Hepatoblastoma in Children

Hepatoblastoma is the most common primary liver malignancy in children, accounting for approximately 1% of all pediatric cancers. It is an embryonal tumor believed to arise from immature liver precursor cells.

Typically occurs in young children, with a median age of diagnosis around 18 months
Characterized by diverse histological patterns reflecting various stages of liver development
Often associated with elevated alpha-fetoprotein (AFP) levels
Treatment advances have significantly improved outcomes in recent decades

Epidemiology

Incidence:
- 1.2-1.5 cases per million children per year
- Accounts for 90% of liver tumors in children under 5 years
Age distribution:
- 80% of cases occur before 3 years of age
- Rare in children over 5 years old
- Can occur in neonates and even prenatally
Gender: Slight male predominance (male to female ratio of 1.5-2:1)
Geographic variation:
- Higher incidence in East Asian and Pacific Island populations
- Lower incidence in North American black children
Trends:
- Increasing incidence over the past few decades
- Possibly related to improved survival of premature infants and better detection methods

Etiology and Risk Factors

Genetic predisposition:
- Familial Adenomatous Polyposis (FAP):
  - Associated with germline APC mutations
  - 847-fold increased risk of hepatoblastoma
- Beckwith-Wiedemann Syndrome:
  - Overgrowth syndrome associated with abnormalities on chromosome 11p15
  - 2280-fold increased risk of hepatoblastoma
- Other syndromes: Simpson-Golabi-Behmel syndrome, Trisomy 18
Prematurity and low birth weight:
- 20-30 fold increased risk in very low birth weight infants (<1500g)
- Possible link to neonatal intensive care treatments
Parental exposures:
- Paternal occupational exposure to metals
- Maternal alcohol consumption during pregnancy
Molecular pathogenesis:
- Activation of the Wnt/β-catenin pathway (CTNNB1 mutations in 70-90% of cases)
- NFE2L2 mutations leading to oxidative stress pathway activation
- Chromosomal gains (1q, 2, 8, 20) and losses (4q, 11q)

Pathology and Classification

Gross appearance:
- Well-circumscribed, solitary mass (80% of cases)
- Can be multifocal (20% of cases)
- Variable consistency: soft and fleshy to firm and nodular
Histological classification (WHO 2022):
- Epithelial type:
  - Fetal (well-differentiated and crowded)
  - Embryonal
  - Macrotrabecular
  - Small cell undifferentiated
- Mixed epithelial and mesenchymal type:
  - With teratoid features
  - Without teratoid features
Immunohistochemistry:
- Positive for: AFP, Glypican-3, β-catenin (nuclear)
- Negative for: CK7, CK19 (helps differentiate from hepatocellular carcinoma)
Molecular classification:
- C1: Fetal histology, few copy number changes
- C2: Embryonal/mixed histology, chromosomal instability, CTNNB1 mutations
- C2B: C2 with HNF1A deletion
- C3: Aggressive tumors, CK19 positive, CTNNB1 and NFE2L2 mutations

Clinical Presentation

Common presenting symptoms:
- Asymptomatic abdominal mass (most common)
- Abdominal pain or discomfort
- Abdominal distension
- Weight loss
- Anorexia
Physical examination findings:
- Palpable right upper quadrant mass
- Hepatomegaly
- Rarely, signs of precocious puberty due to hCG secretion
Complications:
- Tumor rupture (rare but life-threatening)
- Intraperitoneal hemorrhage
- Compression of adjacent structures
Metastatic disease:
- Present in 10-20% of cases at diagnosis
- Most common sites: lungs, brain, bone
Paraneoplastic syndromes:
- Thrombocytosis
- Erythrocytosis
- Hypoglycemia (rare)

Diagnosis

Laboratory studies:
- Alpha-fetoprotein (AFP):
  - Elevated in 90% of cases
  - Important for diagnosis, monitoring, and prognosis
  - Age-adjusted interpretation is crucial
- Liver function tests (AST, ALT, bilirubin, albumin)
- Complete blood count
- Coagulation profile
- Beta-hCG (if signs of precocious puberty)
Imaging studies:
- Ultrasound: Initial screening tool
- CT scan:
  - Multiphase contrast-enhanced study
  - Evaluation of local extent and vascular invasion
- MRI:
  - Superior soft tissue contrast
  - Diffusion-weighted imaging
  - Hepatobiliary contrast agents (e.g., gadoxetate disodium)
- Chest CT: Evaluation for pulmonary metastases
- 18F-FDG PET/CT: May be useful for staging and response assessment
Biopsy:
- Core needle biopsy or fine-needle aspiration
- May be deferred if imaging and AFP are diagnostic
- Essential for tumors with low or normal AFP
Genetic testing:
- Germline APC testing in cases of familial adenomatous polyposis
- Consideration of broader cancer predisposition gene panels

Staging and Risk Stratification

PRETEXT system (PRE-Treatment EXTent of disease):
- Based on imaging findings before any treatment
- Divides the liver into four sections
- PRETEXT I-IV based on number of contiguous sections involved
- Additional annotation factors:
  - V: Involvement of hepatic veins/IVC
  - P: Involvement of portal vein
  - E: Extrahepatic abdominal disease
  - F: Multifocality
  - R: Tumor rupture
  - M: Distant metastases
  - N: Lymph node involvement
COG (Children's Oncology Group) Risk Stratification:
- Very Low Risk:
  - PRETEXT I/II, pure fetal histology, low AFP
- Low Risk:
  - PRETEXT I/II, not pure fetal or SCU, AFP >100
- Intermediate Risk:
  - PRETEXT III or focal V/P
- High Risk:
  - PRETEXT IV, metastatic disease, SCU histology, AFP <100
SIOPEL (International Childhood Liver Tumor Strategy Group) Risk Stratification:
- Standard Risk:
  - PRETEXT I-III, no metastases, AFP >100
- High Risk:
  - PRETEXT IV, metastatic disease, tumor rupture, AFP <100

Treatment

Multidisciplinary approach involving:

Chemotherapy:
- Neoadjuvant chemotherapy:
  - Standard risk: Cisplatin monotherapy
  - High risk: Cisplatin + Doxorubicin (PLADO)
  - Goal: Tumor shrinkage and improved resectability
- Adjuvant chemotherapy:
  - Based on risk group and response to neoadjuvant therapy
  - May include additional agents (e.g., carboplatin, 5-FU, vincristine)
Surgery:
- Complete surgical resection is crucial for cure
- Options:
  - Partial hepatectomy
  - Extended hepatectomy
  - Liver transplantation (for unresectable tumors)
- Timing:
  - Primary surgery for very low-risk tumors
  - Delayed surgery after neoadjuvant chemotherapy for most cases
Liver transplantation:
- Indications:
  - Unresectable tumors after chemotherapy
  - PRETEXT IV tumors with favorable biology
- Contraindications:
  - Uncontrolled extrahepatic disease
  - Portal vein thrombosis
Management of metastatic disease:
- Intensified chemotherapy regimens
- Surgical resection of metastases when possible
- Consideration of high-dose chemotherapy with stem cell rescue
- Targeted therapies for refractory disease (e.g., sorafenib, regorafenib)
Radiation therapy:
- Limited role in primary treatment
- May be considered for:
  - Palliation of symptomatic metastases
  - Local control in unresectable disease
Novel and emerging therapies:
- Immunotherapy:
  - Checkpoint inhibitors (e.g., nivolumab, pembrolizumab)
  - CAR-T cell therapy (in early clinical trials)
- Targeted therapies:
  - GPNMB-targeted antibody-drug conjugates
  - MEK inhibitors for RAS-mutated tumors
- Oncolytic virotherapy (e.g., measles virus-based therapies)
Supportive care:
- Nutritional support
- Pain management
- Psychosocial support for patients and families
- Management of treatment-related complications

Prognosis and Follow-up

Overall survival:
- 5-year overall survival: 70-80% for all stages combined
- Very low and low-risk disease: >90% 5-year survival
- Intermediate-risk disease: 80-90% 5-year survival
- High-risk disease: 50-70% 5-year survival
Prognostic factors:
- PRETEXT stage at diagnosis
- Presence of metastases
- Alpha-fetoprotein (AFP) levels and dynamics
- Histological subtype (small cell undifferentiated has worse prognosis)
- Completeness of surgical resection
- Response to neoadjuvant chemotherapy
Recurrence:
- Overall recurrence rate: 10-20%
- Most recurrences occur within 2 years of initial treatment
- Common sites: liver, lungs, brain
Long-term sequelae:
- Hearing loss (cisplatin-induced ototoxicity)
- Cardiotoxicity (anthracycline-induced)
- Growth and developmental delays
- Neurocognitive impairment
- Secondary malignancies
- Liver dysfunction (especially after extensive resection or transplantation)
Follow-up recommendations:
- Frequent follow-up in the first 2 years post-treatment:
  - Physical examination
  - AFP measurements
  - Liver function tests
  - Imaging studies (ultrasound, CT, or MRI)
- Long-term follow-up:
  - Annual check-ups for at least 5 years
  - Monitoring for late effects of treatment
  - Screening for secondary malignancies
- Special considerations for transplant recipients:
  - Close monitoring of immunosuppression
  - Surveillance for graft rejection
  - Screening for post-transplant lymphoproliferative disorder
Psychosocial support:
- Long-term psychological follow-up for patients and families
- Educational and vocational support
- Transition to adult care services
Future directions:
- Refinement of risk stratification using molecular markers
- Development of targeted therapies based on tumor biology
- Optimization of treatment protocols to reduce long-term toxicities
- Improvement in liver transplantation outcomes
- Enhanced survivorship care and long-term follow-up strategies

Hepatoblastoma in Children

What type of tumor is hepatoblastoma?
A malignant liver tumor
What age group is most commonly affected by hepatoblastoma?
Children under 3 years old
What is the approximate incidence rate of hepatoblastoma?
1-1.5 cases per million children per year
What genetic syndrome is strongly associated with hepatoblastoma?
Familial Adenomatous Polyposis (FAP)
What gene is mutated in FAP-associated hepatoblastoma?
APC gene
What is the most common presenting sign of hepatoblastoma?
Abdominal mass
What serum tumor marker is elevated in most hepatoblastoma cases?
Alpha-fetoprotein (AFP)
What imaging modality is typically used for initial evaluation of suspected hepatoblastoma?
Abdominal ultrasound
What imaging study is used for precise staging of hepatoblastoma?
CT scan or MRI of the abdomen
What is the gold standard for hepatoblastoma diagnosis?
Liver biopsy with histological examination
What are the two main histological subtypes of hepatoblastoma?
Epithelial and mixed epithelial/mesenchymal
What staging system is commonly used for hepatoblastoma?
PRETEXT (PRE-Treatment EXTent of disease)
What does POSTTEXT refer to in hepatoblastoma management?
POST-Treatment EXTent of disease
What is the primary goal of neoadjuvant chemotherapy in hepatoblastoma?
To shrink the tumor and make it resectable
What chemotherapy drugs are commonly used in hepatoblastoma treatment?
Cisplatin and doxorubicin
What is the role of surgical resection in hepatoblastoma treatment?
Complete tumor removal is crucial for cure
What is the name of the surgical procedure to remove a portion of the liver?
Partial hepatectomy
In what situation might liver transplantation be considered for hepatoblastoma?
For unresectable tumors confined to the liver
What is the approximate 5-year overall survival rate for children with hepatoblastoma?
70-80%
What factor is associated with a poorer prognosis in hepatoblastoma?
Metastatic disease at diagnosis
What is the most common site of metastasis in hepatoblastoma?
Lungs
What is the role of radiation therapy in hepatoblastoma treatment?
Limited; mainly used for palliation in advanced cases
What is the typical duration of chemotherapy for standard-risk hepatoblastoma?
4-6 months
What is the role of AFP monitoring during and after hepatoblastoma treatment?
To assess treatment response and monitor for recurrence
What prenatal factor has been associated with an increased risk of hepatoblastoma?
Very low birth weight
What is the male to female ratio in hepatoblastoma incidence?
About 1.5-2:1 (male predominance)
What percentage of hepatoblastoma cases are diagnosed in children under 18 months of age?
Approximately 90%
What is the role of TACE (Transarterial Chemoembolization) in hepatoblastoma treatment?
Used in some cases to shrink tumors before surgery
What is the recommended frequency of follow-up imaging in the first two years after treatment?
Every 3-4 months
What is the approximate relapse rate for localized hepatoblastoma?
10-20%

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Hepatoblastoma in Children