg) in serum and hepatitis-B core antigen in the liver tissue were detected in 18% and 11% of cases, respectively. This coupled with high frequency of cirrhosis especially in the younger children indicated that early seroconversion from HBeAg to anti-HBe in association with severe liver injury plays an important role in development of HCC[28]. In a large cohort of chronic hepatitis-B children from India, HCC was detected in 4.3% at an age between 9 to 14 years with elevated transaminases, however 80% didn’t have cirrhosis[39].

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Figure 3 Radiological images in children with hepatocellular carcinoma. A and B: 14 and half years old boy with chronic hepatitis-B (Immunoclearance phase), HBeAg+, DNA 5 log, AFP = 3 ng/mL (normal), with a segment 3 lesion (2.5 cm × 2.4 cm), BCLC stage A. Contrast-enhanced CT (CECT) image showing enhancement of the lesion (arrow) in the arterial phase (A) and washout in delayed venous phase (B) in a background of non-cirrhotic liver; C: 10 mo old boy with infantile cholestasis, bile salt export pump (BSEP) deficiency on immunostaining, incidentally found to have lesion in segment II and IVa abutting the capsule, BCLC stage B. The lesion was T2 hyperintense with enhancement in the arterial phase (arrows) and washout in the delayed phase; D and E: 8-1/2 yr old boy with decompensated chronic liver disease, chronic hepatitis-B (Immunoclearance phase), HBeAg+, DNA 7 log, AFP = 250000 ng/mL, with multifocal HCC, BCLC stage D, Child-Pugh C. Contrast-enhanced CT (CECT) image showing heterogenous lesion (arrows, D and E) involving whole of the right lobe with enhancement in the arterial phase in few lesions (arrows, E) in a background of cirrhotic liver with nodular margins (open black arrows, E), ascites (star, D) and collaterals (black solid arrows, E) and splenomegaly (star, E); F: 14 yr old girl with hepatic venous outflow tract obstruction, ascites, portal hypertension, incidentally found to have a lesion in segment 4 (1 cm × 1 cm), BCLC stage D, Child-Pugh C. Contrast-enhanced CT (CECT) image showing enhancement of lesion in the arterial phase (arrow).

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Figure 4 Liver histology images in children with hepatocellular carcinoma. A and B: 15 yr old boy with HBeAg negative chronic hepatitis-B, DNA 4 log, precore mutant, AFP = 150000 ng/mL, with a large HCC in right lobe, with portal vein thrombosis, BCLC stage C, Child Pugh A, underwent right hepatectomy. Low power view showing tumor nodules separated by fibrous bands (arrow), adjacent non-malignant parenchyma (star) (100 ×, HE stain) (A). High power view showing malignant nuclear details with prominent nucleoli and eoisnophilic cytoplasm (400 ×, HE stain) (B); C and D: 14 and half years old boy with chronic hepatitis-B (Immunoclearance phase), HBeAg+, DNA 5 log, AFP = 3 ng/mL (normal), with a segment 3 lesion (2.5 cm × 2.4 cm), BCLC stage A, underwent non-anatomic resection. Low power view of tumor showing broadened trabeculae (arrows) (100 ×, HE stain) (C). Trabeculae with malignant cytological features - nuclear atypia and anisocytosis (200 ×, HE stain) (D).

Numerous risk factors for development of HBV related HCC have been studied in adults. Concomitant liver insults like hepatitis-C, human immunodeficiency virus, alcohol intake, smoking, non-alcoholic fatty liver disease, diabetes, ingestion of aflatoxin from Aspergillus flavum are common in adults but have not been studied in children[11]. Similarly, numerous genetic associations are known in adults with HBV-HCC, namely loss of heterozygosity on the KIF1b locus, deletion or chromosomal loss of DLC1 (Deleted in Liver Cancer 1) locus, mutations in cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene, promoter region of the Minichromosome maintenance protein-7 (MCM7) gene and enhancer II (EnhII), basal core promoter (BCP) and precore regions of HBV[40]. It has been shown that Pre-S mutations, C1653T, T1753V, and A1762T/G1764A are associated with an increased risk of HCC[41]. A recent study from China on mother-cord-infant pairs has shown that the HCC-risk mutations were present in the mothers’ peripheral blood and cord blood but mostly absent in peripheral blood of 7-mo-old infants. Further, in 56 mother-child pairs with documented mother to child transmission of infection, it was shown that HCC mutations evolved over first 15 years of age - Pre-S deletion in genotype B2; C1653T, G2946A/C, C1T/A, A7C, and pre-S1 start codon mutation in genotype C2; and A1762T/G1764A and G1896A in both the genotypes, the mutations consecutively increased in frequencies with increasing age[42].

Tyrosinemia type I or hepatorenal tyrosinemia is caused by deficiency of enzyme fumaryl acetoacetate hydrolase (FAH). Due to blockage in the last step of the tyrosine degradation pathway, there is accumulation of toxic metabolites - maleylacetoacetate, fumarylacetoacetate (FAA), and succinylacetone (SA) - which lead to hepatic and renal manifestations of the disease and carcinogenesis. The incidence of HCC in tyrosinemia is reported to be 14%-75%, the prevalence increases with age of the child[43,44]. Nitisinone [2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, (NTBC)] blocks the enzyme parahydroxyphenylpyruvic acid dioxygenase, which is the second step in the tyrosine degradation pathway, and thus prevents accumulation of FAA and SA. Usage of NTBC along with low tyrosine diet leads to survival rates greater than 90% in these children. Further, if NTBC is started early (within 30 d of birth), there is reduction in incidence of HCC from 37% to 1%, and need of LT from 71% to 26%[43-45]. However, animal models have shown that NTBC treatment fails to normalize the tyrosinemia-induced alterations in expression of transcripts encoding proteins involved in protein turnover, signal transduction, and cell growth and proliferation[46]. One of the studies on 16 children who underwent LT at a median age of 16 mo has shown the presence of HCC in 12 (75%) liver explants - 7 were multifocal, 3 with microvascular invasion, and all were well differentiated. There was 86% tumor-free survival at a median of 6.6 years[47]. Contrastingly, report from Iran has shown that HCC was present in 5 (23%) of the 22 explants, the diagnosis was confirmed before LT in 2 children[48].

Among the list of Progressive familial intrahepatic cholestasis (PFIC) disorders, Bile salt export pump (BSEP) deficiency or PFIC type-2 children are especially predisposed at a young age to develop HCC (Figure 3). There is poor excretion of bile salts through the canalicular membrane leading to constant exposure of hepatocytes to bile salts with chronic inflammation and carcinogenesis. Studies from United States and Europe showed that HCC occurs in 5%-15% of children with BSEP deficiency at a young age (13 to 28 mo)[49-52]. Children with D482G mutations have less severe disease and portal hypertension, while HCC is common in those with non-D482G mutations[51]. From the largest cohort of 128 European children, single-strand conformation polymorphism analysis and sequencing of ABCB11 gene identified high risk of HCC (38% vs 10%) in children with presence of 2 protein-truncating mutations[52]. Exome sequencing of the genomes of humans affected by BSEP and of Mdr2 knock-out mice revealed that a very few somatic mutations accumulated over time in the cancer genes. This stands in contrast to adults with HCC as well as other malignancies where a number of mutations accumulate over a period of time. Further, in BSEP individuals and animals, there is massive gene amplification that affected components of signal transduction pathways, such as the ErbB, the PI3K/Akt and the mitogen-activated protein kinase (MAPK) signalling pathways and in particular, activators of c-Jun-N terminal kinases (JNK)[53]. Another study has provided further pathophysiologic insights into BSEP mediated HCC. It showed that BSEP expression is severely diminished in HCC patients associated with alteration of farsenoid-X receptor (regulatory nuclear receptors) with increase in (FXR-α1/FXR-α2) ratio, the later is induced by inflammation and may be reversible[54].

HCC has also been described in a new variant of PFIC with severe cholestasis - TJP2 (tight junction protein 2) deficiency. Protein truncating mutations in TJP2 gene cause failure of protein localization and disruption of tight junction structure leading to severe cholestatic liver disease. In presence of these mutations, Claudin (CLDN1) fails to localise normally to cholangiocyte borders and biliary canaliculus margins, despite normal protein levels. In the unusually hostile environment of the canalicular and cholangiocytic membranes, exposure to high concentrations of detergent bile acids due to TJP2 deficiency lead to hepatobiliary disintegrity, producing severe liver injury and HCC[55,56]. Finally, in multidrug resistance protein-3 (MDR3) deficiency (PFIC type 3), HCC has been reported but is less common than BSEP deficiency[57].

In Glycogen storage disorders, HCC develops on a soil of adenoma (adenoma-carcinoma sequence). Adenomas are common in Glycogen storage disorder (GSD) type I (glucose-6-phosphatase deficiency) with a frequency of 16%-75%. Most of these are seen in the second and third decade with a mean age between 11 to 19 years. In comparison to adenomas in general population, adenomas of GSD-Ia children are more in number, bilobar in distribution, and without any gender predisposition. There is regression in size and number of adenomas with good metabolic control. Malignant transformation in such adenomas occurs rarely, and in view of rarity of the event as well as the disease, it is difficult to estimate the overall risk[58-61]. However, the risk is related to size, number and duration of adenomas, and their recurrence[60]. There is no effective biomarker as alpha-fetoprotein (AFP) and carcinoembryonic antigen levels are often normal in this setting. In a genetic study, it has been shown that chromosomal aberrations are present in 60% of GSD-Ia adenomas which is almost comparable to general population adenomas, but simultaneous gain of chromosome 6p and loss of 6q were only seen in GSD-Ia adenomas. Moreover, these adenomas also showed reduced expression of insulin-like growth factor-2 receptor (IGF2R) and large tumour suppressor kinase-1 (LATS1) candidate tumor suppressor genes at 6q in more than 50%. This indicates a possible role of chromosome 6q in malignant transformation of such adenomas[62].

Type III GSD (debrancher enzyme deficiency, or Forbes disease, or limit dextrinosis) differs from type I in that the liver enzymes are elevated with hepatocellular injury, and evidence of ballooning degeneration and fibrosis. Adenomas are seen in 4%-25% of patients. Malignant transformation takes place less often, but is almost always in the background of cirrhosis[63,64]. Liver cancer is rarely seen in Type 4 GSD (brancher enzyme deficiency, or Andersen’s disease, or Amylopectinosis), but has never been reported in types 6 and 9 diseases[18].

Individuals with homozygous (PiZZ) alpha-1-antitrypsin deficiency (A1ATD) are at an increased risk for liver damage, cirrhosis and HCC. Liver cancer is rare in the pediatric age group but has been reported[22]. In a recent systemic review, the prevalence of HCC in adults with A1ATD is 1.3% with a low yearly cumulative rate of HCC than other causes of cirrhosis (0.88% per year vs 2.7% for hepatitis-C cirrhosis)[65,66]. However, autopsy data in adults has shown the prevalence of HCC of 16%[67]. Animal models of A1ATD have shown that approximately 69% of the PiZZ mice develop tumors by 16-19 mo of age and HCC was present without evidence of pre-cancerous lesions or benign adenoma. There was upregulation of Cyclin-D gene, and elevation of c-Fos and melanoma cell adhesion molecule (MCAM), all three factors involved in cell proliferation, tumorigenesis and metastasis[68]. The liver injury is related to increased oxidative stress with an upregulation of redox- regulating genes and reduction in levels of antioxidant enzymes[69].

Alagille’s syndrome is a multisystem disorder characterized by bile ductal paucity and chronic cholestasis. Mutations/deletions in two genes are known to cause Alagille’s syndrome: JAGGED1 (encoding the Notch signaling pathway ligand JAGGED1) in 89% and NOTCH2 (encoding one of the Notch receptors) in a small minority. Carcinogenesis in Alagille’s syndrome is rare but reported in children and adults[23,70,71]. HCC in Alagille’s syndrome is seen in first or second decade in a background of cirrhosis with extensive pruritus[71]. Constitutive intracellular domain of Notch2 signalling in the liver leads to up-regulation of pro-proliferative genes and proliferation of hepatocytes and biliary epithelial cells, and stimulates diethylnitrosamine induced HCC formation in mice[72]. Recently, yes associated protein (YAP), which is a transcriptional co-activator and is responsible to make cancer cells proliferate in an anchorage independent fashion and become apoptosis resistant, has been shown to act by upregulating JAGGED-1 and activation of NOTCH pathway in mouse models and humans with HCC, colorectal and pancreatic cancers[73]. This may have putative role in Alagille’s syndrome related HCC, and need to be studied.

Nodular transformation in livers of children with congenital portosystemic shunts (CPSS) is related to differential vascular supply[74]. Such nodules may be benign or malignant. Two largest reviews on CPSS and largest series from France have shown that extra-hepatic CPSS (59%) is slightly more common than intra-hepatic CPSS (41%)[74-76]. The common communications are patent ductus venosus, portal vein to inferior vena cava (IVC), or left portal venous system to IVC[74]. Liver masses have been described in both extra-hepatic (35%) and intra-hepatic (13%) types at a median age of 8 years, however the malignant tumors (hepatoblastoma, HCC and sarcoma) are specifically described in extrahepatic variety. As per available literature, HCC is seen in 2.5% of CPSS cases[76]. Shunt occlusion leads to reduction in size of benign tumors like focal nodular hyperplasia and hepatic adenoma, however for malignant tumors, resection and shunt occlusion or LT is indicated[74].

Biliary atresia: Study from King’s College London has shown that the prevalence of HCC in biliary atresia is 1.3% (5 out of 387). All except one were below 5 years of age (range 1.1-4.9 years)[77]. On the other hand, biliary atresia constitutes 0-30% among all causes of pediatric HCC, particularly from the West, however the figures may indicate a referral and surveillance bias[18,22,23,26,27]. Cancer in biliary atresia develops on a soil of biliary cirrhosis with ongoing chronic necroinflammation and destructive cholangitis[77,78].

Budd-Chiari syndrome: HCC is a known complication of Budd-Chiari syndrome in adults with a 5-year cumulative incidence of 4%. It commonly develops in a liver with nodular regenerative hyperplasia, and is more commonly associated with male gender, factor-V Leiden mutation and inferior vena cava obstruction[79]. We have described HCC in a 14 years old girl with Budd-Chiari syndrome and Celiac disease[80] (Figure 3).

Other liver disorders: Autoimmune hepatitis (AIH) and Wilson disease (WD) are two commonest chronic liver diseases in older children[81]. From a systematic review and meta-analysis on adults with AIH, the risk of HCC is 3.06 per 1000 patient-years, slightly lower than that with other causes of cirrhosis in adults like hepatitis-B, C, or primary biliary cholangitis[82]. The risk of HCC is related to presence of cirrhosis at the time of diagnosis of AIH (OR = 4.08) and abnormal transaminases at final observation (OR = 3.66)[82,83]. Although incidence of HCC in children is rare, but as AIH is a common pediatric liver condition so it is important to be aware of the carcinogenesis risk in the long term. Copper accumulation in WD is said to be protective against tumorigenesis. The estimated annual risk of HCC from a Dutch study on 140 adults with WD followed up over 15 years was calculated to be 0.09%[84]. From another multicenter European study of 1186 WD patients, the prevalence of HCC was found to be 0.67%[85]. Hence, the risk is significantly low in WD to advocate regular HCC surveillance. Non-alcoholic fatty liver disease, type 2 diabetes, hereditary hemochromatosis and porphyria (acute intermittent and porphyria cutanea tarda) carry high risk of development of HCC in adults, but not in children[86].

Certain genetic cancer syndromes confer high risk of development of HCC in the absence of a metabolic, infectious or vascular disease of liver (Figure 1). Sporadic HCC developing in the absence of a known or unknown liver disease or genetic cancer predisposition is seen in 0-62% of children with HCC, the proportion is high in areas with low endemicity of HBV infection[10,12,13,18,22,23,27-29,31].

Ultrasound typically shows presence of a heterogenous hyperechoic mass of variable size with increased vascularity[2]. For further characterization of the mass, a dynamic imaging, either contrast-enhanced computerized tomography (CECT) or magnetic resonance (CEMR) imaging is needed. Typical characteristics of HCC on dynamic imaging are hyper-enhancement in the arterial phase (10-20 s) and washout in the portal venous (60-80 s) and delayed venous (3-5 min) phases. The “enhancement” is because of the intranodular arterial supply of HCC, while “washout” is related to early venous drainage of the contrast, progressive enhancement of background cirrhotic liver, reduced intra-nodular portal venous drainage, tumoral hypercellularity with corresponding reduction in extracellular volume, and intrinsic hypoattenuation/hypointensity[88] (Figure 1). From the recent adult systematic review and meta-analysis, it was found that CEMR has higher sensitivity (82% vs 66%) and lower negative likelihood ratio (0.20 vs 0.37) over CECT for the diagnosis of HCC[89]. It has been proposed that in adults with non-typical characteristics on imaging, combined interpretation of dynamic and hepatobiliary phase of Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI with diffusion-weighted imaging (DWI) can improve the diagnostic yield of HCC[90]. Although MR avoids radiation hazard to young children, in view of technical complexity, expertise, availability, susceptibility to motion artifacts, need for intubation and poor image quality in presence of ascites, CT is mostly preferred to look for tumor extent, vascular invasion, resectability and metastases[91]. Contrast-enhanced ultrasound (CEUS) has been shown to be promising in children with an advantage of minimizing the exposure to ionizing radiation. In a study on 44 children with focal liver lesions, agreement between CEUS and other imaging modality (CT or MR) was seen in 85%, with the specificity and negative predictive value of CEUS of 98% and 100%, respectively[92]. Sonovue^® (sulfur hexafluoride with phospholipid shell), used as contrast for CEUS, has been tested for other indications in pediatric age-group and is found to be extremely safe[93].

Serum AFP elevation, not very sensitive, but has a fairly good specificity for detection of HCC in at risk population with liver disease. In adults, it also has a role in prognostication and surveillance[91]. Because of the low incidence of HCC in pediatric age-group and the fact that AFP levels are elevated in presence of regeneration, the exact role of surveillance with AFP may be limited. Nevertheless, the levels are mostly high (67%-92%), as high up to 1400000 ng/mL[7,12-14,16,18,22,26,27] (Tables 1 and 2). Caution should be taken in children with tyrosinemia with very high AFP values, where a serial change from the baseline should be considered more informative. Other tumor markers like fucosylated AFP or Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), des-gamma-carboxy prothrombin (DCP) or protein adducts in absence of vitamin-K absence (PIVKA-II), glypican-3, Golgi protein-73, hepatocyte growth factor, insulin growth factor 1 and transforming growth factor-β1 have not been prospectively studied in children[90].

As per the adult literature on HCC, American association for study of liver diseases (AASLD) does not suggest biopsy in patients with cirrhosis with a lesion radiologically suggestive of HCC. For lesions which are indeterminate on imaging, repeating a different imaging, or with another contrast, or biopsy is suggested to confirm the diagnosis[91]. APASL consensus suggests biopsy when the nodule is non-hypervascular, or hypervascular without washout with a size of ≥ 1 cm[90]. No such recommendations exist for pediatric age-group. However, we suggest that in children without cirrhosis, histological evaluation should be done. While in those without cirrhosis, diagnosis should be based on suggestive imaging and high AFP.

Most of the groups working on pediatric liver tumors like Group for Epithelial liver tumors of the International Society of Pediatric Oncology (SIOPEL), Pediatric Oncology group (POG), Children’s Cancer Group (CCG) and Japanese study group for Pediatric Liver tumor (JPLT) have been using pre-treatment extent of tumor (PRETEXT) staging system. This system has been recently updated by the Children’s Hepatic tumors International Collaboration (CHIC), and has been found to be a powerful predictor of overall survival of children with hepatoblastoma and HCC. In contrast to adult HCC, where size and number based classifications are more popular for purpose of decision about resection, transplantation or palliation, the PRETEXT system is based on determining number of contiguous tumor-free liver sections - left lateral, left medial, right anterior and right posterior. These sections are divided from right to left by (1) right hepatic vein, (2) Cantlie’s line, and (3) a plane extending along hepatic fissure and umbilical portion of left portal vein. The stage is determined by calculating the number of contiguous sections that have to be resected to completely remove the tumor. The stage further includes annotation factors like V (hepatic venous or inferior vena cava involvement), P (portal vein involvement), E (extrahepatic disease contiguous with main liver tumor), F (multifocality), R (tumor rupture), C (caudate lobe involvement), N (lymph node metastases) and M (distant metastases)[95]. Application of Milan criteria and BCLC staging system in children is limited[14,18,22,23].

Table 3 summarizes various treatment modalities and outcome of children with HCC[6-8,10,12-18,23-31,38,96-101]. The main factors considered for decision making in adults with HCC are (1) Liver functional status - ascites, albumin, bilirubin, alkaline phosphatase, portal vein thrombosis, Child-Turcotte-Pugh (CTP) score; (2) tumor factors - size and number of nodules, extent, vascular invasion, presence of metastases, TNM staging, AFP levels; (3) portal hypertension - presence of varices, hepatic venous pressure gradient (HVPG); (4) general status of patient - performance status, symptoms[11,90,91,102,103]. Most of the clinical experience obtained from treatment of hepatoblastoma has been applied for treatment of HCC in children. The best option for non-metastatic HCC tumors is complete surgical removal either by resection or LT. Resection offers good cure rates, however only 27% (range 10%-67%) of tumors are resectable. Over a period of 4 decades there has been a dramatic improvement in the 5-year survival rates of children with HCC from 4%-10% to 56%-80% - the change is primarily related to increased surveillance and improvement in surgical techniques, particularly LT[7,8,10,12,28,29,35,96-98]. An algorithmic approach for management of these children is presented in Figure 2. All children with non-metastatic HCC should be assessed for resection or LT to achieve optimal outcomes. Systemic neoadjuvant chemotherapy can be used in children awaiting LT to serve as a “bridge” to LT and prevent disease progression. Interventional radiology techniques using transarterial locoregional chemotherapy can be tried in older children with large unresectable tumors and to control tumor burden as a “bridge” to resection or LT.

Resection: As per AASLD, resection is only recommended in those adults with a single nodule and CTP class A without evidence of portal hypertension[91]. However, the guidelines differ in the Asia-Pacific region and a more aggressive approach is followed[90]. As per Japanese guidelines, patients with CTP A or B are considered for resection and/or radiofrequency ablation even with 1-3 nodules, up to or more than 3 cm in diameter, but without portal vein invasion or extrahepatic spread[102]. Hong Kong consensus further extends this to suggest resection in intrahepatic portal vein or branch hepatic vein invasion, or with a single extrahepatic metastasis in selected patients, but not with main portal vein invasion[103]. In children, resection rates from the eastern part of the world, where HBV is the commonest cause of pediatric HCC, vary from < 10% to 27%[6,28,29,31,97,98]. With improvement in surgical expertise, the resection rates in pediatric HCC have improved to 40% in the latest series from China with a median survival of more than 30 mo[12,38]. From the SEER database of 60 children with HCC who underwent resection, the 5-year survival rate was 53%[30].

Chemotherapy: There are several trials in adults with HCC where neoadjuvant and adjuvant therapies have been used but none has been convincing enough to translate into a recommendation. The survival rates following chemotherapy in HCC in adults have been dismal. AASLD suggests against the usage of adjuvant therapy following successfully resected or ablated HCC in adults[91]. SIOPEL and POG/CCG have done trials in pediatric HCC on the lines of hepatoblastoma[16,27,100]. SIOPEL-1 study analyzed the outcome of 37 children, who received pre-operative chemotherapy of 1 to 6 PLADO courses (cisplatin and doxorubicin). Response was partial in 49%, while others had either no response or disease progression. Resection was possible in 17 (46%) of these children with successful tumor excision in 36%, while 51% never became resectable. At a median follow-up of 75 mo, 8 (28%) children survived, all with complete resection. There was a dismal outcome of 28% at 5 years. PRETEXT stage and metastases predicted survival in that group of children[27]. In the POG/CCG trial, children with HCC were randomly assigned to receive regimen A (cisplatin, vincristine and fluorouracil) or regimen B (PLADO). There was a poor 5-year event free survival of 19% ± 6% with no difference between the two regimens. Survival and outcome depended on the stage of disease - all 8 stage I patients with complete resection survived post chemotherapy, while 18 (47%) of 38 patients with advanced (stage III or IV) disease had an event (progression, death or new neoplasm) before surgery, and only 2 (10%) of 20 who received chemotherapy became resectable[16]. From the more recent SIOPEL 2 and 3 studies evaluating outcome in 85 children with super PLADO (cisplatin, carboplatin and doxorubicin), 13 patients had upfront surgery. Of the remaining 72, only 29 (40%) showed response to chemotherapy and 39 (46%) never became resectable. Complete resection (including LT) was achievable in 40%. Survival was more with resection or LT (59%) vs not (10%). Tumor-free margin at resection was predictive of good outcome[100]. The results were comparable to the older studies conducted by the German Society for Pediatric Oncology and Hematology (GPOH) where the chemotherapy used were ifosfamide, cisplatin and doxorubicin in HB-89 trial, with addition of carboplatin and ifosfamide in HB-94 trial. The overall survival rates were 33% and 32%, respectively[104]. The more recent trial from GPOH (HB-99) showed 3-year event free and overall survival of children with HCC after primary complete resection followed by 2 cycles of carboplatin/etoposide of 72% and 89%, respectively. However, these figures were 12% and 20% in those with non-resectable malignancy[105]. Cytopenias, vomitings, opportunistic infections, ototoxicity, nephrotoxicity, myocardial toxicity and elevation of transaminases are common side-effects to be looked after[16,27,105].

Sorafenib: This is a novel multikinase inhibitor against Raf kinase and vascular endothelial growth factor receptor, along with anti-proliferative and anti-angiogenic properties. From the multi-center randomized placebo controlled phase III study, usage of Sorafenib in adults with advanced HCC has been shown to improve time to tumor progression (median 5.5 mo vs 2.8 mo) and overall survival (10.7 mo vs 7.9 mo)[106]. Further a randomized controlled study found that the combination of Sorafenib and Doxorubicin in adults was superior to Doxorubicin alone in terms of better overall survival (6.4 mo vs 2.8 mo) and progression-free survival (6.0 mo vs 2.7 mo)[107]. From the German GPOH group, Sorafenib when used in combination with PLADO in children with HCC showed tumor regression in 4 out of 7 unresectable tumors. There was decrease in AFP levels in four children who had very high levels. Hand-foot-skin reaction was seen in 7 (58%) of 12 children[108].

Targeted therapies: Various targeted therapies based on the pathogenic mechanisms of oncogenesis and cell proliferation are under trials in adults with HCC. The common biological pathways for target are VEGF receptor (Sorafenib, Bevacizumab, Brivanib, Sunitinib), epidermal growth factor (Erlotinib), mammalian target of rapamycin (Everolimus), tyrosine kinase receptor for hepatocyte growth factor, cMET (Tivantinib), combined VEGF and cMET (Cabozantinib) and programmed cell death receptor (anti-PD-1, Nivolumab)[2].

Liver transplantation: Liver transplantation offers best cure for HCC in a cirrhotic liver in terms of oncological viewpoint by enabling the widest possible resection margins and simultaneously ensuring complete removal of the diseased liver at risk of developing HCC[90]. The commonest criterion used in adults to decide candidacy for LT is Milan criteria which includes single tumor with diameter less than 5 cm, or tumor foci up to 3 in number each one not exceeding 3 cm, without any vascular invasion or extrahepatic involvement. Application of Milan criteria has been shown to improve the survival after LT in adults from 30% to 75%[91]. However in Asia, where living donors are the mainstay for LT and there are no restrictions imposed by the national organ allocation system, the criteria for LT are more liberal[90]. Most countries like Hong Kong and Taiwan are using extended criteria like University of California San Francisco (UCSF) criteria, i.e., solitary tumor ≤ 65 mm in diameter, or 2-3 tumors, each with diameter ≤ 45 mm and total tumor diameter ≤ 80 mm, and without radiological evidence of vascular invasion or distant metastasis, with acceptable long term survival rates[90,103]. Similarly in Japan, patients beyond Milan criteria or those with recurrent HCC with CTP A or B are sometimes considered for LT[102]. Usage of these criteria is limited to case series in children. Transplantation in children outside Milan criteria has a fairly good outcome of 72%-83% at 5 years[18,22,23]. Various series have shown that the outcome post LT in children with HCC is related to PRETEXT stage, recurrence of disease, vascular and lymph node invasion, size of tumor and distant metastases[10,12,15,16,22,24,27,30,38,99-101]. A recent analysis of ELTR data of 175 pediatric HCC showed that children with inherited liver disease (ILD) have better survival after LT in comparison to children without ILD and adults with ILD[25] (Table 3). There is no head to head prospective series comparing resection vs LT in children with HCC. However as per the SEER database, the 5-year survival rates are better with LT (85%) in contrast to resection (53%) (hazard ratio 0.05, 95%CI: 0.003-0.94)[30].

Radiological interventions: Radiological interventions like radiofrequency ablation (RFA), transarterial embolization (bland), transarterial chemo-embolization (TACE, with doxorubicin drug eluting beads), hepatic arterial infusion chemotherapy (HAIC, with low dose 5-fluorouracil and cisplatin with or without systemic interferon therapy) and transarterial radio-embolization (TARE, using yttrium-90 microspheres) are routinely used in adults with advanced HCC for downstaging and those listed for LT. AASLD suggests using one of the radiological techniques for adult patients (1) listed as per Milan criteria to decrease progression of disease and subsequent dropout from the waiting list, (2) outside Milan to bring them into the LT criteria, and (3) who are not candidates for resection or LT to improve their survival[91]. As HCC nodules receive their blood supply preferentially from the branches of hepatic artery, catheters placed into hepatic artery are used to obliterate tumor vascular supply and also to inject chemotherapeutic agents (TACE). Absolute contraindications for endovascular therapy include surgically resectable tumor, intractable systemic infection, advanced liver disease (CTP > 8 or BCLC stage C), hepatic encephalopathy, lung shunt fraction > 20% and hepatic encephalopathy. Relative contraindications are biliary obstruction, tumor > 10 cm or burden > 50% of liver, bilirubin > 3 mg/dL, albumin < 2 gm/dL, impaired renal function, AST > 5 times upper limit of normal and presence of extrahepatic metastases. Common side effects include elevation of bilirubin and transaminases, and post-embolization syndrome (pain, malaise, low grade fever). In Asian countries, TACE is frequently offered to adults with early HCC, or in combination with ablation when the nodules are more than 3 or exceed 3 cm in diameter[102,103]. There is limited data on radiological interventions in children with HCC[109]. Two series from China comprising 110 children with HCC have shown that overall survival with resection, TACE and no treatment is 29-38, 4-14 and 2-5 mo, respectively[12,38]. Moreover in children with advanced HCC, TACE offered 4.8 mo of survival benefit in comparison to standard treatment[38]. Special considerations related to sedation and procedure should be taken - like there is more risk of post-embolization syndrome and arterial spasm[109].