General Information

Hepatoblastoma and Hepatocellular Carcinoma
        Epidemiology
        Risk factors
        Diagnosis
        Prognosis
        Risk factors
Undifferentiated Embryonal Sarcoma of the Liver
Infantile Choriocarcinoma of the Liver
Epithelioid Hemangioendothelioma

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation therapists, pediatric oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%.[1] Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Liver cancer is a rare malignancy in children and adolescents and is divided into two major histologic subgroups: hepatoblastoma and hepatocellular carcinoma. The incidence of hepatic tumors in children 14 years and younger is 2.4 per 100,000, of which 2 per 100,000 are hepatoblastoma.

The incidence of hepatoblastoma in the United States appears to have doubled in the last 25 years, whereas the incidence of hepatocellular carcinoma in the United States has minimal variance between the ages of 0 and 19 years and has not changed appreciably over time.[3,4] The cause for the increase in incidence of hepatoblastoma is unknown, but the increasing survival of very low birth weight premature infants, which is known to be associated with hepatoblastoma, may contribute.[5] In Japan, the risk of hepatoblastoma in children who weighed less than 1,000 g at birth are 15 times the risk in normal birth weight children.[6] Other data has confirmed the high incidence of hepatoblastoma in very low birth weight premature infants.[7]

The age of onset of liver cancer in children is related to tumor histology. Hepatoblastomas usually occur before the age of 3 years, and approximately 90% of malignant liver tumors in children aged 4 years and younger are hepatoblastomas.[4]

The incidence of hepatocellular carcinoma is negligible in children aged 14 years and younger.[SEER Cancer Statistics Review] In several Asian countries, the incidence of hepatocellular carcinoma in children is 10 times more than that in North America. The high incidence appears to be related to the incidence of perinatally acquired hepatitis B, which can be prevented in most cases by vaccination and administration of hepatitis B immune globulin to the newborn.[8]

The overall survival rate for children with hepatoblastoma is 70%,[9-11] but is only 25% for those with hepatocellular carcinoma.[4,12,13]

The incidence of hepatoblastoma is increased 1,000 to 10,000-fold in infants and children with Beckwith-Wiedemann syndrome (BWS).[14,15] Hepatoblastoma is also increased in hemihypertrophy,[16] an overgrowth syndrome caused by the same epigenetic changes in chromosome 11p15.5 that cause many cases of BWS, but in a genetically mosaic fashion.[15,17] BWS can be caused by either genetic mutations and be familial, or much more commonly, by epigenetic changes and be sporadic. Either mechanism can be associated with an increased incidence of embryonal tumors including Wilms tumor and hepatoblastoma.[15] The gene dosage and ensuing increase in expression of insulin-like growth factor 2 (IGF 2) has been implicated in the macrosomia and embryonal tumors in BWS and hemihypertrophy.[15,18] When sporadic, the types of embryonal tumors associated with BWS have frequently also undergone somatic changes in the BWS locus and IGF 2.[19,20] All children with BWS or isolated hemihypertrophy should be screened regularly by ultrasound to detect abdominal malignancies at an early stage. Screening using AFP levels has helped in the early detection of hepatoblastoma in children with BWS or hemihypertrophy.[21] Other somatic overgrowth syndromes, such as Simpson-Golabi-Behmel syndrome, may also be associated with hepatoblastoma.[22]

There is an association between hepatoblastoma and familial adenomatous polyposis (FAP); children in families that carry the APC gene are at an 800-fold increased risk for hepatoblastoma. However, hepatoblastoma occurs in less than 1% of FAP family members, so ultrasound and AFP screening for hepatoblastoma in members of families with FAP is controversial.[23-25] The predisposition to hepatoblastoma may be limited to a specific subset of APC mutations.[26] It has been recommended that all children with hepatoblastoma be examined for congenital hypertrophy of the retinal pigment epithelium, a marker of APC mutation carriers in 70% of polyposis families.[24] In the absence of APC germline mutations, childhood hepatoblastomas do not have somatic mutations in the APC gene; however, they frequently have mutations in the beta-catenin gene, the function of which is closely related to APC.[27]

Hepatocellular carcinoma is associated with hepatitis B and hepatitis C infection,[28-30] especially in children with perinatally acquired hepatitis B virus. Widespread hepatitis B immunization has decreased the incidence of hepatocellular carcinoma in Asia.[8] Compared with adults, the incubation period from hepatitis virus infection to the genesis of hepatocellular carcinoma is extremely short in a small subset of children with perinatally acquired virus. Mutations in the met/hepatocyte growth factor receptor gene occur in childhood hepatocellular carcinoma, and this could be the mechanism that results in a shortened incubation period.[31] Several specific types of nonviral liver injury and cirrhosis are associated with hepatocellular carcinoma in children including tyrosinemia and biliary cirrhosis. Hepatocellular carcinoma may also arise in very young children with mutations in the bile salt export pump ABCB11, which causes progressive familial hepatic cholestasis.[32]

A biopsy of the tumor is always indicated to secure the diagnosis of a liver tumor except:

• In infants with hepatic hemangiomas or hemangioendotheliomas, which can be diagnosed by imaging.
• In infantile hepatic choriocarcinoma, which can be diagnosed by imaging and markedly elevated beta-human chorionic gonadotropin (beta-hCG).[33]

The alpha-fetoprotein (AFP) and beta-hCG tumor markers are very helpful in diagnosis and management of liver tumors.

Cure of hepatoblastoma or hepatocellular carcinoma requires gross tumor resection. If a hepatoblastoma is completely removed, the majority of patients survive, but less than one-third of patients have lesions amenable to complete resection at diagnosis. Thus, it is critically important that a child with probable hepatoblastoma be evaluated by a pediatric surgeon experienced in the resection of hepatoblastoma in children.

Chemotherapy can often decrease the size and extent of hepatoblastoma, allowing complete resection.[9-11,34,35] Orthotopic liver transplantation provides an additional treatment option for patients whose tumor remains unresectable after preoperative chemotherapy;[35-37] however, the presence of microscopic residual tumor at the surgical margin does not preclude a favorable outcome.[38,39] This is probably because additional courses of chemotherapy generally are administered after resection to all patients except those with stage I and pure fetal histology, whether the resection occurs before or after chemotherapy.[9,10,39]

While hepatocellular carcinoma is often extensively invasive or multicentric, hepatoblastoma is most often unifocal. Therefore, resection is possible more often in hepatoblastoma than hepatocellular carcinoma, in which less than 30% are resectable. Orthotopic liver transplantation has also been successful in selected children with hepatocellular carcinoma.[37]

Ninety percent of patients with hepatoblastoma and two-thirds of patients with hepatocellular carcinoma have a serum tumor marker, AFP, that parallels disease activity. The level of AFP at diagnosis and rate of decrease in AFP during treatment should be compared to the age-adjusted normal range. Elevation of AFP levels is not diagnostic of hepatic malignancy.[40] Lack of a significant decrease of AFP levels with treatment may predict a poor response to therapy.[41] Absence of elevated AFP levels at diagnosis occurs in a few percentage of children with hepatoblastoma and appears to be associated with poor prognosis, as well as with the small cell undifferentiated variant of hepatoblastoma.[38,42-46]

Beta-hCG levels may also be elevated in children with hepatoblastoma or hepatocellular carcinoma, which may result in isosexual precocity in boys.[47,48] Extremely high levels of beta-hCG are associated with infantile choriocarcinoma of the liver.

The incidence of hepatoblastoma is increased 1,000 to 10,000-fold in infants and children with Beckwith-Wiedemann syndrome (BWS).[14,15] Hepatoblastoma is also increased in hemihypertrophy,[16] an overgrowth syndrome caused by the same epigenetic changes in chromosome 11p15.5 that cause many cases of BWS, but in a genetically mosaic fashion.[15,17] BWS can be caused by either genetic mutations and be familial, or much more commonly, by epigenetic changes and be sporadic. Either mechanism can be associated with an increased incidence of embryonal tumors including Wilms tumor and hepatoblastoma.[15] The gene dosage and ensuing increase in expression of insulin-like growth factor 2 (IGF 2) has been implicated in the macrosomia and embryonal tumors in BWS and hemihypertrophy.[15,18] When sporadic, the types of embryonal tumors associated with BWS have frequently also undergone somatic changes in the BWS locus and IGF 2.[19,20] All children with BWS or isolated hemihypertrophy should be screened regularly by ultrasound to detect abdominal malignancies at an early stage. Screening using AFP levels has helped in the early detection of hepatoblastoma in children with BWS or hemihypertrophy.[21] Other somatic overgrowth syndromes, such as Simpson-Golabi-Behmel syndrome, may also be associated with hepatoblastoma.[22]

There is an association between hepatoblastoma and familial adenomatous polyposis (FAP); children in families that carry the APC gene are at an 800-fold increased risk for hepatoblastoma. However, hepatoblastoma occurs in less than 1% of FAP family members, so ultrasound and AFP screening for hepatoblastoma in members of families with FAP is controversial.[23-25] The predisposition to hepatoblastoma may be limited to a specific subset of APC mutations.[26] It has been recommended that all children with hepatoblastoma be examined for congenital hypertrophy of the retinal pigment epithelium, a marker of APC mutation carriers in 70% of polyposis families.[24] In the absence of APC germline mutations, childhood hepatoblastomas do not have somatic mutations in the APC gene; however, they frequently have mutations in the beta-catenin gene, the function of which is closely related to APC.[27]

Hepatocellular carcinoma is associated with hepatitis B and hepatitis C infection,[28-30] especially in children with perinatally acquired hepatitis B virus. Widespread hepatitis B immunization has decreased the incidence of hepatocellular carcinoma in Asia.[8] Compared with adults, the incubation period from hepatitis virus infection to the genesis of hepatocellular carcinoma is extremely short in a small subset of children with perinatally acquired virus. Mutations in the met/hepatocyte growth factor receptor gene occur in childhood hepatocellular carcinoma, and this could be the mechanism that results in a shortened incubation period.[31] Several specific types of nonviral liver injury and cirrhosis are associated with hepatocellular carcinoma in children including tyrosinemia and biliary cirrhosis. Hepatocellular carcinoma may also arise in very young children with mutations in the bile salt export pump ABCB11, which causes progressive familial hepatic cholestasis.[32]

Undifferentiated embryonal sarcoma of the liver (UESL) is the third most common liver malignancy in children and adolescents, comprising 9% to 13% of liver tumors. It presents as an abdominal mass, often with pain or malaise, usually between the ages of 5 and 10 years. Widespread infiltration throughout the liver and pulmonary metastasis are common. It may appear solid or cystic on imaging, frequently with central necrosis. Distinctive features are characteristic intracellular hyaline globules and marked anaplasia on a mesenchymal background.[49] Many UESL contain diverse elements of mesenchymal cell maturation, such as smooth muscle and fat.

It is important to make the diagnostic distinction between UESL and biliary tract rhabdomyosarcoma (BTR) as they share some common clinical and pathologic features but treatment differs between the two as shown in Table 1.[50] (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.)

It has been suggested that some UESLs arise from mesenchymal hamartomas of the liver (MHL), which are large benign multicystic masses that present in the first 2 years of life.[50] Strong clinical and histological evidence suggest that UESL can arise within a preexisting MHL. In a report of 11 cases of UESL, five arose in association with MHL, and transition zones between the histologies were noted.[51] Many MHLs have a characteristic translocation with a breakpoint at 19q13.4 and several UESLs have the same translocation.[52,53] Some UESLs arising from MHLs may have complex karyotypes not involving 19q13.4.

Choriocarcinoma of the liver is a very rare tumor that appears to originate in the placenta and presents with a liver mass in the first few months of life. Infants are often unstable due to hemorrhage from the tumor. Clinical diagnosis may be made without biopsy based on extremely high serum beta-hCG levels and normal AFP levels for age.[33]

Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer that occurs in the liver and other organs. (Refer to the Hemangioendothelioma section in the PDQ summary on Childhood Soft Tissue Sarcoma Treatment for more information.)

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