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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 139AHepatic Tumors

, MD.

Primary tumors of the liver in infants and children are rare, comprising only 1.1% of malignancies in children younger than 20 years of age.1–3 In the United States, 100 to 150 children younger than 20 years are diagnosed with a malignant hepatic tumor each year. Hepatoblastoma accounts for 66% of these tumors and hepatocellular carcinoma for most of the remaining cases.

The incidence of malignant liver tumors in children < 15 years of age has increased from 1.4 per million in 1975 to 1979 to 1.7 per million in 1990 to 1995. For hepatoblastoma, the incidence rose from 0.8 per million to 1.5 per million during those periods. In contrast, the incidence for hepatocellular carcinoma decreased from 0.6 per million to 0.2 per million during the same periods. In Caucasian children the rate is 1.6 per million, compared with 1.3 per million in African American children. Table 139A.1 describes the incidence, congenital anomalies, and environmental factors associated with hepatoblastoma and hepatocellular carcinoma.1–3

Table 139A.1. Epidemiology of Hepatoblastoma and Hepatocellular Carcinoma.

Table 139A.1

Epidemiology of Hepatoblastoma and Hepatocellular Carcinoma.

Loss of heterozygosity of chromosome 11p15 has been described in children with hepatoblastoma, Wilms’ tumor, rhabdomyosarcoma, and in patients with Beckwith-Wiedemann syndrome (BWS).4 The localization of the insulin-like growth factor 2 (IGF-2) gene in chromosome 11p15 suggests that overexpression of this gene is associated with the somatic overgrowth of BWS and the development of embryonal tumors, including hepatoblastoma.5 The association between very low birth weight and hepatoblastoma has been described, suggesting that factors associated with prematurity and its treatment may play a role in the development of hepatoblastoma.1

Hepatocellular carcinoma appears to be a complication of previous hepatic damage due to metabolic or inflammatory disorders (see Table 139A.1). Prolonged exposure to anabolic steroids, toxin-contaminated foods (aflatoxins), as well as other potential hepatic carcinogens (pesticides, vinyl chloride) have also been associated with the development of hepatocellular carcinoma.3,6 As demonstrated in Taiwan during the past decade, universal hepatitis B immunization prevents the carrier state in children and can dramatically reduce the incidence of hepatocellular carcinoma in this population.7

Pathologic Characteristics


Hepatoblastoma is an embryonal tumor containing hepatic epithelial parenchyma. It is most often unifocal, nonencapsulated, and arises in a noncirrhotic liver. It most commonly involves the right lobe but can be multi-centric in origin in a small number of patients.8 Approximately 20% of the patients have developed metastatic disease at the time of diagnosis, with the lungs and intra-abdominal lymph nodes being the most common sites involved. The gross appearance is of a multi-nodular mass with areas of necrosis and hemorrhage.

Microscopically, hepatoblastoma can be of either pure epithelial or mixed epithelial-mesenchymal histology.9 The pure epithelial type hepatoblastomas contain either fetal or embryonal cells or an admixture of the two. Mixed epithelial-mesenchymal tumors contain mesenchymal (osteoid, chondroid) or squamous elements and, often, evidence of extramedullary hematopoiesis.

Patients with completely resected hepatoblastoma at diagnosis and with pure fetal histology have a much better outcome when compared with all other histologic types.9 In patients with residual disease after initial surgery (advanced stages) the presence of mitosis is associated with a poor prognosis, while the presence of undifferentiated mesenchymal or squamous elements is associated with an improved survival.9

Hepatocellular Carcinoma

Hepatocellular carcinoma in children has a greater tendency to involve both lobes of the liver and is often extensively invasive or multi-centric; therefore, resection is rarely feasible. It shows more areas of hemorrhage and necrosis than hepatoblastoma. The pattern of metastatic dissemination is similar to that for hepatoblastoma.10–12

Microscopically, hepatocellular carcinoma in children is similar to that observed in adults. A distinctive fibrolamellar variant of hepatocellular carcinoma occurs in noncirrhotic livers of adolescents and young adults and has been reported to be associated with a better chance of survival.11

Clinical Presentation and Diagnosis

Enlargement of the abdomen due to an asymptomatic mass in an otherwise healthy child is the most common presentation. Anorexia, weight loss, vomiting, and abdominal pain are usually associated with advanced disease or hepatocellular carcinoma. Rarely, it may present as an acute abdominal crisis secondary to tumor rupture. Jaundice is extremely rare. Infrequent features include hemihypertrophy and other features associated with BWS. It can also present with precocious puberty secondary to the secretion of beta-human chorionic gonadotropin (β-LCG). Mild normochromic-normocytic anemia is commonly seen, and thrombocytosis is a frequent finding. Occasionally, hepatic enzymes can be elevated; however, elevation of bilirubin is infrequent.

Alpha-fetoprotein (AFP) is the most valuable laboratory test for the diagnosis and monitoring of hepatic tumors. AFP is a normal globulin present during fetal life, synthesized in the liver and fetal yolk-sac. Elevated levels of AFP are seen during the newborn period, and adult levels are reached by about 1 year of age; age must, therefore, be taken into consideration when interpreting AFP results. The biologic half-life of AFP is 5 to 7 days. The level of AFP can be utilized to monitor response to therapy and disease recurrence.13 Lectin-affinity immunoelectrophoresis can differentiate AFP derived from hepatoblastoma from that derived from benign inflammatory or regenerative hepatic disease.14 Levels of carcinoembryonic antigen (CEA) and ferritin can also be increased in hepatocellular carcinoma.15 The fibrolamellar variant of hepatocellular carcinoma can be associated with an abnormality of the vitamin B12-binding protein, which can occasionally be used to monitor disease status and response to therapy.15

Plain radiographs of the abdomen frequently demonstrate the presence of a right upper quadrant mass, and calcifications may be noted in approximately 6% of the malignant tumors. Ultrasonography is a reliable and noninvasive imaging technique for establishing the presence of an intrahepatic mass. It aids in differentiating solid from cystic masses and in determining the presence of vascular extension. Computed tomography (CT) is the most commonly used imaging study to determine both local and distant extent of tumor involvement. Due to the multi-planar nature of magnetic resonance imaging (MRI), this technique is rapidly replacing CT as a predictor of tumor resectability. Features, such as the presence of multiple lesions and portal hypertension, may increase the suspicion of hepatocellular carcinoma.

Tumor staging is frequently used to determine prognosis and planning therapy. In North America, the most widely used staging system is based on the extent of tumor and surgical resectability.16 The International Society of Pediatric Oncology (SIOP) has developed a preoperative staging system that permits a radiologic staging, using the main veins and bile ducts to identify the number of liver sectors involved by the tumor.17



Cure of children with liver tumors is only possible when complete surgical excision is achieved. Unfortunately, complete excision is feasible in less than 60% of patients with hepatoblastoma at the time of diagnosis. Moreover, due to the frequent extension to both lobes of the liver and its multi-centric origin, complete surgical excision is seldom accomplished for patients with hepatocellular carcinoma. Morbidity and mortality from liver resection ranges from 10 to 25% in various series, mainly due to hemorrhage and complications of massive transfusion.18 New surgical techniques and careful patient management during and after surgery have minimized the risks associated with liver resection.

Liver Transplantation

Orthotopic liver transplantation has been employed as a means of achieving aggressive surgical control of primary hepatic tumors. Overall survival for patients undergoing liver transplantation for all types of hepatic malignancies range from 20 to 40%, with a tumor recurrence rate of approximately 50%.19–21 Survival for children with hepatoblastoma has ranged from 50 to 83% and less than 50% for those with hepatocellular carcinoma.22–25 Despite these somewhat encouraging results, problems with donor shortage, life-long immunosuppression following transplantation, and risks of tumor recurrence or development of a second malignancy have continued to limit the use of liver transplantation for children with unresectable malignant tumors.26


Chemotherapy has become an important part of the therapy for patients with hepatic tumors. It has been used as adjuvant therapy for patients who undergo complete tumor resection at the time of diagnosis, to induce tumor shrinkage preoperatively in those tumors considered unresectable, or when primary resection is hazardous.

Adjuvant chemotherapy for patients who initially undergo surgical resection of the tumor (stage I) was initially documented to be of benefit in a report by Evans and colleagues27 Only 1 of 16 patients who received adjuvant chemotherapy developed distant metastasis, compared with 7 of 11 patients who had surgery alone. The 3-year disease-free survival was 94% and 36%, respectively. Most recently, cisplatin-based chemotherapy has resulted in greater than 90% survival for patients with stage I or II disease.16,28

Chemotherapeutic regimens—using cisplatin/doxorubicin, with or without ifosfamide;16,29,30 cisplatin/vincristine/5-fluorouracil;28 or carboplatin/epirubicin31—have been used preoperatively in children with unresectable hepatoblastoma, which has resulted in tumor resectability in more than 75% of the patients and an overall survival of approximately 65%.

The recently closed Pediatric Intergroup Hepatoma Study (CCG 8881/POG 8945) randomized patients with hepatoblastoma and hepatocellular carcinoma to receive treatment with cisplatin/vincristine/5-fluorouracil or cisplatin/doxorubicin.32,33 The overall survival and disease-free survival for patients with hepatoblastoma was 71% and 63%, respectively. There was no statistically significant difference between the two therapeutic regimens (Table 139A.2). The regimen with cisplatin/vincristine/5-fluorouracil, however, resulted in considerably less toxicity. Children with completely excised tumor (stage I) of pure fetal histology on this study received therapy with doxorubicin alone. All these patients are alive without evidence of disease. This evidence suggests that no further therapy may be required for this small group of patients.28

Table 139A.2. Intergroup Hepatoma Study (CCG 8881/POG 8945).

Table 139A.2

Intergroup Hepatoma Study (CCG 8881/POG 8945).

Patients with hepatocellular carcinoma have consistently been treated according to therapeutic trials for hepatoblastoma, despite the belief that the two malignancies are completely different. All patients with hepatocellular carcinoma entered into the Intergroup Hepatoma Study who had complete tumor excision followed by adjuvant cisplatin-based chemotherapy survived, compared with only 12 of 33 patients treated before the consistent use of adjuvant chemotherapy.18,33 In contrast, survival for patients with advanced-stage hepatoblastoma was uniformly poor, with therapy failing in 23 of 26 patients with stage III disease and in 12 of 13 patients with stage IV disease.


Survival remains dismal for children with hepatic malignancies whose tumors remain unresectable after systemic chemotherapy. Alternative therapeutic approaches, such as chemoembolization, may induce surgical resectability and improve the outcome for these children. Chemoembolization refers to the intra-arterial coadministration of chemotherapeutic and vascular occlusive agents to treat malignant disease. Recent studies have demonstrated the efficacy and safety of chemoembolization for the treatment of hepatocellular carcinomas34,35 and hepatic metastasis of colo-rectal carcinomas.36 Chemoembolization can provide a chance of tumor resection for those patients with hepatocellular carcinoma who were initially judged to be unresectable37–39 and is efficacious as a strategy to minimize the risk of tumor progression before orthotopic liver transplantation.40

Chemoembolization has been shown to be effective in children.41–43 In a recent study, 11 children (6 hepatoblastoma, 3 hepatocellular carcinoma, 2 undifferentiated sarcoma) with unresectable tumors after systemic therapy were treated with chemoembolization.44 Surgical resection (complete or microscopic) was later feasible in 5 patients, and 3 remain alive with no evidence of disease for > 3 years. Repetitive courses of chemoembolization were given and were well tolerated. Transient elevation of liver function tests, coagulopathy, fever, nausea and vomiting, and abdominal pain were the most common toxicities. Hepatic chemoembolization is an attractive alternative for children who continue to have unresectable tumors after systemic chemotherapy or for children with nonmetastatic hepatocellular carcinoma.

Radiation Therapy

There is little experience or information on the use of radiation therapy in the management of liver tumors in children. A report from the Institut Gustave-Roussy suggested that radiation therapy to a total dose of 25 to 45 Gy combined with chemotherapy can play a role in local control of disease in patients with minimal postoperative residual hepatoblastoma and in those whose tumors remain unresectable after systemic chemotherapy.45 No benefit of radiation therapy was found in patients with hepatocellular carcinoma.

Limiting factors for the use of radiation therapy for pediatric patients with liver tumors include the low radiation dose tolerance of the normal liver tissue, the interference with liver regeneration following surgery and the potential interference with the administration of chemotherapy. New radiation technology may improve the usefulness of this therapeutic modality in the care of pediatric patients with liver tumors.


Reduction of the morbidity and long-term toxicity associated with chemotherapy for children with hepatoblastoma is a major goal. Development of new therapeutic approaches for the treatment of children with unresectable, metastatic, or recurrent hepatoblastoma is also needed. New therapeutic approaches for the treatment of children with hepatocellular carcinoma must be found. Epidemiologic and molecular biology studies must continue to further characterize factors associated with the development of liver malignancies in children.


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Bookshelf ID: NBK20791


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