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Primary liver cancer forms in the tissues of the liver. Secondary liver cancer spreads to the liver from another part of the body. Learn about liver cancer and find information on how we support and care for children and teens with liver cancer before, during, and after treatment.
The Solid Tumor Center at Dana-Farber/Boston Children's Cancer and Blood Disorders Center treats children and teens with a variety of solid malignancies, including bone and soft tissue tumors, liver and kidney tumors, neuroblastomas, retinoblastomas and rare tumors. Our doctors provide unparalleled expertise in the diagnosis, treatment and management of these diseases.
Your child's care team will include pediatric oncologists, radiation oncologists, surgeons, pathologists, radiologists, and nurses with expertise in treating your child's specific type of cancer.
Our physicians are focused on family-centered care: From your first visit, you'll work with a team of professionals who are committed to supporting your family's needs. We consider you and your child integral parts of the care team. Our specialists will collaborate with you to customize a treatment plan that takes the needs of your child and your family into account.
As well as providing access to a range of innovative clinical trials through Dana-Farber/Boston Children's, we are New England's Phase I referral center for the Children's Oncology Group, which means we're able to offer clinical trials unavailable at other regional centers.
Your child will have access to long-term treatment and childhood cancer survivor support through Dana-Farber's David B. Perini, Jr. Quality of Life Clinic.
From diagnosis through treatment and survivorship, our team will be able to answer all of your questions about your child's care.
Find out more about our Solid Tumor Center, including the diseases we treat and our specialized programs for bone and soft tissue tumors, liver tumors, neuroblastoma, rare tumors, and retinoblastoma.
The liver is one of the largest organs in the body. It has four lobes and fills the upper right side of the abdomen inside the rib cage. Three of the many important functions of the liver are:
Liver cancer is rare in children and adolescents (teenagers). There are two main types of childhood liver cancer:
The treatment of two less common types of childhood liver cancer is also discussed in this summary:
Epithelioid hemangioendothelioma is a rare cancer of the blood vessels that occurs in the liver and other organs. See the Epithelioid hemangioendothelioma section in the PDQ summary on Childhood Soft Tissue Sarcoma Treatment for more information.
This summary is about the treatment of primary liver cancer (cancer that begins in the liver). Treatment of metastatic liver cancer, which is cancer that begins in other parts of the body and spreads to the liver, is not discussed in this summary. Primary liver cancer can occur in both adults and children. However, treatment for children is different than treatment for adults. See the PDQ summary on Adult Primary Liver Cancer Treatment for more information.
Anything that increases your chance of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your child’s doctor if you think your child may be at risk.
Risk factors for hepatoblastoma include the following:
Risk factors for hepatocellular carcinoma include the following:
Patients with tyrosinemia or progressive familial intrahepatic disease may receive a liver transplant before there are signs or symptoms of cancer.
Signs and symptoms are more common after the tumor gets big. Other conditions can cause the same signs and symptoms. Check with your child’s doctor if your child has any of the following:
The following tests and procedures may be used:
The following test may be done on the sample of tissue that is removed:
The prognosis (chance of recovery) and treatment options depend on the following:
Prognosis may also depend on:
For childhood liver cancer that recurs (comes back) after initial treatment, the prognosis and treatment options depend on:
Childhood liver cancer may be cured if the tumor is small and can be completely removed by surgery. Complete removal is possible more often for hepatoblastoma than for hepatocellular carcinoma.
The process used to find out if cancer has spread within the liver or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment.
The following tests and procedures may be used in the staging process for hepatoblastoma and hepatocellular carcinoma:
Two staging systems are used for childhood liver cancer:
The liver is divided into 4 vertical sections.
In stage 1, the cancer is found in one section of the liver. Three sections of the liver that are next to each other do not have cancer in them.
In stage 2, cancer is found in one or two sections of the liver. Two sections of the liver that are next to each other do not have cancer in them.
In stage 3, one of the following is true:
In stage 4, cancer is found in all four sections of the liver.
In stage I, the tumor was in the liver only and all of the cancer was removed by surgery.
In stage II, the tumor was in the liver only. After the cancer was removed by surgery, a small amount of cancer remains that can only be seen with a microscope.
In stage III:
In stage IV, the cancer has spread to other parts of the body, such as the lung or brain.
Cancer can spread through tissue, the lymph system, and the blood:
When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.
The metastatic tumor is the same type of cancer as the primary tumor. For example, if childhood liver cancer spreads to the lung, the cancer cells in the lung are actually liver cancer cells. The disease is metastatic liver cancer, not lung cancer.
Recurrent childhood liver cancer is cancer that has recurred (come back) after it has been treated. The cancer may come back in the liver or in other parts of the body.
Different types of treatments are available for children with liver cancer. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment.
Because cancer in children is rare, taking part in a clinical trial should be considered. Some clinical trials are open only to patients who have not started treatment.
Treatment will be overseen by a pediatric oncologist, a doctor who specializes in treating children with cancer. The pediatric oncologist works with other healthcare providers who are experts in treating children with liver cancer and who specialize in certain areas of medicine. It is especially important to have a pediatric surgeon with experience in liversurgery who can send patients to a liver transplant program if needed. Other specialists may include the following:
Side effects from cancer treatment that begin during or after treatment and continue for months or years are called late effects. Late effects of cancer treatment may include:
Some late effects may be treated or controlled. It is important to talk with your child's doctors about the effects cancer treatment can have on your child. (See the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information).
When possible, the cancer is removed by surgery.
Factors that affect the type of surgery used include the following:
Chemotherapy is sometimes given before surgery, to shrink the tumor and make it easier to remove. This is called neoadjuvant therapy. Even if the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given chemotherapy or radiation therapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.
Watchful waiting is closely monitoring a patient’s condition without giving any treatment until signs or symptoms appear or change.
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). Treatment using more than one anticancer drug is called combination chemotherapy. The way the chemotherapy is given depends on the type and stage of the cancer being treated.
Chemoembolization of the hepatic artery (the main artery that supplies blood to the liver) is a type of regional chemotherapy used to treat childhood liver cancer. The anticancer drug is injected into the hepatic artery through a catheter (thin tube). The drug is mixed with a substance that blocks the artery, cutting off blood flow to the tumor. Most of the anticancer drug is trapped near the tumor and only a small amount of the drug reaches other parts of the body. The blockage may be temporary or permanent, depending on the substance used to block the artery. The tumor is prevented from getting the oxygen and nutrients it needs to grow. The liver continues to receive blood from the hepatic portal vein, which carries blood from the stomach and intestine.
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, beads, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.
Radioembolization of the hepatic artery (the main artery that supplies blood to the liver) is a type of internal radiation therapy used to treat childhood liver cancer. A very small amount of a radioactive substance is attached to tiny beads that are injected into the hepatic artery through a catheter (thin tube). The beads are mixed with a substance that blocks the artery, cutting off blood flow to the tumor. Most of the radiation is trapped near the tumor to kill the cancer cells. This is done to relieve symptoms and improve quality of life for children with hepatocellular carcinoma.
Percutaneous ethanol injection is a cancer treatment in which a small needle is used to inject ethanol (alcohol) directly into a tumor to kill cancer cells.
Hepatocellular carcinoma that is linked to the hepatitis B virus is not common in children in the United States. Antiviral drugs that treat infection caused by the hepatitis B virus are being studied in the treatment of hepatocellular carcinoma.
Information about clinical trials is available from the NCI Web site.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.
Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.
Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's listing of clinical trials.
Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your child's condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.
Treatment of stages I and II hepatoblastoma may include the following:
Treatment of stage III hepatoblastoma may include the following:
The treatment of stage IV hepatoblastoma often includes chemotherapy and surgery. Combination chemotherapy is given to shrink the cancer in the liver and cancer that has spread to other parts of the body, such as the lungs or brain. After chemotherapy, imaging tests are done to check whether the cancer can be removed by surgery. Treatment may include one or more of the following:
Treatment of stages I and II hepatocellular carcinoma may include the following:
Treatment of stage III hepatocellular carcinoma and PRETEXT stage 4 hepatocellular carcinoma may include the following:
Treatment of stage IV hepatocellular carcinoma that was staged after surgery may include the following:
For children with advanced hepatocellular carcinoma, radioembolization may be used to relieve symptoms and improve quality of life.
Antiviral drugs that treat infection caused by the hepatitis B virus have also been used in the treatment of hepatocellular carcinoma.
Treatment of undifferentiatedembryonalsarcoma of the liver may include the following:
Treatment of choriocarcinoma of the liver in infants may include the following:
Treatment of recurrenthepatoblastoma may include the following:
Treatment of recurrenthepatocellular carcinoma may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood liver cancer. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your child's doctor about clinical trials that may be right for your child. General information about clinical trials is available from the NCI Web site.
For more information from the National Cancer Institute about childhood liver cancer, see the following:
For more childhood cancer information and other general cancer resources, see the following:
This information is provided by the National Cancer Institute.
This information was last updated on August 22, 2014.
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
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 follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Liver cancer is a rare malignancy in children and adolescents and is divided into two
major histologic subgroups: hepatoblastoma and hepatocellular carcinoma.
The incidence of 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. 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.
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%. Neonates with hepatoblastoma have comparable outcomes to older children up to age 5 years. The overall 5-year survival rate is 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.
Risk factors associated with hepatoblastoma and hepatocellular carcinoma are described in Table 1.
Aicardi syndrome 
Alagille syndrome 
Beckwith-Wiedemann syndrome 
Familial adenomatous polyposis 
Glycogen storage diseases I–IV 
Hepatitis B and C 
Low-birth-weight infants 
Progressive familial intrahepatic cholestasis 
Trisomy 18, other trisomies 
The incidence of hepatoblastoma is increased 1,000-fold to 10,000-fold in infants and children with Beckwith-Wiedemann syndrome. 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.
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. 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. 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.
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.
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.
Hepatocellular carcinoma is associated with hepatitis B and hepatitis C infection in adults,
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.
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 hepatocellular carcinoma 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. Orthotopic liver transplantation provides an additional treatment option for patients whose tumor remains unresectable after preoperative chemotherapy; however, the presence of microscopic residual tumor at the surgical margin does not preclude a favorable outcome. 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.
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.
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.
Beta-hCG levels may also be elevated in children with hepatoblastoma or hepatocellular carcinoma, which may result in isosexual precocity in boys. Extremely high levels of beta-hCG are associated with infantile choriocarcinoma 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.)
Undifferentiated Embryonal Sarcoma of the Liver
Biliary Tract Rhabdomyosarcoma
Age at Diagnosis
Median age 10.5 y
Median age 3.4 y
Often arises in the right lobe of the liver
Often arises in the hilum of the liver
Frequently; jaundice is a common presenting symptom
Surgery and chemotherapy
Surgery (usually biopsy only), radiation therapy, and chemotherapy
aAdapted from Nicol et al.
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. Some UESLs arising from mesenchymal hamartomas of the liver may have complex karyotypes not involving 19q13.4.
Choriocarcinoma of the liver is a very rare tumor that appears to originate in the placenta and presents with a liver mass in the first few months of life. Infants are often unstable due to hemorrhage 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.)
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Albrecht S, Hartmann W, Houshdaran F, et al.: Allelic loss but absence of mutations in the polyspecific transporter gene BWR1A on 11p15.5 in hepatoblastoma. Int J Cancer 111 (4): 627-32, 2004.
Clericuzio CL, Chen E, McNeil DE, et al.: Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia. J Pediatr 143 (2): 270-2, 2003.
Buonuomo PS, Ruggiero A, Vasta I, et al.: Second case of hepatoblastoma in a young patient with Simpson-Golabi-Behmel syndrome. Pediatr Hematol Oncol 22 (7): 623-8, 2005 Oct-Nov.
Aretz S, Koch A, Uhlhaas S, et al.: Should children at risk for familial adenomatous polyposis be screened for hepatoblastoma and children with apparently sporadic hepatoblastoma be screened for APC germline mutations? Pediatr Blood Cancer 47 (6): 811-8, 2006.
Hirschman BA, Pollock BH, Tomlinson GE: The spectrum of APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. J Pediatr 147 (2): 263-6, 2005.
Koch A, Denkhaus D, Albrecht S, et al.: Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene. Cancer Res 59 (2): 269-73, 1999.
Park WS, Dong SM, Kim SY, et al.: Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res 59 (2): 307-10, 1999.
Yoon JM, Burns RC, Malogolowkin MH, et al.: Treatment of infantile choriocarcinoma of the liver. Pediatr Blood Cancer 49 (1): 99-102, 2007.
Boman F, Bossard C, Fabre M, et al.: Mesenchymal hamartomas of the liver may be associated with increased serum alpha foetoprotein concentrations and mimic hepatoblastomas. Eur J Pediatr Surg 14 (1): 63-6, 2004.
Blohm ME, Vesterling-Hörner D, Calaminus G, et al.: Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age. Pediatr Hematol Oncol 15 (2): 135-42, 1998 Mar-Apr.
Pritchard J, Brown J, Shafford E, et al.: Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach--results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol 18 (22): 3819-28, 2000.
Czauderna P, Otte JB, Aronson DC, et al.: Guidelines for surgical treatment of hepatoblastoma in the modern era--recommendations from the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL). Eur J Cancer 41 (7): 1031-6, 2005.
Otte JB, Pritchard J, Aronson DC, et al.: Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 42 (1): 74-83, 2004.
Austin MT, Leys CM, Feurer ID, et al.: Liver transplantation for childhood hepatic malignancy: a review of the United Network for Organ Sharing (UNOS) database. J Pediatr Surg 41 (1): 182-6, 2006.
Zsíros J, Maibach R, Shafford E, et al.: Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study. J Clin Oncol 28 (15): 2584-90, 2010.
Schnater JM, Aronson DC, Plaschkes J, et al.: Surgical view of the treatment of patients with hepatoblastoma: results from the first prospective trial of the International Society of Pediatric Oncology Liver Tumor Study Group. Cancer 94 (4): 1111-20, 2002.
Van Tornout JM, Buckley JD, Quinn JJ, et al.: Timing and magnitude of decline in alpha-fetoprotein levels in treated children with unresectable or metastatic hepatoblastoma are predictors of outcome: a report from the Children's Cancer Group. J Clin Oncol 15 (3): 1190-7, 1997.
Brown J, Perilongo G, Shafford E, et al.: Pretreatment prognostic factors for children with hepatoblastoma-- results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1. Eur J Cancer 36 (11): 1418-25, 2000.
Perilongo G, Shafford E, Maibach R, et al.: Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology--SIOPEL 2. Eur J Cancer 40 (3): 411-21, 2004.
D'Antiga L, Vallortigara F, Cillo U, et al.: Features predicting unresectability in hepatoblastoma. Cancer 110 (5): 1050-8, 2007.
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Meyers RL, Rowland JR, Krailo M, et al.: Predictive power of pretreatment prognostic factors in children with hepatoblastoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 53 (6): 1016-22, 2009.
Schneider DT, Calaminus G, Göbel U: Diagnostic value of alpha 1-fetoprotein and beta-human chorionic gonadotropin in infancy and childhood. Pediatr Hematol Oncol 18 (1): 11-26, 2001 Jan-Feb.
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Stocker JT: Hepatic tumors in children. Clin Liver Dis 5 (1): 259-81, viii-ix, 2001.
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Shehata BM, Gupta NA, Katzenstein HM, et al.: Undifferentiated embryonal sarcoma of the liver is associated with mesenchymal hamartoma and multiple chromosomal abnormalities: a review of eleven cases. Pediatr Dev Pathol 14 (2): 111-6, 2011 Mar-Apr.
Stringer MD, Alizai NK: Mesenchymal hamartoma of the liver: a systematic review. J Pediatr Surg 40 (11): 1681-90, 2005.
O'Sullivan MJ, Swanson PE, Knoll J, et al.: Undifferentiated embryonal sarcoma with unusual features arising within mesenchymal hamartoma of the liver: report of a case and review of the literature. Pediatr Dev Pathol 4 (5): 482-9, 2001 Sep-Oct.
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.
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. 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 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  and is associated with AFP normal for age at presentation.
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. 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. 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. 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. 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.; [Level of evidence: 3iiA] Fibrolamellar hepatocellular carcinoma has also been reported in infants.
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.
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Malogolowkin MH, Katzenstein HM, Meyers RL, et al.: Complete surgical resection is curative for children with hepatoblastoma with pure fetal histology: a report from the Children's Oncology Group. J Clin Oncol 29 (24): 3301-6, 2011.
Trobaugh-Lotrario AD, Tomlinson GE, Finegold MJ, et al.: Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors. Pediatr Blood Cancer 52 (3): 328-34, 2009.
Rowland JM: Hepatoblastoma: assessment of criteria for histologic classification. Med Pediatr Oncol 39 (5): 478-83, 2002.
Gunawan B, Schäfer KL, Sattler B, et al.: Undifferentiated small cell hepatoblastoma with a chromosomal translocation t(22;22)(q11;q13). Histopathology 40 (5): 485-7, 2002.
Conran RM, Hitchcock CL, Waclawiw MA, et al.: Hepatoblastoma: the prognostic significance of histologic type. Pediatr Pathol 12 (2): 167-83, 1992 Mar-Apr.
Haas JE, Feusner JH, Finegold MJ: Small cell undifferentiated histology in hepatoblastoma may be unfavorable. Cancer 92 (12): 3130-4, 2001.
Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002.
Honeyman JN, Simon EP, Robine N, et al.: Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 343 (6174): 1010-4, 2014.
Lack EE, Neave C, Vawter GF: Hepatocellular carcinoma. Review of 32 cases in childhood and adolescence. Cancer 52 (8): 1510-5, 1983.
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Katzenstein HM, Krailo MD, Malogolowkin MH, et al.: Fibrolamellar hepatocellular carcinoma in children and adolescents. Cancer 97 (8): 2006-12, 2003.
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Cruz O, Laguna A, Vancells M, et al.: Fibrolamellar hepatocellular carcinoma in an infant and literature review. J Pediatr Hematol Oncol 30 (12): 968-71, 2008.
Prokurat A, Kluge P, Kościesza A, et al.: Transitional liver cell tumors (TLCT) in older children and adolescents: a novel group of aggressive hepatic tumors expressing beta-catenin. Med Pediatr Oncol 39 (5): 510-8, 2002.
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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).
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.
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. 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.
Revisions and radiologic examples of the PRETEXT staging system were published in 2007.
Any stage may have involvement of:
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:
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.
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%.
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%.
The COG study COG-AHEP0731 (Combination Chemotherapy in Treating Children With Newly Diagnosed Hepatoblastoma) incorporates the following risk groups:
Aronson DC, Schnater JM, Staalman CR, et al.: Predictive value of the pretreatment extent of disease system in hepatoblastoma: results from the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study. J Clin Oncol 23 (6): 1245-52, 2005.
Roebuck DJ, Olsen Ø, Pariente D: Radiological staging in children with hepatoblastoma. Pediatr Radiol 36 (3): 176-82, 2006.
Roebuck DJ, Aronson D, Clapuyt P, et al.: 2005 PRETEXT: a revised staging system for primary malignant liver tumours of childhood developed by the SIOPEL group. Pediatr Radiol 37 (2): 123-32; quiz 249-50, 2007.
Perilongo G, Brown J, Shafford E, et al.: Hepatoblastoma presenting with lung metastases: treatment results of the first cooperative, prospective study of the International Society of Paediatric Oncology on childhood liver tumors. Cancer 89 (8): 1845-53, 2000.
Perilongo G, Maibach R, Shafford E, et al.: Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N Engl J Med 361 (17): 1662-70, 2009.
Douglass E, Ortega J, Feusner J, et al.: Hepatocellular carcinoma (HCA) in children and adolescents: results from the Pediatric Intergroup Hepatoma Study (CCG 8881/POG 8945). [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-1439, 420, 1994.
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
Historically, complete surgical resection of the primary tumor has been required to cure
malignant liver tumors in children.; [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.; [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).
Liver transplantation has recently been associated with significant success in the treatment of children with unresectable hepatic tumors.[Level of evidence: 3iiA] A review of the world experience has documented a posttransplant survival rate of 70% to 80% for children with hepatoblastomas. 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. 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. 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. 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.
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.
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. 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 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  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.
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] SIOPEL has reported a pilot study of high-risk hepatoblastoma patients. In SIOPEL-3HR, cisplatin alternating with carboplatin/doxorubicin was administered 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 a second trial, cisplatin was dose-intensified (timing, every 2 weeks) in a single-arm prospective study. Three-year event-free survival (EFS) was 76% and OS was 83%. Toxicity was significant but acceptable.[Level of evidence: 2A]
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.
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.
The utility of radiation therapy is questioned because the liver cannot tolerate high doses of radiation.
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, 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.
Although HBV-related hepatocellular carcinoma is not common in children in the United States, nucleotide/nucleoside analog HBV inhibitor treatment improved postoperative prognosis in HBV-related hepatocellular carcinoma. In the randomized controlled trial, antiviral treatment significantly decreased hepatocellular carcinoma recurrence and
hepatocellular carcinoma-related death, with hazard ratios (HR) of 0.48 (95% confidence interval [CI], 0.32–0.70) and 0.26 (95% CI, 0.14–0.50), respectively, in multivariate Cox analyses. Patients who received antiviral treatment had
significantly decreased early recurrence (HR, 0.41; 95% CI, 0.27–0.62) and improved liver function
6 months after surgery compared with the controls (P< .001).
Other treatment approaches such as transarterial chemoembolization (TACE), have been used for patients with inoperable stage III hepatoblastoma. 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.
Cryosurgery, intratumoral injection of alcohol, and radiofrequency ablation can successfully treat small (<5 cm) tumors in adults with cirrhotic livers. 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. TACE has been used in a few children to successfully shrink tumor size to permit resection. 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.)
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Baertschiger RM, Ozsahin H, Rougemont AL, et al.: Cure of multifocal panhepatic hepatoblastoma: is liver transplantation always necessary? J Pediatr Surg 45 (5): 1030-6, 2010.
Beaunoyer M, Vanatta JM, Ogihara M, et al.: Outcomes of transplantation in children with primary hepatic malignancy. Pediatr Transplant 11 (6): 655-60, 2007.
Guiteau JJ, Cotton RT, Karpen SJ, et al.: Pediatric liver transplantation for primary malignant liver tumors with a focus on hepatic epithelioid hemangioendothelioma: the UNOS experience. Pediatr Transplant 14 (3): 326-31, 2010.
Malek MM, Shah SR, Atri P, et al.: Review of outcomes of primary liver cancers in children: our institutional experience with resection and transplantation. Surgery 148 (4): 778-82; discussion 782-4, 2010.
Héry G, Franchi-Abella S, Habes D, et al.: Initial liver transplantation for unresectable hepatoblastoma after chemotherapy. Pediatr Blood Cancer 57 (7): 1270-5, 2011.
Suh MY, Wang K, Gutweiler JR, et al.: Safety of minimal immunosuppression in liver transplantation for hepatoblastoma. J Pediatr Surg 43 (6): 1148-52, 2008.
Browne M, Sher D, Grant D, et al.: Survival after liver transplantation for hepatoblastoma: a 2-center experience. J Pediatr Surg 43 (11): 1973-81, 2008.
Faraj W, Dar F, Marangoni G, et al.: Liver transplantation for hepatoblastoma. Liver Transpl 14 (11): 1614-9, 2008.
Heaton N, Faraj W, Melendez HV, et al.: Living related liver transplantation in children. Br J Surg 95 (7): 919-24, 2008.
Reyes JD, Carr B, Dvorchik I, et al.: Liver transplantation and chemotherapy for hepatoblastoma and hepatocellular cancer in childhood and adolescence. J Pediatr 136 (6): 795-804, 2000.
Otte JB: Should the selection of children with hepatocellular carcinoma be based on Milan criteria? Pediatr Transplant 12 (1): 1-3, 2008.
Sevmis S, Karakayali H, Ozçay F, et al.: Liver transplantation for hepatocellular carcinoma in children. Pediatr Transplant 12 (1): 52-6, 2008.
Madanur MA, Battula N, Davenport M, et al.: Staged resection for a ruptured hepatoblastoma: a 6-year follow-up. Pediatr Surg Int 23 (6): 609-11, 2007.
Feusner JH, Krailo MD, Haas JE, et al.: Treatment of pulmonary metastases of initial stage I hepatoblastoma in childhood. Report from the Childrens Cancer Group. Cancer 71 (3): 859-64, 1993.
Zsiros J, Brugieres L, Brock P, et al.: Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol 14 (9): 834-42, 2013.
Robertson PL, Muraszko KM, Axtell RA: Hepatoblastoma metastatic to brain: prolonged survival after multiple surgical resections of a solitary brain lesion. J Pediatr Hematol Oncol 19 (2): 168-71, 1997 Mar-Apr.
Habrand JL, Nehme D, Kalifa C, et al.: Is there a place for radiation therapy in the management of hepatoblastomas and hepatocellular carcinomas in children? Int J Radiat Oncol Biol Phys 23 (3): 525-31, 1992.
Yin J, Li N, Han Y, et al.: Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol 31 (29): 3647-55, 2013.
Xianliang H, Jianhong L, Xuewu J, et al.: Cure of hepatoblastoma with transcatheter arterial chemoembolization. J Pediatr Hematol Oncol 26 (1): 60-3, 2004.
Malogolowkin MH, Stanley P, Steele DA, et al.: Feasibility and toxicity of chemoembolization for children with liver tumors. J Clin Oncol 18 (6): 1279-84, 2000.
Wang S, Yang C, Zhang J, et al.: First experience of high-intensity focused ultrasound combined with transcatheter arterial embolization as local control for hepatoblastoma. Hepatology 59 (1): 170-7, 2014.
Zhang Z, Liu Q, He J, et al.: The effect of preoperative transcatheter hepatic arterial chemoembolization on disease-free survival after hepatectomy for hepatocellular carcinoma. Cancer 89 (12): 2606-12, 2000.
Zhou XD, Tang ZY: Cryotherapy for primary liver cancer. Semin Surg Oncol 14 (2): 171-4, 1998.
Lencioni RA, Allgaier HP, Cioni D, et al.: Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 228 (1): 235-40, 2003.
Chen MS, Li JQ, Zheng Y, et al.: A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 243 (3): 321-8, 2006.
Lubienski A: Hepatocellular carcinoma: interventional bridging to liver transplantation. Transplantation 80 (1 Suppl): S113-9, 2005.
van Laarhoven S, van Baren R, Tamminga RY, et al.: Radiofrequency ablation in the treatment of liver tumors in children. J Pediatr Surg 47 (3): e7-e12, 2012.
Hawkins CM, Kukreja K, Geller JI, et al.: Radioembolisation for treatment of pediatric hepatocellular carcinoma. Pediatr Radiol 43 (7): 876-81, 2013.
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.
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.
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 EFS.
Patients whose tumors remain unresectable should be considered for liver transplantation. In the presence of features predicting unresectability, early coordination with a pediatric liver transplant service is desirable.
The outcome for metastatic hepatoblastoma at diagnosis is poor, but long-term survival and cure is possible. Survival rates at 3 to 5 years range from 20% to 60%.
The standard regimen is four courses of cisplatin/vincristine/fluorouracil  or doxorubicin/cisplatin combination chemotherapy  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%. A prospective feasibility trial of dose-dense, cisplatin-based chemotherapy and radical surgery in 62 patients with high-risk hepatoblastoma (SIOPEL-4 [NCT00077389]) resulted in a 3-year EFS of 76% and 3-year OS of 83%.[Level of evidence: 3iiDi] In this study, of 37 patients with distant metastases, 27 (78%) were surviving disease free at 3 years.
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,; [Level of evidence: 3iiA] high-dose cisplatin/etoposide, continuous-infusion doxorubicin, radiation therapy, or chemoembolization by hepatic arterial infusion.
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 Web site.
Reynolds M, Douglass EC, Finegold M, et al.: Chemotherapy can convert unresectable hepatoblastoma. J Pediatr Surg 27 (8): 1080-3; discussion 1083-4, 1992.
von Schweinitz D, Hecker H, Harms D, et al.: Complete resection before development of drug resistance is essential for survival from advanced hepatoblastoma--a report from the German Cooperative Pediatric Liver Tumor Study HB-89. J Pediatr Surg 30 (6): 845-52, 1995.
Malogolowkin MH, Katzenstein H, Krailo MD, et al.: Intensified platinum therapy is an ineffective strategy for improving outcome in pediatric patients with advanced hepatoblastoma. J Clin Oncol 24 (18): 2879-84, 2006.
Molmenti EP, Wilkinson K, Molmenti H, et al.: Treatment of unresectable hepatoblastoma with liver transplantation in the pediatric population. Am J Transplant 2 (6): 535-8, 2002.
Meyers RL, Katzenstein HM, Krailo M, et al.: Surgical resection of pulmonary metastatic lesions in children with hepatoblastoma. J Pediatr Surg 42 (12): 2050-6, 2007.
Katzenstein HM, Rigsby C, Shaw PH, et al.: Novel therapeutic approaches in the treatment of children with hepatoblastoma. J Pediatr Hematol Oncol 24 (9): 751-5, 2002.
Palmer RD, Williams DM: Dramatic response of multiply relapsed hepatoblastoma to irinotecan (CPT-11). Med Pediatr Oncol 41 (1): 78-80, 2003.
Qayed M, Powell C, Morgan ER, et al.: Irinotecan as maintenance therapy in high-risk hepatoblastoma. Pediatr Blood Cancer 54 (5): 761-3, 2010.
Zsíros J, Brugières L, Brock P, et al.: Efficacy of irinotecan single drug treatment in children with refractory or recurrent hepatoblastoma--a phase II trial of the childhood liver tumour strategy group (SIOPEL). Eur J Cancer 48 (18): 3456-64, 2012.
Sue K, Ikeda K, Nakagawara A, et al.: Intrahepatic arterial injections of cisplatin-phosphatidylcholine-Lipiodol suspension in two unresectable hepatoblastoma cases. Med Pediatr Oncol 17 (6): 496-500, 1989.
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.
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. 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. (Refer to the PDQ summary on Adult Primary Liver Cancer
Treatment for more information.)
Liver transplantation has been successful therapy for children with unresectable hepatocellular carcinoma; survival is about 60% with most deaths resulting from tumor recurrence.
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. 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. (Refer to the PDQ summary on Adult Primary Liver Cancer
Treatment for more information.)
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. 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.)
Bilik R, Superina R: Transplantation for unresectable liver tumors in children. Transplant Proc 29 (7): 2834-5, 1997.
Romano F, Stroppa P, Bravi M, et al.: Favorable outcome of primary liver transplantation in children with cirrhosis and hepatocellular carcinoma. Pediatr Transplant 15 (6): 573-9, 2011.
Laine J, Jalanko H, Saarinen-Pihkala UM, et al.: Successful liver transplantation after induction chemotherapy in children with inoperable, multifocal primary hepatic malignancy. Transplantation 67 (10): 1369-72, 1999.
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 resection of the primary tumor mass in the liver when possible. Neoadjuvant chemotherapy can be effective in decreasing an unresectable primary tumor mass, resulting in resectability. 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.[Level of evidence: 3iiiA] Most 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. 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.
Chowdhary SK, Trehan A, Das A, et al.: Undifferentiated embryonal sarcoma in children: beware of the solitary liver cyst. J Pediatr Surg 39 (1): E9-12, 2004.
Baron PW, Majlessipour F, Bedros AA, et al.: Undifferentiated embryonal sarcoma of the liver successfully treated with chemotherapy and liver resection. J Gastrointest Surg 11 (1): 73-5, 2007.
Kim DY, Kim KH, Jung SE, et al.: Undifferentiated (embryonal) sarcoma of the liver: combination treatment by surgery and chemotherapy. J Pediatr Surg 37 (10): 1419-23, 2002.
Webber EM, Morrison KB, Pritchard SL, et al.: Undifferentiated embryonal sarcoma of the liver: results of clinical management in one center. J Pediatr Surg 34 (11): 1641-4, 1999.
Bisogno G, Pilz T, Perilongo G, et al.: Undifferentiated sarcoma of the liver in childhood: a curable disease. Cancer 94 (1): 252-7, 2002.
Urban CE, Mache CJ, Schwinger W, et al.: Undifferentiated (embryonal) sarcoma of the liver in childhood. Successful combined-modality therapy in four patients. Cancer 72 (8): 2511-6, 1993.
Okajima H, Ohya Y, Lee KJ, et al.: Management of undifferentiated sarcoma of the liver including living donor liver transplantation as a backup procedure. J Pediatr Surg 44 (2): e33-8, 2009.
Weitz J, Klimstra DS, Cymes K, et al.: Management of primary liver sarcomas. Cancer 109 (7): 1391-6, 2007.
Plant AS, Busuttil RW, Rana A, et al.: A single-institution retrospective cases series of childhood undifferentiated embryonal liver sarcoma (UELS): success of combined therapy and the use of orthotopic liver transplant. J Pediatr Hematol Oncol 35 (6): 451-5, 2013.
Kelly MJ, Martin L, Alonso M, et al.: Liver transplant for relapsed undifferentiated embryonal sarcoma in a young child. J Pediatr Surg 44 (12): e1-3, 2009.
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. 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. 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 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. 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 II COG trial of single-agent sorafenib has been completed in children and the study results are pending. 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.
Malogolowkin MH, Katzenstein HM, Krailo M, et al.: Redefining the role of doxorubicin for the treatment of children with hepatoblastoma. J Clin Oncol 26 (14): 2379-83, 2008.
Llovet JM, Ricci S, Mazzaferro V, et al.: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359 (4): 378-90, 2008.
Schmid I, Häberle B, Albert MH, et al.: Sorafenib and cisplatin/doxorubicin (PLADO) in pediatric hepatocellular carcinoma. Pediatr Blood Cancer 58 (4): 539-44, 2012.
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.
This information was last updated on September 8, 2014.
Many children with cancer receive treatment in the outpatient setting, which allows them to stay in school and continue to develop intellectually and socially. However, returning to school can be an emotional experience; our Back to School Program is designed to ease your child's transition back to the classroom.
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The Expressive Arts Therapy program, sponsored by the Leonard P. Zakim Center for Integrative Therapies, provides adult patients, family members, and caregivers with a variety of options to support well-being during cancer treatment. From live music meditation to painting technique workshops, the program offers a range of creative outlets to suit every interest.
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Find practical tips and suggestions for individuals caring for a family member or friend with cancer, including creating a caregiving plan, finding community resources, and looking after your own well-being.
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More than 1,200 Dana-Farber patients and their families have enjoyed free trips to baseball games, theater shows, museums, and other attractions this year through the Recreational Resources program.
Through all stages of cancer treatment and survivorship, our Spiritual Care staff is available 24 hours a day to provide emotional and spiritual support for adults and pediatric patients and family members.
Integrative therapies, also known as complementary therapies, range from acupuncture and massage to nutritional guidance and music therapy. Patients treated at the Zakim Center credit its services with easing nausea, improving circulation, and reducing pain, stress, and anxiety associated with cancer treatment.
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