Abstract

Liver cancer, predominantly hepatocellular carcinoma, is the second most common cause of cancer-related death in adults. Although infrequent in children, hepatocellular carcinoma is a terrifying diagnosis. Rising levels of obesity and obesity-associated lipid metabolic reprogramming of hepatocytes are increasing the prevalence of lipid-rich hepatocellular carcinoma in young adults. Most pediatric liver cancers occur in otherwise healthy liver, with some exceptions such as progressive familial intrahepatic cholestasis, hereditary tyrosinemia, alpha-1-antitrypsin deficiency, and genetic hemochromatosis. In the last decade, although aggressive multidisciplinary treatments including surgical resection and chemotherapy have remarkably improved patient outcomes in terms of decreased recurrence rate and increased overall survival rate, in children with unresectable liver cancer, the 5-year survival rate is still less than 20%. This chapter provides an overview of malignant epithelial tumors of the liver in children and adolescents. Hepatocellular carcinoma, lipid-rich hepatocellular carcinoma, fibrolamellar carcinoma, and cholangiocellular carcinoma are discussed.

INTRODUCTION

Liver tumors in children and adolescents are catastrophic events. While most occur in otherwise healthy liver, they may be associated with congenital anomalies, genetic syndromes or metabolic conditions. Two significant entities are hepatoblastoma (HBL) and liver carcinoma/hepatocellular carcinoma (HCC). Both neoplasms account for 0.5–1.5% of all childhood neoplasms (1) and 4% of all pediatric orthotopic liver transplantations (OLT). HBL accounts for 67–80% of all pediatric liver cancers worldwide, while 20–33% are HCC. Prevalence of HCC is geographically and demographically dependent and is associated with the prevalence of Hepatitis B in the population (1). Differential diagnosis can be genuinely challenging considering the number of variants and subtypes that have been delineated over the last decade. Known predisposing factors for HCC in childhood and youth are alpha-1-antitrypsin deficiency, hereditary tyrosinemia, genetic hemochromatosis, Wilson’s disease, acute intermittent porphyria, progressive familial intrahepatic cholestasis type 2, mitochondrial ETC disorders, glycogen storages diseases, and transaldolase deficiency. Several neoplastic conditions must also be considered in the differential diagnosis of HCC, including epithelioid hemangioendothelioma of the liver, hemangiosarcoma, malignant rhabdoid tumor of the liver, undifferentiated embryonal sarcoma of the liver, biliary tract rhabdomyosarcoma, and the unique variant of neuroblastoma IVS. Some note should be given about fibrolamellar carcinomas of the liver, which are tumors of adolescence with a predilection for the left liver and have a tendency to be challenging to resect (2–6).

HEPATOCELLULAR CARCINOMA

HCC is the second most common primary liver malignancy in a pediatric setting (27%) following HBL. Vascular tumors and sarcomas constitute the remaining (1, 7). HCC is becoming a common indication for liver transplantation in childhood with an incidence rate of 0.3 to 0.45 individuals per million per year (23%). HCC is diagnosed more commonly in adolescents (10–14 years) but has been described in children age 5 and younger. Male children have a greater predisposition to HCC (3:1). HCC typically presents at a more advanced stage in children than in adults. Overall, only 0.5–1% of all HCCs occur in childhood. HCC has a broad etiologic spectrum including alcoholic cirrhosis, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection and ingestion of aflatoxins from Aspergillus flavum in contaminated food, but these factors show a geographic variation. HCC is most common in central Africa (sub-Saharan regions) and southeast Asia, with an incidence rate of up to 1 per 1,000, most commonly as a result of HBV infection. HCC remains a common diagnosis in areas with high endemic HBV infection rates. There are rates of up to 100% positivity for HBV infection in Taiwan, and 64% positivity for HBV infection in Hong Kong SAR (Special Administrative Region of the People’s Republic of China) (8, 9). The integration of the HBV genome into the neoplasm genome can be detected by immunohistochemistry and demonstrated at the molecular level, but this event is not necessarily oncogenic; alone it does not result in liver carcinogenesis. A secondary promoter (for example, environmental influences or genetic variations) is required for the development of HCC. In several countries, vaccination of neonates has led to a drop in HCC rate in childhood and adulthood.

Numerous genetic abnormalities are associated with HBV-HCC in adults, such as mutations in the cytotoxic T-lymphocyte antigen 4 (CTL A-4) gene, deletion or chromosomal loss of DLC1 (Deleted in Liver Cancer 1) or loss of heterozygosity on the KIF1b promoter region of the Mini-Chromosome Maintenance protein-7 (MCM7) gene and enhancer II (EnhII) (1, 10, 11). Moreover, alterations of the basal core promoter (BCP) and precore regions of HBV have been found. It has been shown that Pre-S mutations (C1653T, T1753V, and A1762T/G1764A) are explicitly associated with an amplified risk of HCC (11, 12). HCV infection is rarer than HBV infection in children and so is less significant etiologically (13). Other non-viral conditions associated with HCC include glycogen storage diseases type 1, 3, and 4 (poor metabolic control, size and number of adenoma, malignant transformation in adenoma), congenital portosystemic shunts (complete absence of portal vein or type 1a, presence of nodular regenerative hyperplasia, adenoma, and dysplasia), hepatic venous outflow tract obstruction/Budd-Chiari syndrome (long-standing obstruction, presence of nodular regenerative hyperplasia, inferior caval vein (IVC) obstruction, Factor V Leiden mutation (14), acute intermittent porphyria, porphyria cutanea tarda, hyper-citrullinemia, tyrosinemia (non-usage of [2-(2-nitro-4-trifluoromethyl-benzoyl)-1,3-cyclohexanedione (Nitisinone, NTBC) or late introduction of NTBC), familial intrahepatic cholestasis (BSEP deficiency, TJP2 mutations, MDR3 deficiency), alpha-1-antitrypsin deficiency (AATD), biliary atresia, Alagille syndrome, autoimmune hepatitis, Wilson’s disease, and genetic hemochromatosis (1). Genetic syndromes predisposing to HCC include ataxia telangiectasia, Fanconi anemia, familial adenomatous polyposis, and neurofibromatosis. Non-metabolic conditions are presented in the following section. Metabolic diseases are discussed separately.

Morphology

Morphology of adult and pediatric HCC are similar. There are several growth patterns including trabecular (plate-like), solid/compact, pseudoglandular/acinar, and scirrhous (scleroting architectural pattern). Cytologic variants include pleomorphic cells, clear cells, and sarcomatous cells (spindle cells or bizarre giant cells). The cytoplasm of the tumor cells is stained with Hep Par 1, a monoclonal antibody (clone OCH1E5.2.10) in a granular manner, without canalicular or zonal accentuation. The antigen detected by Hep Par 1 appears specifically associated with the mitochondrial membrane of hepatocytes. The use of antigen retrieval (high pH buffer) and a detection kit which eliminates non-specific biotin reactivity allows the pathologist to use Hep Par 1, which is highly effective on formalin-fixed, paraffin embedded tissues. Cautious use of Hep Par 1 antibody in a panel with other positive (AFP, carcinoembryonic antigen with a polyclonal antibody, CD10) as well as negative (epithelial membrane antigen, carcinoembryonic antigen with a monoclonal antibody, CD15) markers of hepatocellular differentiation may assist in accurate diagnosis of hepatocellular carcinoma (Figure 1). Epithelial cell adhesion molecule (EPCAM) expression seems to be far more robust in pediatric than adult HCC (7, 40). In the future, transcriptomics studies may reveal additional data comparing adult and pediatric HCC.

Figure 1

Microphotographs of hepatocellular carcinoma. A. Solid pattern showing large hepatocytes organized in a solid architecture (top of the figure) contrasting with the lobular arrangement of non-tumoral hepatocytes (bottom of the figure) (Hematoxylin-Eosin (more...)

HEPATOCELLULAR ADENOMA AND FOCAL NODULAR HYPERPLASIA

In the differential diagnosis, we should mention hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH). A large multicenter study resulted in genotype-phenotype classifications of four subtypes of adenomas, including biallelic loss of TCF-1 gene/HNF1α HCA (42%), WNT pathway mutation/β-catenin-activated HCA (12.5%), inflammatory HCA, and nonmutated/non-inflammatory HCA (82, 83). The genotype-phenotype HCA classification is paramount because certain genotype-phenotypes are associated with HCC: 7% in HNF1α mutated adenoma, 13% in noninflammatory/nonmutated adenomas, and 46% in β-catenin-activated HA (83). An inflammatory HCA has the distinctive features of sinusoidal dilatation and perivascular lymphocytic inflammation with immunohistochemical evidence of serum amyloid associated (SAA) protein. Immunohistochemical staining of FNH with glutamine synthetase shows characteristic map-like labeling. FNH is a hyperplastic liver lesion and should be considered a response to a pre-existing arterial malformation (84). Although FNH can occur as multiple lesions in one-fifth of cases, it is usually a solitary hepatic lesion discovered incidentally. FNH is a common tumor lesion, second only to hemangioma and at least ten times more common than HCA. Imaging is crucial; ultrasound is highly distinctive in detecting FNH, and both CT scan and MRI are highly reliable techniques in diagnosing FNH (85). Although FNH does not require a liver biopsy for the diagnosis due to good imaging criteria, biopsy may be important if the patient is outside of the typical age range. FNH is a benign lesion with very low risk of rupture and hemorrhage, and is treated with conservative management unless it becomes symptomatic (86).

FNH presents grossly as a well-demarcated non-encapsulated lesion of 4–5 cm in diameter and harboring a central or slightly eccentric scar. Histologically, FNH shows a nodular-shaped architecture with normal hepatic plate architecture and no atypia, fibrous bands radiating from the central or slightly eccentric scar which contain “portal tract-like areas” with bile ductular proliferation, lack of interlobular bile ducts, and thickening of eccentrically located blood vessels. Reticulin stain demonstrates intact reticulin framework which is characteristically lost in malignant hepatic lesions (87). On macroslides, the central scar contains large vessels with fibromuscular hyperplasia, intense lymphocytic infiltrate, and bile duct proliferation, as well as normal hepatocytes with regeneration. Polyclonal carcinoembryonic antigen is useful to reveal a hepatic origin but does not distinguish between benign and malignant tumors. Reticulin histochemical stain plays a major role in pinpointing hepatic adenomas.

Although hepatic adenomas are more common in women of reproductive age, they are not extremely rare in children and adolescents. Hepatic adenomas are usually rare in males and have been associated with oral contraception and anabolic steroid use, but most importantly various metabolic disorders, such as glycogen storage disorder and galactosemia, can exhibit hepatic adenomas, even in childhood. It is rare to see marked elevations in liver enzymes. Genetic analysis can prove neoplastic etiology. Although multiple adenomas can occur, they usually are solitary. There is no liver cirrhosis as background, and differential diagnosis from macro-regenerative nodules is essential. Grossly, hepatic adenomas do not have a capsule, and there is no surrounding fibrosis. Microscopically, hepatocytes are arranged 1 to 3 cell plates thick with a normal appearance. Cytologically, the nucleus to cytoplasmic ratio is normal, but some mild variation in cell size may occur. Atypia is minimal or absent. Mitotic figures are nil or occasionally present, but steatosis, lipofuscin pigment deposition, and Mallory’s hyaline can be seen. There are no portal tracts, which are seen in both adenomas and HCCs. A useful feature in distinguishing an adenoma from a well-differentiated HCC is the presence of an intact reticulin framework. The protein FPA can be detected in the serum of children with malignant hepatocellular tumors, but it may not be specific. AFP is absent in adenomas. Similarly, glypican-3, which is a protein encoded by the GPC3 gene that is absent in adenomas and positive in HCCs or dysplastic nodules, although HCCs with negative glypican-3 immunostaining, can be seen. The differential diagnosis with FNH relies on the presence of fibrotic areas with bile ductules and abnormal blood vessels. Liver cirrhosis can help differentiate an adenoma from the large regenerative nodule. Therapy consists of surgical excision. Because of the risk of life-threatening hemorrhage, excisional procedures are strongly indicated for lesions that could not be differentiated on needle biopsy. In the presence of adenomatosis, liver transplantation is essential.

In young patients with a gene mutation predisposing to colorectal carcinoma (for example, TP53 and FAP), colorectal malignancy with metastatic disease can occur at an early stage. Metastatic colon cancer needs to be excluded in these patients, and immunohistochemistry may help in this direction. Two antibodies may be beneficial: CDX2 and CK20. CDX2 (Caudal Type Homeobox 2), a gene that directs early embryogenesis in mice, is a marker for gastrointestinal differentiation, especially colorectal differentiation. CK20 or K20, is an antibody for antigen 20 of the keratin intermediate filaments of the cytoskeleton (88). If the tumor is metastatic in origin and arises from the colorectal portion of the gut, both stains should be positive. Also, in the differential diagnosis, a primary cholangiocellular carcinoma must be excluded. The antibodies CK7 and CK19 are appropriate markers for differentiation. Both antibodies are positive in the tissue of a primary cholangiocellular carcinoma (89–91).

As indicated above, three antibodies are useful in highlighting the diagnosis of a primary hepatocellular carcinoma: HepPar1, glypican-3, and AFP. The combination of three positive antibodies aids in the diagnosis of HCC. Three antibodies may help in the differential diagnosis with malignant lymphoma: CD45 or common leukocyte antigen, CD3 (T-lymphocyte marker), and CD20 (B-lymphocyte marker). However, immunohistochemistry may not be necessary because cell cytology, tumor growth pattern, and desmoplasia help to exclude a malignant hematological neoplasm. Malignant lymphomas have little cytoplasm and no nested and trabecular growth pattern with a fibrotic stroma. Appropriately, the presence of synaptophysin and chromogranin are useful in identifying a neuroendocrine tumor, considering the nested and trabecular growth pattern can be a classic pattern for neuroendocrine neoplasms.

LIPID-RICH HEPATOCELLULAR CARCINOMA

The most common histological patterns of HCC are solid, trabecular, pseudoglandular, and scirrhous, with three recognized cytologic variants: pleomorphic, clear cell, and sarcomatoid. In the clear cell variant, cytoplasmic changes are related to glycogen and/or lipid accumulation (lipid-rich HCC, LR-HCC) within the tumor cells. In cytologic samples of low-grade lipid-containing hepatic neoplasms, differentiation of neoplastic cells from benign steatotic cells can be extremely challenging (92–94). Fine-needle aspirates of benign lesions contain rigid cores and large tissue fragments, while LR-HCC shows a breakdown of the reticulin framework (visualized with a routine special stain) with scattered cells and a fine granular-appearing background. LR-HCC is an uncommon HCC variant and needs to be taken into consideration, particularly now that non-alcoholic steatohepatitis and fatty cell change are more common in adolescence and youth (95–98).

FIBROLAMELLAR CARCINOMA

FLC or fibrolamellar variant of HCC is a rare variant of HCC, and recent investigations have identified a specific molecular signature (99–103). This neoplasm affects adolescents and youth with no significant gender prevalence primarily. FLC chiefly affects Caucasians. Unlike HCC, FLC is never associated with a history of parenchymal liver disease. Liver cirrhosis and underlying metabolic disorders are not associated with this tumor. Although broadly considered a variant of HCC, it has been suggested that it ought to be reported as a distinct clinical and histopathologic entity (41, 100). FLC accounts for up to almost one-tenth of all HCCs. Moreover, FLC accounts for up to one-third of all pediatric HCCs.

The characteristic histological features of this neoplasm provide the grounds for the singularity of this neoplasm. The Fibrolamellar Carcinoma Consortium is an institutional collaboration involving Memorial Sloan-Kettering Cancer Center (MSKCC), the University of California at San Francisco (UCSF), and Johns Hopkins Hospital. The Consortium was developed to address the challenges associated with investigating FLC, such as small study samples and the lack of awareness of the disease within the oncology community, and with identifying new treatment options. The Consortium presented the pooled demographic, clinical, pathologic, treatment, and survival data of 95 patients with FLC seen at the three institutions from 1986–2011 (104).

Pathology

Microscopically, the tumor is made of large polygonal cells with copious eosinophilic cytoplasm (about 50 microns, that is, approximately double the size of a normal human hepatocyte, which is 20–30 microns) with granular character and large nuclei containing prominent nucleoli. At low magnification, thick fibrous collagen bands are seen transecting the tumor (Figure 2A). They may partially encircle or surround the tumor cells. On histology, pale cytoplasmic bodies (pale bodies) or ground glass cells and PAS-positive hyaline globules and copper depositions are also seen (Figure 2B). Bile is observed using negative Prussian Perl’s blue iron stain. In the differential diagnosis of FLC, sclerotic variant of HCC should be mentioned, which rarely harbors the parallel (or almost parallel) running collagen bands. Vascular invasion and necrosis may be seen. Radiological calcification may also be confirmed on histology.

Figure 2

Fibrolamellar carcinoma. A. Tumor tissue showing extensive intratumoral lamellar bands of collagen (blue) separating large polygonal cells (Masson’s trichromic stain, scale bar: 50 µm). B. Tumor tissue showing large polygonal cells with (more...)

A controversial issue is the “mixed” FLC and HCC, but molecular pathology may resolve this dilemma in the future. Additional features that can be encountered are trabecular, adenoid or pelioid patterns that need to be taken into consideration when evaluating needle or open biopsy. Metastases to the regional lymph nodes, peritoneum, and lungs are commonly seen. Immunohistochemistry is an important ancillary tool. FLC shows HepPar-1, keratin 7, epithelial membrane antigen (EMA), CD68 and carcinoembryonic antigen (polyclonal antibody, p-CEA).

Immunohistochemically, there is usually a lack of expression of AFP, synaptophysin, and chromogranin. The p-CEA is shown in a canalicular pattern due to cross-reactivity to biliary glycoprotein I existing in bile canaliculi of healthy liver and HCC. Of note, the monoclonal CEA is usually negative. These findings have suggested to some authors that FLC may be a hybrid neoplasm of hepatobiliary type. FLC may also be positive for antibodies against CAM5.2 (a low molecular weight cytokeratin panel against keratin 7 and keratin 8 present on secretory epithelia but not on stratified squamous epithelia), AE1–3 (a pan-cytokeratin markers grouping low and high molecular weight antibodies), and neurotensin. AAT is usually inconsistently expressed. CK19 is usually negative (105). There may be an expression of epithelial growth factor receptor (EGFR), and human epidermal growth factor receptor (Her-2) (106). Electron microscopy reveals copious mitochondria (107). Pale bodies contain fibrinogen. There is an abundance of rough endoplasmic reticulum (ER) in the neoplastic cells, which may also show dense core neuroendocrine-like granules. However, the neoplastic cells are not positive for neuroendocrine markers by immunohistochemistry (vide supra) or immunogold-marked electron microscopy. Differential diagnoses include sclerosis-accompanied adenosquamous carcinoma, cholangiocellular carcinoma, which is markedly glandular and mucin-positive (108), and FNH. FNH is smaller in size than FLC. FNH contains bile ductular proliferating associated stroma (fibrous) and inflammatory cells. Microscopically, FNH has neither gross bile staining nor hepatocyte atypia. Also, FLC must be differentiated from the sclerosing variant of HCC, which shows no oncocytic change of the neoplastic cells. This tumor is smaller in size than the tumor cells of FLC and shows a typical pseudoglandular pattern. Other differential diagnoses include metastatic carcinoma with sclerotic stroma (a full history is invaluable), neuroendocrine tumors (neuroendocrine markers proof by immunohistochemistry is useful), and paraganglioma, which harbors a Zellballen growth pattern, round/ovoid nuclei without atypia, vascular stroma but no dense fibrosis and is positive for neuroendocrine markers (109). A clear cell variant of FLC has also been described. (110). In addition to classic FLC, the neoplastic clear cells with empty cytoplasm have ballooning and rarefactive changes to their mitochondria (100).

A fusion gene between DNAJB1 and PRKACA characteristically distinguishes FLC from conventional HCC (103). This genetic abnormality is found with loss of genetic material on chromosome 19. It leads to the unusual combination of two genes, DNAJB1 and PRKACA. DNAJB1 is a DnaJ (Hsp40) homolog, subfamily B, member 1 (DNAJB1) or a transcriptional target of forkhead box protein E3 (FOXE3) in a pathway apparently crucial for the development of the eye. PRKACA encodes one of the catalytic subunits of protein kinase A. The “chimeric” gene, which in turn produces an abnormal protein product, is an unusual combination of the two normal proteins. Common pathways that are altered in HCC, such as β-catenin and p53, are not differentially controlled in FLC. Occasionally, there is also an upregulation of other pathways including EGFR, MAPK, PI3K, and RAS (111). In 2015, Riehle et al. highlighted some of these pathways, showing that mTORC1 is activated in FLC and has been found in association with fibroblast growth factor receptor 1 (FGFR1) overexpression. This data supports the use of FGFR1 inhibitors in patients with FLC (112). Recently, data from the Fibrolamellar Carcinoma Consortium has identified and updated overall survival of FLC (104). About 3/4 of patients with FLC undergo surgical resection and/or OLT and 1/3 receive perioperative therapy. Preoperative chemotherapy, including external beam radiation, and TACE with doxorubicin are the milestones of the perioperative therapy. Chemotherapy agents used in FLC include cisplatin, doxorubicin, fluoropyrimidines, gemcitabine, irinotecan, and oxaliplatin. Postoperative adjuvant chemotherapy and/or radiation should also be considered as relevant options (104).

PEDIATRIC METABOLIC CONDITIONS PREDISPOSING TO HEPATOCELLULAR CARCINOMA

This section lists metabolic conditions that may predispose to the development of HCC. Liver cirrhosis has been considered a precursor of HCC irrespective of etiology because dysplasia can occur in the setting of a regenerating nodule, but this argument is mainly relevant for adult HCC. In childhood, pediatric metabolic conditions play a major role. About one-third of pediatric cases of HCC are associated with cirrhosis, while liver cirrhosis is present in two-thirds to 90% of adult-onset HCC. The list of pediatric metabolic conditions may be not complete but illustrates most of these conditions. This list includes alpha-1-antitrypsin (AAT) deficiency, hereditary tyrosinemia 1, glycogen storage diseases types I, III, and IV, genetic hemochromatosis, Wilson’s disease, acute intermittent porphyria, progressive familial intrahepatic cholestasis type 2, mitochondrial electron transport chain (ETC) disorders, and transaldolase deficiency. However, in some of the above conditions, HCC does not occur at the pediatric age. The most prominent disease in this category of predisposing conditions to HCC is AATD.

CHOLANGIOCELLULAR CARCINOMA

Cholangiocellular carcinoma (CCA) is very rare in childhood and youth, accounting for less than 1% of all malignancies in these age groups. CCA arises from the epithelial lining of the bile ducts and harbors a poor prognosis. In a review of the scientific literature and the “Surveillance, Epidemiology, and End Results” (SEER) Program Database, Newsome et al. found 22 individual cases of pediatric CCA published between 1946 and January 2016 (169). Details of these cases can be found in Tables 2 and 3 of the SEER analyses (170–189). Briefly, the patients had a median age of diagnosis of 15 years (range 3–18 years), of which 20 (91%) had one or more gastrointestinal comorbidities with congenital distortions of the biliary tract and primary sclerosing cholangitis (PSC) being the most prevalent. PSC is a long-term progressive hepatobiliary disease with involvement of the liver, gallbladder, and extrahepatic biliary tract characterized by inflammation and scarring of the bile ducts with potential evolution to liver cirrhosis and liver failure. Abdominal pain, jaundice, and pruritus are the most common clinical signs. In eight patients, cancer antigen (CA) 19–9 was reported, and it was increased (>129 U/mL) in four of them (50%). The SEER database program analysis and the scientific literature evidence showed that after a median follow-up time of 8 months (range 0–60 months), 12 (54.6%) patients had died, 9 (40.9%) patients were alive, and 1 (4.6%) had no reported survival data. Most pediatric cases had underlying risk factors for CCA, such as PSC, while in adults only an estimated 30% of CCAs occurred in patients with an underlying risk factor (108, 190–194). In adults, underlying risk factors include bile duct cysts, primary sclerosing cholangitis (specifically with inflammatory bowel disease), Caroli Disease, and hepatolithiasis. Choledocholithiasis, cholangitis, hepatitis C (HCV), hepatitis B (HBV) and cirrhosis have been considered potential risk factors as well (108, 169). There is a potential association of these tumors with viral infections (hepatitis B virus, hepatitis C virus) and alcohol use, which has been seen increasingly when compared with classic textbook associations of liver flukes (Opisthorchis viverrinii and Clonorchis sinensis) and primary sclerosing cholangitis. Other chronic inflammatory processes of the biliary tract have also been associated with CCA. In addition, congenital disorders such as BA and PIFC have been identified as comorbidities. Congenital malformations of the biliary tree, such as choledochal cysts and Caroli disease, may present with obstructive cholestasis; however, patients may be asymptomatic and diagnosed later in life.

CONCLUSION

In regard to hepatocellular lesions, although diagnosis is typically made using diagnostic imaging, anatomical pathology and histology with ancillary studies still play an enormous role in the 21^st century. Currently, OLT for unresectable HCC can be curative. Risk factors for recurrence should be considered for HCC only, taking into account factors found in metabolic conditions predisposing to the development of primary neoplasms of the liver. Children and adolescents with underlying metabolic conditions should have a regular follow-up in adulthood. CCA is very rare in pediatrics but is not impossible and must be considered by pediatricians and pediatric pathologists, as well as the risk factors for this tumor.

Acknowledgement: Dr. Sergi’s research has been funded by the generosity of the Stollery Children’s Hospital Foundation and supporters of the Lois Hole Hospital for Women through the Women and Children’s Health Research Institute (WCHRI, Grant ID #: 2096), Hubei Province Natural Science Funding for Hubei University of Technology (100-Talent Grant for Recruitment Program of Foreign Experts Total Funding: Digital PCR and NGS-based diagnosis for infection and oncology, 2017–2022), Österreichische Krebshilfe Tyrol (Krebsgesellschaft Tirol, Austrian Tyrolean Cancer Research Institute, 2008), Austrian Research Fund (Fonds zur Förderung der wissenschaftlichen Forschung, FWF, Grant ID L313-B13), Canadian Foundation for Women’s Health, Cancer Research Society (von Willebrand factor gene expression in cancer cells), Canadian Institutes of Health research (Omega-3 Fatty Acids for Treatment of Intestinal Failure Associated Liver Disease: A Translational Research Study), and the Saudi Cultural Bureau, Ottawa, Canada. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of Interest: The author declares no potential conflicts of interest with respect to research, authorship and/or publication of this article.

Copyright and permission statement: The author confirms that the materials included in this chapter do not violate copyright laws. Where relevant, appropriate permissions have been obtained from the original copyright holder(s). All original sources have been appropriately acknowledged and/or referenced.

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Doi: https://doi​.org/10.36255​/exonpublications​.livercancer.2021.ch1