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This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 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 following health care professionals 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 children and adolescents with cancer have been outlined by the American Academy of Pediatrics. 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 website.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close monitoring because late effects of therapy 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 the following two major histologic subgroups:
Other, less common, histologies include the following:
Liver tumors are rare in children. Their diagnoses may be challenging, in part, because of the lack of consensus regarding a classification system. Systematic central histopathological review of these tumors performed as part of pediatric collaborative therapeutic protocols has allowed the identification of histologic subtypes with distinct clinical associations. As a result, histopathology has been incorporated within the Children's Oncology Group (COG) protocols and, in the United States, as a risk-stratification parameter used for patient management.
The COG Liver Tumor Committee sponsored an International Pathology Symposium in 2011 to discuss the histopathology and classification of pediatric liver tumors (hepatoblastoma, in particular), and work towards an International Pediatric Liver Tumors Consensus Classification that would be required for international collaborative projects. Twenty-two pathologists and experts in pediatric liver tumors, including those serving as central reviewers for the COG, European Société Internationale d'Oncologie Pédiatrique (International Society of Paediatric Oncology), Gesellschaft für Pädiatrische Onkologie und Hämatologie (Society for Paediatric Oncology and Haematology), and Japanese Study Group for Pediatric Liver Tumors protocols, as well as pediatric oncologists and surgeons specialized in this field, reviewed more than 50 pediatric liver tumor cases. They discussed classic and newly reported entities, and criteria for their classification. This symposium represented the first collaborative step toward developing a classification that may lead to a common treatment-stratification system incorporating tumor histopathology. The results of this international classification for pediatric liver tumors have been published. It is too soon to know whether the international classification system will be generally accepted among pediatric pathologists. A standardized, clinically meaningful classification is needed to allow the integration of new biological parameters and tumor genetics, which could improve future patient management and outcome.
For information on the histology of each childhood liver cancer subtype, refer to the following histology sections of this summary:
Genomic Abnormalities in Hepatoblastoma and Hepatocellular Carcinoma
Genomic abnormalities related to hepatoblastoma include the following:
Genomic abnormalities related to hepatocellular carcinoma include the following:
Historically, the four major study groups (International Childhood Liver Tumors Strategy Group [previously known as Société Internationale d'Oncologie Pédiatrique–Epithelial Liver Tumor Study Group (SIOPEL)], Children's Oncology Group [COG], Gesellschaft für Pädiatrische Onkologie und Hämatologie [Society for Paediatric Oncology and Haematology], and Japanese Study Group for Pediatric Liver Tumors) have had disparate risk stratification categories, making it difficult to compare outcomes across continents. All groups are now using the PRE-Treatment EXTent of tumor (PRETEXT) grouping system as part of the risk stratification.
The primary treatment goal for patients with liver cancer is surgical extirpation of all disease. Therefore, the risk grouping designed to stratify treatment depends heavily on factors related to safe surgical resection of the tumor. This risk grouping uses imaging to define factors that determine the likelihood of safe and successful surgical resection.
The importance of high-quality, cross-sectional imaging to evaluate children with hepatoblastoma is paramount because the risk stratification that defines treatment is very dependent on imaging analysis. Three-phase computed tomography scanning (non-contrast, arterial, and venous) or magnetic resonance imaging (MRI) with contrast agents are used for imaging. MRI with gadoxetate disodium (Eovist), a gadolinium-based agent that is preferentially taken up and excreted by hepatocytes, is being used with increased frequency and may improve detection of multifocal disease.
There are two grouping systems used for hepatoblastoma and hepatocellular carcinoma that radiographically define the extent of liver involvement by the tumor:
In SIOPEL studies, all children with hepatoblastoma have been treated with chemotherapy before attempted resection of the primary tumor. Hence, surgical staging has not been possible.
PRETEXT and POSTTEXT Groups
PRETEXT is now used by the major multicenter trial groups as a central component of risk stratification schemes that define treatment of hepatoblastoma. The PRETEXT groups were devised by the SIOPEL for their first trial, SIOPEL-1  and revised for SIOPEL-3 in 2007. PRETEXT is based on an analysis of cross-sectional imaging of the extent of tumor involvement of the four main sections of the liver:
PRETEXT group assignment I, II, III, or IV is determined by the number of contiguous uninvolved sections of the liver. PRETEXT is further annotated with a V, P, E, M, C, F, N, or R depending on extension of tumor beyond the hepatic parenchyma of the major sections.
Annotations have been added to identify multifocality (F) and preoperative tumor rupture (R). (Refer to Table 1 for detailed descriptions of the PRETEXT groups and annotations.)
The extent of tumor involvement of the major vessels and its effect on venous inflow and outflow is critical knowledge for the surgeon and can affect surgical outcomes. Portal involvement of the main portal vein and/or both right and left portal veins can be further described as the following:
The same vascular involvement definitions apply to venous involvement, V0–V3. Vascular involvement is critical in determining the resectability of a liver tumor. It should be noted that there are differences in the definitions of vascular involvement used by the COG and major liver surgery centers in the United States compared with SIOPEL definitions used in Europe.
Although PRETEXT can be used to predict tumor resectability, there are limitations. The distinction between real invasion beyond the anatomic border of a given hepatic section and the compression and displacement by the tumor can be very difficult, especially at diagnosis. Additionally, distinguishing between vessel encroachment and involvement can be difficult, particularly if inadequate imaging is obtained. The PRETEXT group assignment has a moderate degree of interobserver variability, and the preoperative PRETEXT group agrees with postoperative pathologic findings only 51% of the time, with overstaging in 37% of patients and understaging in 12% of patients.
Because distinguishing PRETEXT group assignment is difficult, central review of imaging is generally performed in major clinical trials. For patients not enrolled on clinical trials, expert radiologic review should be considered in questionable cases in which the PRETEXT group assignment affects choice of treatment.
The posttreatment extent of disease (POSTTEXT) is typically obtained after every two cycles of chemotherapy, about 10 days after the completion of a chemotherapy cycle. It has been shown that most chemotherapy response occurs after the first two cycles of chemotherapy. Also, a study that evaluated surgical resectability after two versus four cycles of chemotherapy showed that many tumors may be resectable after two cycles.
Hepatoblastoma and hepatocellular carcinoma prognosis by PRETEXT group
The 5-year overall survival (OS) in the first international study of hepatoblastoma, in which the study protocol called for treatment of children with preoperative doxorubicin and cisplatin chemotherapy and included children with metastasis, was as follows:[5,6]
The second international study compared 3-year OS among hepatoblastoma patients without extrahepatic disease by PRETEXT group. The 3-year OS was as follows:
The study also prospectively analyzed patients' OS by the presence of intraabdominal extrahepatic disease without distant metastasis (OS, 58%) and with distant metastases (OS, 44%). Patients who underwent orthotopic liver transplant are included in all of the international study results.
The 5-year OS by PRETEXT group for hepatocellular carcinoma was as follows:
The COG is investigating prospective grouping of hepatoblastoma patients using the PRETEXT system to determine the timing of surgery and the timing of early notification of liver transplant centers (COG-AHEP0731).
Postsurgical Staging for Childhood Liver Cancer (Historical)
A staging system based on operative findings and surgical resectability was used for many years in the United States to group children with liver cancer. This staging system was used to determine treatment.[10,11,12] Currently other risk stratification systems are used to classify patients and determine treatment strategy (refer to Table 3 for more information).
Hepatoblastoma prognosis by postsurgical stage
Stages I and II
In stage I hepatoblastoma, the tumor is completely resected.
In stage II hepatoblastoma, microscopic residual tumor remains after resection.
Approximately 20% to 30% of children with hepatoblastoma are stage I or II. Prognosis varies depending on the subtype of hepatoblastoma:
In stage III hepatoblastoma, there are no distant metastases and one of the following is true:
Approximately 50% to 70% of children with hepatoblastoma are stage III. The 3- to 5-year OS rate for children with stage III hepatoblastoma is less than 70%.[5,7,12,13,17]
Stage IV (distant metastases)
In stage IV hepatoblastoma, there is distant metastasis regardless of the extent of liver involvement.
Approximately 10% to 20% of children with hepatoblastoma are stage IV. The 3- to 5-year OS rate for children with stage IV hepatoblastoma varies widely, from 20% to approximately 60%, based on published reports.[5,6,7,12,13,17]
Hepatocellular carcinoma prognosis by postsurgical stage
Many of the improvements in survival in childhood cancer have been made using new therapies that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare potentially better therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment, comparing the results with those previously obtained with standard therapy.
Because of the relative rarity of cancer in children, all children with liver cancer should be considered for entry onto a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists with experience treating tumors of childhood is required to determine and implement optimal treatment.
Historically, complete surgical resection of the primary tumor has been required to cure malignant liver tumors in children.[2,3,4,5,6]; [Level of evidence: 3iiiA] This approach continues to be the goal of definitive surgical procedures, and surgical resection is often combined with other treatment modalities (e.g., liver transplant, chemotherapy). However, postoperative complications are common and associated with worsened overall survival in patients with advanced hepatoblastoma.
There are three ways in which surgery is used to treat primary pediatric liver cancer:
The timing of the surgical approach is critical. For this reason, surgeons with experience in pediatric liver resection and transplantation are involved early in the decision-making process for determining optimal timing and extent of resection. In children and adolescents with primary liver tumors, the surgeon has to be prepared to perform a highly sophisticated liver resection after confirmation of the diagnosis by pathological investigation of intraoperative frozen sections. While complete surgical resection is important for all liver tumors, it is especially true for hepatocellular carcinoma because curative chemotherapy is not available.
If the tumor can be completely excised by an experienced surgical team, less postoperative chemotherapy may be needed. If the tumor is determined to be unresectable and preoperative chemotherapy is to be administered, it is very important to frequently consult with the surgical team concerning the timing of resection, as prolonged chemotherapy can lead to unnecessary delays and, in rare cases, tumor progression.
Early involvement with an experienced pediatric liver surgeon is especially important in patients with PRETEXT III or IV disease, involvement of major liver vessels (V+ [venous] or P+ [portal]), or low alpha-fetoprotein (AFP) levels. Although vascular involvement was initially thought to be a contraindication to resection, experienced liver surgeons are often able to perform aggressive approaches while avoiding transplantation.[9,10]; [Level of evidence: 3iiA] Accomplishing a complete resection is imperative because rescue transplant of incompletely resected patients has an inferior outcome compared with patients who are transplanted as the primary surgical therapy.
The decision as to which surgical approach to use depends on many factors including the following:
The approach taken by the Children's Oncology Group (COG) in North American clinical trials is to perform surgery initially when a complete resection can be accomplished with a simple, negative-margin hemihepatectomy. COG has studied the use of PRETEXT and POSTTEXT to determine the optimal approach and timing of surgery (refer to the Tumor Stratification by Imaging and Postsurgical Staging for Childhood Liver Cancer section of this summary for more information).
Orthotopic liver transplantation
Liver transplantation has recently been associated with significant success in the treatment of children with unresectable hepatic tumors.[13,14,15][Level of evidence: 3iiA] A review of the world experience has documented a posttransplant survival rate of 70% to 80% for children with hepatoblastomas.[12,16,17] Intravenous invasion, positive lymph nodes, and contiguous spread did not have a significant adverse effect on outcome. It has been suggested that adjuvant chemotherapy after transplant may decrease the risk of tumor recurrence.
Evidence (orthotopic transplantation):
Application of the Milan criteria for UNOS selection of recipients of deceased donor livers is controversial. It should be noted that the Milan criteria for liver transplantation is directed toward adults with cirrhosis and hepatocellular carcinoma. It does not apply to children and adolescents with hepatocellular carcinoma, especially those without cirrhosis. Living-donor liver transplant is more common with children and the outcome is similar to those receiving cadaveric liver transplant.[23,24] In hepatocellular carcinoma, vascular invasion, distant metastases, lymph node involvement, tumor size, and male gender were significant risk factors for recurrence. Because of the poor prognosis in patients with hepatocellular carcinoma, liver transplant should be considered for disorders such as tyrosinemia and familial intrahepatic cholestasis early in the course, before the development of liver failure and malignancy.
Surgical resection for metastatic disease
Surgical resection of distant disease has also contributed to the cure of children with hepatoblastoma. Resection of pulmonary metastases is recommended when the number of metastases is limited [25,26,27] and is often performed at the same time as resection of the primary tumor. When possible, resection of areas of locally invasive disease, such as in the diaphragm, and of isolated brain metastasis is recommended.
Chemotherapy regimens used in the treatment of hepatoblastoma and hepatocellular carcinoma are described in their respective sections (refer to the Treatment of Hepatoblastoma and the Treatment of Hepatocellular Carcinoma sections of this summary for more information). Chemotherapy has been much more successful in the treatment of hepatoblastoma than in hepatocellular carcinoma.[4,5,29,30,31,32,33]
Preoperative chemotherapy has been shown to be of benefit in children with hepatoblastoma; however, the use of postoperative chemotherapy after definitive surgical resection or liver transplant requires further investigation.
The utility of radiation therapy is questioned because the liver cannot tolerate high doses of radiation.[30,34]
Radiation therapy, even in combination with chemotherapy, has not cured children with unresectable tumors. There may be a role for radiation therapy in the management of incompletely resected hepatoblastoma,[30,34] although a study of 154 patients with hepatoblastoma did not confirm this finding. This study showed that radiation therapy and/or second resection of positive margins may not be necessary in patients with incompletely resected hepatoblastoma whose residual tumor is microscopic.
Other Treatment Approaches
Other treatment approaches such as transarterial chemoembolization (TACE) have been used for patients with inoperable hepatoblastoma.[36,37] TACE has been used in a few children to successfully shrink the tumor to permit resection. Chemotherapy followed by TACE followed by high-intensity focused ultrasound showed promising results in China for PRETEXT III and IV patients, some of whom were resectable but did not undergo surgery because of parent refusal.
Transarterial radioembolization with yttrium-90 resin beads has been used to palliate children with hepatocellular carcinoma. (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)
The annual incidence of hepatoblastoma in the United States appears to have doubled from 0.8 (1975–1983) to 1.6 (2002–2009) per 1 million children aged 19 years and younger.[1,2] The cause for this increase is unknown, but the increasing survival of very low-birth-weight premature infants, which is known to be associated with hepatoblastoma, may contribute. In Japan, the risk of hepatoblastoma in children who weighed less than 1,000 g at birth is 15 times the risk in normal birth-weight children. Other data has confirmed the high incidence of hepatoblastoma in very low-birth-weight premature infants. Attempts to identify factors resulting from treatment of infants born prematurely have not revealed any suggestive causation of the increased incidence of hepatoblastoma.
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.
Conditions associated with an increased risk of hepatoblastoma are described in Table 2.
Aicardi syndrome is presumed to be an X-linked condition reported exclusively in females, leading to the hypothesis that a mutated gene on the X chromosome causes lethality in males. It is classically defined as agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms, with a characteristic facies. Additional brain, eye, and costovertebral defects are often found.
Beckwith-Wiedemann syndrome and hemihyperplasia
The incidence of hepatoblastoma is increased 1,000-fold to 10,000-fold in infants and children with Beckwith-Wiedemann syndrome.[9,18] Hepatoblastoma is also increased in hemihypertrophy, now termed hemihyperplasia, a condition that results in asymmetry between the right and left side of the body when a body part grows faster than normal.[19,20]
Beckwith-Wiedemann syndrome is most commonly caused by epigenetic changes and is sporadic. It may also be caused by genetic mutations and be familial. Either mechanism can be associated with an increased incidence of embryonal tumors, including Wilms tumor and hepatoblastoma. The expression of both IGFR2 alleles and ensuing increased expression of insulin-like growth factor 2 (IGF-2) has been implicated in the macrosomia and embryonal tumors in Beckwith-Wiedemann syndrome.[9,21] When sporadic, the types of embryonal tumors associated with Beckwith-Wiedemann syndrome have frequently also undergone somatic changes in the Beckwith-Wiedemann syndrome locus and IGF-2.[22,23] The genetics of tumors in children with hemihyperplasia have not been clearly defined.
To detect abdominal malignancies at an early stage, all children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia are screened regularly for multiple tumor types by abdominal ultrasound. Screening using alpha-fetoprotein (AFP) levels has also helped in the early detection of hepatoblastoma in these children. Because hepatoblastoma in Beckwith-Wiedemann syndrome is detected at an early stage and tumors are small, it has been suggested that treatment after surgery may be minimized.
Familial adenomatous polyposis
There is an association between hepatoblastoma and familial adenomatous polyposis (FAP); children in families that carry the APC gene have an 800-fold increased risk for hepatoblastoma. However, hepatoblastoma has been reported to occur in less than 1% of FAP family members, so screening for hepatoblastoma in members of families with FAP using ultrasound and AFP levels is controversial.[10,11,12,25] However, one study of 50 consecutive children with apparent sporadic hepatoblastoma reported five children (10%) had APC germline mutations. Current evidence cannot rule out the possibility that predisposition to hepatoblastoma may be limited to a specific subset of APC mutations. Another study of children with hepatoblastoma found a predominance of the mutation in the 5' region of the gene, but some patients had mutations closer to the 3' region. This preliminary study provides some evidence that screening children with hepatoblastoma for APC mutations and colon cancer may be appropriate.
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.
A biopsy of the tumor is always indicated to secure the diagnosis of a liver tumor except in the following circumstances:
The AFP and beta-hCG tumor markers are very helpful in diagnosis and management of liver tumors. Although AFP is elevated in most children with hepatic malignancy, it is not pathognomonic for a malignant liver tumor. The AFP level can be elevated due to a benign tumor, as well as a malignant solid tumor. AFP is very high in neonates and steadily falls after birth. The half-life of AFP is 5 to 7 days, and by age 1 year, it should be less than 10 ng/mL.
Prognosis and Prognostic Factors
The 5-year overall survival (OS) rate for children with hepatoblastoma is 70%.[31,32] Neonates with hepatoblastoma have comparable outcomes to older children up to age 5 years.
Individual childhood cancer study groups have attempted to define the relative importance of a variety of prognostic factors present at diagnosis and in response to therapy.[34,35]
Factors affecting prognosis include the following:
Surgery: Cure of hepatoblastoma requires gross tumor resection. Hepatoblastoma is most often unifocal and thus, resection may be possible. If a hepatoblastoma is completely removed, the majority of patients survive, but because of vascular or other involvement, 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 who is experienced in the resection of hepatoblastoma in children and has access to a liver transplant program.
Chemotherapy: Chemotherapy often decreases the size and extent of hepatoblastoma, allowing complete resection.[36,37,38,39,40] Orthotopic liver transplantation provides an additional treatment option for patients whose tumor remains unresectable after preoperative chemotherapy;[41,42] however, the presence of microscopic residual tumor at the surgical margin does not preclude a favorable outcome.[43,44] This may be due to the additional courses of chemotherapy that are administered before or after resection.[36,37,43]
(Refer to Table 4 for more information on outcomes associated with specific chemotherapy regimens.)
Ninety percent of patients with hepatoblastoma and two-thirds of patients with hepatocellular carcinoma exhibit the serum tumor marker AFP, which parallels disease activity. The level of AFP at diagnosis and rate of decrease in AFP levels during treatment are compared with the age-adjusted normal range. Lack of a significant decrease of AFP levels with treatment may predict a poor response to therapy.
Absence of elevated AFP levels at diagnosis (AFP less than 100 ng/mL) occurs in a small percentage of children with hepatoblastoma and appears to be associated with very poor prognosis, as well as with the small cell undifferentiated variant of hepatoblastoma. Some of these variants do not express INI1 due to INI1 mutation and may be considered rhabdoid tumors of the liver; all small cell undifferentiated hepatoblastomas should be tested for loss of INI1 expression by immunohistochemistry.[46,47,48,49,50,51]
Beta-hCG levels may also be elevated in children with hepatoblastoma or hepatocellular carcinoma, which may result in isosexual precocity in boys.[52,53]
Refer to the Histology section of this summary for more information.
Other variables have been suggested as poor prognostic factors, but the relative importance of their prognostic significance has been difficult to define. In the SIOPEL-1 study, a multivariate analysis of prognosis after positive response to chemotherapy showed only one variable, PRETEXT, predicted OS, while metastasis and PRETEXT predicted event-free survival (EFS). In an analysis of the intergroup U.S. study from the time of diagnosis, pure fetal histology, small cell undifferentiated histology, and AFP less than 100 ng/mL were prognostic in a log rank analysis. PRETEXT was prognostic among patients designated group III, but not group IV.
Additional variables include the following:
Hepatoblastoma arises from precursors of hepatocytes and can have several morphologies, including the following:
Most often the tumor consists of a mixture of epithelial hepatocyte precursors. About 20% of tumors have stromal derivatives such as osteoid, chondroid, and rhabdoid elements. Occasionally, neuronal, melanocytic, squamous, and enteroendocrine elements are found. The following two histologic subtypes have clinical relevance:
Pure fetal histology hepatoblastoma
Analysis of patients with initially resected hepatoblastoma tumors (before receiving chemotherapy) has suggested that patients with pure fetal histology tumors have a better prognosis than do patients with an admixture of more primitive and rapidly dividing embryonal components or other undifferentiated tissues. Studies have reported the following:
Thus, complete resection of a pure fetal hepatoblastoma may preclude the need for chemotherapy.
Small cell undifferentiated hepatoblastoma
Small cell undifferentiated hepatoblastoma is an uncommon hepatoblastoma variant that represents a few percent of all hepatoblastomas. It tends to occur at a younger age (6–10 months) compared with other cases of hepatoblastoma [50,58] and is associated with AFP levels that are normal for age at presentation.[49,58]
Histologically, small cell undifferentiated hepatoblastoma is typified by a diffuse population of small cells with scant cytoplasm resembling neuroblasts.
Occasional small cell undifferentiated hepatoblastomas are identical to malignant rhabdoid tumors and have the following characteristic abnormalities:
Patients with small cell undifferentiated hepatoblastoma whose tumors are unresectable have an especially poor prognosis. Patients with stage I tumors appear to have increased risk of treatment failure when small cell elements are present. For this reason, completely resected tumors composed of pure fetal histology or of mixed fetal and embryonal cells must have a thorough histologic examination as small foci of undifferentiated small cell histology indicates a need for aggressive chemotherapy. Aggressive treatment for this histology is under investigation in the current COG study, COG-AHEP0731. In this study, hepatoblastoma that would otherwise be considered very low or low risk is upgraded to intermediate risk if any small cell undifferentiated elements are found (refer to Table 3 for more information).
There are significant differences among childhood cancer study groups in risk stratification used to determine treatment, making it difficult to compare results of the different treatments administered. Table 3 demonstrates the variability in the definitions of risk groups.
Treatment of Hepatoblastoma
Cisplatin-based chemotherapy has resulted in a survival rate of more than 90% for children with PRETEXT AND POST-Treatment EXTent (POSTTEXT) I and II resectable disease before or after chemotherapy.[37,39,47]
Chemotherapy regimens used in the treatment of hepatoblastoma and their respective outcomes are described in Table 4. (Refer to the Tumor Stratification by Imaging and Postsurgical Staging for Childhood Liver Cancer section of this summary for information describing each stage.)
Treatment options for newly diagnosed hepatoblastoma depend on the following:
Treatment options for hepatoblastoma that is resectable at diagnosis
Approximately 20% to 30% of children with hepatoblastoma have resectable disease at diagnosis. Prognosis varies depending on the histologic subtype:
The treatment of hepatoblastoma that can be resected at diagnosis depends on the tumor histology.
Treatment options for hepatoblastoma of pure fetal histology include the following:
Evidence (complete surgical resection followed by watchful waiting or chemotherapy):
Treatment options for hepatoblastoma of non–pure fetal histology include the following:
Evidence (gross surgical resection [with or without microscopic margins] and preoperative and/or postoperative chemotherapy):
Second resection of positive margins and/or radiation therapy may not be necessary in patients with incompletely resected hepatoblastoma whose residual tumor is microscopic and who receive subsequent chemotherapy.[43,51]
Results of chemotherapy clinical trials are described in Table 4.
Treatment options for hepatoblastoma that is not resectable or not resected at diagnosis
Tumor rupture at presentation, resulting in major hemorrhage that can be controlled by transcatheter arterial embolization or partial resection to stabilize the patient, does not preclude a favorable outcome when followed by chemotherapy and definitive surgery.
Treatment options for hepatoblastoma that is not resectable or is not resected at diagnosis include the following:
In recent years, almost all children with hepatoblastoma have been treated with chemotherapy, and in European centers, children with resectable hepatoblastoma are treated with preoperative chemotherapy, which may reduce the incidence of surgical complications at the time of resection.[39,43,47] Preoperative chemotherapy has been shown to be of benefit in children with hepatoblastoma. In contrast, an American intergroup study of treatment of children with hepatoblastoma encouraged resection at the time of diagnosis for all tumors amenable to resection without undue risk. The study (COG-P9645) did not treat children with stage I tumors of pure fetal histology with preoperative or postoperative chemotherapy unless they developed progressive disease. In this study, most PRETEXT III and all PRETEXT IV tumors were treated with chemotherapy before resection or transplant.
Patients whose tumors remain unresectable should be considered for liver transplantation.[39,41,67,68,69,70] In the presence of features predicting unresectability, early coordination with a pediatric liver transplant service is critical.
Evidence (chemotherapy followed by reassessment of surgical resectability and complete surgical resection):
Chemotherapy followed by TACE followed by high-intensity focused ultrasound showed promising results in China for PRETEXT III and IV patients with hepatoblastoma, some of whom were resectable but did not undergo surgical resection because of parent refusal.
Treatment options for hepatoblastoma with metastases at diagnosis
The outcome for metastatic hepatoblastoma at diagnosis is poor, but long-term survival and cure is possible.[36,37,38] Survival rates at 3 to 5 years range from 20% to 60%.[51,77,78]
Treatment options for hepatoblastoma with metastases at diagnosis include the following:
The standard combination chemotherapy regimen is four courses of cisplatin/vincristine/fluorouracil  or doxorubicin/cisplatin [39,54,77] followed by attempted complete tumor resection. If the tumor is completely removed, two postoperative courses of the same chemotherapy are usually given. Study results for different chemotherapy regimens have been reported (refer to Table 4 for more information).
High-dose chemotherapy with stem cell rescue does not appear to be more effective than standard multiagent chemotherapy.
Evidence (chemotherapy followed by reassessment of surgical resectability; complete surgical resection of the primary tumor and extrahepatic disease followed by additional chemotherapy):
In patients with resected primary tumor, any remaining pulmonary metastasis is surgically removed, if possible. A review of patients treated on a U.S. intergroup trial suggested that resection of metastasis may be done at the time of resection of the primary tumor.[Level of evidence: 3iiA]
If extrahepatic disease is in complete remission after chemotherapy, and the primary tumor remains unresectable, an orthotopic liver transplantation may be performed.[44,51,54,74]
The outcome results are discrepant for patients with lung metastases at diagnosis who undergo orthotopic liver transplantation after complete resolution of lung disease in response to pretransplant chemotherapy. Some studies have reported favorable outcomes for these groups,[44,51,74] while others have noted high rates of hepatoblastoma recurrence.[41,67,70,71] All of these studies are limited by small patient numbers; further study is needed to better define outcomes for this subset of patients.
If extrahepatic disease is not resectable after chemotherapy or the patient is not a transplant candidate, alternative treatment approaches include the following:
Treatment options under clinical evaluation for newly diagnosed hepatoblastoma
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI website.
All patients with metastatic hepatoblastoma and patients with any stage or PRETEXT group of hepatoblastoma and initial AFP less than 100 ng/mL are treated with the novel combination of vincristine, irinotecan, and temsirolimus (VIT) to estimate the response rate of this new combination of agents. This regimen includes two cycles of up-front VIT in the initial 6 weeks of therapy. Patients who respond to VIT will continue to receive this combination. Responding patients will receive a total of six cycles of cisplatin, 5-flouorouracil, and vincristine (C5VD) therapy with two more cycles of VIT (total of four). Nonresponding patients will receive only the six cycles of C5VD after the up-front window therapy.
Treatment options for progressive or recurrent hepatoblastoma
The prognosis for a patient with recurrent or progressive hepatoblastoma depends on several factors, including the following:
Treatment options for recurrent or progressive hepatoblastoma include the following:
If possible, isolated metastases should be resected completely in patients whose primary tumor is controlled. A retrospective study of patients in SIOPEL studies 1, 2, and 3 showed a 12% incidence of recurrence after complete remission by imaging and AFP. Outcome after recurrence was best if the tumor was amenable to surgery. Of patients who underwent chemotherapy and surgery, 3-year EFS was 34% and OS was 43%.[Level of evidence: 3iiA]
Treatment in a clinical trial should be considered if all of the recurrent disease cannot be surgically removed. Phase I and phase II clinical trials may be appropriate and should be considered.
The annual incidence of hepatocellular carcinoma in the United States is 0.8 per 1 million children between the ages of 0 and 14 years and 1.5 per 1 million adolescents aged 15 to 19 years. In several Asian countries, the incidence of hepatocellular carcinoma in children is 10 times higher 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.
Fibrolamellar hepatocellular carcinoma, a subtype of hepatocellular carcinoma that is unrelated to cirrhosis, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection, generally occurs in adolescents and young adults, but has been reported in infants.
Conditions associated with hepatocellular carcinoma are described in Table 5.
Alagille syndrome is an autosomal dominant genetic syndrome involving the bile ducts of the liver with a characteristic facies. It also often involves the heart and blood vessels in the brain and kidney. It is usually caused by mutation in or deletion of the JAG1 gene.
Hepatitis B and hepatitis C infection
In children, hepatocellular carcinoma is associated with perinatally acquired HBV, whereas in adults it is associated with chronic HBV and HCV infection.[6,7,8] Widespread hepatitis B immunization has decreased the incidence of hepatocellular carcinoma in Asia. 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 could be one mechanism that results in a shortened incubation period. Hepatitis C infection is associated with development of cirrhosis and hepatocellular carcinoma that takes decades to develop and is generally not seen in children. Cirrhosis in children, compared with cirrhosis in adults, is much less commonly involved in the development of hepatocellular carcinoma, and is found in only 20% to 35% of children with hepatocellular carcinoma tumors.
Specific types of nonviral liver injury and cirrhosis that are associated with hepatocellular carcinoma in children include the following:
Refer to the Diagnosis subsection in the Hepatoblastoma section of this summary for more information.
The 5-year overall survival (OS) rate is 42% for children and adolescents with hepatocellular carcinoma. The 5-year survival for hepatocellular carcinoma may be dependent on stage; in an intergroup chemotherapy study conducted in the 1990s, seven of eight stage I patients survived and less than 10% of stage III and IV patients survived.[1,13] An analysis of Surveillance, Epidemiology, and End Results (SEER) data found a 5-year OS rate of 24%, 10-year rate of 23%, and 20-year rate of 8% in patients aged up to 19 years, suggesting improved outcome related to more recent treatment. In a multivariate analysis of the SEER data, surgical resection, localized tumor, and non-Hispanic ethnicity all had improved outcome. Complete surgical resection versus incomplete resection was associated with 60% versus 0% OS.[Level of evidence: 3iiiA]
Cure of hepatocellular carcinoma requires gross tumor resection. However, hepatocellular carcinoma is often extensively invasive or multicentric, and less than 30% are resectable. Orthotopic liver transplantation has been successful in selected children with hepatocellular carcinoma.
The cells of hepatocellular carcinoma are epithelial in appearance. Hepatocellular carcinoma commonly arises in the right lobe of the liver.
A distinctive histologic variant of hepatocellular carcinoma, termed fibrolamellar carcinoma, has been described in the livers of older children and young adults and, rarely, in infants. This histology is characterized by a fusion transcript created by deletion of a 400 kb section of chromosome 19, which was found in 15 of 15 tumors that were tested.
Fibrolamellar carcinoma is thought to be associated with an improved prognosis and is not associated with cirrhosis.[17,18,19] Unlike nonfibrolamellar hepatocellular carcinoma in adults, fibrolamellar hepatocellular carcinoma in older children and adults is not clearly increasing in incidence over time. The improved outcome in older studies may be related to a higher proportion of tumors being less invasive and more resectable in the absence of cirrhosis; the outcome in recent prospective studies, when compared stage for stage and PRETEXT group to PRETEXT group, is not different from other hepatocellular carcinomas.[20,21]; [Level of evidence: 3iiA]
Hepatocellular carcinoma, not otherwise specified (NOS)
Hepatocellular carcinoma, NOS is also known as transitional liver cell tumor. This tumor with characteristics of both hepatoblastoma and hepatocellular carcinoma is a rare neoplasm that is found in older children and adolescents, and has a putative intermediate position between hepatoblasts and more mature hepatocyte-like tumor cells. The tumor cells may vary in regions of the tumor between classical hepatoblastoma and obvious hepatocellular carcinoma. In the international consensus classification, these tumors are referred to as hepatocellular carcinoma, NOS. The tumors are usually unifocal and may have central necrosis at presentation. Response to chemotherapy has not been rigorously studied but is felt to be much like hepatocellular carcinoma.
Treatment of Hepatocellular Carcinoma
Treatment options for newly diagnosed hepatocellular carcinoma depend on the following:
Treatment options for hepatocellular carcinoma that is resectable at diagnosis
Treatment options for hepatocellular carcinoma that is resectable at diagnosis include the following:
Surgical resection and chemotherapy are the mainstays of treatment for resectable hepatocellular carcinoma.
Evidence (surgical resection followed by chemotherapy):
Despite improvements in surgical techniques, chemotherapy delivery, and patient supportive care in the past 20 years, clinical trials of cancer chemotherapy for childhood hepatocellular carcinoma have not shown improved survival.
Treatment options for nonmetastatic hepatocellular carcinoma that is not resectable at diagnosis
The use of neoadjuvant chemotherapy or transarterial chemoembolization (TACE) to enhance resectability or liver transplant, which may result in complete resection of tumor, is necessary for cure.
Treatment options for nonmetastatic hepatocellular carcinoma that is not resectable at diagnosis include the following:
Evidence (chemotherapy and/or TACE followed by reassessment of surgical resectability and complete surgical resection of the primary tumor):
Evidence (chemotherapy and/or TACE followed by reassessment of surgical resectability; treatment options for unresectable primary tumor after chemotherapy and/or TACE):
If the primary tumor is not resectable after chemotherapy and the patient is not a transplant candidate, alternative treatment approaches used in adults include the following:
There is little or no data on the use of these alternative treatment approaches in children.
Limited data from a European pilot study suggest that sorafenib was well tolerated in 12 newly diagnosed children and adolescents with advanced hepatocellular carcinoma when given in combination with standard chemotherapy with cisplatin and doxorubicin. Further study is needed to define its role in the treatment of children with hepatocellular carcinoma.
Cryosurgery, intratumoral injection of alcohol, and radiofrequency ablation can successfully treat small (<5 cm) tumors in adults with cirrhotic livers.[30,32,33] Some local approaches such as cryosurgery, radiofrequency ablation, and TACE that suppress hepatocellular carcinoma tumor progression are used as bridging therapy in adults to delay tumor growth while on a waiting list for cadaveric liver transplant. (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)
Treatment options for hepatocellular carcinoma with metastases at diagnosis
No specific treatment has proven effective for metastatic hepatocellular carcinoma in the pediatric age group. In two prospective trials, cisplatin plus either vincristine/fluorouracil or continuous infusion doxorubicin was ineffective in adequately treating 25 patients with metastatic hepatocellular carcinoma.[13,20] Occasional patients may transiently benefit from treatment with cisplatin/doxorubicin therapy, especially if localized hepatic tumor shrinks adequately to allow resection of disease and metastases disappear or become resectable.
Treatment options for hepatitis B virus (HBV)–related hepatocellular carcinoma
Although HBV-related hepatocellular carcinoma is not common in children in the United States, nucleotide/nucleoside analog HBV inhibitor treatment improves postoperative prognosis in children and adults treated in China.
Treatment options for HBV-related hepatocellular carcinoma include the following:
Evidence (antiviral therapy):
Treatment options for progressive or recurrent hepatocellular carcinoma
The prognosis for a patient with recurrent or progressive hepatocellular carcinoma is extremely poor.
Treatment options for progressive or recurrent hepatocellular carcinoma include the following:
Undifferentiated embryonal sarcoma of the liver (UESL) is a distinct clinical and pathologic entity and accounts for 2% to 15% of pediatric hepatic malignancies.
UESL 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 is 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. Many UESL contain diverse elements of mesenchymal cell maturation, such as smooth muscle and fat. Undifferentiated sarcomas, like small cell undifferentiated hepatoblastomas, should be examined for loss of INI1 expression by immunohistochemistry to help rule out rhabdoid tumor of the liver.
It is important to make the diagnostic distinction between UESL and biliary tract rhabdomyosarcoma because they share some common clinical and pathologic features but treatment differs between the two, as shown in Table 6. (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.)
Distinctive histologic features are intracellular hyaline globules and marked anaplasia on a mesenchymal background.
Strong clinical and histological evidence suggests that UESL can arise within preexisting mesenchymal hamartomas of the liver, which are large benign multicystic masses that present in the first 2 years of life. In a report of 11 cases of UESL, five arose in association with mesenchymal hamartomas of the liver, and transition zones between the histologies were noted. Many mesenchymal hamartomas of the liver have a characteristic translocation with a breakpoint at 19q13.4 and several UESLs have the same translocation.[4,5] Some UESLs arising from mesenchymal hamartomas of the liver may have complex karyotypes not involving 19q13.4.
Treatment Options for Undifferentiated Embryonal Sarcoma of the Liver
UESL is rather rare. Only small series have been published regarding treatment.
The overall survival (OS) of children with UESL appears to be substantially better than 50% when combining reports, although all series are small and most may be selected to report successful treatment.; [Level of evidence: 3iiA]; [8,9,10,11,12,13,14,15,16][Level of evidence: 3iiiA]
Treatment options for UESL include the following:
The generally accepted approach is resection of the primary tumor mass in the liver when possible. However, use of aggressive chemotherapy regimens seems to have improved the OS. Neoadjuvant chemotherapy can be effective in decreasing the size of an unresectable primary tumor mass, resulting in resectability.[8,9,10,11] Most patients are treated with chemotherapy regimens often used for pediatric rhabdomyosarcoma or Ewing sarcoma without cisplatin.; [Level of evidence: 3iiA]; [8,9,10,11,12,13,14,15,16][Level of evidence: 3iiiA]
Evidence (surgical resection and chemotherapy):
Liver transplantation has on occasion been used successfully to treat an otherwise unresectable primary tumor.[14,16,17]
Choriocarcinoma of the liver is a very rare tumor that appears to originate in the placenta during gestation and presents with a liver mass in the first few months of life. Metastasis from the placenta to maternal tissues occurs in many cases, necessitating beta-human chorionic gonadotropin (beta-hCG) testing of the mother. Infants are often unstable at diagnosis because of hemorrhage of the tumor. Clinical diagnosis may be made without biopsy based on tumor imaging of the liver associated with extremely high serum beta-hCG levels and normal alpha-fetoprotein (AFP) levels for age.
Cytotrophoblasts and syncytiotrophoblasts are both present. The former are closely packed nests of medium-sized cells with clear cytoplasm, distinct cell margins, and vesicular nuclei. The latter are very large multinucleated syncytia formed from the cytotrophoblasts.
Treatment Options for Infantile Choriocarcinoma of the Liver
Treatment options for infantile choriocarcinoma of the liver include the following:
Initial surgical removal of the tumor mass may be difficult because of its friability and hemorrhagic tendency. Often surgical removal of the primary tumor is performed after neoadjuvant chemotherapy.
Maternal gestational trophoblastic tumors are exquisitely sensitive to methotrexate, and many women, including those with distant metastases, are cured with single-agent chemotherapy. Maternal and infantile choriocarcinoma both come from the same placental malignancy. The combination of cisplatin, etoposide, and bleomycin, as used in other pediatric germ cell tumors, has been effective in some patients and is followed by resection of residual mass. Use of neoadjuvant methotrexate in infantile choriocarcinoma, although often resulting in a response, has not been uniformly successful.
Epithelioid hemangioendothelioma 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.)
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood liver cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Cellular Classification of Childhood Liver Cancer
Added Figure 1 about the clinicopathological characteristics and the mutational status of the CTNNB1, APC, and NFE2L2 genes (cited Eichenmüller et al. as reference 2).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood liver cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Liver Cancer Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
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The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Childhood Liver Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/liver/hp/child-liver-treatment-pdq. Accessed <MM/DD/YYYY>.
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Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.
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For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.
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Last Revised: 2015-07-22
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