Hepatocellular Carcinoma in Pediatric Age
Hepatocellular Carcinoma in Pediatric Age
Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver that arises from hepatocytes. While it is the most common primary liver cancer in adults, it is relatively rare in children, accounting for approximately 0.5-1% of all pediatric malignancies.
- Second most common primary liver malignancy in children (after hepatoblastoma)
- More aggressive behavior compared to hepatoblastoma
- Often diagnosed at advanced stages due to non-specific symptoms
- Requires a multidisciplinary approach for optimal management
Epidemiology
- Incidence: 0.5-1.0 cases per million children per year
- Age distribution:
- Bimodal distribution: peaks at 0-4 years and 10-14 years
- More common in adolescents compared to younger children
- Gender: Slight male predominance (male to female ratio of 1.2-1.5:1)
- Geographic variation:
- Higher incidence in regions with endemic hepatitis B virus (HBV) infection
- More common in East and Southeast Asia, sub-Saharan Africa
Etiology and Risk Factors
- Chronic liver disease:
- Viral hepatitis (HBV, HCV)
- Cirrhosis (various causes)
- Metabolic disorders:
- Tyrosinemia type 1
- Glycogen storage diseases (types I and IV)
- Alpha-1 antitrypsin deficiency
- Wilson's disease
- Genetic conditions:
- Familial adenomatous polyposis (FAP)
- Progressive familial intrahepatic cholestasis (PFIC)
- Alagille syndrome
- Other factors:
- Congenital portosystemic shunts
- Biliary atresia
- Hepatic vascular malformations
Pathophysiology
- Multistep process of hepatocarcinogenesis:
- Chronic liver injury and inflammation
- Hepatocyte regeneration and fibrosis
- Accumulation of genetic and epigenetic alterations
- Key molecular pathways involved:
- WNT/β-catenin signaling
- p53 tumor suppressor pathway
- Telomerase activation
- MAPK and PI3K/AKT/mTOR pathways
- Differences from adult HCC:
- Lower frequency of TERT promoter mutations
- Higher prevalence of chromothripsis
- Distinct mutational signatures in fibrolamellar variant
Clinical Presentation
- Often asymptomatic in early stages
- Common presenting symptoms:
- Abdominal pain or discomfort
- Palpable abdominal mass
- Weight loss
- Fatigue
- Signs of advanced disease:
- Jaundice
- Ascites
- Hepatomegaly
- Fever
- Paraneoplastic syndromes:
- Hypercalcemia
- Erythrocytosis
- Hypoglycemia
- Complications:
- Portal hypertension
- Tumor rupture (rare but life-threatening)
Diagnosis
- Imaging studies:
- Ultrasound: initial screening tool
- CT scan: multiphase contrast-enhanced study
- MRI: superior soft tissue contrast, diffusion-weighted imaging
- 18F-FDG PET/CT: metabolic activity, metastatic disease
- Laboratory tests:
- Liver function tests (ALT, AST, bilirubin, albumin)
- Alpha-fetoprotein (AFP) - elevated in 60-90% of cases
- Viral hepatitis markers (HBsAg, anti-HCV)
- Coagulation profile (PT, INR)
- Biopsy:
- Core needle biopsy or fine-needle aspiration
- Histopathological examination
- Immunohistochemistry (e.g., Glypican-3, Hep Par 1, Arginase-1)
- Staging:
- PRETEXT system (PRE-Treatment EXTent of disease)
- Barcelona Clinic Liver Cancer (BCLC) staging system
Treatment
Multidisciplinary approach involving:
- Surgical resection:
- First-line treatment for resectable tumors
- Partial hepatectomy or liver transplantation
- Liver transplantation:
- For unresectable tumors meeting Milan criteria
- Consideration of living donor transplantation
- Locoregional therapies:
- Transarterial chemoembolization (TACE)
- Radiofrequency ablation (RFA)
- Stereotactic body radiation therapy (SBRT)
- Systemic therapy:
- Multikinase inhibitors (e.g., sorafenib, lenvatinib)
- Immunotherapy (e.g., nivolumab, pembrolizumab)
- Chemotherapy (limited role, used in combination regimens)
- Management of underlying liver disease:
- Antiviral therapy for hepatitis B or C
- Treatment of metabolic disorders
- Supportive care:
- Pain management
- Nutritional support
- Psychosocial support
Prognosis
- Overall survival:
- 5-year survival rate: 20-30% for all stages combined
- Significantly better for early-stage, resectable disease
- Prognostic factors:
- Tumor stage at diagnosis
- Presence of cirrhosis
- Alpha-fetoprotein levels
- Vascular invasion
- Response to initial therapy
- Challenges:
- High recurrence rate after resection (up to 70% at 5 years)
- Limited treatment options for advanced disease
- Long-term complications of chronic liver disease
- Future directions:
- Improved screening strategies for high-risk populations
- Development of targeted therapies and immunotherapies
- Optimization of liver transplantation protocols
Hepatocellular Carcinoma in Pediatric Age
- What is the most common primary liver malignancy in children?
Hepatoblastoma, followed by hepatocellular carcinoma (HCC) - At what age does pediatric HCC typically occur?
Usually in children over 5 years old, with a peak incidence in adolescence - Which genetic condition significantly increases the risk of pediatric HCC?
Familial Adenomatous Polyposis (FAP) - What metabolic disorder is associated with an increased risk of pediatric HCC?
Glycogen storage disease type I and III - What viral infection is a major risk factor for pediatric HCC in endemic areas?
Hepatitis B virus (HBV) infection - Which imaging modality is considered the gold standard for diagnosing pediatric HCC?
Contrast-enhanced MRI - What serum biomarker is commonly elevated in pediatric HCC?
Alpha-fetoprotein (AFP) - What is the most common presenting symptom of pediatric HCC?
Abdominal pain or discomfort - Which staging system is commonly used for pediatric HCC?
PRETEXT (PRE-Treatment EXTent of disease) staging system - What is the primary treatment modality for localized pediatric HCC?
Surgical resection - In cases where complete surgical resection is not possible, what is the recommended treatment?
Liver transplantation - What chemotherapy regimen is commonly used in pediatric HCC?
PLADO (cisplatin and doxorubicin) - Which targeted therapy has shown promise in treating advanced pediatric HCC?
Sorafenib - What is the role of radiation therapy in pediatric HCC?
Limited, mainly used for palliation or in combination with other treatments - What is the overall 5-year survival rate for pediatric HCC?
Approximately 30-40%, but varies widely based on stage at diagnosis - How does the prognosis of pediatric HCC compare to adult HCC?
Generally worse than adult HCC, due to more advanced disease at presentation - What is fibrolamellar HCC?
A distinct subtype of HCC that occurs in children and young adults without underlying liver disease - How does fibrolamellar HCC differ from conventional HCC in terms of AFP levels?
Fibrolamellar HCC typically does not produce elevated AFP levels - What genetic alteration is characteristic of fibrolamellar HCC?
DNAJB1-PRKACA gene fusion - What is the recommended follow-up schedule for children after HCC treatment?
Every 3-4 months for the first 2 years, then every 6 months for 3 years, and annually thereafter - What is the role of transarterial chemoembolization (TACE) in pediatric HCC?
Used for unresectable tumors or as a bridge to transplantation - How does pediatric HCC differ from hepatoblastoma in terms of age of onset?
HCC typically occurs in older children, while hepatoblastoma is more common in children under 3 years old - What is the significance of portal vein invasion in pediatric HCC?
Associated with poor prognosis and often indicates unresectable disease - Which growth factor receptor is often overexpressed in pediatric HCC?
Insulin-like growth factor 2 receptor (IGF2R) - What is the role of needle biopsy in diagnosing pediatric HCC?
Used when imaging and AFP levels are inconclusive, but carries a risk of tumor seeding - How does chronic hepatitis C infection contribute to pediatric HCC risk?
It can lead to cirrhosis, which increases the risk of HCC development - What is the significance of multifocal HCC in children?
Often indicates advanced disease and may preclude surgical resection - How does obesity impact the risk and prognosis of pediatric HCC?
Obesity increases the risk of non-alcoholic fatty liver disease, which can progress to HCC - What is the role of immunotherapy in treating pediatric HCC?
Emerging treatment option, with checkpoint inhibitors showing promise in early trials - How does the presence of cirrhosis affect the treatment approach for pediatric HCC?
Cirrhosis often limits surgical options and may necessitate liver transplantation
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