Hepatoblastoma

Hepatoblastoma is the most common primary malignant liver tumour in children under four years of age, usually presenting with a large painless abdominal mass which is heterogeneous on imaging and raised AFP.

Description

Hepatoblastoma is a rare malignant tumour of the liver that typically occurs in infancy and early childhood. It is the most common liver cancer in children, with the majority of cases diagnosed within the first three years of life. Hepatoblastoma originates from immature liver cells and may present as a single mass or multiple tumours within the liver.

Pathogenesis

The exact cause of hepatoblastoma is unknown, but it is thought to result from the abnormal growth and proliferation of immature liver cells. Several genetic mutations have been associated with hepatoblastoma, including alterations in the Wnt/β-catenin pathway, which plays a key role in liver development.

Subtypes

Hepatoblastoma can be classified histologically into several subtypes, each of which has unique characteristics and may respond differently to treatment.

• Epithelial Hepatoblastoma: This is the most common subtype and further divided into three groups:
  • Foetal (Pure Foetal Histology) Hepatoblastoma: It is characterised by cells that resemble normal foetal hepatocytes. This subtype is often associated with a good prognosis and high survival rate.
  • Embryonal Hepatoblastoma: It features cells resembling embryonic liver cells. This subtype is usually aggressive and has a worse prognosis compared to the foetal subtype.
  • Mixed Epithelial Hepatoblastoma: This subtype is a mixture of foetal and embryonal cells and is the most common type of epithelial hepatoblastoma.
• Macrotrabecular Hepatoblastoma: Rare. This subtype is similar to hepatocellular carcinoma, with cells forming thick trabeculae.
• Small Cell Undifferentiated (SCU) Hepatoblastoma: Rare and aggressive subtype, characterised by small cells with high nuclear-to-cytoplasmic ratios.
• Mixed Epithelial-Mesenchymal Hepatoblastoma: This subtype has both epithelial and mesenchymal components, including osteoid and chondroid tissues, and it can be further classified into those with and without teratoid features.

Epidemiology, Risk Factors, and Associations

Hepatoblastoma is a rare disease, with an incidence of approximately one case per million children. It is more common in males than females.

Genetic syndromes and chromosomal abnormalities have also been linked with an increased risk of hepatoblastoma:

• Beckwith-Wiedemann Syndrome (BWS): Most commonly associated genetic syndrome. BWS is a growth regulation disorder that can result in large body size, large organs, and other symptoms. Children with BWS are at a higher risk for several types of cancer, including hepatoblastoma.
• Familial Adenomatous Polyposis (FAP): Second most common risk factor. FAP is a hereditary disorder characterised by the development of numerous polyps in the colon and rectum. Children with FAP have an increased risk of developing hepatoblastoma.
• Hemihypertrophy: Enlargement of one side of the body compared to the other.
• Li-Fraumeni syndrome and other TP53-related disorders
• Very low birth weight: Infants who weigh less than 1500 grams (about 3.3 pounds) at birth.
• Other associations: Gardner syndrome, type 1A glycogen storage disease, and trisomy 18

Clinical Features

• Abdominal swelling or a palpable mass in the abdomen is the most common presenting symptom.
• Other symptoms may include loss of appetite, weight loss, vomiting, and jaundice.

Complications

• Metastasis: Commonly to the lungs; detected via chest imaging.
• Vascular Invasion: Involvement of the hepatic and portal veins.
• Biliary Obstruction: Demonstrable on MR cholangiopancreatography (MRCP).
• Local Invasion: Infiltration into adjacent structures, assessable on cross-sectional imaging.
• Post-Treatment Changes: Including fibrosis and architectural distortion post-chemotherapy or post-surgical resection.
• Recurrence: Detected on follow-up imaging studies, often requiring contrast-enhanced CT or MRI for evaluation.

Pathological Features

Biochemistry

• Elevated levels of alpha-fetoprotein (AFP) – Occurs in 90% of cases. AFP is a protein produced by the liver and yolk sac of a developing foetus. After birth, levels of AFP in the blood decrease and are usually undetectable by the first year of life in healthy children and adults. In adults and children, normal levels of AFP are usually less than 10 nanograms per millilitre (ng/mL).
• May also be associated with elevated human chorionic gonadotropin (HCG), manifesting with features of precocious puberty in boys

Morphology

Hepatoblastomas are typically well-circumscribed, solid masses with a variable appearance, ranging from tan-yellow to soft and friable with areas of haemorrhage or necrosis.

Histopathology

Hepatoblastomas can be classified into two main types: epithelial and mixed epithelial/mesenchymal.

• The epithelial type is more common and can further subdivided into several subtypes, including foetal, embryonal, macrotrabecular, and small cell undifferentiated.
• These tumours often show an increase in AFP, which is secreted by the tumour cells.

Radiological Features

General Features

• Large (usually >10 cm), well-defined, solid, heterogenous liver mass, more commonly in the right lobe
• Haemorrhage, necrosis, calcification
• May have portal or hepatic invasion
  • May be difficult to distinguish from compression
  • Favoured to represent tumour thrombus (vs. bland thrombus) if there is vascular dilatation, contiguity with the primary mass, enhancement on contrast phase, internal arterial flow on colour Doppler.

US

Ultrasound is often the initial imaging modality used and may show a heterogeneous mass in the liver.

• Usually hyperechoic to liver, often heterogeneous
  • Acoustic shadowing may represent to echogenic Ca²⁺
  • Hypoechoic/anechoic foci from necrosis, hemorrhage
  • May have spoke-wheel appearance
• Pulsed Doppler: Portal or hepatic venous tumour thrombus may show arterial waveforms in venous lumen
• Color Doppler: Often hypovascular or varying amount of disorganised vascularity

Radiography

• CXR: May demonstrate metastases
• AXR: May demonstrate paucity of bowel gas in the right upper quadrant and mass effect on bowel

MRI

• T1: Generally hypointense to normal liver. High signal intensity foci of intratumoral haemorrhage.
• T2: Heterogeneous intermediate signal intensity but usually hyperintense to normal liver ± hypointense fibrous bands, haemorrhage ± internal hyperintense cystic/necrotic foci
• T1 C+ FS: Paediatric LI-RADS workgroup recommends MR with hepatobiliary contrast agent at all imaging time points. Heterogeneous enhancement, usually less than background liver on all phases.
• DWI: Restricted diffusion

CT

• Protocol: Paediatric LI-RADS recommends late arterial & portal venous phase imaging
• Non-contrast: Well-defined, low-attenuation masses ± coarse calcification
• Contrast: Heterogeneous enhancement (less than background liver) representing histological components of the tumour and areas of necrosis or haemorrhage. Useful for assessing the presence of vascular invasion and detect metastatic disease, most commonly in the lungs

NM

• PET: Not typically used for diagnosis. May be useful in staging and follow-up.

Staging

The staging of hepatoblastoma is based on the PRETEXT (PRETreatment EXTent of disease) system, which considers the number of liver sections involved by the tumour and the presence of contiguous extrahepatic disease, vascular involvement, and metastases. PRETEXT group is determined by number of contiguous (i.e. adjacent) hepatic sections that must be resected to remove tumour.

• PRETEXT I: The tumour is in one section of the liver (with three contiguous unaffected sections, i.e. only left lateral or right posterior involved)
• PRETEXT II: The tumour is in two contiguous sections of the liver.
• PRETEXT III: The tumour is in three sections of the liver.
• PRETEXT IV: The tumour is in all four sections of the liver.

Several annotations are used to provide further information about the extent of the disease:

• V: Vascular involvement. This could involve the portal vein (PV) or the hepatic veins/Inferior Vena Cava (HV/IVC).
• E: Extrahepatic disease. This indicates disease that has spread outside of the liver.
• M: Metastatic disease. This indicates that the disease has spread to distant sites in the body.
• R: Ruptured tumour. This indicates that the tumour has ruptured, either spontaneously or due to trauma.

POSTTEXT (posttreatment extent of tumour) is determined using the same method.

Differential Diagnosis

• Hepatocellular carcinoma (HCC): The main differential diagnosis, although it is much less common in young children. It tends to manifests after age 5 and in children with underlying liver disease (e.g. cirrhosis secondary to biliary atresia, Fanconi anaemia, glycogen storage disease). Serum AFP raised.
• Mesenchymal Harmatoma: Benign. Generally a large multiseptated cystic mass in child under 2 years. Calcifications are uncommon. Serum AFP is normal.
• Infantile hepatic haemangioma: Benign. Associated with high output congestive heart failure (classically a large heart on CXR). Aorta above the hepatic branches of the coeliac trunk is often enlarged relative to branches below due to differential flow. Associated with skin haemangiomas and Kasabach-Meritt Syndrome. Endothelial growth factor is elevated.
• Infantile haemangioendothelioma (IHE) is a vascular tumour and enhances much more than background liver (cf. hepatoblastoma which is hypoenhancing). IHE is distinguished by intense nodular or corrugated peripheral enhancement with centripetal fill-in on delayed phase images.
• Metastatic disease: Metasis to the liver from other primary tumours, such as neuroblastoma, Wilms’ tumour (nephroblastoma), rhabdomyosarcoma, leukaemias and lymphomas.

Management

• The primary treatment for hepatoblastoma is surgical resection, with the goal of complete removal of the tumour.
• Preoperative chemotherapy is often given to shrink the tumour and make surgery more feasible.
• Liver transplantation may be considered for children with unresectable tumours.
• Postoperative chemotherapy is typically given to eradicate any remaining microscopic disease.
• Prognosis depends on several factors, including the stage of the disease at diagnosis, the child’s response to treatment, and the presence or absence of metastatic disease.
• In the event of recurrence, treatment options may include further surgery, additional chemotherapy, radiation therapy, and/or participation in clinical trials exploring new treatment approaches.