Pediatric Hepatocellular Carcinoma

Updated: Mar 12, 2020
Author: Paulette Mehta, MD, MPH; Chief Editor: Max J Coppes, MD, PhD, MBA 


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.


Laboratory studies

The following studies are useful in the workup of pediatric hepatocellular carcinoma:

  • Serologies for hepatitis B and C
  • Liver function tests
  • Coagulation studies
  • Measurement of serum ammonia level
  • Measurement of α-fetoprotein (AFP) and, to a lesser extent, β-human chorionic gonadotropin (β-hCG) levels
  • 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:

  • Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the liver to determine tumor margins and vasculature if surgical resection is anticipated.
  • Ultrasonography to screen patients at high risk for hepatocellular carcinoma.
  • Bone scanning and MRI of the brain to determine the status of metastatic spread to the skeleton and neuraxis, respectively.
  • Chest radiography to monitor pulmonary metastatic disease.
  • Venous Doppler studies to exclude the possibility of deep venous thrombosis if extremity swelling, edema, or pain is noted.


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.


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.


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.


Although no cause of pediatric hepatocellular carcinoma has been clearly elucidated, the risk factors for children and adolescents include the following:

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.


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.



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.


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]




Elements to ascertain include a prior history of hepatitis B or hepatitis C, chronic cirrhosis, or other diseases that tend to induce liver dysfunction. Co-infection with human immunodeficiency virus (HIV) may further enhance a patient's risk of developing hepatocellular carcinoma (HCC).

Patients typically report abdominal pain, weight loss, and diminished appetite. In patients with a history of chronic liver disease, a change in routine symptoms may indicate the presence of a liver tumor.

Most children with hepatocellular carcinoma present with a slowly enlarging, right upper-quadrant mass that may be found during a routine physical examination, brought to medical attention by the patient, or discovered by the patient's parents. Many children also experience localized pain, nausea, and vomiting. Nearly 25% of patients present with jaundice.[12]

In adults, chronic hepatitis secondary to alcohol exposure, viral hepatitis, and hereditary hemochromatosis are predisposing factors. Aflatoxins and other environmental factors also are likely to play a role in the pathogenesis in adults. In contrast, children are far more likely to have inherited errors of metabolism, such as tyrosinemia or urea cycle enzymopathies. Liver diseases that cause cirrhosis (eg, alpha-1 antitrypsin deficiency) increase the risk of developing hepatocellular carcinoma.

Children with biliary atresia, chronic cholestasis, or glycogen-storage diseases are at increased risk. Symptoms can be masked in children with preexisting hepatic diseases, and, accordingly, a change in a chronic disease pattern merits careful consideration for the possibility of a new malignancy.

Physical Examination

The physical examination often reveals abnormalities attributable to a hepatic tumor. In advanced cases, or when the primary tumor is large, the liver may be palpable below the right costal margin. In addition, deep palpation often reveals pain, especially over the site of the liver. Scleral icterus and other signs of jaundice are frequently present. The patient's history may indicate weight loss, the extent of which may be observed during the examination.

In patients in whom metastatic disease of the lungs is suspected, percussion of the lungs may reveal a difference in density; this finding suggests a pleural effusion. Other painful sites discovered on the examination should lead to radiographic imaging to determine the extent of malignant spread, particularly if the patient has bone pain at presentation.



Differential Diagnoses



Laboratory Studies

The laboratory profile in hepatocellular carcinoma (HCC) should include serologies for hepatitis B and C. Additionally, the extent of hepatic dysfunction, as demonstrated by the presence of altered liver function tests, coagulopathies, or hyperammonemia, should be evaluated. Tests for amebiasis and echinococcosis may be helpful in patients who are at risk for these diseases.

Approximately 50% of patients have elevated α-fetoprotein (AFP) levels and, to a lesser extent, abnormal levels of β-human chorionic gonadotropin (β-hCG). These serum markers of fetal hepatocytic function are useful not only for diagnostic purposes, but also for monitoring tumor response to therapy.

Rarely, polycythemia occurs because of extrarenal erythropoietin production by the malignantly transformed hepatocytes. Serum sodium and calcium levels should also be obtained, because of the association of hyponatremia and hypercalcemia with the paraneoplastic syndrome secondary to excess production of parathyroid hormone–related protein (PTH-rP) and antidiuretic hormone (ADH).

Vitamin B12–binding protein levels may be elevated in children with the fibrolamellar variant of hepatocellular carcinoma. These levels may be followed as markers of disease burden.

Imaging Studies

The initial staging evaluation should include, but is not limited to, chest, abdomen, and pelvic computed tomography (CT) scanning. Hepatocellular carcinoma has a typical radiographic appearance of increased dye uptake during the arterial phase.

If surgical resection is anticipated, use magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the liver to best determine tumor margins and vasculature. Ultrasonography may be helpful to screen patients at high risk for hepatocellular carcinoma.

Additional scans that may be helpful in the staging workup include a bone scan and an MRI scan of the brain to determine the status of metastatic spread to the skeleton and neuraxis, respectively.

Chest radiography is an important tool to monitor pulmonary metastatic disease and, when appropriate, malignant pleural effusions.

Because affected patients may have underlying hepatic dysfunction or deficits in liver function because of bulky tumor burden, deficiencies in coagulation function may occur. In this setting, deep venous thromboses may complicate the patient's course. If extremity swelling, edema, or pain is noted, venous Doppler studies may be performed to exclude the possibility of deep venous thromboses.

Chou et al evaluated the test performance of imaging modalities and found that CT and MRI have higher sensitivity than ultrasonography without contrast for detection of hepatocellular carcinoma and that the sensitivity of MRI is higher than that of CT. The investigators also found that for evaluation of focal liver lesions, the sensitivities of ultrasonography with contrast, CT, and MRI for hepatocellular carcinoma are similar.[13]



Liver biopsy is the most important procedure to consider when hepatocellular carcinoma is suspected and when imaging studies combined with the AFP level do not provide a conclusive diagnosis.

Needle biopsies are generally not recommended, especially in the setting of cirrhosis, because it may be easy to overlook the findings of malignantly transformed hepatocytes in a small specimen, and the diagnosis may be missed. Seeding the biopsy tract with tumor during a needle biopsy is also a concern.

If definitive tumor resection is planned, the biopsy should preferably be done by the surgeon who will eventually perform the hepatectomy.

Histologic Findings

Histologic examination of tumor tissue in children with classic hepatocellular carcinoma reveals large polygonal cells with central nuclei, frequent mitotic figures and, often, invasion into surrounding hepatic tissue or adjacent abdominal structures. Areas of hemorrhage and necrosis, which may complicate the interpretation of needle biopsy specimens, are common.

A distinct histologic variation, termed fibrolamellar carcinoma, occurs with relatively high frequency in children and young adults. Tumor cells in this subtype are circumscribed characteristically by bundles of acellular collagen, creating either trabeculae or large nodules of tumor islands. Interestingly, in the fibrolamellar variant, levels of vitamin B12-binding protein are significantly elevated and rise and fall concomitantly with successful or unsuccessful disease control. Claims that the fibrolamellar variant has a better prognosis than hepatocellular carcinoma have not been substantiated, and contradicting evidence is available.[2]


Although no staging system has been uniformly adopted, a staging method proposed by the Children's Cancer Group and Southwest Oncology Group incorporates tumor bulk with surgical resection. The staging and classification for hepatocellular carcinoma draw on location, resectability, and response to any presurgical therapy given to the patient.

The proposed staging system is as follows:

  • Clinical group I: Complete resection of the tumor.

  • Clinical group IIa: Completely resectable after presurgical irradiation or chemotherapy.

  • Clinical group IIb: Residual disease confined to either left or right lobe of the liver after presurgical irradiation or chemotherapy.

  • Clinical group IIIa: Residual or unresectable tumor involves both left and right lobes of the liver.

  • Clinical group IIIb: Regional node involvement.

  • Clinical group IV: Distant metastatic spread (usually to the lungs or bone).


Medical and Surgical Care

Medical care

Hepatocellular carcinoma (HCC) is most easily treated in its earliest stages. Because patients often present with advanced disease, for which treatment modalities are limited at best, emphasis has been placed on screening for hepatocellular carcinoma in at-risk patients. Patients with chronic hepatitis B have a relative risk of developing hepatocellular carcinoma that is 100-fold greater than that of uninfected persons.[6] Thus, patients with chronic hepatitis B or hepatitis C are recommended to have an α-fetoprotein level obtained each year. If the level is 29 ng/mL or higher, continued surveillance is recommended at least annually.

Ultrasonography is also recommended at similar intervals for patients who are at risk. Suspicious lesions warrant biopsy; however, in patients who are found to have a lesion larger than 2 cm and an α-fetoprotein level in excess of 200 ng/mL, biopsy may not be necessary because the likelihood of hepatocellular carcinoma is virtually 100% in these cases.

Surgical care

Surgical resection must be undertaken by a surgeon familiar with liver tumor management. Underlying coagulation defects may complicate the surgery. Pathologic analysis that shows no remaining cells is the goal of resection. Although the liver is capable of regeneration, overly aggressive resection may predispose the patient to liver failure and death. Transarterial embolization and chemoembolization have been used with limited success.


Management by a pediatric oncology health care team is required. This team should include individuals from the following areas of specialty:

  • Diagnostic radiology
  • Infectious diseases
  • Metabolic disorders
  • Nursing
  • Pharmacy
  • Psychiatry
  • Radiation oncology
  • Social work
  • Surgery

Further Inpatient Care

Follow-up of patients with hepatocellular carcinomas (HCCs) varies. For the child who requires only surgery, good postoperative management of the surgical site and assessment of liver function tests may be sufficient. If the α-fetoprotein or vitamin B12–binding protein levels are abnormal, these markers of tumor burden, in addition to previously abnormal imaging studies, necessitate close follow-up monitoring. Patients with abnormal scans also require follow-up monitoring, usually at 2- to 3-month intervals or sooner if clinically indicated.

Grade III to grade IV mucositis, grade III to grade IV myelosuppression, febrile neutropenia, anorexia, and cachexia most likely occur in the patient who receives chemotherapy. These problems require hospitalization and management by a team of individuals who are versed in the toxicities of high-dose chemotherapy.

Diet and Activity


Vitamin K supplementation may help patients with a coagulation defect.


Activity depends on the overall health of the individual after surgery or chemotherapy.



Medication Summary

Unfortunately, complete surgical resection of hepatocellular carcinoma (HCC) is possible in fewer than 30% of children at diagnosis. Hepatocellular carcinoma is only partially chemosensitive; thus, chemotherapy and radiation have limited efficacy as adjuvant or neoadjuvant therapy, although one or both are often used to temporarily control disease.

In patients who are chemosensitive, chemotherapy may allow a meaningful reduction in tumor size before surgical control, in some cases rendering unresectable tumors resectable. Several combination chemotherapy regimens have been used.

One widely used regimen in children is doxorubicin and cisplatin (PLADO). The resectability rate and, hence, the survival rate are higher among children who respond to neoadjuvant chemotherapy compared with children who do not.[2]

Alternative regimens include the following:

  • Ifosfamide, carboplatin, and etoposide (ICE)

  • 5-Fluorouracil in combination with vincristine, doxorubicin, and cyclophosphamide[14]

  • Gemcitabine and carboplatin (potentially active against hepatocellular carcinoma)

Trials in adults have demonstrated the efficacy of tyrosine kinase inhibitors, such as sorafenib, in patients with locally advanced hepatocellular carcinoma. The efficacy and safety of these agents in children remain to be determined.[15, 16]

Chemoembolization into isolated branches of the hepatic artery may benefit patients with nonmetastatic but unresectable or recurrent tumor. This is the more commonly used approach in adults in whom systemic chemotherapy has had essentially no impact on disease-free survival.

Because the liver plays a key role in chemically inactivating many chemotherapeutic agents, the child with an underlying liver disease or extensive hepatic involvement with hepatocellular carcinoma warrants careful observation. Numerous reports associate hepatic coma with chemotherapy initiation.

Antineoplastic agents

Class Summary

Chemotherapy is used for tumor size reduction to allow for subsequent resection, in the setting of positive resection margins after surgery, and as palliation in the setting of advanced regional or metastatic disease.

When given postoperatively, chemotherapy is usually initiated approximately 4 weeks after surgery to allow liver regeneration. A minimum of 2 weeks should pass after surgery before administration of cytotoxic agents.

These drugs have achieved partial response rates in patients. Although suggested doses are supplied, these doses widely vary among protocols, and the information cannot be used to design patient treatment plans.

Doxorubicin (Adriamycin, Rubex)

An anthracycline antibiotic derived from Streptomyces peucetius susp caesius. Doxorubicin is a DNA-intercalating agent that interferes with DNA and RNA synthesis.

Cisplatin (Platinol)

A planar, inorganic compound that interacts with DNA. The mechanism of action is to cause intrastrand crosslinks that interfere with replication.


Prodrug inhibits thymidine synthesis and is incorporated into RNA and DNA. Specific to the S phase of the cell cycle.


Class Summary

Antineoplastic induced vomiting is stimulated through the chemoreceptor trigger zone (CTZ), which then stimulates the vomiting center (VC) in the brain. Increased activity of central neurotransmitters, dopamine in CTZ, or acetylcholine in VC appears to be a major mediator for inducing vomiting. Following administration of antineoplastic agents, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With serotonin release and subsequent binding to 5-HT3–receptors, vagal neurons are stimulated and transmit signals to the VC, resulting in nausea and vomiting.

Antineoplastic agents may cause nausea and vomiting so intolerable that patients may refuse further treatment. Some antineoplastic agents are more emetogenic than others. Prophylaxis with antiemetic agents before and following cancer treatment is often essential to ensure administration of the entire chemotherapy regimen.

The 5-HT antagonists are highly effective at controlling cisplatin-induced nausea.

Ondansetron (Zofran)

Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin).