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Introduction
Background
Hepatocellular carcinoma (HCC) is an aggressive hepatic neoplasm that most commonly affects adults.
Nevertheless, children who are affected with biliary atresia, infantile cholestasis, glycogen-storage diseases,
and a wide array of cirrhotic diseases of the liver are predisposed to developing hepatocellular carcinoma.

The 2 pathological subtypes are classic hepatocellular carcinoma and fibrolamellar carcinoma. Although
surgical resection remains the mainstay of curative therapy, adjunctive chemotherapeutic and radiotherapeutic
strategies are also helpful. The presenting signs and symptoms, epidemiology, biology, and current therapeutic
strategies for hepatocellular carcinoma follow.

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.1 Karyotypic abnormalities are not common.
Although children and adolescents are unlikely to have chronic liver disease, congenital liver disorders increase
the chance of developing hepatocellular carcinoma. These findings are suggestive of a multihit model of
malignant transformation in hepatic tissue.

Frequency
United States

Primary liver tumors are uncommon in children and adolescents, accounting for approximately 0.5-2% of all
neoplasms in these age groups. Annual incidence in children is approximately 0.5 cases per million. This is the
second most common hepatic malignancy in children after hepatoblastoma.

International

The international incidence is highly associated with endemic hepatitis B exposure such as Southeast Asia and
sub-Saharan Africa. In China, aflatoxin exposure has been associated with the development of hepatocellular
carcinoma in the fifth, sixth, and seventh decades of life.

Mortality/Morbidity
Morbidity and mortality directly correlate with surgical resectability of the primary tumor. Although
chemotherapy and radiation control may improve in the clinical course, in selected patients, the overriding
objective of these modalities is to render the tumor completely resectable. (See Surgical Care for details.)

Race
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 adolescents and
children (0.5 cases per million population), ethnic data are not readily available for these age groups. Most
studies of hepatocellular carcinoma have involved patients of Asian descent.

Sex
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 infection the life time risk of developing
hepatocellular carcinoma is 50% for men and 20% for women.

Age
The incidence is lower in infants and higher in children and adolescents. The patient is usually an older school-
aged child or adolescent, often with no preexisting diagnosis of cirrhotic liver disease. In patients with
underlying liver dysfunction, the likelihood of developing the condition increases with age.

Clinical
History
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 for developing hepatocellular carcinoma (HCC). Most patients complain of 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 patients 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, vomiting, and weight loss.
Nearly 25% of patients present with jaundice.

In adults, chronic hepatitis secondary to alcohol exposure, infection with 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 comparison, children are far more likely to have inherited errors of
metabolism, such as tyrosinemia or urea cycle enzymopathies. Liver diseases that cause cirrhosis increase risk
for developing hepatocellular carcinoma (eg, alpha-1 antitrypsin deficiency).

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
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 location of the liver. Scleral icterus and other signs of jaundice
are frequent. The patient's history also may indicate weight loss, the extent of which may be observed during
the examination. In patients in whom metastatic disease to the lungs is in question, percussion of the lungs
may reveal a difference in density, suggesting a pleural effusion. Other painful sites discovered on the
examination should lead to radiographic imaging to determine the extent of malignant spread. This is
particularly true for bone pain at presentation.

Causes
Although no cause has been clearly elucidated, the risk factors for children and adolescents include a history of
hepatitis B or C, alpha-1 antitrypsin deficiency, hereditary tyrosinemia, Gaucher disease, congenital biliary
atresia, urea cycle defects, severe iron overload (as occurs with thalassemia or sickle cell disease requiring
chronic blood transfusion), or other forms of chronic cirrhosis or liver dysfunction. Acquired hepatitis C from
blood product transfusions is an important risk factor because the risk of hepatocellular carcinoma in patients
with chronic hepatitis C and cirrhosis is highest (2-8% per year).

In areas of the world where hepatitis B or C are endemic, the incidence is likely to be proportionally increased
in children and adolescents.

Differential Diagnoses

Amebiasis
Hepatoblastoma

Other Problems to Be Considered

Capillary hemangioma
Cavernous hemangioma
Metastatic tumor from a nonhepatic primary site

Workup
Laboratory Studies

• Laboratory profile in hepatocellular carcinoma (HCC) should include serologies for hepatitis B and C
and should evaluate the extent of hepatic dysfunction shown by the presence of altered liver function
tests, coagulopathies, or hyperammonemia. Tests for amebiasis and echinococcus may be helpful in
patients who may have these diseases.
• Approximately 50% of patients demonstrate elevated a-fetoprotein (AFP) levels and, to a lesser extent,
abnormal levels of beta human chorionic gonadotropin (b-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. A serum sodium, calcium level should also be obtained , due to association
of hypercalcemia and hyponatremia as part of 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

• Initial staging evaluation should include, but is not limited to, chest, abdomen, and pelvic CT scanning.
If surgical resection is anticipated, use 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 to develop hepatocellular carcinoma. Hepatocellular carcinoma has a typical radiographic
appearance of increased dye uptake during the arterial phase.
• Additional scans that may be helpful in the staging workup include a bone scan and MRI 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.

Procedures

• Liver biopsy is the most important procedure to consider when hepatocellular carcinoma is suspected
and when imaging combined with AFP do not provide a conclusive diagnosis.
• Needle biopsies are generally not recommended, especially in the setting of cirrhosis, because
overlooking the findings of malignantly transformed hepatocytes in a small specimen may be easy,
and the diagnosis may be missed. Seeding the biopsy tract with tumor during a needle biopsy is a
concern.
• If definitive tumor resection is planned, this biopsy should preferable be performed by the surgeon who
is eventually going to 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 specimen, 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 B12 binding protein are significantly elevated and rise and fall
concomitantly with successful or unsuccessful disease control. Claims that the fibrolamellar variant is
associated with a better prognosis compared with hepatocellular carcinoma have not been
substantiated, and contradicting evidence is noted.1
Staging

• 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 affected patient.
• The proposed staging system is as follows:
o Clinical group 1 - Complete resection of the tumor
o Clinical group IIa - Completely resectable after presurgical irradiation and/or chemotherapy.
o Clinical group IIb - Residual disease confined to either left or right lobes of the liver after
presurgical irradiation or chemotherapy.
o Clinical group III - Residual or unresectable tumor involves both left and right lobes of the liver
o Clinical group IIIb - Regional node involvement
o Clinical group IV - Distant metastatic spread (usually to the lungs and/or bone)