Hepatoblastoma (ORPHA:449)
A malignant hepatic tumor, typically affecting the pediatric population, arising mostly in an otherwise healthy liver. The most common signs are abdominal distension and abdominal mass. Sometimes patients present with anorexia, weight loss, fatigue. Most HBLs are sporadic, but some cases are associated with genetic factors, especially overgrowth syndromes, such as Beckwith-Wiedemann syndrome (BWS) or hemihypertrophy, and familial adenomatous polyposis (FAP).
Epidemiology
Hepatoblastoma (HB) accounts for about 0,5-2% of all pediatric tumors and for 2/3 of primary hepatic tumors in children. Its incidence is estimated to be 1/1,000,000 in Europe and 1-1,5/1,000,000 in USA. A slight male predilection (1.5:1 to 2:1) has been observed. The incidence of HBL in children has been increasing by about 5% annually.
Clinical description
The age of disease onset lies in infancy or early childhood (median age of occurrence is 18 months and 90% of HBs present before 5 years). The most common signs are: (1) abdominal distension and abdominal mass, (2) anorexia, weight loss, fatigue, (3) abdominal pain, nausea and vomiting, (4) jaundice is less frequently observed, (5) anemia and thrombocytosis detected by laboratory tests. Rare cases present with precocious puberty/virilization due to beta-human chorionic gonadotropin (hCG) secretion by the tumor. FAP and BWS are associated with an increased risk of HB. Trisomy 13 and 18, Goldenhar syndrome, Noonan syndrome, Fragile X syndrome, Sotos syndrome, Prader-Willi syndrome, Prune belly syndrome, Aicardi syndrome and neurofibromatosis type 1 may also predispose to HB. Genetic syndromes are associated with 20% of HB cases. High-risk patients are those with distant metastases, very low initial alpha-fetoprotein (AFP) level (under 100 ng/ml), older age (over 8 years), tumor rupture at diagnosis and/or tumor involvement of all 4 hepatic sections.
Etiology
The etiology of HB is still unknown. However, it is hypothesized to derive from primary hepatoblasts, and likely from less differentiated hepatic stem cells or human fetal liver multi-potent progenitor cells (hFLMPCs). Mutations of the genes APC (5q21-q22), AXIN1 (16p13.3) and AXIN2 (17q24.1), that prevent degradation of beta-catenin, have been found in syndromic forms of HB but have rarely been described in sporadic HB. However, a high rate of oncogenic mutations of the beta-catenin gene (CTNNB1; 3p21) (60%-70%) has been reported in HB and it is thought to be associated with constitutive activation of the Wnt/beta-catenin signaling pathway. Overall, Wnt pathway abnormalities account for up to 90% of genetic defects in hepatoblastoma tumor.
Differential diagnosis
Differential diagnosis includes: (1) hemangioma and infantile hemangioendothelioma (IHE), (2) hepatic mesenchymal hamartoma, (3) focal nodular hyperplasia (FNH), (4) pediatric hepatocellular carcinoma (HCC), (5) undifferentiated embryonal sarcoma of the liver (UESL), (6) embryonal rhabdomyosarcoma (eRMS), (7) rhabdoid tumor of the liver, (8) hepatic adenoma.
Management and treatment
A diagnostic tumor biopsy should be mandatory for all patients with primary liver tumor. HB is definitely a surgical tumor. Surgery remains the cornerstone of management and complete resection is crucial for cure. In most cases complete resection of the tumor can be achieved with a partial hepatectomy (hemihepatectomy). The PRETEXT (PRETreatment EXtent of Disease) system (based on liver anatomy and imaging) is used for assessment of chemotherapy response and planning the extent of liver resection. Resection at diagnosis is currently recommended for very low risk tumors (PRETEXT I/II, M-, surgically resectable at diagnosis (VPEFR-), and additionally in PRETEXT II: age under 8 years, AFP over100 ng/ml) and only when a segmentectomy or hemihepatectomy with at least 1 cm margin on middle hepatic vein and/or bifurcation of portal vein is possible. For unresectable tumors, preoperative chemotherapy (mostly systemic or, in highly selected cases, transcatheter arterial chemoembolization [TACE], sometimes combined with systemic chemotherapy) is used. Total hepatectomy with liver transplantation is a treatment option for HB in conditions where the tumors remain unresectable after chemotherapy or for multifocal HB invading all 4 sections of the liver. 10-20% of all HB cases require liver transplantation. In most cases postoperative chemotherapy is used routinely.
Prognosis
Current prognosis for patients with resectable tumors and no high risk features is fairly favorable (90%), whereas the outcome for those with metastases is around 50-70%, while the prognosis of patients with non-resectable or recurrent disease is relatively poor (around 20-30%). Relapse in HB occurs in less than 12% of the children who have achieved complete remission.

                            Last update: 
                            July 2020


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