Practice Essentials
Hepatocellular carcinoma (HCC) is an aggressive hepatic neoplasm that most commonly affects adults. Nevertheless, children with biliary atresia, infantile cholestasis, glycogen-storage diseases, and a wide array of cirrhotic liver diseases are predisposed to developing hepatocellular carcinoma. [1]
The 2 pathologic subtypes are classic hepatocellular carcinoma and fibrolamellar carcinoma. Surgical resection is the mainstay of curative therapy, although adjunctive chemotherapeutic and radiotherapeutic strategies are also used.
Signs and symptoms
Most children with hepatocellular carcinoma present with a slowly enlarging, right upper-quadrant mass. In advanced cases, or when the primary tumor is large, the liver may be palpable below the right costal margin.
Patients typically report abdominal pain, weight loss, and diminished appetite. Many patients also experience nausea and vomiting. Scleral icterus and other signs of jaundice may be present.
See Presentation for more detail.
Diagnosis
Laboratory studies
The following studies are useful in the workup of pediatric hepatocellular carcinoma:
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Serologies for hepatitis B and C
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Liver function tests
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Coagulation studies
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Measurement of serum ammonia level
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Measurement of α-fetoprotein (AFP) and, to a lesser extent, β-human chorionic gonadotropin (β-hCG) levels
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Measurement of serum sodium and calcium levels (because of the association of hyponatremia and hypercalcemia with the paraneoplastic syndrome secondary to excess production of parathyroid hormone–related protein and antidiuretic hormone)
Imaging studies
The initial staging evaluation should include chest, abdomen, and pelvic computed tomography (CT) scanning. Other imaging studies to consider include the following:
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Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the liver to determine tumor margins and vasculature if surgical resection is anticipated.
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Ultrasonography to screen patients at high risk for hepatocellular carcinoma.
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Bone scanning and MRI of the brain to determine the status of metastatic spread to the skeleton and neuraxis, respectively.
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Chest radiography to monitor pulmonary metastatic disease.
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Venous Doppler studies to exclude the possibility of deep venous thrombosis if extremity swelling, edema, or pain is noted.
Procedures
Liver biopsy is the most important procedure to consider when hepatocellular carcinoma is suspected and when imaging results coupled with the AFP level do not provide a conclusive diagnosis.
See Workup for more detail.
Management
Surgical resection remains the mainstay of curative therapy for pediatric hepatocellular carcinoma; however, chemotherapy and radiation can be helpful as adjuvant or neoadjuvant treatment. One widely used chemotherapeutic regimen in children is doxorubicin and cisplatin (PLADO).
See Treatment and Medication for more detail.
Pathophysiology
The pathophysiology of hepatocellular carcinoma is not clearly understood; however, underlying liver dysfunction, especially cirrhosis, is a predisposing condition. In contrast to adults, most pediatric hepatocellular carcinomas arise de novo, without underlying liver abnormalities. [2] Karyotypic abnormalities are not common.
Although children and adolescents are unlikely to have chronic liver disease, congenital liver disorders increase the likelihood of developing hepatocellular carcinoma. These findings are suggestive of a multihit model of malignant transformation in hepatic tissue.
Etiology
Although no cause of pediatric hepatocellular carcinoma has been clearly elucidated, the risk factors for children and adolescents include the following:
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Hereditary tyrosinemia
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Congenital biliary atresia
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Urea cycle defects
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Severe iron overload (as occurs with thalassemia or sickle cell disease requiring chronic blood transfusion)
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Other forms of chronic cirrhosis or liver dysfunction
Acquired hepatitis C virus infection from blood product transfusions is an important risk factor because the risk of hepatocellular carcinoma is highest in patients with chronic hepatitis C and cirrhosis (2-8% per year). [3]
In areas of the world where hepatitis B and hepatitis C are endemic, the incidence is likely to be proportionally increased in children and adolescents.
Epidemiology
United States data
Primary liver tumors are uncommon in children and adolescents, accounting for about 0.5-2% of all neoplasms in these age groups. The annual incidence in children is approximately 0.5 cases per million population. Hepatocellular carcinoma is the second most common hepatic malignancy in children after hepatoblastoma. [4]
International data
The international incidence is highly associated with endemic hepatitis B exposure in areas such as Southeast Asia and sub-Saharan Africa. [1] In China, aflatoxin exposure has been linked to the development of hepatocellular carcinoma in the fifth, sixth, and seventh decades of life. [5]
Race-, sex-, and age-related demographics
In older adults, race may play a role in the development of hepatocellular carcinoma; however, excluding environmental factors from these determinations is difficult. Because the condition is so rare in children and adolescents, ethnic data are not readily available for these age groups. Most studies of hepatocellular carcinoma have involved patients of Asian descent.
Because most congenital forms of liver dysfunction (eg, urea cycle defects, storage diseases, hereditary hemochromatosis) are inherited in an autosomal recessive manner, the female-to-male occurrence ratio in children and adolescents is equal. After congenital hepatitis B virus infection, the lifetime risk of developing hepatocellular carcinoma is 50% for men and 20% for women. [6]
The incidence of pediatric hepatocellular carcinoma is lower in infants than in children and adolescents. The typical patient is an older school-aged child or adolescent, often with no preexisting diagnosis of cirrhotic liver disease. In patients with underlying hepatic dysfunction, the likelihood of developing hepatocellular carcinoma increases with age.
Prognosis
Morbidity/mortality
Morbidity and mortality directly correlate with the surgical resectability of the primary tumor. Although chemotherapy and radiation may improve the clinical course in selected patients, the overriding objective of these modalities is to render the tumor completely resectable.
Survival
Surgery is the mainstay of treatment in hepatocellular carcinoma; thus, factors such as multifocal tumor, vascular invasion, and presence of metastatic disease, which preclude surgical resection, are important prognostic factors for survival. [2, 7]
Liver transplantation may play a role in the treatment of children with advanced disease; however, survival rates have not exceeded 30% at 2 years' follow-up, and distant metastatic disease precludes this therapeutic strategy.
However, one study noted favorable outcomes in children with cirrhosis, hepatocellular carcinoma, and no extrahepatic disease after primary orthotopic liver transplantation. In 8 of 10 patients studied, no tumor recurrence was observed after a median follow-up of 4 years. [8]
Another study found that surgical resection resulted in superior patient survival compared with liver transplantation. Of 413 patients studied, 1- and 5-year survival rates were similar in both groups; however, survival rates were significantly improved in resected patients with hepatocellular carcinoma and model end-stage liver disease (MELD) scores of less than 10. Surgical resection should remain the first line of therapy for patients with hepatocellular carcinoma who are candidates for resection. [9]
Although chemotherapeutic and radiotherapeutic modalities are associated with numerous toxicities, even a temporary reduction in tumor size can greatly enhance a child's quality of life by alleviating tumor-associated pain and hepatic dysfunction.
Earlier claims that fibrolamellar carcinoma is associated with better outcomes than hepatocellular carcinoma have not been substantiated. [2]
Future directions
Identification of hepatocellular carcinoma in a young patient requires a careful evaluation for a preexisting underlying liver disorder. With careful staging and adjuvant therapy, many patients can be treated with intent-to-cure, especially if localized disease is identified in the initial staging workup.
This disease awaits the results of a well-organized clinical trial to best determine which chemotherapeutic agents, duration of therapy, and use of radiation might best benefit affected children. The formation of the Children's Oncology Group within the United States suggests that a clinical trial specifically designed to answer these questions may be forthcoming.
The Paediatric Hepatic International Tumour Trial (PHITT) is the largest clinical trial undertaken in pediatric patients with liver cancer. [10] This study is a collaboration between the European Study Group for Paediatric Liver Tumours, Children’s Oncology Group, and Japanese Study Group for Pediatric Liver Tumors and will be conducted at centers across several continents. Among the objectives of PHITT are to determine whether pediatric hepatocellular carcinoma (HCC) is biologically different from adult HCC and to develop a comprehensive and highly validated panel of diagnostic and prognostic biomarkers. [11]
