Gail E. Tomlinson and Howard M. Katzenstein
Liver tumors represent approximately 1% of all childhood cancers. There are approximately 100 to 150 new cases of liver cancer diagnosed in children each year in the United States.1 Hepatoblastoma is the most common malignant tumor of the liver and accounts for two thirds of all liver cancer in children.2 Hepatoblastoma occurs almost always in the very young child, with a mean age of onset of approximately 18 to 20 months and 95% of cases occurring before 5 years of age. The incidence of hepatoblastoma has approximately doubled over the past few decades.3 Hepatoblastoma is considered an embryonal tumor because histologically, tumor cells resemble cells seen in the developing liver.
Hepatocellular carcinoma is the primary liver malignancy in older children and adolescents. The male-to-female ratio is approximately 1.5:1 for hepatoblastoma and hepatocellular carcinoma. Other less common liver tumors include undifferentiated embryonal sarcoma, rhabdoid tumor, angiosarcoma, rhabdomyosarcoma of the biliary tract, cholangiocarcinoma, and other germ cell tumors. One third of all tumors of the liver in children turn out to be benign entities that include vascular tumors (hemangioendotheliomas), mesenchymal hamartomas, and adenomas.4
As with most types of pediatric cancers, the underlying causes are largely unknown; however, several genetic syndromes are associated with hepatoblastoma, and epidemiologic studies have provided some clues to their etiology.
Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by large birth weight, macroglossia, omphalocoele, and visceromegaly. Children with BWS are at risk of developing embryonal tumors including Wilms tumors, hepatoblastoma, neuroblastoma, and adrenocorticocarcinoma. A national registry of children with BWS reports that the risk of children with BWS developing hepatoblastoma is 2280-fold higher than the general population and that the risk for hepatoblastoma was significantly higher than for Wilms or any other type of cancer in children with BWS. Screening children with BWS with periodic abdominal ultrasounds and serum alpha-fetoprotein levels every 3 months during the first decade of life may be associated with detection at an early stage and is therefore recommended.5
Familial adenomatous polyposis (FAP), an autosomal dominant syndrome characterized primarily by polyp growth in the colon which begins in adolescence and without intervention progresses to colon cancer, is also associated with a high risk of hepatoblastoma.6 Mutation in the causative adenomatous polyposis coli (APC) gene can be readily detected in children with hepatoblastoma who have a family history of early onset colon cancer. These children are clearly at risk for polyps and colon cancer and need follow-up with lifelong surveillance. It is less clear how great the risk of carrying such a cancer predisposition is in other children with hepatoblastoma without a clear history of FAP, but it has been suggested that children with hepatoblastoma be screened for APC mutations and also that asymptomatic children from FAP families be screened for mutation carrier status and for hepatoblastoma if APC mutations are detected.
In addition to BWS and FAP, several other syndromes have been reported in association with hepatoblastoma, including Simpson-Golabie-Behmel syndrome and trisomy 8. Multiple uncommon genetic syndromes associated with hepatic cirrhosis are also associated with the development of hepatocellular carcinoma. These include progressive familial intrahepatic cholestasis that presents with neonatal hepatic cirrhosis and is associated with mutation of the ABCB11 gene, Allagille syndrome associated with congenital heart disease and intrahepatic cholestasis, hereditary tyrosinemia, and glycogen storage disease. In addition, children with Fanconi anemia who are treated with androgenic steroids are at risk of developing hepatocellular carcinoma.
By far the strongest risk factor associated with the risk of developing hepatocellular carcinoma is infection with hepatitis B and C viruses. In areas of Asia where infection with hepatitis B and C has been historically high, hepatocellular carcinoma has accounted for the majority of malignant liver tumors in children. With the introduction of the hepatitis B vaccine, rates of hepatocellular carcinoma have been shown to decrease significantly.7
Several studies demonstrated an increased risk of hepatoblastoma in children of parents who smoke.8 An early study that surveyed parental occupations in children with hepatoblastoma determined a higher incidence of parental occupational history of exposure to welding, petroleum products, and paints and pigments.
A history of prematurity is associated with an increased risk of hepatoblastoma, and it has been demonstrated that the risk is inversely related to birth weight.9 The risk associated with prematurity, along with the increased survival of low birth weight infants over recent decades may contribute to the overall increased incidence of liver tumors observed in children over the past 2 decades. It is unclear, however, as to whether the increased risk in expremature infants is related to disruption of critical developmental pathways by premature birth, key exposures in the neonatal nursery, increased sensitivity of the neonatal liver, or a combination of these factors.
Hepatoblastoma occurs most often in the right lobe of the liver. Upon inspection either by imaging or by gross pathology, the tumor appears most often as a single expansile mass. Histological examination shows hepatoblastomas to be composed of primitive epithelial cells that resemble the developing liver. Most hepatoblastomas are composed of a mixture of cells resembling the fetal and embryonal liver (Table 458-1).
Table 458-1. Risk Factors for Malignant Liver Tumors in Children
Liver tumors in children of all ages most commonly present as an asymptomatic mass, although occasionally they are identified incidentally in patients with other symptoms, such as abdominal pain, nausea and vomiting, fever, and weight loss. Symptoms may sometimes indicate tumor rupture. The vast majority of children will have no evidence of underlying liver disease as jaundice, ascites, and abnormal liver function tests are usually not observed at presentation. Hepatoblastoma should be considered in patients with predisposing conditions such as a history of prematurity, hemihypertrophy, Beckwith-Weidemann syndrome, or a history of familial colon cancer. Hepatocellular carcinoma most commonly presents in an asymptomatic patient but sometimes arises in patients with a history of hepatitis B or C infection, cirrhosis, or other underlying disorders, such as tyrisonemia, galactosemia, glycogen storage disease, and –1 antitrypsin deficiency. Less common malignancies like undifferentiated sarcoma of the liver, rhabdoid tumor of the liver, and angiosarcoma do not have a pathognomonic presentation. Malignant involvement of the liver is more common as a metastatic site of neuroblastoma, Wilms tumor, sarcomas, lymphoma, and leukemia.
Benign tumors may be asymptomatic when diagnosed incidentally as a palpable mass or may present with nonspecific abdominal complaints. Hemangiomas and hemangioendotheliomas typically present in infancy and may present with congestive heart failure or consumptive coagulopathy as part of the Kassa-bach-Merritt syndrome. Adenomas may occur in teenage girls with a history of oral contraceptive use. Mesenchymal hamartomas and focal nodular hyperplasia are other benign entities observed in childhood.
DIAGNOSIS AND WORKUP
Anemia and thrombocytosis are nonspecific findings sometimes observed at presentation. Abnormalities of liver function tests are usually mild, if present, with the exception of patients with known underlying liver disease. Serum alpha-fetoprotein (AFP) levels should be determined on all patients with liver tumors and when elevated are usually a sign of malignant disease. Because liver tumors are common in the first year of life, AFP levels must be evaluated using age-appropriate normals for infants in whom AFP levels are high and decline to the adult normal during the first year of life. AFP levels are elevated in most hepatoblastoma patients and approximately half of hepatocellular carcinoma patients at diagnosis. AFP levels are normal in a very small portion of high-risk hepatoblastoma patients, fibrolamellar hepatocellular carcinoma, undifferentiated sarcoma, and rhabdoid tumor of the liver.
Ultrasound is usually the first radiographic study performed to verify the clinical findings of a liver or abdominal mass. The characteristic appearance of a vascular tumor on ultrasound can make the diagnosis of a hemangioma. Computerized tomography (CT) scan or magnetic resonance imaging (MRI) of the abdomen provide a more detailed image of the tumor, including whether tumors are unifocal or multifocal as well as whether the tumor is potentially resectable. CT scan of the chest should be performed preoperatively in all patients suspected of malignant disease as the lungs are the primary site of metastatic disease. Angiographic studies may be needed to define the vascular blood supply of the liver in determining whether or not a tumor is resectable. Metastatic disease to bone, bone marrow, and brain are extremely rare, and imaging and evaluation of these sites should be considered if clinical symptoms suggest possible involvement.
The surgical resectability of the tumor and the lack of metastatic disease are the most important prognostic variables in both hepatoblastoma and hepatocellular carcinoma. The PRETEXT (pretreatment extent of disease) system divides the liver into 4 segments, and the number and pattern of affected segments are used to guide resectability of hepatoblastoma and can predict outcome and guide therapy.10 Tumor pathology can also be predictive of outcome. Patients with pure fetal histology hepatoblastoma that is completely resected have an excellent outcome, whereas patients with small cell undifferentiated histology do poorly and are often associated with a low AFP (< 100 ng/mL) at diagnosis, another unfavorable prognostic feature. The fibrolamellar variant of hepatocellular carcinoma has been thought by some to confer a survival advantage. However, the pediatric data demonstrated that although these patients may have a slightly prolonged overall survival, their overall outcome is no different from other hepatocellular carcinoma patients.11 The decline of AFP is important as patients with hepatoblastoma who have a > 1 log decline over the entire course of therapy have an improved outcome.12 Unfortunately, the rate of decline of AFP has not been able to identify patients at increased risk of earlier relapse during the course of treatment.
Surgical resection is the hallmark of curative therapy for both hepatoblastoma and hepato-cellular carcinoma. Liver transplantation is a viable option for surgical resection and offers curative therapy for both of these diseases as well.13,14 Because of the rarity of liver tumors, it is important to consider referral to surgeons with expertise or to liver transplant centers as soon as possible in any patient who is considered to have unresectable disease at diagnosis. Only about half of children with hepatoblastoma and one third of patients with hepatocellular carcinoma can have their tumors resected at diagnosis. Patients who do not have a complete resection at diagnosis typically receive a longer course of chemotherapy treatment and therefore are at greater risk for long-term side effects. The role and importance of surgical resection of metastatic sites is unknown and needs to be studied in future trials. However, extrahepatic disease is a contraindication to liver transplantation; therefore, the aggressive removal of metastatic foci should be used to render a patient free of extrahepatic disease and eligible for liver transplantation.
Chemotherapy is effective in improving the resectability of patients with hepatoblastoma. The regimens used in North America have differed from treatment protocols used in Europe. Cisplatin and doxorubicin are uniformly thought to be the most effective agents. Cisplatin, 5-flourourcil, and vincristine have produced excellent outcomes in the one third of patients with low-risk disease, resectable at diagnosis. The role of doxorubicin appears to be in patients with disease that is unresectable or metastatic. Other studies have included carboplatin, ifosfamide, and etoposide in treatment regimens, but there is little single-agent data establishing the efficacy of these agents. The rarity of liver tumors has hampered the ability to find novel efficacious drugs in the typical phase I and II setting. Irinotecan and oxaliplatin are 2 newer agents that may have some utility in the treatment of malignant liver tumors.
Chemotherapy has been used in the treatment of hepatocellular carcinoma, but in most patients it has been ineffective in making a tumor resectable or eradicating metastatic disease. The same chemotherapy drugs used for the treatment of hepatoblastoma have often been used for hepatocellular carcinoma in combined trials but with little efficacy.14,15 Adult trials have also incorporated interferon without much additional benefit. Because of the ineffectiveness of chemotherapy, exploring all surgical options and rapid consideration of liver transplantation should be the approach for hepatocellular carcinoma so that the tumor does not spread during periods of using ineffective chemotherapy. Pediatric hepatocellular carcinoma should not be considered in the same manner as adult hepatocellular carcinoma, and separate transplant criteria need to be established for pediatric patients who develop the disease at a different time in life, often arise from different etiologies, and have a different spectrum of underlying comorbidities that may affect the outcome. Novel therapeutic approaches are desperately needed to improve the resectability of hepatocellular carcinoma and overall survival. Tyrosine kinase inhibitors are a new class of agents that have shown some early promise.
Interventional procedures such as chemo-embolization, radio frequency ablation, and cryosurgery have shown some ability to induce liver tumor shrinkage but are used fairly rarely in children.16
Outcomes in patients with undifferentiated sarcoma of the liver are improved with the combination of surgical resection and sarcoma-type therapy both in the pre- and postoperative settings. Rhabdoid tumor of the liver shows some chemoresponsiveness with ifosfamide being identified as potentially the most active drug, but therapeutic regimens used to treat this aggressive malignancy have achieved suboptimal results, and surgical resection is also critical for achieving a cure. Radiation therapy has not routinely been used in the treatment of malignant liver tumors but has been used in palliative care settings.
Hemangiomas and hemangioendotheliomas may require treatment if they are causing symptoms. Surgical resection should be considered first if possible, but if not feasible then steroids are typically first-line therapy. Interferon may also be effective but has shown some significant side effects, particularly permanent spastic dyplegia, in infants which cautions against routine use early in life.
Patients with hepatoblastoma or hepatocellular carcinoma that can be resected do well, whereas those who remain unresectable do poorly. Chemotherapy can render some hepatoblastoma tumors resectable, but this is rarely the case in patients with hepatocellular carcinoma. Metastatic disease portends a poor outcome in all primary malignant liver tumors.