Pediatric hepatocellular carcinoma (ORPHA:33402)
A rare, aggressive and malignant hepatic tumor arising from the hepatocytes. It develops mainly in children over 10 years of age, either in a cirrhotic background, or more commonly in a non-cirrhotic background (70% of cases).
Epidemiology
Primary liver malignancies are rare in children and adolescents. Hepatocellular carcinoma (HCC) constitutes less than 25% of them. Annual incidence is about 1/2,000,000, with higher incidence rates found in sub-Saharan Africa and Southeast Asia as a result of endemic hepatitis B (HBV) and aflatoxin exposure. HCC is found more frequently in males (2-3:1). Incidence is higher among adolescents (1/1,250,000).
Clinical description
HCC mostly develops in pediatric patients with no underlying liver disease, unlike in adults, when it is usually associated with hepatic cirrhosis due to alcohol intake. Pediatric HCC is mostly found in children and adolescents and rarely in children under 5 years of age. The main presenting manifestations are abdominal mass with pain, swelling and discomfort, weight loss, and anorexia. Splenomegaly, nausea, vomiting and jaundice are less commonly observed. Metastases to the mediastinal lymph nodes, lungs, brain and bone marrow are common in advanced disease (25% at presentation). HCC may be associated with congenital diseases, such as biliary atresia, tyrosinemia type 1 (in 50% of cases), alpha-1-antitrypsin deficiency, progressive familial intrahepatic cholestasis, Alagille or Gardner syndrome, Wilson or glycogen storage diseases I-IV, Fanconi anemia, familial adenomatous polyposis (FAP), focal nodular hyperplasia and hemochromatosis. A specific HCC variant, fibrolamellar carcinoma (FLC), occurs in older children and young adults, and has an equally dismal prognosis despite a slower growth and less tendency to metastasize.
Etiology
The pathophysiology of HCC is not well understood. Underlying liver dysfunction is the main predisposing condition (HBV, HCV). Children with neonatal hepatitis, intrahepatic cholestasis, biliary atresia, glycogen-storage diseases and other types of cirrhotic diseases are predisposed to the tumor. The Wnt/beta-catenin pathway is frequently activated via stabilizing mutations in beta-catenin: some patients have been found to harbor mutations in the CTNNB1 (3p21) and MET (7q31) genes. TP53 (17p13.1) gene and the TERT promoter are mutated in 25-30% and 60% of HCC cases, respectively. However, so far, the key genomic alteration in HCC has not yet been identified, and no mutation is used in clinical practice to predict a therapeutic response.
Diagnostic methods
Diagnosis is based on the clinical manifestations, elevated alpha-fetoprotein (AFP) in 50% of cases, histological findings, and on liver imaging. A slowly enlarging mass may be found on physical examination. Abnormal levels of beta human chorionic gonadotropin (b-hCG) may also be detected (rare). Ultrasound typically shows a heterogeneous hyperechoic mass with increased vascularity. Chest CT and abdominal CT/MRI scans with intravenous contrast should be performed for initial staging. Other imaging techniques may also be required to determine possible metastatic spread.
Differential diagnosis
The main differential diagnosis is hepatoblastoma, the most common hepatic tumor in the pediatric population in Western countries. Others include focal nodular hyperplasia (FNH), hepatic adenoma and undifferentiated embryonal sarcoma, as well as other less common liver malignancies.
Management and treatment
At-risk patients should be monitored closely. Screening for HBV and HCV should be performed. Monitoring with ultrasound and AFP every 6 months for all cirrhotic children, those with chronic HBV infection, inherited metabolic diseases or congenital porto-systemic shunts is suggested. The mainstay of curative therapy in non-metastatic patients is primary complete surgical resection (possible in about 25% of presenting children), delayed surgical resection (after neo-adjuvant chemotherapy) or liver transplantation (often across the Milan criteria). Transarterial chemo-embolization (TACE), radio-embolization (TARE) and radiofrequency ablation (RFA) are possible palliative options. Immunotherapies (CAR T cells, PD-1/PD-L1 and CTLA-4 checkpoint inhibitors) are newly emerging field for HCC.
Prognosis
The prognosis currently depends on success rates of resection in resectable tumors. 5-year survival rates are moderate in low stage tumors but these rates drop below 20-30% in advanced disease.

                            Last update: 
                            October 2019


                            - Expert reviewer(s): 
                            Pr Piotr CZAUDERNA  - Dr Maciej MURAWSKI