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First Published Online July 21, 2008
The Oncologist, Vol. 13, No. 7, 812-820, July 2008; doi:10.1634/theoncologist.2008-0011
© 2008 AlphaMed Press
Liver Tumors in Children
Jason B. Littena,
Gail E. Tomlinsonac
Departments of aPediatrics and
bInternal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
cGreehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas
Key Words. Pediatric cancer • Liver tumor • Hepatoblastoma
Correspondence: Gail E. Tomlinson, M.D., Ph.D., University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78229, USA. Telephone: 210-562-9001; Fax: 210-562-9014; e-mail: tomlinsong{at}uthscsa.edu
Received January 14, 2008;
accepted for publication April 5, 2008;
first published online in THE ONCOLOGIST Express on July 21, 2008.
Disclosure: The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.
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Learning Objectives
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After completing this course, the reader should be able to:- Describe the current epidemiologic trends in hepatoblastoma.
- Identify the genetic syndromes that are seen in a subset of liver tumors.
- Assess the need for complete tumor resection in the treatment of liver tumors in children as well as the increasingly important option of liver transplantation for those patients with unresectable tumors.
- Discuss the impact of the hepatitis vaccine in reducing the incidence of hepatocellular carcinoma.
- Explain the prognostic impact of different histologic subtypes of hepatoblastoma.
- Promote the need for future clinical trials in testing new agents for hepatocellular carcinoma in children.
- Employ the different staging systems used in liver tumors, including the traditional North American postsurgical staging system and the European presurgical staging system using imaging.
This article is available for continuing medical education credit at CME.TheOncologist.com.
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ABSTRACT
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Malignant liver tumors account for slightly >1% of all pediatric malignancies, with roughly 150 new cases of liver tumors diagnosed in the U.S. annually. The embryonal tumor, hepatoblastoma, accounts for two thirds of malignant liver tumors in children. Other liver malignancies in children include hepatocellular carcinoma, sarcomas, germ cell tumors, and rhabdoid tumors. Benign tumors of the liver in children include vascular tumors, hamartomas, and adenomas. There is an apparent increase in the incidence of hepatoblastoma with perinatal exposures and decreased premature infant mortality as postulated causes for this increased risk. The known causes and associations of liver tumors in children as well as the approaches to diagnosis and treatment of children are discussed in this review article.
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INTRODUCTION
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Malignant liver tumors account for slightly >1% of all pediatric malignancies. Approximately 100–150 new cases of liver tumors are diagnosed in the U.S. annually [1]. Two thirds of liver tumors in children are malignant [2]. Unlike liver tumors in adults, in which the predominant histology is hepatocellular carcinoma, hepatoblastoma accounts for two thirds of liver tumors in children [1, 2]. Other liver malignancies in children include sarcomas, germ cell tumors, and rhabdoid tumors, as well as the more familiar hepatocellular carcinoma. Benign tumors of the liver in children include vascular tumors, hamartomas, adenomas, and focal nodular hyperplasia. The histology and anatomy of a pediatric liver tumor guides the treatment and prognosis.
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CHANGES IN INCIDENCE OF PEDIATRIC HEPATIC TUMORS
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There are several suggestions that the incidence of malignant liver tumors is increasing in the U.S. Surveillance, Epidemiology, and End Results data from 1972–1992 showed a 5% annual increase [1]. Other data showed that liver cancer represented 2% of all malignancies in infants in the early 1980s with the incidence doubling to 4% 10 years later [3]. Although the numbers forming the basis of this increasing rate are small, it has been suggested that our improvements in technology, care, and outcomes for premature infants have been driving forces in this increase in incidence. Investigations initially reported by a Japanese group [4], and later confirmed by U.S. investigators [5, 6], revealed that hepatoblastoma is more commonly diagnosed in children with a history of prematurity than in full-term infants. Interestingly, those tumors that arise in ex-premature infants do not present at a younger age than those of term infants.
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HEPATOBLASTOMA: THE MOST COMMON PEDIATRIC LIVER TUMOR
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Hepatoblastoma is the most common malignant tumor of the liver in children. For poorly understood reasons, hepatoblastoma occurs in males significantly more frequently than it does in females [2]. Hepatoblastomas are composed of cells resembling the developing fetal and embryonic liver, hence the classification as an embryonal tumor. Indeed, the cells comprising hepatoblastoma mark similarly to hepatic stem cells, defined as pluripotent hepatoblasts capable of differentiating into hepatocytes or cholangiocytes [7, 8]. Hepatoblastoma is diagnosed in very young children with a peak in the newborn period reflecting those tumors that developed prenatally, and an overall median age at diagnosis of 18 months, as shown in Figure 1. Only 5% of new hepatoblastoma cases are diagnosed in children >4 years of age.
Most commonly, these tumors present in the right lobe of the liver [9]. Histologically, these tumors can be divided into epithelial or mixed epithelial/mesenchymal tissue. The majority of hepatoblastomas are epithelial and consist of a mixture of embryonal and fetal cell types (Fig. 2). Approximately 5% of hepatoblastomas are of the small cell undifferentiated subtype. This subtype is associated with a worse prognosis [10].
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Figure 1. Age distribution of hepatoblastoma derived from 254 sequential cases representing all stages and histologies of hepatoblastoma. An initial peak is seen at birth reflecting tumors developing during gestation. The median age of all children with hepatoblastoma is 18 months and the oldest age is 78 months. Ninety-nine percent of cases were observed to occur by age 5 years of age (unpublished data).
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Figure 2. Distribution of histologic subtypes of hepatoblastoma. The majority are epithelial and consist of embryonal and fetal cell types. Pure fetal histology accounts for approximately 7% of hepatoblastomas and is associated with a favorable prognosis. Small cell undifferentiated hepatoblastoma accounts for 5% of hepatoblastoma cases and is associated with a poor prognosis.
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HEPATOCELLULAR CARCINOMA
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Hepatocellular carcinoma, the second most common malignancy of the liver in children, is markedly distinct from hepatoblastoma. Most cases of hepatocellular carcinoma are diagnosed after 10 years of age. Hepatocellular carcinoma is the most common hepatic malignancy of adolescents. Often, hepatocellular carcinoma is associated with known hepatic viral infection or cirrhosis, and while it can take decades for malignancy to develop, occasionally cases are seen in very young children.
Previous reports from Southeast Asia cite an annual incidence of pediatric hepatic tumors that is roughly four times higher than western reports in children <15 years of age [11]. This finding is largely based on the high hepatitis carrier rate, with a Taiwanese report stating that 80% of primary liver tumors in children were hepatocellular carcinoma. With the introduction of hepatitis B vaccine in Southeast Asia, however, there has been a marked reduction in the incidence of hepatocellular carcinoma, although the impact of the hepatitis B vaccine has mainly reduced the incidence of liver tumors in males [12]. Occasionally, malignant tumors in children are seen with features of both hepatocellular carcinoma and hepatoblastoma. These tumors are more common in children with a diagnosis at later ages than that typical of hepatoblastoma.
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SARCOMAS AND OTHER MALIGNANT TUMORS OF THE LIVER
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The third most common hepatic malignancy, after hepatoblastoma and hepatocellular carcinoma, is undifferentiated embryonal sarcoma [13, 14]. These tumors occur in children 5–10 years of age and are mesenchymal in appearance. While the vast majority of vascular tumors of the liver in childhood are benign hemangioendotheliomas, angiosarcoma of the liver is a particularly aggressive malignant subtype with a poor prognosis [15, 16]. Embryonal rhabdomyosarcomas arise from biliary ducts and usually arise in children <5 years of age [17]. These children typically present with jaundice secondary to biliary obstruction and have been treated in a similar fashion to those with rhabdomyosarcoma in other sites. Primary extragonadal germ cell tumors within the hepatic parenchyma have been reported [18], but the hepatic parenchyma is more commonly seen as a site of germ cell tumor metastases [19].
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BENIGN TUMORS OF THE LIVER
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Benign tumors of the liver account for almost 30% of all liver tumors in children. Between 40 and 50 cases are diagnosed in the U.S. per year, with hemangioendothelioma being the most common benign tumor. These vascular tumors are usually diagnosed in the first 6 months of life and show a preponderance in whites and females [20]. Hemangiomas are characterized by a period of rapid growth followed by involution. Although benign in their pathology and potential to metastasize, these tumors are still associated with significant morbidity and mortality, leading to the classic triad of hepatomegaly, congestive heart failure, and anemia [21]. These children may also present with consumptive coagulopathy (Kasaback-Merrit syndrome) and bleeding [22]. Ateriovascular malformations are rarer than hemangioendothelioma but may have a similar presentation [23, 24]. Mesenchymal hamartoma is a benign entity that can sometimes be seen on a prenatal ultrasound, but usually presents as an asymptomatic abdominal mass after a period of rapid growth and can cause compression of adjacent tissue but is curable by resection [25].
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GENETICS AND PEDIATRIC LIVER TUMORS
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Hepatoblastoma is associated with several genetic syndromes and familial cancer predisposition conditions, such as familial adenomatous polyposis [26] and Beckwith-Wiedemann syndrome [27] in addition to several other rare syndromes, as listed in Table 1. Similar to other embryonal tumors, altered imprinting at the 11–15 locus has been observed in hepatoblastoma [28]. Other compelling evidence suggests that acquired aberrations in the β-catenin/Wnt pathways are important in the pathogenesis of hepatoblastoma [29, 30]. Acquired chromosomal changes in tumors include numerical chromosomal changes, most commonly trisomies of chromosomes 2, 8, and 20 [31]. Rearrangements involving the pericentric region of chromosome 1 also appear to be important in hepatoblastoma, with roughly 18% of hepatoblastomas displaying an imbalanced translocation involving this region [32, 33]. Finally, epigenetic changes in methylation patterns of DNA may be altered in hepatoblastoma [34].
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ENVIRONMENTAL FACTORS
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There is limited but compelling evidence that parental exposures are associated with a higher incidence of liver tumors and, more specifically, hepatoblastoma. Children from parents who have been exposed to metals used in soldering and welding, petroleum, or paints are at a higher risk for hepatoblastoma [35]. Recent reports have also implicated parental smoking as a risk factor for hepatoblastoma [36, 37].
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PRESENTATION AND ASSESSMENT OF A LIVER MASS
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The child with a liver tumor usually presents with a painless palpable abdominal mass. Occasionally, precocious puberty can be observed from the β-human chorionic gonadotropin β–HCG–eluting tumor. Likewise, thrombocytosis is frequently observed secondary to increased levels of thrombopoietin secreted by the tumor [38]. Sometimes children will complain of abdominal pain or constipation, but these children generally have normal liver function and are not jaundiced. An important exception to this general rule is in the context of viral hepatitis and hepatocellular carcinoma. These children may be jaundiced and have hepatic cirrhosis. A subset of heptocellular carcinoma, the fibrolamellar variant, is an exception in that the adjacent liver, like that in hepatoblastoma, is normal appearing. Generally, children with liver masses display normal growth and development unless they show the phenotypes associated with Beckwith-Wiedemann syndrome or the other genetic cancer predisposition syndromes associated with liver tumors listed in Table 1. These syndromes, however, collectively are seen in <20% of liver tumors.
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EVALUATION
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All children with a palpable abdominal mass usually undergo either an initial plain film x-ray or an ultrasound; however, definitive characterization of the mass requires a computed tomography (CT) or magnetic resonance imaging (MRI) scan. Calcifications can be seen in a minority of liver tumors. A chest CT is an important aspect of the workup because the lung parenchyma is the most common distant site for metastasis. A CBC typically displays mild normocytic and normochromic anemia with thrombocytosis. Any child with a suspected liver tumor should have  -fetoprotein (AFP) and β-HCG serum assays. AFP is markedly elevated in >90% of hepatoblastoma cases and in many cases of hepatocellular carcinoma, and it returns to normal with effective therapy [39]. Likewise, β-HCG is a hormone commonly produced by liver tumors and, in excess, can result in precocious puberty. Caution should be taken in normal term infants who can have AFP levels in excess of 100,000 ng/ml; however, with a half-life of approximately 1 week, the AFP level normalizes to <10 ng/ml over the first few months of life.
Because of the association between familial adenomatous polyposis and hepatoblastoma, obtaining a thorough family history is an important aspect of the management of a child with a liver tumor and his family, with particular attention to any family history of colon cancer or colonic polyps.
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STAGING
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Historically, North Americans have staged liver tumors similar to other solid tumors, with surgical resectability and the presence of metastases as the primary criteria (Table 2). The European staging system considers only the pretreatment extent of disease (i.e., the PRETreatment EXTent of disease scoring system [PRETEXT]), and was developed by the Childhood Liver Tumor Strategy Group of the Société Internationale d'Oncologie Pédiatrique, SIOPEL [40]. As shown in Figure 3, the PRETEXT staging system divides the liver into four sectors, and the number of segments involved by tumor indicates stage. A lettering system further indicates extrahepatic involvement. This staging system has been useful in determining treatment plans and offers good prognostic value for overall and disease-free survival outcomes [41, 42].
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Figure 3. The PRETreatment EXTent of disease scoring system (PRETEXT) involves classification of liver tumors by dividing the liver on imaging into four sectors and determining how many sectors are involved by tumors. Extension of the tumor is also included in the staging as follows: V indicates extension into the vena cava and/or all three hepatic veins; P indicates extension into the main branch and/or both the left and right branches of the portal vein; E indicates extrahepatic disease, and unlike P and V is rare and must be biopsy proven; M indicates the presence of distant metastases [54, 55].
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TREATMENT
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Through the work of cooperative groups around the world, treatment of hepatoblastoma has improved markedly over the past several decades. During this time, therapy has evolved from surgery alone with a poor prognosis to multimodal therapy, with some patients achieving a >90% long-term survival probability [43]. This improvement is seen most clearly for those children with initially unresectable hepatoblastoma. A comparison of European and North American trials is shown in Table 3.
Hepatocellular carcinoma is so infrequent in children that these patients have often been treated according to hepatoblastoma regimens, albeit with far less success. Recently, sorafenib, a multikinase inhibitor, was approved by the U.S. Food and Drug Administration for the first-line treatment of hepatocellular carcinoma after a study in adults demonstrated efficacy in advanced-stage hepatocellular carcinoma [44], but no data exist on its use in children. The approach to treatment of less common malignant tumors of the liver parallels the approach to the tumors with similar histology, that is, a primary hepatic sarcoma is generally treated like sarcomas in other anatomical sites.
Surgical resection is the most important therapeutic modality for the treatment of hepatic tumors. The surgeon must carefully evaluate the tumor and surrounding anatomy with MRI, CT, and/or a hepatic angiogram to determine if the tumor is resectable. At the time of resection, surrounding lymph nodes are sampled and submitted for pathologic review. If pulmonary nodules are present, an attempt at resection should be made, because this is thought to improve survival. Primary resection alone can be curative in the case of benign liver tumors and stage I hepatoblastoma of pure fetal histology.
Because of the large tumor bulk and involvement of multiple liver sectors, a primary resection is not possible in >60% of cases [45]. Therefore, systemic neoadjuvant chemotherapy is necessary and often shows impressive results. In those patients with initially unresectable tumors, an early decline in serum AFP with chemotherapy suggests a favorable outcome [41].
Recent cooperative group protocols for hepatoblastoma and hepatocellular carcinoma have involved vincristine, cisplatin, and fluorouracil in four cycles [46]. Doxorubicin has also been noted as an active agent and continues to be used throughout Europe [47]. Toxicity in previous North American trials has limited its use [46]; however, there are ongoing discussions regarding the reintroduction of doxorubicin in North American clinical trials.
Despite aggressive chemotherapy, 25%–30% of initially unresectable tumors remain resistant to treatment. Radiation is not an important therapeutic consideration in the treatment of hepatic tumors because of the normal liver parenchyma's limited maximum-tolerated dose [48].
The strategy of a complete hepatectomy and subsequent orthotopic liver transplantation has been used with success in treating unresectable liver tumors. Currently, liver malignancies account for roughly 1 in 50 liver transplantations in children. A series of 31 patients, published in 2000, showed that the post-transplant 5-year survival rate for hepatoblastoma was 86%, and this rate was 83% for hepatocellular carcinoma. As immunosuppressive regimens have improved, a steady improvement in the success of hepatic transplant patients has been seen [49, 50]. In addition, living donor transplantation has become an option [49, 50]. Ongoing questions regarding the management of post-transplant patients surround the use of adjuvant chemotherapy and the prioritization of transplant candidates [51].
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FUTURE DIRECTIONS
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While amenability to surgical resection and surgical technique advances remain the most important aspects of pediatric liver tumor therapy, new chemotherapeutic agents with less toxicity are needed. Imaging modalities such as positron emission tomography CT [52] and anti-AFP imaging [53] hold promise for better surgical outcomes and greater sensitivity for residual or relapsed disease. As more is understood regarding the molecular pathways in hepatoblastoma, it is hoped that additional targeted therapies will be developed.
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AUTHOR CONTRIBUTIONS
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Conception/design: Jason B. Litten, Gail E. Tomlinson
Administrative support: Jason B. Litten, Gail E. Tomlinson
Collection/assembly of data: Jason B. Litten, Gail E. Tomlinson
Data analysis and interpretation: Gail E. Tomlinson
Manuscript writing: Jason B. Litten, Gail E. Tomlinson
Final approval of manuscript: Jason B. Litten, Gail E. Tomlinson
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Learning Objectives
Abstract