Liver Tumors
Rebecka L. Meyers
Angela D. Trobaugh-Lotrario
Marcio H. Malogolowkin
Howard M. Katzenstein
Dolores H. López-Terrada
Milton J. Finegold
HISTORICAL CONTEXT
Benign and malignant liver tumors in children are rare; the vast majority of them are sporadic; however, they can be associated with predisposing conditions (e.g., hepatitis) or familial cancer syndromes.1,2 Complete surgical resection, especially of malignant tumors, continues to be the most important determinant of long-term survival for these children. Although the associated morbidity and mortality of surgical resection of liver tumors have significantly decreased over the years,3 less than a third of hepatic tumors are amenable to upfront surgical resection. The use of neoadjuvant chemotherapy has significantly improved survival by increasing the number of patients who can ultimately undergo tumor resection. Multidisciplinary, multi-institutional, international cooperative trials have facilitated continued improvements across multiple realms for children with liver tumors. This has included improvement in overall survival, particularly for those with hepatoblastoma (HB); and reduction in morbidity through reductions in the long-term toxicity of therapy. Collaborative initiatives have also led to the development of common staging and pathology criteria for these tumors, as well as a better understanding of their biology and epidemiology.4,5 Additionally, advances in radiographic imaging have allowed for better preoperative diagnosis and subsequent surgical planning. Due to the small numbers of children diagnosed each year with liver tumors, ongoing international cooperation is necessary for continued improvement in the outcomes and for the advancement in the knowledge of the genetics and biology of these tumors.
DIFFERENTIAL DIAGNOSIS
A majority of hepatic masses in children are malignant. The differential diagnosis of liver tumors in children includes epithelial tumors, mixed epithelial, and mesenchymal tumors, undifferentiated rhabdo- and angiosarcomas, germ cell tumors, and metastatic or secondary tumors. In addition to these broad categories, a new consensus classification for pediatric liver tumors was recently developed4 following an International Liver Tumors Pathology Symposium sponsored by the Children’s Oncology Group (COG) and a subsequent International Pediatric Liver tumors Biology Symposium sponsored by European Network for Cancer Research in Children and Adolescents and by International Society for Pediatric Oncology (SIOPEL). SIOPEL was formerly the acronym for Société Internationale d’Oncologie Pédiatrique—Epithelial Liver Tumor Study Group; the group has been recently renamed as International Childhood Liver Tumors Strategy Group but continues to use its historic acronym, SIOPEL.
Table 28.1 shows the New International Consensus Classification for Pediatric Tumors of the Liver. The reader of this chapter should note that this entire chapter is organized according to this new classification system and should refer back to this table often while reading the chapter.
Rarely one may encounter metastatic hepatic lesions or contiguous invasion from primary pediatric solid tumors, such as neuroblastoma, Wilms tumor, or pancreatoblastoma, as the primary presenting feature of a solid tumor. Hepatic involvement in hematologic malignancies such as hemophagocytic lympho-histiocytosis (HLH), Langerhans cell histiocytosis (LCH), mega-karyoblastic leukemia (M7), or even acute myeloid leukemias may occasionally mimic a primary hepatic malignancy. A variety of benign tumors can also occur in children, the most common of which are vascular tumors6 (Fig. 28.1). Other benign and intermediate malignant potential tumors include mesenchymal hamartoma, biliary cystadenoma, hepatic adenoma, focal nodular hyperplasia (FNH), macroregenerative nodules, germ cell tumors, and inflammatory myofibroblastic tumors.7 Non-neoplastic masses such as vascular malformations, congenital and acquired cysts, abscess, hematoma, and fatty infiltration of the liver may occasionally be confused with liver tumors (Fig. 28.2). Hepatic hematoma or infarction should be suspected in any child with a history of hepatic trauma or in newborns with sepsis and coagulopathy, especially if there is a history of perinatal birth trauma, thrombocytopenia, or hemodynamic collapse requiring cardiopulmonary resuscitation. Congenital liver cysts are rare and represent a spectrum ranging from large simple cysts, intrahepatic choledochal cyst, and ciliated hepatic foregut cyst. Acquired cysts might be bacterial, hydatid, or amoebic abscess.
Age at presentation and serum level of alpha fetoprotein (AFP) are important considerations in the differential diagnosis of a liver tumor (Table 28.2).8,9 HB is most common in very young children; more than 80% of children with HB are under the age of 3 at diagnosis.10 Other rare malignant liver tumors in infants and young children include teratoma, rhabdoid tumor, and biliary rhabdomyosarcoma.6 Benign tumors in this age group include infantile hepatic hemangioma and mesenchymal hamartoma. In older children and adolescents, the main malignant liver tumors in the differential diagnosis are hepatocellular carcinoma (HCC) and undifferentiated sarcoma of the liver. HCC in this age group consists of a heterogeneous group of tumors, including tumors with features of both HB and HCC (termed HC-NOS), de novo HCC, HCC developing in children with underlying metabolic or cirrhotic liver disease, and fibrolamellar carcinomas.11,12 Aggressive hepatocellular tumors in older children with intermediate features between HB and HCC were previously, and somewhat imprecisely, dubbed “transitional cell liver tumors (TCLT).” The new international consensus classification designates these tumors as hepatocellular malignant neoplasm—not otherwise specified (HC-NOS).4 The median age at diagnosis for HCC is about 12 years, but HCC has been described in children as young as 1 year in cases of congenitally acquired hepatitis B and underlying cholestatic/metabolic disease.13,14
Very high AFP suggests a diagnosis of HB, although AFP concentrations may be elevated in HCC, germ cell tumors, and benign liver tumors such as mesenchymal hamartoma15 or infantile hemangioma.16 Other potentially premalignant conditions such as viral hepatitis or tyrosinemia may present with high serum AFP,17 although in these situations the AFP level is usually not as high as in HB. Importantly, high serum fetal protein is found in normal infants in whom normally elevated perinatal AFP concentrations
gradually decline until 6 to 8 months of age. Consequently, in children younger than 1 year, it may be difficult to distinguish physiologic elevation of AFP from AFP secreted by a malignant tumor. Moreover, AFP is often secreted at high levels in the regenerating liver and/or after ischemic liver injury. A spontaneous decline in the AFP level without any treatment is a good argument in favor of physiologic, not neoplastic, origin. Low AFP is seen in some children with HCC, other malignant liver tumors like rhabdoid and sarcomas, and benign tumors. Beware that a false low AFP level may sometimes occur in HB due to lab error, in which the presence of extremely high AFP overwhelms the assay technique and generates an erroneously low result,18 a phenomenon known as the “hook effect.” Occasionally, AFP levels may be very low in HB, even the well-differentiated fetal type, and those with primarily small undifferentiated cells, most often in infants.19
gradually decline until 6 to 8 months of age. Consequently, in children younger than 1 year, it may be difficult to distinguish physiologic elevation of AFP from AFP secreted by a malignant tumor. Moreover, AFP is often secreted at high levels in the regenerating liver and/or after ischemic liver injury. A spontaneous decline in the AFP level without any treatment is a good argument in favor of physiologic, not neoplastic, origin. Low AFP is seen in some children with HCC, other malignant liver tumors like rhabdoid and sarcomas, and benign tumors. Beware that a false low AFP level may sometimes occur in HB due to lab error, in which the presence of extremely high AFP overwhelms the assay technique and generates an erroneously low result,18 a phenomenon known as the “hook effect.” Occasionally, AFP levels may be very low in HB, even the well-differentiated fetal type, and those with primarily small undifferentiated cells, most often in infants.19
TABLE 28.1 Pediatric Tumors of the Liver, International Consensus Classification4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Regardless of the AFP level, unless the tumor has unequivocal radiographic characteristics of a benign tumor, such as an infantile hemangioma, biopsy is recommended. Ultrasound (US)- or CT-guided percutaneous biopsy by coaxial technique is the most common approach to tumor biopsy. Multiple cores of tumor are desirable to allow for a larger amount of tissue for biologic study and genetic testing. When possible one core of normal liver and 2 or 3 cores of tumor should be frozen for biologic and genetic testing. In patients with high AFP level, the main aim is to distinguish between HB, transitional-type liver tumors, and HCC. In patients with normal AFP, the main aim is to distinguish benign tumors from small cell undifferentiated HB, rhabdoid tumor, fibrolamellar HCC, sarcomas, and metastatic tumors.
EPITHELIAL TUMORS
Hepatocellular Epithelial Tumors: Malignant. Hepatoblastoma (HB); HC-NOS; and Hepatocellular Carcinoma (HCC)
Hepatoblastoma (HB)
(Mixed epithelial, mesenchymal, and teratoid subtypes of hepatoblastoma are included in this epithelial section)
Epidemiology. HB is the cause of 80% of all malignant liver neoplasms in children and accounts for 91% of the malignant tumors in children younger than 5 years.1 The incidence of HB throughout the world is 0.5 ± 1.5 cases per million children with a male:female ratio of HB of 2:1.5 Some epidemiologic studies in the United States suggest that the HB incidence rates in the United States have increased from 0.6 to 1.2 per million in the past 2 decades,1,20 which could be a consequence of improved survival rates of very low birth weight (VLBW, birth weight <1,500 g) premature babies. VLBW is a potent risk factor for HB that is independently associated with congenital abnormalities.5,20 The odds ratio of the occurrence of HB was 17.18 for babies weighing less than 1,500 g versus 1.56 for those weighing more than 2,500 g.20 Preterm and VLBW babies may be exposed to potential newborn intensive care risk factors such as light, oxygen, irradiation, plastics, medications, and total parenteral nutrition (TPN)21 during a stage in development when the liver is growing rapidly and mechanisms for detoxification of endogenous and exogenous substances are undeveloped.
HB is associated with several constitutional genetic syndromes including progressive familial intrahepatic cholestasis (PFIC), renal or adrenal agenesis, fetal alcohol syndrome, Prader-Willi syndrome, and Beckwith-Wiedemann syndrome (BWS)5,22,23 (Table 28.3). BWS is characterized by overgrowth, an umbilical defect (either an umbilical hernia or omphalocele), and macroglossia. Children with BWS associated with chromosome 11p abnormalities and aberrant imprinting have a high relative risk of developing HB, particularly patients with hemihypertrophy.24,25 Cases of HB have also been associated with hemihypertrophy, TPN-related cholestasis, and type I glycogen storage disease.26 Environmental factors including maternal use of oral contraceptives, exposure to metals, and smoking may also play a role in the development of HB.5
Several distinct developmental pathways known to be altered in HB are detailed in Table 28.4 .27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65 Wnt/β-catenin. Nuclear and cytoplasmic accumulations of β-catenin, whose oncogenic mutations lead to chromosomal instability and aberrant Wnt/β-catenin signaling, may be a hallmark of HB tumorigenesis.35,66 Several studies of sporadic HB have
identified mutations or deletions clustered in exon 3 of CTNNB1, the gene for β-catenin.56,67 Wnt ligand-binding site coding at exon 3 is required for β-catenin degradation by serine/threonine phosphorylation of β-catenin using the APC/Axin/GSK3β protein complex. Therefore, mutation or absence of this site leads to β-catenin cytoplasmic accumulation. Accumulated β-catenin binds TCF/LEF transcription factors, translocates to the nucleus, and activates the expression of many target genes, including those involved in cell proliferation (e.g., c-myc and cyclin D1), antiapoptosis (e.g., survivin), invasion (e.g., matrix metalloproteinases), and angiogenesis (e.g., VEGF).27,68 A significant increase in the risk of HB has been noted in families with familial adenomatous polyposis and Gardner syndrome,69 due to APC gene mutations, involved in β-catenin ubiquitination. Survivors of HB who have this syndrome are at risk for developing familial adenomatous polyposis and liver tumors at a young age. The important role of Wnt pathway activation in HB pathogenesis was confirmed by Cairo and colleagues by genetic and expression profiling a series of clinically annotated HBs. They demonstrated that HB stem-like phenotype requires interplay between Wnt and Myc oncogene signaling, and that specific Wnt/β-catenin molecular signature in HB varies according to the differentiation stage of the tumors and is predictive of their clinical behavior.50,70 Recently, Hedgehog signaling and insulin-like growth factor (IGF)/phosphatidylinositol-3′ kinase (PI3K)/AKT signaling were identified as stimulating the pathway of Wnt signaling. Therefore, high activation of Wnt signaling by several diverse pathways appears to be strongly correlated with the pathogenesis of HB.
identified mutations or deletions clustered in exon 3 of CTNNB1, the gene for β-catenin.56,67 Wnt ligand-binding site coding at exon 3 is required for β-catenin degradation by serine/threonine phosphorylation of β-catenin using the APC/Axin/GSK3β protein complex. Therefore, mutation or absence of this site leads to β-catenin cytoplasmic accumulation. Accumulated β-catenin binds TCF/LEF transcription factors, translocates to the nucleus, and activates the expression of many target genes, including those involved in cell proliferation (e.g., c-myc and cyclin D1), antiapoptosis (e.g., survivin), invasion (e.g., matrix metalloproteinases), and angiogenesis (e.g., VEGF).27,68 A significant increase in the risk of HB has been noted in families with familial adenomatous polyposis and Gardner syndrome,69 due to APC gene mutations, involved in β-catenin ubiquitination. Survivors of HB who have this syndrome are at risk for developing familial adenomatous polyposis and liver tumors at a young age. The important role of Wnt pathway activation in HB pathogenesis was confirmed by Cairo and colleagues by genetic and expression profiling a series of clinically annotated HBs. They demonstrated that HB stem-like phenotype requires interplay between Wnt and Myc oncogene signaling, and that specific Wnt/β-catenin molecular signature in HB varies according to the differentiation stage of the tumors and is predictive of their clinical behavior.50,70 Recently, Hedgehog signaling and insulin-like growth factor (IGF)/phosphatidylinositol-3′ kinase (PI3K)/AKT signaling were identified as stimulating the pathway of Wnt signaling. Therefore, high activation of Wnt signaling by several diverse pathways appears to be strongly correlated with the pathogenesis of HB.
 Figure 28.1 Radiographic appearance of the most common benign and malignant neoplastic masses of the liver in children. (a) Mesenchymal Hamartoma a complex multicystic mass with solid septae; (b) Focal Nodular Hyperplasia with arrow pointing to classic stellate central scar; (c) Diffuse Infantile Hepatic Hemagioma with multiple nodules showing peripheral contrast enhancement; (d) PRETEXT II Hepatoblastoma; (e) PRETEXT IV +P Hepatocellular Carcinoma with involvement of main portal vein; (f) Metastatic Tumor, two nodules of metastatic colorectal carcinoma in right anterior and posterior sections. |
 Figure 28.2 Differential diagnosis: radiographic appearance of non-neoplastic masses and cysts. (a) Multiple small bacterial abscess in a child with chronic granulomatous disease; (b) Inspissated bile lake in a child with biliary atresia and cholangitis; (c) organizing hematoma in a newborn with sepsis and coagulopathy; (d) infarction of right lobe liver and hepatic abscess (with air fluid level) in a premature baby with necrotizing enterocolitis; (e) acquired cyst is an amoebic abscess in a toddler with fever; (f) congenital cyst is a ciliated foregut cyst in an infant with abdominal distension and feeding difficulties. |
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TABLE 28.3 Genetic Syndromes Associated with Pediatric Liver Tumors | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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TABLE 28.4 Signaling Pathways, miRNAs, and Epigenetic Abnormalities in Pediatric Liver Tumors | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Telomerase and MYC. Activation of telomerase, which maintains telomere length and is required for cell immortalization, has been reported as a prognostic factor in HB.71,72 Recently, telomerase reverse transcriptase (TERT), a catalytic component of human telomerase, was identified as one of cofactors of β-catenin to bind TCF/LEF transcription factors. Therefore, telomerase activation might activate the expression of many target genes of Wnt. In addition, the TERT promoter contains MYC binding sites. The highly malignant HB shows significantly high expression of MYC and MYC-related genes.50 Since MYC will be activated as one of the Wnt signal target genes, TERT expression might be activated by MYC, suggesting that a vicious cycle may exist in HB and contribute to develop the highly malignant HB.56
Notch. Notch, a pathway involved in stem cell self-renewal and differentiation that is aberrantly activated in other malignancies, is crucial for cholangiocytic lineage differentiation.73,74 DLK1 (delta-like protein/preadipocyte factor 1/fetal antigen 1 or DLK/Pref1) is a Notch ligand that is highly upregulated in both HCC and HB.42,55
Sonic Hedgehog. Sonic Hedgehog signaling pathway is important for liver regeneration and may play a role in HCC.75,76 In HB, increased expression of multiple genes in this pathway has been reported, including Sonic Hedgehog (SHH), Patched (PTCH), the transcription factor GLI,36,37 and the HHIP gene promoter for methylation.77
IGF2/H19. Epigenetic changes of IGF2, also resulting in downstream activation of PI3K and MAP kinase signaling, have been associated with BWS, Silver-Russell syndrome, and embryonal tumors, including HB, by several mechanisms.49,61,78
PI3K/AKT. Hartmann and colleagues investigated PI3K/AKT pathway activation in HB and identified a PIK3CA gene mutation in a case of HB, and strong p-AKT, p-GSK-3beta, and p-mTOR expressions have been documented in HB cell lines.41 Hepatocyte growth factor (HGF)/cMET signaling is another signaling pathway mediated by PI3K/AKT that is reportedly involved in HB survival.44
Pathology of Hepatoblastoma. HBs are usually single, well-circumscribed masses arising in an otherwise normal liver. At initial diagnosis, HBs are solitary in about 80% of patients, multifocal in about 20%, and located in the right lobe in about 60%. HBs are generally grossly heterogeneous tumors, with mixtures of diverse microscopic components, which may include both epithelial and mesenchymal elements (Fig. 28.3). Gross appearance, including color and cut surface, will vary depending on the presence of hemorrhage, necrosis, and the prevalence of components such as osteoid, which may be calcified, and is more prevalent in post-chemotherapy specimens (Fig. 28.4). Tumors that have been pretreated with chemotherapy are usually firm, and well delineated with pale fibrotic areas and calcifications.
Guidelines for the optimal gross and histologic workup of HB have been formulated in a College of American Pathologists protocol.79 A detailed gross description includes information about Couinaud segment (functional liver segments) involvement; number and size of tumor nodules; multifocality; and macroscopic vascular involvement, including detailed analyses of portal vein, hepatic vein, and/or retrohepatic vena cava involvement. For the evaluation of surgical resection margins and the assessment of microscopic residual disease, it is recommended that surgeons and pathologists work closely together using colored sutures and/or inking to identify critical margin areas, especially as they relate to the vascular and biliary trees. Extensive sampling of the tumor is essential to identify the diverse histopathologies and to collect and process fresh tissue for molecular characterization.
 Figure 28.3 Resection at diagnosis of pure fetal HB. Untreated without prior chemotherapy exposure. |
 Figure 28.4 Mixed HB. Postchemotherapy specimen with abundant necrosis and osteoid. |
Microscopically, HBs are usually heterogeneous tumors that display combinations of epithelial, mesenchymal, undifferentiated, or other components80 (Fig. 28.5). An internationally agreed-upon pathologic classification of the histologic subtypes of HB has recently been published4 (Table 28.5). HB subtypes are rarely homogeneous; about 85% contain at least some fetal and embryonal components.81 When pure fetal histology (PFH) HB, also referred to as “well-differentiated fetal,” has very little mitotic activity (up to 2 per 10 high-power [40×] fields), it carries a very favorable prognosis, and if completely resected does not require chemotherapy (Fig. 28.6).82 Other subtypes of fetal HB include mitotically active (“crowded”), pleomorphic/poorly differentiated, and anaplastic as defined in Table 28.5. The embryonal pattern almost always occurs in combination with fetal components, and areas of transition from fetal to embryonal cells are common. In contrast to fetal HB, bile production is rare in predominantly embryonal tumors, but both types display extramedullary hematopoiesis as in the normal fetal liver. Macrotrabecular HB has more than five cells in micronodules and the cells may be fetal, embryonal, or indistinguishable from those of adult-type HCC (Fig. 28.7).83 Originally termed “anaplastic,” Haas et al.84 proposed the term “small cell undifferentiated (SCU) subtype” in 1989 (Fig 28.8). The impact of small-foci SCU histology upon prognosis is not yet clear, and it is being studied in the current COG trial AHEP-0731. Clearly the prognosis is poor when SCU is the dominant histologic phenotype, especially in infants, in patients
with low serum AFP levels, and when they fail to express INI85,86 (Fig. 28.9), and may in fact represent malignant rhabdoid tumors.85 A large proportion of HB (about 45% when examined after chemotherapy) demonstrate a mixed epithelial and mesenchymal phenotype. When the epithelial cells resemble bile duct components, they are referred to as “cholangioblasts.” The mixed phenotype can be further subdivided into those with stromal derivatives only, including cartilage, skeletal muscle, and osteoid-like bone formation, the latter being more commonly present after chemotherapy,81,87 versus teratoid HB with primitive endodermal and neuroepithelial components. Other than the favorable prognosis with well-differentiated fetal and the poor prognosis with undifferentiated small cells, the various histotypes are not currently known to have prognostic importance. Although worse prognosis with macrotrabecular subtypes has been suspected, its impact has never reached statistical significance.88
with low serum AFP levels, and when they fail to express INI85,86 (Fig. 28.9), and may in fact represent malignant rhabdoid tumors.85 A large proportion of HB (about 45% when examined after chemotherapy) demonstrate a mixed epithelial and mesenchymal phenotype. When the epithelial cells resemble bile duct components, they are referred to as “cholangioblasts.” The mixed phenotype can be further subdivided into those with stromal derivatives only, including cartilage, skeletal muscle, and osteoid-like bone formation, the latter being more commonly present after chemotherapy,81,87 versus teratoid HB with primitive endodermal and neuroepithelial components. Other than the favorable prognosis with well-differentiated fetal and the poor prognosis with undifferentiated small cells, the various histotypes are not currently known to have prognostic importance. Although worse prognosis with macrotrabecular subtypes has been suspected, its impact has never reached statistical significance.88
 Figure 28.5 Histologic appearance of mixed HB (F, fetal; E, embryonal; Bl, blastema; EMH, extramedullary hematopoiesis). |
TABLE 28.5 Histologic Subtypes Hepatoblastoma—International Consensus Classification4 | ||||||||||||||||||||||||||
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 Figure 28.6 Histologic appearance of fetal HB: (a) well-differentiated with no mitoses; (b) mitotically active (“crowded fetal”). |
 Figure 28.7 Histologic appearance of macrotrabecular HB, to be distinguished from HCC. |
Imaging, Staging, PRETEXT, Risk Group Stratification in Hepatoblastoma. Radiographic Imaging. Appropriate high-quality radiographic imaging remains an essential diagnostic step in the preoperative evaluation of all liver tumors. It is usually difficult to establish the diagnosis of a liver lesion based on imaging alone. Usually, the first study is an abdominal US, which will localize the tumor within the liver and offer some clues regarding its possible character. The typical sonographic appearance of HB and HCC is of a large, heterogeneous (usually predominantly hyperechoic), and vascular mass. The use of US contrast agents in children is currently experimental, but the results in adults suggest that they may be helpful for identifying and characterizing hypervascular liver lesions.89 In the immediate preoperative assessment of patients with vascular involvement, Doppler US is particularly
valuable in helping to differentiate between overt vascular invasion and thrombus, or simple vessel compression by mass effect. In such cases, it is very helpful for the surgeon to be present as the US examination is being performed.
valuable in helping to differentiate between overt vascular invasion and thrombus, or simple vessel compression by mass effect. In such cases, it is very helpful for the surgeon to be present as the US examination is being performed.
 Figure 28.8 Histologic appearance of SCU, INI negative. |
 Figure 28.9 INI negative SCU HB. Positive nuclei in leukocytes only. |
Radiographically HCC may be difficult to distinguish from HB. The presence of associated cirrhosis would suggest HCC but is often absent in children. Both tumors are typically large (unless HCC is detected by screening in a cirrhotic patient). While HCC is more commonly multifocal, HB may be multifocal as well. In both diagnoses, there may be calcification, venous invasion, and lung metastases. Non-lung metastases (for example, to bone) are rare in HB and favor a diagnosis of HCC or rhabdoid. Identification of a central fibrous “scar” suggests fibrolamellar carcinoma or FNH.90
The gold standard for hepatic imaging includes (1) the triphasic contrast-enhanced abdominal CT and (2) magnetic resonance imaging (MRI) with hepatocyte-specific contrast agents (e.g., gadoxetate disodium or gabobenate dimeglumine) and sequences that include diffusion-weighted as well as delayed hepatobiliary phase imaging with the contrast agents noted earlier. With contrast CT, the three imaging phases include the arterial phase, the venous phase, and the delayed phase. The arterial phase shows the hepatic arterial supply to the liver and may be useful for the detection of small hypervascular lesions, for example small HCC or metastatic lesions.91 Images in the venous phase of contrast usually maximize visualization of tumor margins and are best for assessment of portal and hepatic venous involvement; the hepatic veins usually opacify with contrast almost simultaneously with the portal veins. Delayed sequences may be helpful in establishing the differential from hemangiomas, which often wash out on delayed images. However, if for some reason only one scan is to be performed, it should be done in the portal venous phase.92 In addition, in every case of a suspicion of a malignant lesion, high-resolution spiral chest CT should be performed in order to visualize potential lung metastases. With the new generation of CT scanners there is a slight risk of overdiagnosis of very small lesions (below 0.5 to 1 cm), which in fact may rather represent benign lesions rather than true metastatic foci, and even if they are neoplastic in origin, their clinical significance may be controversial.93,94 One should also keep in mind relatively frequent occurrence of lung atelectasis in basal lung segments in children undergoing CT under general anesthesia.
An alternative and increasingly excellent imaging technique for liver tumors is MRI with hepatocyte-specific contrast administration. MRI is prone to motion artifact in small children, and its accessibility may be limited due to costs, including the costs associated with the need for general anesthesia in young children. On MRI, HB is homogeneously slightly hypointense on T1-weighted images and hyperintense on T2-weighted images relative to adjacent liver parenchyma.95 Mixed tumors demonstrate more heterogeneous signal intensity characteristics.95 HCCs are heterogeneous (but predominantly hypointense) on T1-weighted images, and mildly hyperintense in comparison with normal liver on T2-weighted images.96 Contrast-enhanced T1-weighted HCC images show a similar pattern to CT, with early arterial enhancement and reduced signal intensity in the portal venous phase.97 In adults, new MRI contrast agents such as ferucarbotran98 and mangafodipir99 appear to increase the sensitivity for the detection of HCC, but the results are as yet inconsistent.100 In children, experience with the MRI contrast agent gadolinium gababinate dimegluonone gd-EOB-DTPA was recently reported in HB.101 Early results clearly show anatomic differentiation of benign versus malignant tumors with a clarity that is unobtainable with standard contrast agents.102
There are case reports using positron emission tomography (PET) for the detection of recurrent HB, especially in the situation of a rising AFP and negative results after standard imaging (US, CT, MRI). However, caution is warranted since both false-negative and false-positive results have been reported.103 PET-CT is more commonly used in adult HCC for prognostication and staging; however, pediatric experience with this modality is limited.
Risk Group Stratification. Risk group stratification has differed between the different study groups: COG, SIOPEL, German Pediatric Oncology Haematology (GPOH), and Japanese Pediatric Liver Tumor Study Group (JPLT) (Table 28.6). Historically the
COG legacy groups Children’s Cancer Study Group (CCSG) and Pediatric Oncology Group (POG) used the Evans staging system that relied upon the results of an attempt at surgical resection at diagnosis in all patients. In the current COG trial, AHEP-0731, the risk stratification is a hybrid of the traditional Evan’s stage, PRE-Treatment EXTent of tumor (PRETEXT) determination of resectability at diagnosis (Fig. 28.10), AFP level at diagnosis, and presence or absence of unfavorable histologic subtype.104 The
disparate risk classification schemes of the four major study groups have made it difficult to compare the outcomes of past studies across the oceans, although all groups have increasingly used the PRETEXT grouping system in some way.
COG legacy groups Children’s Cancer Study Group (CCSG) and Pediatric Oncology Group (POG) used the Evans staging system that relied upon the results of an attempt at surgical resection at diagnosis in all patients. In the current COG trial, AHEP-0731, the risk stratification is a hybrid of the traditional Evan’s stage, PRE-Treatment EXTent of tumor (PRETEXT) determination of resectability at diagnosis (Fig. 28.10), AFP level at diagnosis, and presence or absence of unfavorable histologic subtype.104 The
disparate risk classification schemes of the four major study groups have made it difficult to compare the outcomes of past studies across the oceans, although all groups have increasingly used the PRETEXT grouping system in some way.
TABLE 28.6 Use of PRETEXT in Current Risk Stratification Schemes of COG, SIOPEL, GPOH, JPLT, and Proposed New Stratification Scheme to be Adopted Internationally by All Treatment Groups110 | |||||||||||||||||||||||||||||||||||
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 Figure 28.10 PRETEXT, anatomic extent of tumor to define resectability. Referred to as POST-TEXT after chemotherapy. |
TABLE 28.7 Definitions of PRETEXT/POST-TEXT Group (I, II, II, IV) and Annotations (V, P, E, M, C, F, N, R) | |||||||||||||||||||||||||||
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Over the past 10 years, individual study groups have attempted to define the relative importance of a variety of suspected prognostic factors present at diagnosis and in response to therapy.88,105,106,107,108,109 SIOPEL good prognostic factors have included low PRETEXT at diagnosis (PRETEXT I, II, and III tumors) (Table 28.7).109 In COG, good prognosis has been shown for stage I tumors resected at diagnosis and tumors with PFH.82,88 Poor prognostic factors identified individually in these trials include advanced PRETEXT IV tumors, metastatic disease at diagnosis, AFP<100 at diagnosis, and SCU histology.88,109 Other variables, such as tumor rupture prior to diagnosis, tumor multifocality, macrovascular tumor invasion, extrahepatic tumor extension, age at diagnosis, and very high (>1 million) or borderline low (100 to 1,000) AFP, have been suggested as poor prognostic factors, but the relative importance of their prognostic significance has been difficult to define.110 Factors in response to treatment that had been hypothesized as poor prognostic factors include poor response or progressive disease on chemotherapy, gross positive surgical margins, surgically unresectable tumor, and tumor relapse.
Efforts to define clinical prognosis in HB have historically been challenging due to the low numbers of patients, even in multicenter trials. To address this challenge, the Children’s Hepatic Tumor International Collaboration (CHIC) initiative was formed to combine the results of multicenter trials by SIOPEL, COG, JPLT, and GPOH over the past 20 years and thereby gain enhanced statistical power in the interrogation of prognostic factors. In cooperation with the data management group CINECA, CHIC created a data set that includes comprehensive data on all children treated on 11 separate trials by the 4 major HB study groups between 1989 and 2008, a total of 1,603 patients.110,111 This statistical effort is ongoing, has been reported in its preliminary form at international meetings, is in the process of peer-reviewed publication, and is being used to define a new global risk stratification system that will be adopted internationally (Table 28.8).
Chemotherapy for Hepatoblastoma. The addition of adjuvant and neoadjuvant chemotherapy to the multidisciplinary treatment strategy for HB improved survival outcomes dramatically. Cisplatin is considered to be the most active chemotherapy agent in the treatment of HB.112 Chemotherapy regimens that have included cisplatin achieved response rates up to 97% in low-risk patients and a resection rate of up to 80%.105,113,114,115,116,117,118,119,120,121,122 In fact, cisplatin alone is curative in most children with standard-risk HB and is the current standard SIOPEL treatment for these patients.117,118 Summary results of the major international trials over the past 2 decades are shown in Table 28.9.105,113,114,115,116,117,118,119,120,121,122
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