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Liver cancer is a rare malignancy in children and adolescents and is divided into the following two major histologic subgroups:
Other, less common, histologies include the following:
Liver tumors are rare in children. Their diagnoses may be challenging, in part, because of the lack of consensus regarding a classification system. Systematic central histopathological review of these tumors performed as part of pediatric collaborative therapeutic protocols has allowed the identification of histologic subtypes with distinct clinical associations. As a result, histopathology has been incorporated within the Children's Oncology Group (COG) protocols and, in the United States, as a risk-stratification parameter used for patient management.
The COG Liver Tumor Committee sponsored an International Pathology Symposium in 2011 to discuss the histopathology and classification of pediatric liver tumors (hepatoblastoma, in particular) to develop an International Pediatric Liver Tumors Consensus Classification that would be required for international collaborative projects. The results of this international classification for pediatric liver tumors have been published. This standardized, clinically meaningful classification will allow the integration of new biological parameters and tumor genetics within a common pathologic language in order to help improve future patient management and outcome.
For information on the histology of each childhood liver cancer subtype, refer to the following sections of this summary:
Historically, the four major study groups (International Childhood Liver Tumors Strategy Group [previously known as Société Internationale d'Oncologie Pédiatrique–Epithelial Liver Tumor Study Group (SIOPEL)], Children's Oncology Group [COG], Gesellschaft für Pädiatrische Onkologie und Hämatologie [Society for Paediatric Oncology and Haematology], and Japanese Study Group for Pediatric Liver Tumors) have had disparate risk stratification categories, making it difficult to compare outcomes across continents. All groups are now using the PRE-Treatment EXTent of tumor (PRETEXT) grouping system as part of the risk stratification.
Tumor Stratification by Imaging
The primary treatment goal for patients with liver cancer is surgical extirpation of the primary tumor. Therefore, the risk grouping designed depends heavily on factors determined by imaging that are related to safe surgical resection of the tumor, as well as the PRETEXT grouping. These imaging findings are termed annotation factors.
The use of high-quality, cross-sectional imaging to evaluate children with hepatoblastoma is of paramount importance because the risk stratification that defines treatment is very dependent on imaging analysis. Three-phase computed tomography scanning (noncontrast, arterial, and venous) or magnetic resonance imaging (MRI) with contrast agents are used for imaging. MRI with gadoxetate disodium, a gadolinium-based agent that is preferentially taken up and excreted by hepatocytes, is being used with increased frequency and may improve detection of multifocal disease.
The imaging grouping systems used to radiologically define the extent of liver involvement by the tumor is designated as:
PRETEXT and POSTTEXT Group Definitions
PRETEXT is used by the major multicenter trial groups as a central component of risk stratification schemes that define treatment of hepatoblastoma. PRETEXT is based on the Couinaud eight-segment anatomic structure of the liver using cross-sectional imaging. The PRETEXT system divides the liver into four parts, called sections. The left lobe of the liver consists of a lateral section (Couinaud segments I, II, and III) and a medial section (segment IV), whereas the right lobe consists of an anterior section (segments V and VIII) and a posterior section (segments VI and VII) (refer to Figure 1). PRETEXT groups were devised by the SIOPEL for their first trial, SIOPEL-1  and revised for SIOPEL-3 in 2007.
Figure 1. PRETEXT is distinct from Couinaud 8-segment (I–VIII) anatomic division of the liver. PRETEXT defines 4 'Sections'. Boundaries of each section defined by the right and middle hepatic veins, and umbilical fissure. Reprinted by permission from Copyright Clearance Center: Springer Nature, Modern Pathology, Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium, Dolores López-Terrada, Rita Alaggio, Maria T de Dávila, et al., Copyright © 2013.
PRETEXT group assignment I, II, III, or IV is determined by the number of contiguous uninvolved sections of the liver. PRETEXT is further described by annotation factors, defined as V, P, E, M, C, F, N, or R, depending on extension of tumor beyond the hepatic parenchyma of the major sections (refer to Table 1 for detailed descriptions of the PRETEXT groups and Table 2 for descriptions of the annotation factors).
Annotation factors identify the extent of tumor involvement of the major vessels and its effect on venous inflow and outflow, which is critical knowledge for the surgeon and can affect surgical outcomes. There were differences in the definitions of gross vascular involvement used by the COG and major liver surgery centers in the United States compared with SIOPEL definitions used in Europe; these differences have been resolved in the definitions to be used in an international trial that begins in 2018.
Although PRETEXT can be used to predict tumor resectability, there are limitations. The distinction between real invasion beyond the anatomic border of a given hepatic section and the compression and displacement by the tumor can be very difficult, especially at diagnosis. Additionally, distinguishing between vessel encroachment and involvement can be difficult, particularly if inadequate imaging is obtained. The PRETEXT group assignment has a moderate degree of interobserver variability, and in a report published in 2005 using data from the SIOPEL-1 study, the preoperative PRETEXT group agreed with postoperative pathologic findings only 51% of the time, with overstaging in 37% of patients and understaging in 12% of patients.
Because distinguishing PRETEXT group assignment is difficult, central review of imaging is critical and is generally performed in all major clinical trials. For patients not enrolled on clinical trials, expert radiologic review should be considered in questionable cases in which the PRETEXT group assignment affects choice of treatment.
The POSTTEXT is determined after chemotherapy. It has been shown that the greatest chemotherapy response, measured as decreases in tumor size and alpha-fetoprotein (AFP) level, occurs after the first two cycles of chemotherapy.[6,7] Also, a study that evaluated surgical resectability after two versus four cycles of chemotherapy showed that many tumors may be resectable after two cycles.
Hepatoblastoma prognosis by PRETEXT group and annotation factor
The Children's Hepatic tumor International Collaboration (CHIC) analyzed survival in a collaborative database of 1,605 patients with hepatoblastoma treated on eight separate multicenter clinical trials, with central review of all tumor imaging and histologic details. Patients who underwent orthotopic liver transplant are included in all of the international study results.
Survival at 5 years, unrelated to annotation factors, was found to be the following:
When each annotation factor was examined separately, regardless of the PRETEXT group or other annotation factors present in each patient, the 5-year overall survival (OS) was found to be the following:
Hepatocellular carcinoma prognosis by PRETEXT group and annotation factor
The 5-year OS by PRETEXT group for hepatocellular carcinoma in SIOPEL-1 was found to be the following:
Evans Surgical Staging for Childhood Liver Cancer (Historical)
The COG/Evans staging system is based on operative findings and surgical resectability and has been used for many years in the United States to group children with liver cancer. This staging system was used to determine treatment in past years (refer to Table 3).[11,12,13] Currently, other risk stratification systems are used to classify patients and determine treatment strategy (refer to Table 5 for more information).
Hepatoblastoma prognosis by Evans surgical stage
Stages I and II
Approximately 20% to 30% of children with hepatoblastoma are stage I or II. Prognosis varies depending on the subtype of hepatoblastoma:
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%.[13,14]
Approximately 10% to 20% of children with hepatoblastoma are stage IV. The 3- to 5-year OS rate for children with stage IV hepatoblastoma varies widely, from 20% to approximately 60%, based on published reports.[13,14,17,18,19,20] Postsurgical stage IV is equivalent to any PRETEXT group with annotation factor M.[8,21,22]
Hepatocellular carcinoma prognosis by Evans surgical stage
Children with stage I hepatocellular carcinoma have a good outcome.
Stage II is too rarely seen to predict outcome.
Stages III and IV
Stages III and IV are usually fatal.[10,24]
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 and comparing the results with those previously obtained with standard therapy.
Because of the relative rarity of cancer in children, all children with liver cancer should be considered for entry onto a clinical trial when one is available. Treatment planning by a multidisciplinary team of cancer specialists with experience treating tumors of childhood is required to determine and implement optimal treatment.
Historically, complete surgical resection of the primary tumor has been required to cure malignant liver tumors in children.[2,3,4,5,6]; [Level of evidence: 3iiiA] This approach continues to be the goal of definitive surgical procedures, which are often combined with chemotherapy. In patients with advanced hepatoblastoma, postoperative complications are associated with worsened overall survival.
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 who have experience performing pediatric liver resections and transplants are involved early in the decision-making process for determining optimal timing and extent of resection. Also, the rarity of liver tumors in children has resulted in limited experience and exposure of surgeons to these procedures. In some cases, the patient may need to be referred to another institution for surgery or, more commonly, for liver transplant. Consultation with the surgeon should occur shortly after diagnosis.
In children and adolescents with primary liver tumors, the surgeon has to be prepared to perform a highly sophisticated liver resection after confirmation of the diagnosis by pathological investigation of intraoperative frozen sections. While complete surgical resection is important for all liver tumors, it is especially true for hepatocellular carcinoma because curative chemotherapy is not available. Intraoperative ultrasonography may result in further delineation of tumor extent and location and can affect intraoperative management.
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. If the tumor can be completely excised by an experienced surgical team, less postoperative chemotherapy may be needed.
Early involvement with an experienced pediatric liver surgeon is especially important in patients with PRE-Treatment EXTent of disease (PRETEXT) group III or IV or involvement of major liver vessels (positive annotation factors V [venous] or P [portal]). Although vascular involvement was initially thought to be a contraindication to resection, experienced liver surgeons are sometimes able to successfully resect the tumor and avoid performing a transplant.[11,12,13]; [Level of evidence: 3iiA] Accomplishing the appropriate surgery at resection is critical. Margin-negative resection is imperative because patients who undergo rescue transplants of incompletely resected tumors have an inferior outcome compared with patients who undergo transplant as the primary surgical therapy.[Level of evidence: 3iiiA]
The decision as to which surgical approach to use (e.g., partial hepatectomy, extended resection, or transplant) depends on many factors, including the following:
The approach taken by the Children's Oncology Group (COG) in North American clinical trials is to perform surgery initially when a complete resection can be accomplished with a simple, negative-margin hemihepatectomy. The COG study AHEP0731 (NCT00980460) has studied the use of PRETEXT and POSTTEXT to determine the optimal approach and timing of surgery. POSTTEXT imaging grouping is performed after two and four cycles of chemotherapy to determine the optimal time for definitive surgery (refer to the Tumor Stratification by Imaging and Evans Surgical Staging for Childhood Liver Cancer section of this summary for more information).[6,16]
Orthotopic liver transplant
Liver transplants have been associated with significant success in the treatment of children with unresectable hepatic tumors.; [18,19,20][Level of evidence: 3iiA] A review of the world experience has documented a posttransplant survival rate of 70% to 80% for children with hepatoblastomas.[15,21,22,23] Intravenous vascular invasion, positive lymph nodes, and contiguous extrahepatic spread did not have a significant adverse effect on outcome. It has been suggested that adjuvant chemotherapy after transplant may decrease the risk of tumor recurrence but its use has not been studied definitively in a randomized clinical trial.
Evidence (orthotopic liver transplant):
Application of the Milan criteria for UNOS selection of recipients of deceased donor livers is controversial.[28,29] The Milan criteria for liver transplantation are directed toward adults with cirrhosis and hepatocellular carcinoma. The criteria do not apply to children and adolescents with hepatocellular carcinoma, especially those without cirrhosis. Living-donor liver transplant is more common in children and the outcome is similar to those undergoing cadaveric liver transplant.[30,31] In hepatocellular carcinoma, gross vascular invasion, distant metastases, lymph node involvement, tumor size, and male sex were significant risk factors for recurrence. Because of the poor prognosis in patients with hepatocellular carcinoma, liver transplant should be considered for disorders such as tyrosinemia and familial intrahepatic cholestasis early in the course, before the development of liver failure and malignancy.
Surgical resection for metastatic disease
Surgical resection is often recommended, but the rate of cure in children with hepatoblastoma has not been fully determined. Resection of metastases, when possible, is often recommended, including the areas of locally invasive disease (e.g., diaphragm) and isolated brain metastases. Resection of pulmonary metastases should be considered if the number of metastases is limited.[32,33,34,35] In an American study of 20 patients who presented with pulmonary metastases, only nine patients underwent surgical resection. The timing of pulmonary resection in relation to definitive resection of the primary tumor varied (two patients before, five patients simultaneously, and two patients after primary resection). Eight of the nine patients survived. Of 20 children with relapse restricted to the lungs, all patients received salvage chemotherapy, 13 had pulmonary surgery, 8 had metastasectomy, and 5 had biopsy only. Of these patients, only 4 of 13 were long-term survivors, two of whom presented with stage I disease and two of whom presented with stage IV disease. Radiofrequency ablation has also been used to treat oligometastatic hepatoblastoma when patients prefer to avoid surgical metastasectomy.[Level of evidence: 3iiiB]
Chemotherapy regimens used in the treatment of hepatoblastoma and hepatocellular carcinoma are described in their respective sections (refer to the Treatment of Hepatoblastoma and the Treatment of Hepatocellular Carcinoma sections of this summary for more information). Chemotherapy has been much more successful in the treatment of hepatoblastoma than in hepatocellular carcinoma.[6,26,37]
The standard of care in the United States is preoperative chemotherapy when the tumor is unresectable and postoperative chemotherapy after complete resection, even if preoperative chemotherapy has already been given. Treatment with preoperative chemotherapy has been shown to benefit children with hepatoblastoma; however, the use of postoperative chemotherapy after definitive surgical resection or liver transplant has not been investigated in a randomized fashion.
Radiation therapy, even in combination with chemotherapy, has not cured children with unresectable hepatic tumors. Although there is no standard indication, radiation therapy may have a role in the management of incompletely resected hepatoblastoma. However, a study of 154 patients with hepatoblastoma showed that radiation therapy and/or second resection of positive margins may not be necessary in some patients with incompletely resected hepatoblastoma and microscopic residual tumor. Stereotactic body radiation therapy is a safe and effective alternative treatment that has been successfully used in hepatocellular carcinoma in adults who are unable to undergo liver ablation/resection. This highly conformal radiotherapeutic technique, when available, may be considered on an individual basis in children with hepatocellular carcinoma.
Other Treatment Approaches
Other treatment approaches include the following:
Special Considerations for the Treatment of Children With Cancer
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 multidisciplinary teams of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close monitoring because late effects of therapy may persist or develop months or years after treatment. (Refer to Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
The annual incidence of hepatoblastoma in the United States appears to have doubled, from 0.8 (1975–1983) to 1.6 (2002–2009) cases per 1 million children aged 19 years and younger.[1,2] The cause for this increase is unknown, but the increasing survival of very low-birth-weight premature infants, which is known to be associated with hepatoblastoma, may contribute. In Japan, the risk of hepatoblastoma in children who weighed less than 1,000 g at birth is 15 times the risk in normal birth-weight children. Other data have confirmed the high incidence of hepatoblastoma in very low-birth-weight premature infants. Attempts to identify factors resulting from treatment of infants born prematurely have not revealed any suggestive causation of the increased incidence of hepatoblastoma.
The age of onset of liver cancer in children is related to tumor histology. Hepatoblastomas usually occur before the age of 3 years, and approximately 90% of malignant liver tumors in children aged 4 years and younger are hepatoblastomas.
Conditions associated with an increased risk of hepatoblastoma are described in Table 4.
Aicardi syndrome is presumed to be an X-linked condition reported exclusively in females, leading to the hypothesis that a mutated gene on the X chromosome causes lethality in males. The syndrome is classically defined as agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms, with a characteristic facies. Additional brain, eye, and costovertebral defects are often found.
Beckwith-Wiedemann syndrome and hemihyperplasia
The incidence of hepatoblastoma is increased 1,000-fold to 10,000-fold in infants and children with Beckwith-Wiedemann syndrome.[9,18] The risk of hepatoblastoma is also increased in patients with hemihyperplasia, previously termed hemihypertrophy, a condition that results in asymmetry between the right and left side of the body when a body part grows faster than normal.[19,20]
Beckwith-Wiedemann syndrome is most commonly caused by epigenetic changes and is sporadic. The syndrome may also be caused by genetic mutations and be familial. Either mechanism can be associated with an increased incidence of embryonal tumors, including Wilms tumor and hepatoblastoma. The expression of both IGFR2 alleles and ensuing increased expression of insulin-like growth factor 2 (IGF-2) has been implicated in the macrosomia and embryonal tumors seen in patients with Beckwith-Wiedemann syndrome.[9,21] When sporadic, the types of embryonal tumors associated with Beckwith-Wiedemann syndrome have frequently also undergone somatic changes in the Beckwith-Wiedemann syndrome locus and IGF-2.[22,23] The genetics of tumors in children with hemihyperplasia have not been clearly defined.
To detect abdominal malignancies at an early stage, all children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia are screened regularly for multiple tumor types by abdominal ultrasonography. Screening using alpha-fetoprotein (AFP) levels has also been quite helpful in the early detection of hepatoblastoma in these children. Because the hepatoblastomas that are discovered early are small, it has been suggested to minimize the use of adjuvant therapy after surgery. However, a careful compilation of published data on 1,370 children with (epi)genotyped Beckwith-Wiedemann syndrome demonstrated that the prevalence of hepatoblastoma was 4.7% in those with Beckwith-Wiedemann syndrome caused by chromosome 11p15 paternal uniparental disomy, less than 1% in the two types of alteration in imprinting control regions, and absent in CDKN1C mutation. The authors recommended that only children with Beckwith-Wiedemann syndrome caused by uniparental disomy be screened for hepatoblastoma using abdominal ultrasonography and AFP levels every 3 months from age 3 months to 5 years.
Familial adenomatous polyposis
There is an association between hepatoblastoma and familial adenomatous polyposis (FAP); children in families that carry the APC gene have an 800-fold increased risk of hepatoblastoma. However, hepatoblastoma has been reported to occur in less than 1% of FAP family members, so screening for hepatoblastoma in members of families with FAP using ultrasonography and AFP levels is controversial.[10,11,12,26] However, one study of 50 consecutive children with apparent sporadic hepatoblastoma reported that five children (10%) had APC germline mutations.
Current evidence cannot rule out the possibility that predisposition to hepatoblastoma may be limited to a specific subset of APC mutations. Another study of children with hepatoblastoma found a predominance of the mutation in the 5' region of the gene, but some patients had mutations closer to the 3' region. This preliminary study provides some evidence that screening children with hepatoblastoma for APC mutations and colon cancer may be appropriate.
In the absence of APC germline mutations, childhood hepatoblastomas do not have somatic mutations in the APC gene; however, hepatoblastomas frequently have mutations in the beta-catenin gene, the function of which is closely related to APC.
Screening children predisposed to hepatoblastoma
An American Association for Cancer Research publication suggested that all children with more than a 1% risk of developing hepatoblastoma be screened. This includes patients with Beckwith-Wiedemann, hemihyperplasia, Simpson-Golabi-Behmel, and trisomy 18 syndromes. Screening is by abdominal ultrasound and alpha-fetoprotein determination every 3 months from birth (or diagnosis) through the fourth birthday, which will identify 90% to 95% of hepatoblastomas that develop in these children.
Genomics of Hepatoblastoma
Genomic abnormalities related to hepatoblastoma include the following:
Similar mutations have been found in many types of cancer, including hepatocellular carcinoma. These mutations render NFE2L2 insensitive to KEAP1-mediated degradation, leading to activation of the NFE2L2-KEAP1 pathway, which activates resistance to oxidative stress and is believed to confer resistance to chemotherapy.
To date, these genetic mutations have not been used to select therapeutic agents for investigation in clinical trials.
A biopsy of a pediatric liver tumor is always indicated to secure the diagnosis of a liver tumor, with the exception of the following circumstances:
The AFP and beta-hCG tumor markers are very helpful in the 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 with either a benign tumor or a malignant solid tumor. AFP is very high in neonates and steadily falls after birth. The half-life of AFP is 5 to 7 days, and by age 1 year, it should be less than 10 ng/mL.
Prognosis and Prognostic Factors
The 5-year overall survival (OS) rate for children with hepatoblastoma is 70%.[37,38] Neonates with hepatoblastoma have outcomes comparable to older children up to age 5 years.
Individual childhood cancer study groups have attempted to define the relative importance of a variety of prognostic factors present at diagnosis and in response to therapy.[40,41] A collaborative group consisting of four study groups (International Childhood Liver Tumors Strategy Group [SIOPEL], COG, Gesellschaft für Pädiatrische Onkologie und Hämatologie [GPOH], and Japanese Study Group for Pediatric Liver Tumor [JPLT]), termed Childhood Hepatic tumor International Collaboration (CHIC), have retrospectively combined data from eight clinical trials (N = 1,605) conducted between 1988 and 2010. The CHIC published a univariate analysis of the effect of clinical prognostic factors present at the time of diagnosis on event-free survival (EFS).[42,43] The analysis confirmed many of the findings described below. The statistically significant adverse factors included the following:
In contrast, in the SIOPEL-2 and -3 studies, infants younger than 6 months had PRETEXT, annotation factors, and outcomes similar to that of older children undergoing the same treatment.[Level of evidence: 3iiA]
In contrast, sex, prematurity, birth weight, and Beckwith-Wiedemann syndrome had no effect on EFS.
A multivariate analysis of these prognostic factors has been published to help develop a new risk group classification for hepatoblastoma. This classification was used to generate a risk stratification schema to be used in international clinical trials. (Refer to the International risk classification model section of this summary for more information.)
Other studies of factors affecting prognosis observed the following:
Chemotherapy: Chemotherapy often decreases the size and extent of hepatoblastoma, allowing complete resection.[45,46,47,48,49] Favorable response of the primary tumor to chemotherapy, defined as either a 30% decrease in tumor size by Response Evaluation Criteria In Solid Tumors (RECIST) or 90% or greater decrease in AFP levels, predicted the resectability of the tumor; in turn, this favorable response predicted overall survival among all CHIC risk groups treated with neoadjuvant chemotherapy on the JPLT-2 Japanese national clinical trial.[Level of evidence: 2A]
Surgery: Cure of hepatoblastoma requires gross tumor resection. Hepatoblastoma is most often unifocal and thus, resection may be possible. If a hepatoblastoma is completely removed, most patients survive, but because of vascular or other involvement, less than one-third of patients have lesions amenable to complete resection at diagnosis. Thus, it is critically important that a child with probable hepatoblastoma be evaluated by a pediatric surgeon; the surgeon should be experienced in the techniques of extreme liver resection with vascular reconstruction and have access to a liver transplant program. In advanced tumors, surgical treatment of hepatoblastoma is a demanding procedure. Postoperative complications in high-risk patients decrease the rate of overall survival.
Orthotopic liver transplant is an additional treatment option for patients whose tumor remains unresectable after preoperative chemotherapy;[52,53] however, the presence of microscopic residual tumor at the surgical margin does not preclude a favorable outcome.[54,55] This may be due to the additional courses of chemotherapy that are administered before or after resection.[45,46,54]
(Refer to Table 6 for more information on outcomes associated with specific chemotherapy regimens.)
Ninety percent of children with hepatoblastoma and two-thirds of children with hepatocellular carcinoma exhibit the serum tumor marker AFP, which parallels disease activity. The level of AFP at diagnosis and rate of decrease in AFP levels during treatment are compared with the age-adjusted normal range. Lack of a significant decrease in AFP levels with treatment may predict a poor response to therapy.
Absence of elevated AFP levels at diagnosis (AFP <100 ng/mL) occurs in a small percentage of children with hepatoblastoma and appears to be associated with very poor prognosis, as well as with the small cell undifferentiated variant of hepatoblastoma. Some of these variants do not express INI1 and may be considered rhabdoid tumors of the liver; all small cell undifferentiated hepatoblastomas are tested for loss of INI1 expression by immunohistochemistry.[57,58,59,60,61,62]
Beta-hCG levels may also be elevated in children with hepatoblastoma or hepatocellular carcinoma, which may result in isosexual precocity in boys.[63,64]
Refer to the Histology section of this summary for more information.
Other variables have been suggested as poor prognostic factors, but the relative importance of their prognostic significance has been difficult to define. In the SIOPEL-1 study, a multivariate analysis of prognosis after positive response to chemotherapy showed that only one variable, PRETEXT, predicted OS, while metastasis and PRETEXT predicted EFS. In an analysis of the intergroup U.S. study from the time of diagnosis, well-differentiated fetal histology, small cell undifferentiated histology, and AFP less than 100 ng/mL were prognostic in a log rank analysis. PRETEXT was prognostic among patients designated group III, but not group IV.[61,65]
Hepatoblastoma arises from precursors of hepatocytes and can have several morphologies, including the following:
Most often the tumor consists of a mixture of epithelial hepatocyte precursors. About 20% of tumors have stromal derivatives such as osteoid, chondroid, and rhabdoid elements. Occasionally, neuronal, melanocytic, squamous, and enteroendocrine elements are found. The following two histologic subtypes have clinical relevance:
Well-differentiated fetal (pure fetal) histology hepatoblastoma
An analysis of patients with initially resected hepatoblastoma tumors (before receiving chemotherapy) has suggested that patients with well-differentiated fetal (previously termed pure fetal) histology tumors have a better prognosis than do patients with an admixture of more primitive and rapidly dividing embryonal components or other undifferentiated tissues. Studies have reported the following:
Thus, complete resection of a well-differentiated fetal hepatoblastoma may preclude the need for chemotherapy.
Small cell undifferentiated histology hepatoblastoma and rhabdoid tumors of the liver
Small cell undifferentiated hepatoblastoma is an uncommon hepatoblastoma variant that represents several percent of all hepatoblastomas. It tends to occur at a younger age (6–10 months) than do other cases of hepatoblastoma [61,70] and is associated with AFP levels that are normal for age at presentation.[60,70]
Histologically, small cell undifferentiated hepatoblastoma is typified by a diffuse population of small cells with scant cytoplasm resembling neuroblasts.
Small cell undifferentiated hepatoblastoma may be difficult to distinguish from malignant rhabdoid tumor of the liver, which has been conflated with small cell undifferentiated hepatoblastoma in past studies. They can be distinguished by the following characteristic abnormalities:
The ongoing international Pediatric Hepatic Malignancy International Treatment Trial (PHITT) designates any childhood liver tumor as rhabdoid tumor of the liver if it contains cells that lack INI1 expression. (Refer to the AHEP1531 trial in the Treatment options under clinical evaluation for hepatoblastoma section of this summary for more information.) Patients with INI1-negative tumors, which are presumed to be related to rhabdoid tumors, may not be entered on the international trial, which addresses treatment of hepatoblastoma that includes small cell undifferentiated histology, hepatocellular carcinoma, and hepatic malignancy of childhood NOS, but not rhabdoid tumor of the liver. In this trial, all patients with histology as assessed by the institutional pathologist consistent with pure small cell undifferentiated hepatoblastoma are required to have testing for INI1/SMARCB1 by immunohistochemistry according to the practices at the institution.
If INI1 is maintained but small cell undifferentiated histology is present, the current literature suggests a worse outcome for these patients. However, because small cell undifferentiated hepatoblastoma and rhabdoid tumor of the liver have not been discriminated in past studies, some of the prognostic features attributed to the former may have been contributed in part by the latter. Published studies of prognostic features related to small cell undifferentiated histology include the following:
The outcomes of the CHIC trial of childhood liver tumors may clarify some of the questions regarding these different histologic and genetic findings.
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 well-differentiated 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 was investigated in the completed COG AHEP0731 [NCT00980460] study, and all tumors were tested for INI1 expression by immunohistochemistry. In this study, hepatoblastoma that would otherwise be considered very low or low risk was upgraded to intermediate risk if any small cell undifferentiated elements were found (refer to Table 5 for more information).
There are significant differences among childhood cancer study groups in risk stratification used to determine treatment, making it difficult to compare results of the different treatments administered. Table 5 demonstrates the variability in the definitions of risk groups.
International risk classification model
The Children's Hepatic tumors International Collaboration (CHIC) developed a novel risk stratification system for use in international clinical trials on the basis of prognostic features present at diagnosis. CHIC unified the disparate definitions and staging systems used by pediatric cooperative multicenter trial groups, enabling the comparison of studies conducted by heterogeneous groups in different countries. Original detailed clinical patient data were extracted from eight published clinical trials using central review of imaging and histology, and prognostic factors were identified by univariate analysis.
Based on the initial univariate analysis of the data combined with historical clinical treatment patterns and data from previous large clinical trials, five backbone groups were selected, which allowed for further risk stratification. Subsequent multivariate analysis was performed on the basis of these backbone groups; the groups were defined according to the following clinical prognostic factors: AFP (≤100 ng/mL), PRETEXT group (I, II, III, or IV), and presence of metastasis (yes or no). The backbone groups are as follows:
Other diagnostic factors (e.g., age) were queried for each of the backbone categories, including the presence of at least one of the following PRETEXT annotations (defined as VPEFR+, refer to Table 2) or AFP less than or equal to 100 ng/mL:
An assessment of surgical resectability at diagnosis was added for PRETEXT I and II patients. Patients in each of the five backbone categories were stratified on the basis of backwards stepwise elimination multivariable analysis of additional patient characteristics, including age and presence or absence of PRETEXT annotation factors (V, P, E, F, and R). Each of these subcategories received one of four risk designations (very low, low, intermediate, or high). The result of the multivariate analysis was used to assign patients to very low-, low-, intermediate-, and high-risk categories, as shown in Figure 3. For example, the finding of an AFP level of 100 to 1,000 ng/mL was significant only among patients younger than 8 years in the backbone PRETEXT III group. The analysis enables prognostically similar risk groups to be assigned to the appropriate treatment groups on upcoming international protocols.
Figure 3. Risk stratification trees for the Children's Hepatic tumors International Collaboration—Hepatoblastoma Stratification (CHIC-HS). Very low-risk group and low-risk group are separated only by their resectability at diagnosis, which has been defined by international consensus as part of the surgical guidelines for the upcoming collaborative trial, Paediatric Hepatic International Tumour Trial (PHITT). Separate risk stratification trees are used for each of the four PRETEXT groups. AFP = alpha-fetoprotein. M = metastatic disease. PRETEXT = PRETreatment EXTent of disease. Reprinted from The Lancet Oncology, Volume 18, Meyers RL, Maibach R, Hiyama E, Häberle B, Krailo M, Rangaswami A, Aronson DC, Malogolowkin MH, Perilongo G, von Schweinitz D, Ansari M, Lopez-Terrada D, Tanaka Y, Alaggio R, Leuschner I, Hishiki T, Schmid I, Watanabe K, Yoshimura K, Feng Y, Rinaldi E, Saraceno D, Derosa M, Czauderna P, Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration, Pages 122–131, Copyright (2017), with permission from Elsevier.
Treatment of Hepatoblastoma
Treatment options for newly diagnosed hepatoblastoma depend on the following:
Cisplatin-based chemotherapy has resulted in a survival rate of more than 90% for children with PRETEXT and POST-Treatment EXTent (POSTTEXT) I and II resectable disease before or after chemotherapy.[46,48,58]
Chemotherapy regimens used in the treatment of hepatoblastoma and their respective outcomes are described in Table 6. (Refer to the Tumor Stratification by Imaging and Evans Surgical Staging for Childhood Liver Cancer section of this summary for information describing each stage.)
Treatment options for hepatoblastoma that is resectable at diagnosis
Approximately 20% to 30% of children with hepatoblastoma have resectable disease at diagnosis. COG surgical guidelines (AHEP0731 [NCT00980460] appendix) recommend tumor resection at diagnosis without preoperative chemotherapy in children with PRETEXT I tumors and PRETEXT II tumors with greater than 1 cm radiographic margin on the vena cava and middle hepatic and portal veins.
Prognosis varies depending on the histologic subtype, as follows:
Treatment options for hepatoblastoma resectable at diagnosis showing non–well-differentiated fetal histology include the following:
Re-resection of positive microscopic margins may not be necessary. Conclusive evidence is lacking for tumors with resection at diagnosis compared with those with positive microscopic margins resected after preoperative chemotherapy.
Evidence (gross surgical resection [with or without microscopic margins] and postoperative chemotherapy):
Second resection of positive margins and/or radiation therapy may not be necessary in patients with incompletely resected hepatoblastoma whose residual tumor is microscopic and who receive subsequent chemotherapy.[54,62]
Results of chemotherapy clinical trials are described in Table 6.
Treatment options for hepatoblastoma of well-differentiated fetal (pure fetal) histology resectable at diagnosis include the following:
Evidence (complete surgical resection followed by watchful waiting or chemotherapy):
A retrospective study of 16 patients with well-differentiated fetal histology treated at multiple institutions had complete surgical resections, but also had elements of (or, in some case, predominance of) small cell histology found in the resected tumor.
Treatment options for hepatoblastoma that is not resectable or not resected at diagnosis
Approximately 70% to 80% of children with hepatoblastoma have tumors that are not resected at diagnosis. COG surgical guidelines (AHEP0731 [NCT00980460] appendix) recommend biopsy without an attempt to resect the tumor at diagnosis in children with PRETEXT II tumors with less than 1 cm radiographic margin on the vena cava and middle hepatic vein and in all children with PRETEXT III and IV tumors.
Tumor rupture at presentation, resulting in major hemorrhage that can be controlled by transcatheter arterial embolization or partial resection to stabilize the patient, does not preclude a favorable outcome when followed by chemotherapy and definitive surgery.
Treatment options for hepatoblastoma that is not resectable or is not resected at diagnosis include the following:
In recent years, almost all children with hepatoblastoma have been treated with chemotherapy, and in European centers, children with resectable hepatoblastoma are treated with preoperative chemotherapy, which may reduce the incidence of surgical complications at the time of resection.[48,54,58] Treatment with preoperative chemotherapy has been shown to benefit children with hepatoblastoma. In contrast, an American intergroup study of treatment of children with hepatoblastoma encouraged resection at the time of diagnosis for all tumors amenable to resection without undue risk. The study (COG-P9645) did not treat children with stage I tumors of well-differentiated fetal histology with preoperative or postoperative chemotherapy unless they developed progressive disease. In this study, most patients with PRETEXT III and all PRETEXT IV tumors were treated with chemotherapy before resection or transplant.
Patients whose tumors remain unresectable after chemotherapy should be considered for liver transplant.[48,52,81,82,83,84,85] In the presence of features predicting unresectability, early coordination with a pediatric liver transplant service is critical. In the COG AHEP0731 (NCT00980460) study, early referral (i.e., based on imaging done after the second cycle of chemotherapy) to a liver specialty center with liver transplant capability was recommended for patients with POSTTEXT III tumors with positive V or P and POSTTEXT IV tumors with positive F.
Evidence (chemotherapy followed by reassessment of surgical resectability and complete surgical resection):
In the United States, unresectable tumors have been treated with chemotherapy before resection or transplant.[45,46,47,69] On the basis of radiographic imaging, most stage III and IV hepatoblastomas are rendered resectable after two cycles of chemotherapy. Some European centers have also used extended resection of selected POSTTEXT III and IV tumors rather than liver transplant.[59,92,93,94]
Chemotherapy followed by TACE followed by high-intensity focused ultrasound showed promising results in China for PRETEXT III and IV patients with hepatoblastoma, some of whom were resectable but did not undergo surgical resection because of parent refusal.
Treatment options for hepatoblastoma with metastases at diagnosis
The outcomes of patients with metastatic hepatoblastoma at diagnosis are poor, but long-term survival and cure is possible.[45,46,47] Survival rates at 3 to 5 years range from 20% to 79%.[55,62,96,97] To date, the best outcomes for children with metastatic hepatoblastoma resulted from treatment with dose-dense cisplatin and doxorubicin, although significant toxicity was also noted (SIOPEL-4 [NCT00077389] trial).[Level of evidence: 2Dii]
Treatment options for hepatoblastoma with metastases at diagnosis include the following:
The standard combination chemotherapy regimen in North America is four courses of cisplatin/vincristine/fluorouracil  or doxorubicin/cisplatin [48,69,96] followed by attempted complete tumor resection. If the tumor is completely removed, two postoperative courses of the same chemotherapy are usually given. Study results for different chemotherapy regimens have been reported (refer to Table 6 for more information).
High-dose chemotherapy with stem cell rescue does not appear to be more effective than standard multiagent chemotherapy.
Evidence (chemotherapy to treat metastatic disease at diagnosis):
In patients with resected primary tumors, any remaining pulmonary metastasis is surgically removed, if possible. A review of patients treated on a U.S. intergroup trial suggested that resection of metastasis may be done at the time of resection of the primary tumor.[Level of evidence: 3iiA]
If extrahepatic disease is in complete remission after chemotherapy, and the primary tumor remains unresectable, an orthotopic liver transplant may be performed.[55,62,69,90]
The outcome results are discrepant for patients with lung metastases at diagnosis who undergo orthotopic liver transplant after complete resolution of lung disease in response to pretransplant chemotherapy. Some studies have reported favorable outcomes for these groups,[55,62,85,90] while others have noted high rates of hepatoblastoma recurrence.[52,81,84,87] All of these studies are limited by small patient numbers; additional study is needed to better define outcomes for this subset of patients. Recent clinical trials have resulted in few pulmonary recurrences in children who underwent liver transplants and presented with metastatic disease.[55,62,99]
If extrahepatic disease is not resectable after chemotherapy or the patient is not a transplant candidate, alternative treatment approaches include the following:
Treatment options for progressive or recurrent hepatoblastoma
The prognosis for a patient with progressive or recurrent hepatoblastoma depends on several factors, including the following:
Treatment options for progressive or recurrent hepatoblastoma include the following:
If possible, isolated metastases are resected completely in patients whose primary tumor is controlled. A retrospective study of patients in SIOPEL studies 1, 2, and 3 showed a 12% incidence of recurrence after complete remission by imaging and AFP. Outcome after recurrence was best if the tumor was amenable to surgery. Of patients who underwent chemotherapy and surgery, the 3-year EFS was 34%, and the OS was 43%.[Level of evidence: 3iiA] Percutaneous radiofrequency ablation has been used as an alternative to surgical resection of oligometastatic hepatoblastoma.[Level of evidence: 3iiiB]
Enrollment 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.
A review of COG phase I and II studies found no promising agents for relapsed hepatoblastoma.
Treatment options under clinical evaluation for hepatoblastoma
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
This is the COG's participation in a large international trial (PHITT) of treatment of all stages of hepatoblastoma and hepatocellular carcinoma in children.
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
The annual incidence of hepatocellular carcinoma in the United States is 0.8 cases per 1 million children between the ages of 0 and 14 years and 1.5 cases per 1 million adolescents aged 15 to 19 years. Although the incidence of hepatocellular carcinoma in adults in the United States has steadily increased since the 1970s, possibly because of the increased frequency of chronic hepatitis C infection, the incidence in children has not increased. In several Asian countries, the incidence of hepatocellular carcinoma in children is 10 times higher than the incidence in children 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 child.
Fibrolamellar hepatocellular carcinoma, a subtype of hepatocellular carcinoma that is unrelated to cirrhosis, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection, generally occurs in adolescents and young adults, but has been reported in infants.
Conditions associated with hepatocellular carcinoma are described in Table 7.
Alagille syndrome is an autosomal dominant genetic syndrome that is usually caused by a mutation in or deletion of the JAG1 gene. It involves the bile ducts of the liver, as well as the heart and blood vessels in the brain and kidney. Patients develop a characteristic facies.
Hepatitis B and hepatitis C infection
In children, hepatocellular carcinoma is associated with perinatally acquired HBV, whereas in adults, it is associated with chronic HBV and HCV infection.[7,8,9] Widespread hepatitis B immunization has decreased the incidence of hepatocellular carcinoma in Asia. Compared with adults, the incubation period from hepatitis virus infection to the genesis of hepatocellular carcinoma is extremely short in a small subset of children with perinatally acquired virus. Mutations in the met/hepatocyte growth factor receptor gene could be one mechanism that results in a shortened incubation period.
Hepatitis C infection is associated with development of cirrhosis and hepatocellular carcinoma that takes decades to develop and is generally not seen in children. Cirrhosis in children, compared with cirrhosis in adults, is much less commonly involved in the development of hepatocellular carcinoma, and is found in only 20% to 35% of children with hepatocellular carcinoma tumors.
Nonviral liver injury
Specific types of nonviral liver injury and cirrhosis that are associated with hepatocellular carcinoma in children include the following:
In an Iranian study, 36 children underwent liver transplant for tyrosinemia. Twenty-two children had liver nodules greater than 10 cm, and in 20 children, the nodules were cirrhotic. Median age at transplant was 3.9 years. Five of 19 children older than 2 years had hepatocellular carcinoma, and no children younger than 2 years had hepatocellular carcinoma in the resected liver.
Genomics of Hepatocellular Carcinoma
Genomic abnormalities related to hepatocellular carcinoma include the following:
TERT mutations were observed in two of four cases tested.TERT mutations are also commonly observed in adults with hepatocellular carcinoma.
Refer to the Diagnosis subsection in the Hepatoblastoma section of this summary for more information.
The 5-year overall survival (OS) rate is 42% for children and adolescents with hepatocellular carcinoma. The 5-year survival for hepatocellular carcinoma may be dependent on stage; in an intergroup chemotherapy study conducted in the 1990s, seven of eight stage I patients survived and less than 10% of stage III and IV patients survived.[1,21] An analysis of Surveillance, Epidemiology, and End Results (SEER) data found a 5-year OS rate of 24%, a 10-year rate of 23%, and a 20-year rate of 8% in patients aged 19 years and younger, suggesting improved outcome related to more recent treatment. In a multivariate analysis of the SEER data, surgical resection, localized tumor, and non-Hispanic ethnicity were all associated with improved outcome. Patients who had a complete surgical resection had an OS rate of 60%, compared with an OS rate of 0% for patients who had an incomplete resection.[Level of evidence: 3iiiA]
Factors affecting prognosis include the following:
Cure of hepatocellular carcinoma requires gross tumor resection. However, hepatocellular carcinoma is often extensively invasive or multicentric, and less than 30% of tumors are resectable. Orthotopic liver transplant has been successful in selected children with hepatocellular carcinoma.[23,24]
The cells of hepatocellular carcinoma are epithelial in appearance. Hepatocellular carcinoma commonly arises in the right lobe of the liver.
A distinctive histologic variant of hepatocellular carcinoma, termed fibrolamellar carcinoma, has been described in the livers of older children and young adults and, rarely, in infants.[4,25] 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 not associated with cirrhosis and was previously thought to be associated with an improved prognosis.[2,25,26] Unlike nonfibrolamellar hepatocellular carcinoma in adults, fibrolamellar hepatocellular carcinoma in older children and adults is not clearly increasing in incidence over time.[2,25] The improved outcomes of patients with fibrolamellar carcinoma in older studies may be related to a higher proportion of tumors being less invasive and more resectable in the absence of cirrhosis. However, the outcomes of patients with fibrolamellar carcinoma in recent prospective studies, when compared stage for stage and PRETEXT group to PRETEXT group, is not different from the outcomes of patients with conventional hepatocellular carcinomas.[27,28]; [Level of evidence: 3iiA]
Hepatocellular neoplasm, not otherwise specified (NOS)
Hepatocellular neoplasm, NOS is also known as transitional liver cell tumor. This tumor, with characteristics of both hepatoblastoma and hepatocellular carcinoma, is a rare neoplasm that is found in older children and adolescents, and has a putative intermediate position between hepatoblasts and more mature hepatocyte-like tumor cells. The tumor cells may vary in regions of the tumor between classical hepatoblastoma and obvious hepatocellular carcinoma. In the international consensus classification, these tumors are referred to as hepatocellular neoplasm, NOS. The tumors are usually unifocal and may have central necrosis at presentation. Response to chemotherapy has not been rigorously studied but is felt to be much like that of hepatocellular carcinoma.
Treatment of Hepatocellular Carcinoma
Treatment options for newly diagnosed hepatocellular carcinoma depend on the following:
Treatment options for hepatocellular carcinoma that is resectable at diagnosis
Treatment options for hepatocellular carcinoma that is resectable at diagnosis include the following:
Surgical resection and chemotherapy are the mainstays of treatment for resectable hepatocellular carcinoma.
Evidence (complete surgical resection followed by chemotherapy):
Evidence (complete surgical resection without chemotherapy):
Despite improvements in surgical techniques, chemotherapy delivery, and patient supportive care in the past 20 years, clinical trials of cancer chemotherapy have not shown improved survival rates for pediatric patients with hepatocellular carcinoma. The International Childhood Liver Tumors Strategy Group (SIOPEL) studies in Europe have observed no improvement in 5-year OS since 1990. The only long-term survivors were patients whose tumors were resectable at diagnosis, which was less than 30% of children entered in the study. However, some liver transplant studies (complete resection with transplant with or without neoadjuvant chemotherapy) have shown OS rates that are superior to the SIOPEL studies.[24,35,36,37,38]
Treatment options for nonmetastatic hepatocellular carcinoma that is not resectable at diagnosis
The use of neoadjuvant chemotherapy or transarterial chemoembolization (TACE) to enhance resectability or liver transplant, which may result in complete resection of tumor, is necessary for cure.
Treatment options for nonmetastatic hepatocellular carcinoma that is not resectable at diagnosis include the following:
Evidence (chemotherapy followed by reassessment of surgical resectability and complete surgical resection of the primary tumor):
Evidence (chemotherapy or TACE followed by reassessment of surgical resectability; treatment options for unresectable primary tumor after chemotherapy or TACE):
If the primary tumor is not resectable after chemotherapy and the patient is not a transplant candidate, alternative treatment approaches used in adults include the following:
There are limited data on the use of these alternative treatment approaches in children.
Limited data from a European pilot study suggest that sorafenib was well tolerated in 12 newly diagnosed children and adolescents with advanced hepatocellular carcinoma when given in combination with standard chemotherapy of cisplatin and doxorubicin. Additional study is needed to define its role in the treatment of children with hepatocellular carcinoma.
Cryosurgery, intratumoral injection of alcohol, and radiofrequency ablation can successfully treat small (<5 cm) tumors in adults with cirrhotic livers.[43,46,47] 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. In a pediatric study of eight patients with hepatocellular carcinoma, two patients died of progressive disease without transplant. Treatment with TACE stabilized disease in six patients, for a mean of 141 days to reach transplant.[Level of evidence: 3iiA] Five patients were alive at the end of the observation period, and one patient died of disease.(Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)
Treatment options for hepatocellular carcinoma with metastases at diagnosis
No specific treatment has proven effective for metastatic hepatocellular carcinoma in the pediatric age group.
In two prospective trials, cisplatin plus either vincristine/fluorouracil or continuous-infusion doxorubicin was ineffective in adequately treating 25 patients with metastatic hepatocellular carcinoma.[21,27] Occasional patients may transiently benefit from treatment with cisplatin/doxorubicin therapy, especially if the localized hepatic tumor shrinks adequately enough to allow resection of disease and the metastatic disease disappears or becomes resectable.
Treatment options for hepatitis B virus (HBV)–related hepatocellular carcinoma
Although HBV-related hepatocellular carcinoma is not common in children in the United States, nucleotide/nucleoside analog HBV inhibitor treatment improves postoperative prognosis in children and adults treated in China.
Treatment options for HBV-related hepatocellular carcinoma include the following:
Evidence (antiviral therapy):
Treatment options for progressive or recurrent hepatocellular carcinoma
The prognosis for a patient with recurrent or progressive hepatocellular carcinoma is extremely poor.
Treatment options for progressive or recurrent hepatocellular carcinoma include the following:
Treatment options under clinical evaluation for hepatocellular carcinoma
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
This is the COG's participation in a large international trial (Pediatric Hepatic Malignancy International Therapeutic Trial [PHITT]) of treatment of all stages of hepatoblastoma and hepatocellular carcinoma in children.
Undifferentiated embryonal sarcoma of the liver (UESL) is a distinct clinical and pathologic entity and accounts for 2% to 15% of pediatric hepatic malignancies.
UESL presents as an abdominal mass, often with pain or malaise, usually between the ages of 5 and 10 years. Widespread infiltration throughout the liver and pulmonary metastasis is common. It may appear solid or cystic on imaging, frequently with central necrosis.
Distinctive features are characteristic intracellular hyaline globules and marked anaplasia on a mesenchymal background. Many UESL tumors contain diverse elements of mesenchymal cell maturation, such as smooth muscle and fat. Undifferentiated sarcomas, like small cell undifferentiated hepatoblastomas, should be examined for loss of INI1 expression by immunohistochemistry to help rule out rhabdoid tumor of the liver.
It is important to make the diagnostic distinction between UESL and biliary tract rhabdomyosarcoma because they share some common clinical and pathologic features but treatment differs between the two, as shown in Table 8. (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.)
Distinctive histologic features are intracellular hyaline globules and marked anaplasia on a mesenchymal background.
Strong clinical and histological evidence suggests that UESL can arise within preexisting mesenchymal hamartomas of the liver, which are large benign multicystic masses that present in the first 2 years of life. In a report of 11 cases of UESL, 5 arose in association with mesenchymal hamartomas of the liver, and transition zones between the histologies were noted. Many mesenchymal hamartomas of the liver have a characteristic translocation with a breakpoint at 19q13.4 and several UESLs have the same translocation.[4,5] Some UESLs arising from mesenchymal hamartomas of the liver may have complex karyotypes not involving 19q13.4.
The overall survival (OS) of children with UESL appears to be substantially better than 50% when combining reports, although all series are small and most may be selected to report successful treatment.; [Level of evidence: 3iiA]; [8,9,10,11,12,13,14,15,16,17][Level of evidence: 3iiiA]
The Childhood Cancer Database, which does not provide central review of pathology or reliable details of nonsurgical treatment, reported on 103 children with UESL diagnosed between 1998 and 2012. The 5-year OS was 86% for all patients and 92% for those treated with combination surgery and chemotherapy. A multivariate analysis of the nonsurgical data revealed statistically significant poorer outcomes for patients with tumors larger than 15 cm. Seven of ten children who presented with metastases and ten of ten children who underwent orthotopic liver transplant survived at least 5 years, but details of their treatment were not presented.
Treatment Options for Undifferentiated Embryonal Sarcoma of the Liver
UESL is rare. Only small series have been published regarding treatment.
Treatment options for UESL include the following:
The generally accepted approach is resection of the primary tumor mass in the liver when possible. Use of aggressive chemotherapy regimens seems to have improved the OS of patients with UESL. Neoadjuvant chemotherapy can be effective in decreasing the size of an unresectable primary tumor mass, resulting in resectability.[8,9,10,11] Most patients are treated with chemotherapy regimens used for pediatric rhabdomyosarcoma or Ewing sarcoma without cisplatin.; [7,20][Level of evidence: 3iiA]; [8,9,10,11,12,13,14,15,16][Level of evidence: 3iiiA]
Evidence (surgical resection and chemotherapy):
Liver transplant has occasionally been used to successfully treat an otherwise unresectable primary tumor.[14,16,18,21]
Treatment Options Under Clinical Evaluation for Undifferentiated Embryonal Sarcoma of the Liver
Choriocarcinoma of the liver is a very rare tumor that appears to originate in the placenta during gestation and presents with a liver mass in the first few months of life. Metastasis from the placenta to maternal tissues occurs in many cases, necessitating beta-human chorionic gonadotropin (beta-hCG) testing of the mother. Infants are often unstable at diagnosis because of hemorrhage of the tumor.
Clinical diagnosis may be made without biopsy on the basis of tumor imaging of the liver associated with extremely high serum beta-hCG levels and normal alpha-fetoprotein (AFP) levels for age.
Cytotrophoblasts and syncytiotrophoblasts are both present. The former are closely packed nests of medium-sized cells with clear cytoplasm, distinct cell margins, and vesicular nuclei. The latter are very large multinucleated syncytia formed from the cytotrophoblasts.
Treatment Options for Infantile Choriocarcinoma of the Liver
Treatment options for infantile choriocarcinoma of the liver include the following:
Initial surgical removal of the tumor mass may be difficult because of its friability and hemorrhagic tendency. Often surgical removal of the primary tumor is performed after neoadjuvant chemotherapy.
Maternal gestational trophoblastic tumors are exquisitely sensitive to methotrexate, and many women, including those with distant metastases, are cured with single-agent chemotherapy. Maternal and infantile choriocarcinoma both come from the same placental malignancy. The combination of cisplatin, etoposide, and bleomycin, as used in other pediatric germ cell tumors, has been effective in some patients and is followed by resection of residual mass. Use of neoadjuvant methotrexate in infantile choriocarcinoma, although often resulting in a response, has not been uniformly successful.
Treatment Options Under Clinical Evaluation for Infantile Choriocarcinoma of the Liver
Careful attention to the clinical history, physical exam, laboratory evaluation, and radiologic imaging is essential for an appropriate diagnosis of vascular liver tumors. If there is any doubt about the accuracy of the diagnosis, a biopsy should be performed.
The different diagnoses of vascular tumors of the liver include the following:
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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.
Editorial changes were made to this summary.
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 NCI website's Email Us. 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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The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Liver Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/liver/hp/child-liver-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389232]
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Last Revised: 2019-06-13
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