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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 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. 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%. 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.)
Hepatoblastoma and Hepatocellular Carcinoma
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 hepatoblastoma in the United States appears to have doubled from 0.8 (1975–1983) to 1.6 (2002–2009) per year per 1 million children aged 19 years and younger.[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. 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.
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.
The incidence of hepatocellular carcinoma in the United States is 0.8 in children between the ages of 0 and 14 years and 1.5 in adolescents aged 15 to 19 years per year per 1 million. 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.
The overall 5-year survival rate for children with hepatoblastoma is 70%,[10,11,12] but is only 42% for those 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.[3,13]
Risk factors associated with hepatoblastoma and hepatocellular carcinoma are described in Table 1.
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.[15,16] 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.[28,29]
Beckwith-Wiedemann syndrome can be caused by 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. The gene dosage 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.[16,30] 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.[31,32] The genetics of tumors in children with hemihyperplasia have not been clearly defined.
All children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia should be screened regularly by ultrasound to detect abdominal malignancies at an early stage. Screening using alpha-fetoprotein (AFP) levels, in addition to abdominal ultrasound, has helped in the early detection of hepatoblastoma in children with Beckwith-Wiedemann syndrome or hemihyperplasia. Other somatic overgrowth syndromes, such as Simpson-Golabi-Behmel syndrome, may also be associated with hepatoblastoma.
Familial adenomatous polyposis
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 has been reported to occur in less than 1% of FAP family members, so ultrasound and AFP screening for hepatoblastoma in members of families with FAP has been controversial.[17,18,19,35]
A study of 50 sequential children with apparent sporadic hepatoblastoma reported five children (10%) had APC mutations. Data to date 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. Perhaps, screening children with hepatoblastoma for APC mutations may be appropriate, as they should be followed for potential colon cancer. This preliminary study provides some evidence that screening children with hepatoblastoma for APC mutations 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.
Hepatitis B and hepatitis C infection
Hepatocellular carcinoma is associated with hepatitis B and hepatitis C infection in adults,[21,22,23] while in children there is an association with perinatally acquired hepatitis B virus. 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 occur in childhood hepatocellular carcinoma, and this 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.
Several specific types of nonviral liver injury and cirrhosis are associated with hepatocellular carcinoma in children, including tyrosinemia and biliary cirrhosis. Tyrosinemia patients should be screened for hepatoblastoma on a regular basis, whether or not they are treated with 2-(2 nitro-4-3 trifluoro-methylbenzoyl)-1, 3-cyclohexanedione. Hepatocellular carcinoma may also arise in very young children with mutations in the bile salt export pump ABCB11, which causes progressive familial hepatic cholestasis. Despite these findings, 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 livers bearing childhood hepatocellular carcinoma tumors.
A biopsy of the tumor is always indicated to secure the diagnosis of a liver tumor except:
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.
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 who is experienced in the resection of hepatoblastoma in children and has access to a liver transplant program.
Chemotherapy can often decrease the size and extent of hepatoblastoma, allowing complete resection.[10,11,12,42,43] Orthotopic liver transplantation provides an additional treatment option for patients whose tumor remains unresectable after preoperative chemotherapy;[43,44,45] however, the presence of microscopic residual tumor at the surgical margin does not preclude a favorable outcome.[46,47] This may be due to the additional courses of chemotherapy that are administered before or after resection for patients with stage I and pure fetal histology and after resection for all other patients.[10,11,47]
Hepatoblastoma is most often unifocal, and resection is often possible. 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.
Tumor marker–related factors
Ninety percent of patients with hepatoblastoma and two-thirds of patients with hepatocellular carcinoma have a serum tumor marker, AFP, which parallels disease activity. The level of AFP at diagnosis and rate of decrease in AFP during treatment should be 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 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.[46,49,50,51,52,53]
Beta-hCG levels may also be elevated in children with hepatoblastoma or hepatocellular carcinoma, which may result in isosexual precocity in boys.[54,55] Extremely high levels of beta-hCG are associated with infantile choriocarcinoma of the liver.
Undifferentiated Embryonal Sarcoma of the Liver
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. Many UESL contain diverse elements of mesenchymal cell maturation, such as smooth muscle and fat. Undifferentiated sarcomas and 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 2. (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, which are large benign multicystic masses that present in the first 2 years of life. Strong clinical and histological evidence suggest that UESL can arise within preexisting mesenchymal hamartomas of the liver. 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.[59,60] Some UESLs arising from mesenchymal hamartomas of the liver may have complex karyotypes not involving 19q13.4.
Infantile Choriocarcinoma of the Liver
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 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 AFP levels for age.
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.)
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. Two histologic subtypes have clinical relevance: pure fetal histology throughout the tumor and foci of small cell undifferentiated cells.
Pure fetal histology hepatoblastoma
Analysis of patients with initially resected hepatoblastoma tumors (prior to receiving chemotherapy) has suggested that those patients with pure fetal histology tumors have a better prognosis than those having an admixture of more primitive and rapidly dividing embryonal components or other undifferentiated tissues. In a study of patients with hepatoblastoma and pure fetal histology tumors, there was a 100% survival rate for patients who received four doses of single-agent doxorubicin. This suggested that patients with pure fetal histology tumors might not need chemotherapy after complete resection of a stage I tumor.[2,3] In the Children's Oncology Group (COG) study COG-P9645, 16 patients with stage I pure fetal histology hepatoblastoma with two or fewer mitoses per 10 high power fields were not treated with chemotherapy. Their retrospective PRETEXT stages were stage I (n = 4), stage II (n = 6), and stage III (n = 2). Survival was 100% with no chemotherapy given. All 16 patients entered on this study were alive with no evidence of disease at a median follow-up of 4.9 years (range, 9 months to 9.2 years). 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 [5,6] and is associated with AFP normal for age at presentation.[5,7]
Histologically, small cell undifferentiated hepatoblastoma is typified by a diffuse population of small cells with scant cytoplasm resembling neuroblasts. The chromosomal abnormalities reported for small cell undifferentiated hepatoblastoma are distinct from those occurring in other hepatoblastoma subtypes and are more similar to those observed in malignant rhabdoid tumors. These abnormalities include translocations involving a breakpoint on chromosome 22q11 and homozygous deletion at the chromosome 22q12 region that harbors the SMARCB1/INI1 gene.[5,9] Lack of detection of INI1 by immunohistochemistry is another characteristic shared by some small cell undifferentiated hepatoblastomas and malignant rhabdoid tumors. A third characteristic shared between small cell undifferentiated hepatoblastomas and malignant rhabdoid tumors is the poor prognosis associated with each.[5,6,10] 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. 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 the Stage Information section of this summary for more information).
The cells of hepatocellular carcinoma are epithelial while hepatoblastoma has a less differentiated embryonal appearance. Hepatocellular carcinoma also differs from hepatoblastoma in that it often arises in a previously abnormal, cirrhotic liver. Both histologic types more commonly arise in the right lobe of the liver. Chronic hepatitis B is the leading cause of hepatocellular carcinoma in children in Asian and African countries; however, underlying liver disease can be identified in less than one-third of the children and adolescents with hepatocellular carcinoma in western countries.
A distinctive histologic variant of hepatocellular carcinoma, termed fibrolamellar carcinoma, has been described in the livers of older children and young adults. Fibrolamellar carcinoma is thought to be associated with an improved prognosis and is not associated with cirrhosis.[13,14,15] 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, because the outcome in recent prospective studies, when compared stage for stage, is not different from other hepatocellular carcinomas.[12,16] Fibrolamellar hepatocellular carcinoma has also been reported in infants.
Transitional liver cell tumor
Transitional liver cell tumor 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. The tumors are usually unifocal and may have central necrosis at presentation. Response to chemotherapy is poor, much like hepatocellular carcinoma.
Undifferentiated embryonal sarcoma of the liver is a distinct clinical and pathologic entity and accounts for 2% to 15% of pediatric hepatic malignancies. Distinctive features are intracellular hyaline globules and marked anaplasia on a mesenchymal background.
These tumors are usually very friable and hemorrhagic and may present with bleeding into the tumor. The diagnosis can be made by imaging and findings of extremely high beta-human chorionic gonadotropin levels.
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.
There are two standard surgical staging systems for pediatric liver tumors. The International Society of Pediatric Oncology Epithelial Liver Tumor Group (SIOPEL) uses a presurgical-based (PRETEXT) staging system, while the Children's Oncology Group (COG) uses a postsurgical-based staging system. The SIOPEL presurgical staging system is used with neoadjuvant chemotherapy followed by definitive surgery, while the COG staging system is based on the findings at time of operation, whenever possible.
Both staging systems are used in the United States, although initial resection of PRETEXT 1 and 2 hepatoblastomas are routinely undertaken in the United States. In a retrospective comparison of the two staging systems at diagnosis using data from patients entered on a North American randomized trial, both staging systems predicted outcome. The presurgical PRETEXT staging system may add prognostic information compared with postsurgical staging alone. The European PRETEXT staging system can also be used to restage patients after surgery, which has been termed POSTTEXT staging. The COG is investigating the use of PRETEXT/POSTTEXT stage before and after chemotherapy to determine the optimal surgical approach (COG-AHEP0731).
Presurgical Staging for Hepatoblastoma and Hepatocellular Carcinoma
The European PRETEXT staging system for hepatoblastoma categorizes the primary tumor based on extent of liver involvement at diagnosis. In Europe, all children with hepatoblastoma are treated with chemotherapy prior to attempted resection of the primary tumor. The liver tumors are staged by interpretation of computerized tomography or ultrasound with or without additional imaging by magnetic resonance. The presence or absence of metastases is noted, but it does not alter the PRETEXT stage. Tumor involvement of the vena cava, hepatic veins, and portal vein, and extrahepatic extension are also noted.
The imaged liver is divided into four sectors and involvement of each sector with tumor is determined. Stage increases and prognosis decreases as the number of liver sectors radiologically involved with tumor increases from one to four.[2,3] Experienced radiologist review is important because it may be difficult to discriminate between real invasion beyond the anatomic border of a given sector and displacement of the anatomic border.[3,4]
PRETEXT stage 1
PRETEXT stage 2
PRETEXT stage 3
PRETEXT stage 4
Any stage may have involvement of:
Hepatoblastoma and hepatocellular carcinoma prognosis by PRETEXT stage
The PRETEXT staging system has a moderate degree of interobserver variability, and the preoperative PRETEXT stage agrees with postoperative pathologic findings only 51% of the time, with overstaging in 37% of patients and understaging in 12% of patients.
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:
The second international study compared 3-year OS among hepatoblastoma patients by PRETEXT stage absent of extrahepatic disease. The 3-year OS was as follows:
The study also prospectively analyzed OS in patients by the presence of intraabdominal extrahepatic disease without distant metastasis (OS, 58%) and distant metastases (OS, 44%). Patients who underwent orthotopic liver transplant are included in all of the international study results. The COG is investigating prospective staging 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).
The 5-year OS for PRETEXT staged hepatocellular carcinoma was as follows:
Postsurgical Staging for Childhood Liver Cancer
A staging system based on operative findings and surgical resectability has been used in the United States to group children with liver cancer. This staging system is used to determine treatment.[10,11,12]
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 is 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%.[1,5,7,12,16]
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 vary widely based on published reports, from 20% to approximately 60%.[1,5,6,7,12,16]
Hepatocellular carcinoma prognosis by postsurgical stage of disease at diagnosis
Treatment Options Under Clinical Evaluation: COG Hepatoblastoma Risk Groups
The COG study COG-AHEP0731 (Combination Chemotherapy in Treating Children With Newly Diagnosed Hepatoblastoma) incorporates the following risk groups:
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 into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists with experience treating tumors of childhood is required to determine and implement optimum treatment.
Historically, complete surgical resection of the primary tumor has been required to cure malignant liver tumors in children.[2,3,4,5]; [Level of evidence: 3iiA] Complete surgical resection of the primary tumor continues to be the goal of definitive surgical procedures, but surgical resection is often combined with other treatment modalities (e.g., chemotherapy) to achieve this goal.
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 should be 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, this is especially true for hepatocellular carcinoma because no effective chemotherapy is 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 stage 3 or 4 disease, involvement of major liver vessels, and low alpha-fetoprotein (AFP) levels. While vascular involvement was initially thought to be a contraindication to resection, experienced liver surgeons are able to perform aggressive approaches avoiding transplantation.[7,8]; [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:
In North American clinical trials, the Children's Oncology Group (COG) has recommended that surgery be performed initially if a complete resection can be accomplished (refer to the Postsurgical Staging for Childhood Liver Cancer section of this summary for more information). COG is investigating the use of PRETEXT stage at diagnosis and after chemotherapy to determine the optimal surgical approach and its timing (COG-AHEP0731).
Orthotopic liver transplantation
Liver transplantation has recently been associated with significant success in the treatment of children with unresectable hepatic tumors.[11,12,13,14][Level of evidence: 3iiA] A review of the world experience has documented a posttransplant survival rate of 70% to 80% for children with hepatoblastomas.[10,15,16] Intravenous invasion, positive lymph nodes, and contiguous spread did not have a significant adverse effect on outcome. It has been suggested that adjuvant chemotherapy following transplant may decrease the risk of tumor recurrence.
There are discrepant results on the outcomes for patients with lung metastases at diagnosis who undergo orthotopic liver transplantation following complete resolution of lung disease in response to pretransplant chemotherapy. Some studies have reported favorable outcomes for this group of patients, while others have noted high rates of hepatoblastoma recurrence.[16,18] All of these studies are limited by small patient numbers; further study is needed to better define outcomes for this subset of patients.
The United Network for Organ Sharing (UNOS) Standard Transplant and Research Files registry reported all children younger than 18 years listed for a liver transplant in the United States from October 1987 through July 2004. Of these children, 135 had hepatoblastoma and 41 had hepatocellular carcinoma and both groups received liver transplant with 5-year survival rates of 69% for hepatoblastoma and 63% for hepatocellular carcinoma. The 10-year survival rates were similar to the 5-year rates.[19,20] In a separate three-institution study for children with hepatocellular carcinoma, the overall 5-year disease-free survival rate was approximately 60%. Application of the Milan criteria for UNOS selection of recipients of deceased donor livers is controversial. However, living donor liver transplants are more common with children and the outcome is similar.[18,23] 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, prior to the development of liver failure and malignancy.
It should be noted that the Milan criteria for liver transplantation is directed toward adults with cirrhosis and hepatocellular carcinoma. It should not be applied to children and adolescents with hepatocellular carcinoma, especially those without cirrhosis.
Special considerations for surgical resection
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.
Microscopic residual disease after resection
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.[16,25] In a European study conducted between 1990 and 1994, 11 patients had tumor found at the surgical margins following hepatic resection and only two patients died, neither of whom had a local recurrence. None of the 11 patients underwent a second resection and only one patient received radiation therapy postoperatively. All of the patients were treated with four courses of cisplatin and doxorubicin prior to surgery and received two courses of postoperative chemotherapy. In another European study of high-risk hepatoblastoma, 11 patients had microscopic residual tumor remaining after initial surgery and received two to four postoperative cycles of chemotherapy with no additional surgery. Of these 11 patients, 9 survived.
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 [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.
In recent years, virtually all children with hepatoblastoma have been treated with chemotherapy, and in some centers, even children with resectable hepatoblastoma are treated with preoperative chemotherapy, which may reduce the incidence of surgical complications at the time of resection.[25,29,30]
In an international study, pre-resection neoadjuvant chemotherapy (doxorubicin and cisplatin) was given to all children with hepatoblastoma with or without metastases. The chemotherapy was well tolerated. Following chemotherapy, and excluding those who received liver transplant (less than 5% of patients), complete resection was obtained in 87% of children. This strategy resulted in an overall survival (OS) of 75% at 5 years after diagnosis for all children entered in the study. Identical overall results were seen in a follow-up international study. The International Society of Pediatric Oncology Epithelial Liver Tumor Group (SIOPEL) compared cisplatin alone with cisplatin and doxorubicin in patients with preoperative standard-risk hepatoblastoma. Standard-risk was defined as tumor confined to the liver and not involving more than three sectors. The rates of resection were similar for the cisplatin (95%) and cisplatin/doxorubicin (93%) groups, as were OS (95% and 93%), respectively.[Level of evidence:1iiA] Another SIOPEL study of high-risk hepatoblastoma patients treated with cisplatin alternating with carboplatin/doxorubicin in a dose intensive fashion. In 74 patients with PRETEXT stage 4 tumors, 22 of whom also had metastases, 31 became resectable and 26 underwent transplant. The 3-year OS of this group was 69% ± 11%. The 3-year OS of all patients with metastases was 62% ± 12%.
In contrast, an American Intergroup protocol for treatment of children with hepatoblastoma encouraged resection at the time of diagnosis for all tumors amenable to resection without undue risk. The protocol (COG-P9645) did not treat children with stage I tumors of purely fetal histology with preoperative or postoperative chemotherapy unless they developed progressive disease. Further study will be needed to determine whether presurgical chemotherapy is preferable to resection followed by chemotherapy for children with PRETEXT stage 2, 3, and 4 hepatoblastoma.
Chemotherapy and metastatic disease
In rare cases, chemotherapy has eradicated pulmonary metastases and eliminated multinodular tumor foci in the liver. Intensive platinum- and doxorubicin-based multidrug chemotherapy can induce complete regressions in approximately 50% of patients, with subsequent 3-year event-free survival of 56%. Chemotherapy has been much more successful in the treatment of hepatoblastoma than in hepatocellular carcinoma.[4,5,29,30,32,33,34]
Limited Role for Radiation Therapy
The utility of radiation therapy is questioned because the liver cannot tolerate high doses of radiation.[33,35]
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,[33,35] although a study of 154 patients with hepatoblastoma did not confirm this finding. This study showed that second resection of positive margins and/or radiation therapy may not be necessary in patients with incompletely resected hepatoblastoma whose residual tumor is microscopic.
For patients with stage IV disease in which extrahepatic disease is controlled, but the primary tumor remains unresectable following standard chemotherapy, radiation therapy has been used as an interim treatment measure prior to surgical re-exploration.
Other Treatment Approaches
Other treatment approaches such as transarterial chemoembolization, have been used for patients with inoperable stage III hepatoblastoma.[36,37]
Cryosurgery, intratumoral injection of alcohol, and radiofrequency ablation can successfully treat small (<5 cm) tumors in adults with cirrhotic livers.[38,39,40,41] Some local approaches such as cryosurgery, radiofrequency ablation, and transarterial chemoembolization 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.[42,43] Transarterial chemoembolization has been used in a few children to successfully shrink tumor size to permit resection. (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)
Treatment Options for Stages I and II
In the Children's Oncology Group (COG) study COG-P9645, stage I pure fetal histology hepatoblastomas with two or fewer mitoses per 10 high power fields were not treated with chemotherapy. Completely excised tumor of purely fetal and favorable histology may be carefully followed without further therapy. A small focus of undifferentiated small cell histology within an otherwise pure fetal histology tumor must be treated with aggressive chemotherapy.
Combination chemotherapy has been demonstrated to have significant benefit in children with hepatoblastoma. Cisplatin-based chemotherapy has resulted in a survival rate of greater than 90% for children with postsurgical stage I and stage II disease.[3,4,5,7]
A randomized clinical trial demonstrated comparable efficacy with cisplatin/vincristine/fluorouracil and cisplatin/doxorubicin in the treatment of hepatoblastoma. Although outcome was nominally higher for children receiving cisplatin/doxorubicin, this difference was not statistically significant, and the combination of cisplatin/vincristine/fluorouracil was significantly less toxic than the doses of cisplatin/doxorubicin, to which it was compared.
Treatment Options for Stage III
In approximately 75% of children and adolescents with initially unresectable hepatoblastoma, tumors can be rendered resectable with cisplatin-based preoperative chemotherapy, and 60% to 65% will survive disease-free.
A North American randomized clinical trial demonstrated comparable efficacy with cisplatin/vincristine/fluorouracil and cisplatin/doxorubicin in the treatment of hepatoblastoma. Although outcome was nominally higher for children receiving cisplatin/doxorubicin, this difference was not statistically significant, and the combination of cisplatin/vincristine/fluorouracil was significantly less toxic than the doses of cisplatin/doxorubicin used.
A combination of ifosfamide, cisplatin, and doxorubicin has also been successfully used in the treatment of advanced-stage disease. A regimen of intensified platinum therapy with alternating cisplatin and carboplatin was associated with a decrease in event-free survival (EFS).
Patients whose tumors remain unresectable should be considered for liver transplantation.[5,11,12,13,14,15] In the presence of features predicting unresectability, early coordination with a pediatric liver transplant service is desirable.
Treatment Options for Stage IV
The outcome for metastatic hepatoblastoma at diagnosis is poor, but long-term survival and cure is possible.[3,6,7] Survival rates at 3 to 5 years range from 20% to 60%.[19,20,21]
The standard regimen is four courses of cisplatin/vincristine/fluorouracil  or doxorubicin/cisplatin combination chemotherapy [5,19] followed by attempted complete tumor resection. If the tumor is completely removed, two postoperative courses of the same chemotherapy should be given.
In a study employing a well-tolerated regimen of doxorubicin/cisplatin chemotherapy, about 50% of patients with metastases at presentation survived 5 years from diagnosis. Half of these survivors had developed progressive disease that was successfully treated with surgery and other interventions. In another study, platinum- and doxorubicin-based multidrug chemotherapy induced complete regression in approximately 50% of patients, with subsequent 3-year EFS of 56%.
Several studies have tested different chemotherapy regimens. A randomized clinical trial compared cisplatin/vincristine/fluorouracil with cisplatin/doxorubicin. Although outcome was nominally higher for children receiving cisplatin/doxorubicin, this difference was not statistically significant, and the combination of cisplatin/vincristine/fluorouracil was less toxic than the regimen of cisplatin/doxorubicin. The cisplatin/doxorubicin used in the international studies appears to be less toxic than that in the North American study. Addition of carboplatin to intensify the cisplatin/doxorubicin may have reduced its efficacy. A regimen of intensified platinum therapy with alternating cisplatin and carboplatin was associated with a decrease in EFS. A combination of ifosfamide, cisplatin, and doxorubicin has also been successfully used in the treatment of advanced-stage disease.
If possible, stage IV patients with resected primary tumor should have remaining pulmonary metastases surgically removed. A review of patients treated on a U.S. Intergroup trial suggested that resection may be done at the time of resection of the primary tumor.[Level of evidence: 3iiA]
Patients whose extrahepatic tumors remain unresectable or who are not transplant candidates should be considered for alternative chemotherapy such as irinotecan,[22,23,24] high-dose cisplatin/etoposide, continuous-infusion doxorubicin, radiation therapy,[3,25] or chemoembolization by hepatic arterial infusion.[18,26]
Treatment Options Under Clinical Evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
The following treatment option is under investigation in a COG clinical trial. Information about ongoing clinical trials is available from the NCI Web site.
In a randomized trial, seven of eight patients with stage I hepatocellular carcinoma survived disease free after adjuvant cisplatin-based chemotherapy. In a survey of childhood liver tumors treated prior to the consistent use of chemotherapy, only 12 of 33 patients with hepatocellular carcinoma who had complete excision of the tumor survived. This suggests that adjuvant chemotherapy may benefit children with completely resected hepatocellular carcinoma. Treatment with cisplatin and doxorubicin may be recommended as adjuvant therapy since these are active agents in the treatment of hepatocellular carcinoma. Despite improvements in surgical techniques, chemotherapy delivery, and patient supportive care in the past 20 years, clinical trials of cancer chemotherapy for hepatocellular carcinoma have not shown improved outcome.
Studies in adults in China suggest that repeated hepatic transarterial chemoembolization before surgery may improve the outcome of subsequent hepatectomy. (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)
The use of neoadjuvant chemotherapy followed by complete gross surgical resection of the primary tumor is necessary for cure.
Liver transplantation has been a successful therapy for children with unresectable hepatocellular carcinoma; survival is about 60% with most deaths resulting from tumor recurrence.[5,6,7,8]
No specific treatment has proven effective for unresectable hepatocellular carcinoma in the pediatric age group. A prospective study of 41 patients who were to receive preoperative cisplatin/doxorubicin chemotherapy resulted in some degree of decrease in tumor size with a decrease in alpha-fetoprotein (AFP) levels in about 50% of patients. The responders had a superior tumor resectability and survival, although the overall survival (OS) was 28% and only those undergoing complete resection survived. Cryosurgery, intratumoral injection of alcohol, and radiofrequency ablation can successfully treat small (<5 cm) tumors in adults with cirrhotic livers.[4,9,10] Some local approaches such as cryosurgery, radiofrequency ablation, and transarterial chemoembolization 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. Transarterial chemoembolization has been used in a few children to successfully shrink tumor size to permit resection.[4,12] (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)
Treatment Options for Presurgically Staged (PRETEXT) Stage 4
Liver transplantation has been successful therapy for children with unresectable hepatocellular carcinoma; survival is about 60% with most deaths resulting from tumor recurrence.[5,6,7]
No specific treatment has proven effective for unresectable hepatocellular carcinoma in the pediatric age group. A prospective study of 41 patients who were to receive preoperative cisplatin/doxorubicin chemotherapy resulted in some degree of decrease in tumor size with a decrease in AFP level in about 50% of patients. The responders had a superior tumor resectability and survival, although the OS was 28% and only those undergoing complete resection survived. The 5-year OS for PRETEXT stage 4 patients, including those with metastasis and/or extrahepatic disease, was 1 in 13. Cryosurgery, intratumoral injection of alcohol, and radiofrequency ablation can successfully treat small (<5 cm) tumors in adults with cirrhotic livers.[4,9,10] Some local approaches such as cryosurgery, radiofrequency ablation, and transarterial chemoembolization 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.[6,11,13] Transarterial chemoembolization has been used in a few children to successfully shrink tumor size to permit resection.[4,12] (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)
Treatment Options for Postsurgically Staged Stage IV
No particular 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.[1,3] Occasional patients may benefit from treatment with cisplatin/doxorubicin therapy, especially if localized hepatic tumor shrinks adequately to allow resection of disease. (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)
Undifferentiated embryonal sarcoma of the liver is so rare that only small series have been published regarding treatment. However, use of aggressive chemotherapy regimens seems to have improved the overall survival (OS). The generally accepted approach is to resect the primary tumor mass in the liver when possible. Neoadjuvant chemotherapy can be effective in decreasing an unresectable primary tumor mass, resulting in resectability.[1,2,3,4] The OS of these children appears to be substantially better than 50% when combining reports, although all series are small and most may be selected to report successful treatment.[1,2,3,4,5,6,7,8] The majority of patients were treated with chemotherapy regimens often used for pediatric rhabdomyosarcoma or Ewing sarcoma without cisplatin.
Liver transplantation has on occasion been used successfully to treat an otherwise unresectable primary tumor.[7,9] In the only prospective series from the Italian and German Soft Tissue Sarcoma Cooperative Groups, patients were treated with conservative surgery or biopsy followed by neoadjuvant chemotherapy consisting of varying combinations of vincristine, cyclophosphamide, dactinomycin, doxorubicin, and ifosfamide. Disease evaluation, usually after four cycles of chemotherapy, was followed by second-look surgery when appropriate to try to remove residual primary tumor followed by additional and/or adjuvant chemotherapy. Ten of 17 patients survived in their first complete remission, and one patient survived in his or her third complete remission.
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 placenta to maternal tissues occurs in many cases, necessitating beta-human chorionic gonadotropin (beta-hCG) testing of the mother. Infants are often anemic and can be unstable at presentation due to hemorrhage from the tumor. Clinical diagnosis may be made without biopsy based on extremely high serum beta-hCG levels and normal alpha-fetoprotein levels for age. Initial surgical removal of the tumor mass may be difficult because of its friability and hemorrhagic tendency. Often surgical removal of the residual 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.
The prognosis for a patient with recurrent or progressive hepatoblastoma depends on many factors, including the site of recurrence, prior treatment, and individual patient considerations. For example, in patients with stage I hepatoblastoma at initial diagnosis, aggressive surgical treatment of isolated pulmonary metastases that develop in the course of the disease may make extended disease-free survival possible.[1,2] Analysis of survival after recurrence demonstrated that some patients treated with cisplatin/vincristine/fluorouracil could be salvaged with doxorubicin-containing regimens, but patients treated with doxorubicin/cisplatin could not be salvaged with vincristine/fluorouracil. Addition of doxorubicin to vincristine/fluorouracil/cisplatin is under clinical evaluation in the Children's Oncology Group (COG) study COG-AHEP0731. Combined vincristine/irinotecan has been used with some success.[Level of evidence: 3iiiA] If possible, isolated metastases should be resected completely in patients whose primary tumor is controlled. Liver transplant should be considered for patients with isolated recurrence in the liver.[6,7,8] 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.
Recurrent Hepatocellular Carcinoma
The prognosis for a patient with recurrent or progressive hepatocellular carcinoma is poor. Chemoembolization or liver transplant should be considered for those with isolated recurrence in the liver.[6,7,8] Phase I and phase II clinical trials may be appropriate and should be considered. (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)
Sorafenib has resulted in improved progression-free survival in adults with advanced hepatocellular carcinoma. For adult patients who received sorafenib, the median survival and time to radiologic progression were about 3 months longer than those who received a placebo. A phase I trial has been completed in children, and a single-agent, phase II COG trial is underway. Limited data from a European pilot study suggest that sorafenib may have been beneficial to 12 newly diagnosed patients with advanced hepatocellular carcinoma when given in combination with standard chemotherapy with cisplatin and doxorubicin.
Treatment options under clinical evaluation for recurrent hepatocellular carcinoma
The following treatment option is under investigation in a COG clinical trial. Information about ongoing clinical trials is available from the NCI Web site.
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.
Treatment Option Overview
Added van Laarhoven et al. as reference 43.
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.
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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
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://cancer.gov/cancertopics/pdq/treatment/childliver/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2013-03-29
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