Pediatr Blood Cancer 2012;59:793799

REVIEW Diagnosis and Staging of Hepatoblastoma: Imaging Aspects

M. Beth McCarville, MD1* and Derek J. Roebuck, FRANZCR2
Imaging plays a pivotal role in the diagnosis and management of children with hepatoblastoma. However, the continuing evolution of imaging technologies and rarity of hepatoblastoma make validation of imaging approaches challenging. In Europe and other parts of the world staging of hepatoblastoma is based on imaging features while in North America it is based on surgical resectability. In this review we discuss the clinical and imaging features that aid in diagnosing and monitoring children with hepatoblastoma. The potential roles of new imaging techniques are presented, and differences between staging systems are addressed. Pediatr Blood Cancer 2012;59:793799. 2012 Wiley Periodicals, Inc.

Key words:

diagnosis; hepatoblastoma; imaging; staging

INTRODUCTION
Imaging plays a pivotal role in managing children with hepatoblastoma. Together with clinical information, imaging features of pediatric liver tumors can be highly suggestive of a specic diagnosis [1,2]. Children with hepatoblastoma undergo imaging of the chest and abdomen for staging, monitoring response to therapy and to detect recurrences. Recent advances in magnetic resonance imaging and molecular imaging techniques offer the potential to improve our understanding of the biological behavior of hepatoblastoma and enhance our ability to detect and characterize these tumors. However, the rapid pace of technological advances and rarity of hepatoblastoma make validating the ideal approach challenging. In Europe staging of hepatoblastoma is based solely on imaging features while in North America staging depends on surgical resectability. Herein, we review the clinical and imaging characteristics of hepatoblastoma and contrast them to other tumors in the differential diagnosis. The current role of imaging modalities, promising new imaging techniques and differences in staging systems are presented.

somewhat complementary, and they rapidly evolve over time. It is therefore acceptable to perform more than one or even all three in individual patients. Technical details of these imaging modalities are complicated, and have been reviewed elsewhere [7].

Ultrasound
The rst imaging study performed in children with a suspected abdominal mass is usually an ultrasound, which has several important attributes. Ultrasound can conrm the hepatic origin of the tumor by evaluating the movement of the mass with respiration or its vascular supply [8]. On sonography hepatoblastoma can appear as a solitary mass, a dominant mass with satellite lesions, as multiple nodules throughout the liver or, rarely, a diffusely inltrative mass involving the entire liver. Most tumors are hyperechoic relative to normal liver but are often inhomogenous due to mesenchymal components. Calcications may be present and appear as punctate or linear hyperechoic foci with posterior shadowing. Areas of internal hemorrhage and necrosis are not uncommon and will appear anechoic [9]. Doppler ultrasound is useful for detecting hepatic and portal venous invasion (Figs. 1 and 2A,C) [10]. The presence of high velocity ow within the tumor and invasion of the portal vein strongly support the diagnosis of a malignant neoplasm. In contrast, hepatic hemangiomas can usually be distinguished from hepatoblastoma when there is enlargement of the celiac axis and decreased caliber of the aorta below it due to vascular shunting into the hepatic mass. Doppler signal obtained from hepatic hemangiomas will demonstrate both arterial and venous ow as well as minimal arterial systolic diastolic ow variation [9]. However, when tumors are large and vessels are compressed, assessment of the portal and hepatic veins with Doppler ultrasound is difcult and computed tomography (CT) or magnetic resonance imaging (MRI) may be preferable. Because it can identify very small blood vessels, ultrasound may be uniquely able to distinguish small peritoneal nodules from

DIAGNOSIS OF HEPATOBLASTOMA
Imaging features of hepatoblastoma are non-specic, but important clues to the diagnosis can be obtained from the history, physical examination, and laboratory ndings. The combination of clinical and appropriate imaging ndings in a child between 6 months and 3 years old is nearly diagnostic of hepatoblastoma. For example, in a child with a liver mass and an elevated serum alpha-fetoprotein (AFP) any one of the following strongly suggests a diagnosis of hepatoblastoma: family history of adenomatous polyposis, history of very low birth weight (<1.5 kg), or BeckwithWiedemann syndrome [14]. Thrombocytosis is commonly associated with hepatoblastoma [5,6], although it is also seen in children with hepatocellular carcinoma [6]. The differential diagnosis of an infant or young child with a liver mass and the imaging features that are useful in distinguishing between them, are discussed below.

IMAGING TECHNIQUES
There are no recent studies comparing the performance of the three major imaging techniques (ultrasound, computed tomography, and magnetic resonance imaging) in the evaluation of primary pediatric liver tumors [7]. This eld is not a priority for research because the tumors are rare, imaging techniques are

1 Department of Radiological Sciences, St. Jude Childrens Research Hospital, Memphis, Tennessee; 2Department of Radiology, Great Ormond Street Hospital, London, UK

*Correspondence to: M. Beth McCarville, MD, Department of Radiological Sciences, MS 220, St. Jude Childrens Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105. E-mail: beth.mccarville@stjude.org Received 8 May 2012; Accepted 8 May 2012

2012 Wiley Periodicals, Inc. DOI 10.1002/pbc.24221 Published online 7 June 2012 in Wiley Online Library (wileyonlinelibrary.com).

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peripheral liver lesions. Detection of peritoneal tumor nodules is crucial for surgical planning and staging. Subtle lesions can easily be missed by ultrasound; CT and MRI may perform better in this regard (Fig. 3C,D). Although ultrasound ndings of hepatoblastoma may overlap other benign and malignant conditions it is extremely useful as a preliminary study. Specically, it can be performed quickly, does not require sedation, can usually accurately localize the tumor, and has the added benet of avoiding ionizing radiation [9].

Computed Tomography
Although many pediatric radiologists prefer MRI for assessment of liver tumors, the convenience of CT, especially because it is better able to detect pulmonary metastases, leads to its common use in evaluating the primary liver mass. Ideally, CT images of the liver should be acquired in the arterial and portal venous phases after administration of intravenous contrast [7]. To minimize radiation exposure, the rest of the trunk should be imaged in only one phase and no pre-contrast imaging should be performed. The CT appearance of hepatoblastoma is extremely variable and

Fig. 1. Oblique ultrasound image shows tumor invading the main portal vein (arrows).

Fig. 2. A: Transverse ultrasound image shows that a large hepatic mass (asterisk) abuts the middle hepatic vein (MHV) but does not cross it into segment 8. This is therefore a PRETEXT II tumor. The MHV is not involved because it is not encased and remains patent, with no intraluminal tumor. The right hepatic vein (RHV) is also uninvolved. B: Multiplanar reconstruction of an MRI study shows similar ndings. The MHV is indicated by arrows. C: Ultrasound of the left lobe in the same patient shows the left hepatic vein (LHV, arrow) and stomach (S). D: T1-weighted MR image obtained 20 minutes after intravenous administration of gadoxetate disodium shows a second tumor nodule (arrow) missed at ultrasound. [Color gure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/pbc]
Pediatr Blood Cancer DOI 10.1002/pbc

Diagnosis, Staging Hepatoblastoma

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Fig. 3. A: Transverse short-tau inversion recovery (STIR) MRI shows a large mass (arrows) arising from the right lobe of the liver. The high signal and dark ow voids seen centrally resemble the central scar often seen in focal nodular hyperplasia. B: Apparent diffusion coefcient map shows that the mass is darker than the normal liver anterior to it. This indicates low water diffusion and therefore high cellularity. The diagnosis of hepatoblastoma was conrmed at biopsy.

depends on the tumors histologic composition. Calcications may be present and are usually small and ne in epithelial tumors and coarse and extensive in mixed mesenchymal-epithelial tumors [9]. Following injection of contrast material hepatoblastoma generally show a heterogenous pattern of enhancement and enhance less than surrounding normal liver. There may be a peripheral rim of enhancement if imaging is performed during the arterial phase. Tumor may involve one, two, three, or all four liver sections. Although coronal and sagittal reconstructed CT images are helpful in determining tumor margins occasionally margins are difcult to determine by CT. In such cases, MRI may provide additional information [9].

Mixed epithelialmesenchymal tumors are typically heterogenous due to varying amounts of internal hemorrhage, necrosis, brosis, calcication, cartilage and septa. Septations appear on MRI as hypointense bands on both T1- and T2-weighted images. Vascular invasion is best depicted with gradient-echo imaging or contrastenhanced MR angiography (MRA). MRA can also detect normal anatomic vascular variations that can guide surgical resection. Therefore, the combination of MRI and MRA can provide the surgeon with complete information for surgical planning [9]. Because of the young age of children with hepatoblastoma, and the need to lie still for prolonged periods for MRI, sedation is usually required. The decision to use MRI or CT to evaluate hepatoblastoma patients will depend on the local institutions practice standards and the radiologists preference. The rapid pace of advances in MRI means imaging guidelines are always short-lived. Several authors have reviewed conventional MRI techniques in pediatric liver tumors [7]. Newer techniques include diffusion-weighted imaging (DWI) and the use of superparamagnetic iron oxide (SPIO) or liver-cell specic contrast agents. DWI estimates the local rate of diffusion of water molecules, which is generally inversely related to cellularity. The resulting data can be manipulated to dene an apparent diffusion coefcient (ADC) for each voxel of a three-dimensional image dataset. Although in principle this allows for some tissue characterization, reports of the use of DWI in distinguishing benign from malignant liver lesions in adults have had variable results. Experience with DWI in pediatric liver tumors is limited (Fig. 3). It seems unlikely that DWI will permit accurate diagnosis without histopathologic conrmation, but it may prove helpful in selecting cellular areas of tumors for biopsy. SPIO contrast agents such as ferumoxides (Endorem1, Guerbet, Aulnay-sous-Bois, France, or Feridex1, Berlex, Wayne, NJ) or ferucarbotran (Resovist1, Bayer, Berlin, Germany) are taken up by reticuloendothelial (RE) cells in normal liver tissue, and lesions containing RE cells (e.g., focal nodular hyperplasia). They increase liver lesion conspicuity by decreasing the signal of normal liver on T2-weighted images. They are infrequently used in children. Liver-cell specic contrast agents such as gadoxetate disodium (Primovist1 or Eovist1, Bayer) circulate in the blood and gradually accumulate in hepatocytes. They increase T1-weighted signals rst in blood vessels and then in normal liver tissue. Therefore, these agents can be used, instead of conventional gadolinium contrast agents, for dynamic vascular imaging while increasing the conspicuity of small liver tumors (Fig. 3D).

Positron Emission Tomography

Positron emission tomography (PET) is potentially useful for diagnosis, staging, assessing response to therapy and detection of recurrence. PET uses positron-emitting radiopharmaceuticals, most commonly the glucose analog uorodeoxyglucose (FDG), to provide images that reect metabolic activity of normal and abnormal tissue. The high rate of glycolysis in tumor cells results in increased transport of FDG into them. Compared to normal cells, malignant cells also exhibit a decreased rate of dephosphorylation leading to intracellular accumulation of FDG, identiable as increased activity on PET images. Normal hepatocytes have relatively decreased glycolysis and high levels of glucose-6-

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) produces multiplanar images of primary liver tumors with excellent depiction of vascular anatomy (Fig. 2B,D). As with CT, the MRI appearance of hepatoblastoma varies with the tumors histologic nature. Epithelial tumors are generally homogenous and appear hypointense on T1-weighted images and hyperintense with T2-weighting.
Pediatr Blood Cancer DOI 10.1002/pbc

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phosphatase, allowing increased dephosphorylation capacity compared to other normal tissue. It has been shown that the enzyme activity of well-differentiated HCC can mimic that of normal hepatocytes, whereas poorly differentiated and aggressive liver tumors exhibit increased glycolysis and reduced dephosphorylation [11]. The value of FDG-PET imaging in adults with benign liver tumors and HCC has been well studied. Approximately 5070% of HCCs accumulate FDG and the degree of FDG avidity increases with increasing tumor histologic grade [11,12]. Caution should be used in extrapolating from the adult experience. Pediatric hepatic tumors are histologically different, and, unlike adult HCC, rarely arise in cirrhotic livers. Although PET generally shows uptake of FDG in hepatoblastoma, the avidity, as in HCC, could depend on tumor subtype and biological behavior. If so, the pure fetal subtype, which has minimal mitotic activity, may demonstrate less FDG avidity than the unfavorable histologic subtypes. We have encountered a child with a large pure fetal hepatoblastoma that was indistinguishable from normal liver parenchyma on FDG-PET imaging (Fig. 4). These observations may limit the clinical utility of FDG-PET in the initial assessment of a liver mass, and we disagree with those who suggest that PET may be helpful in distinguishing hepatoblastoma from focal nodular hyperplasia. Larger studies are needed to explore the association between FDG avidity, hepatoblastoma tumor biology and AFP levels, especially for the less common SCUD and pure fetal types. A benet of PET is the ability to image the entire patient. It is possible, for example, that bone metastases in hepatoblastoma are more common at diagnosis than currently believed, but are missed by conventional imaging. This has already been suggested in studies of adults with HCC. Other potential developments in hepatic PET include the introduction of newer radiopharmaceuticals, for example, 11C-acetate [13].

DIFFERENTIAL DIAGNOSIS
Although a correct pre-operative diagnosis of hepatoblastoma can usually be made, recurring diagnostic dilemmas occur and are discussed below.

Solitary Congenital Liver Tumor

The main alternative diagnosis is rapidly involuting congenital hemangioma (RICH) [14]. A single serum AFP estimation is unlikely to be helpful, because the normal range at birth is high. Although RICH usually has a distinctive imaging appearance, that is, a heterogeneous mass with a rim of enhancing tissue at CT and MRI (Fig. 5), the best strategy to distinguish these two tumors is a short period of observation. RICH rapidly decrease in size [14], AFP falls normally over time, and biopsy should not be necessary in most patients [15].

Diffuse or Numerous Multifocal Tumors in Infancy

The alternative diagnoses are multifocal or diffuse infantile hepatic hemangioma and metastatic neuroblastoma. In the former numerous cutaneous hemangiomas may be present (Fig. 6). Elevated urinary catecholamines, identication of a primary tumor (especially adrenal), or avidity of lesions at 123I-metaiodobenzylguanidine scintigraphy may conrm the diagnosis of neuroblastoma. Although there have been reports of mildly elevated AFP in infants (even
Pediatr Blood Cancer DOI 10.1002/pbc

Fig. 4. A: Axial contrast-enhanced computed tomography (CT) image showing large pure fetal histology hepatoblastoma (arrows). B: Axial positron emission tomography (PET) image of the liver tumor shows no uorodeoxyglucose (FDG) avidity. The lack of FDG avidity may be related to the less aggressive biological activity of this histologic subtype. C: Fused PET-CT axial image at the same level shown in A and B demonstrates uniform FDG avidity throughout the liver and lack of avidity of the tumor. [Color gure can be seen in the online version of this article, available at http:// wileyonlinelibrary.com/journal/pbc]

Diagnosis, Staging Hepatoblastoma

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Fig. 5. Axial contrast-enhanced CT image of rapidly involuting congenital hemangioma (RICH) shows the typical appearance of a large liver mass with a thin outer rim of enhancement (arrows).

when corrected for age) with hepatic hemangiomas, when serum AFP is elevated the diagnosis of multifocal hepatoblastoma is likely [16]. Almost all children with diffuse or multifocal infantile liver hemangiomas can be diagnosed without biopsy [15].

Solitary or Multifocal Tumors Later in Childhood

Many alternative diagnoses, whether benign (e.g., focal nodular hyperplasia) or malignant (e.g., undifferentiated (embryonal) sarcoma or epithelioid hemangioendothelioma), may have suggestive imaging features. If the serum AFP is elevated, only four conditions should be considered. Two of these, yolk sac tumor and metastatic pancreatoblastoma [17], are rare so the differential is usually between hepatoblastoma and hepatocellular carcinoma. Theoretically it may be possible to distinguish between these conditions on the basis of AFP isoforms [18], but this has not been validated. Percutaneous biopsy should be avoided in hepatocellular carcinoma because of the potential for needle tract seeding, and the poor response of this tumor to chemotherapy. Instead, resection is preferable when feasible, even in centers where presurgical chemotherapy would normally be used for other pediatric liver tumors. Hepatocellular carcinoma is relatively more common with increasing age. In the absence of clinical or imaging features suggesting an alternative diagnosis, an age threshold might guide a change in management strategy. However, this threshold has not yet been determined.

METASTATIC DISEASE IN HEPATOBLASTOMA

Remarkably, the incidence of lung metastasis at diagnosis has remained about 20% over time in trials conducted by different oncology groups [1,19,20]. Both the PRETEXT and COG systems rely on CT of the lungs to detect pulmonary metastases. However, even experienced pediatric radiologists have difculty distinguishing benign from malignant lesions with CT [21]. Although the existing literature suggests bilaterality [22], the presence of more than three nodules [22], and sharply dened nodule margins [21] as signs of malignancy, additional studies are needed to better dene malignant nodule characteristics [21].
Pediatr Blood Cancer DOI 10.1002/pbc

Fig. 6. Axial T1-weighted MR images (A) before and (B) after contrast-enhancement demonstrate marked enhancement of innumerable liver hemangiomas in this infant with diffuse hepatic hemangiomas. C: This coronal T1-weighted post-contrast MR image demonstrates numerous cutaneous hemangiomas (straight arrows) often seen in these patients, in addition to liver hemangiomas (curved arrows).

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revised and claried in 2005 [24]. The patient is assigned a PRETEXT number from I to IV, which is equal to the highest number of contiguous liver sections free of tumor, subtracted from four [24]. Additional criteria dene manifestations of tumor spread, which may be useful for risk stratication or research purposes. A more detailed discussion of PRETEXT staging can be found in the manuscript by Meyers et al. included in this Special Report.

It should be noted that eligibility for the recently concluded SIOPEL 4 study required a patient without other dening features of high risk (AFP <100 mg/L, tumor rupture, PRETEXT IV, intra-abdominal tumor extension, or vascular involvement) to have at least one pulmonary nodule >10 mm or two >5 mm in diameter (R. Maibach, personal communication). The question of what degree of pulmonary tumor burden requires additional treatment in a standard risk patient is unanswered. Bone and cerebral metastases are rare at diagnosis, but are sometimes seen at relapse. Paraneoplastic hypercalcemia [23] may cause imaging evidence of decreased bone density and even fractures (Fig. 7). Because paraneoplastic metabolic bone disease is apparently more common than skeletal metastases, routine bone scintigraphy at diagnosis is not recommended [7,24,25].

Childrens Oncology Group (COG) Staging

The COG staging system for hepatoblastoma is dened by the extent of tumor resection and tumor histology before initiation of chemotherapy. Stage I disease is dened as complete surgical resection with negative margins; stage II, gross total resection with microscopic residual disease at surgical margins or preoperative or intra-operative tumor rupture; stage III, unresectable tumors or partially resected tumors with residual measurable tumor or patients with abdominal lymph node involvement; stage IV, metastatic disease with complete or incomplete tumor resection. Patients with stage I disease are further categorized as having either favorable histology (FH), dened as pure fetal histology with minimal mitotic activity, or standard histology, dened as not pure fetal and not small cell undifferentiated (SCUD).

STAGING
Although several systems have previously been recommended to stage hepatoblastoma only two are in widespread current use.

PRETEXT Staging
The PRETEXT system was originally devised by the International Childrens Liver Tumor Strategy Group (SIOPEL) to represent the extent of the tumor within the liver before treatment, as a proxy for difculty of resection, and to record any local or distant extrahepatic spread, or vascular involvement [1]. It was rst used for risk stratication in the SIOPEL 2 trial and was

Comparison of the PRETEXT and COG Staging Systems

These systems are to some extent complementary. In a retrospective comparison (at diagnosis and before chemotherapy) in 178 patients, Meyers et al. [26] found that both staging systems were signicantly associated with patient outcome. When COG staged patients were stratied by PRETEXT stage they found that the PRETEXT system had superior predictive ability for the COG stage III cohort because PRETEXT identied patients in this group who were at a high risk of death. They concluded that PRETEXT stage at diagnosis was valuable in identifying patients who were good candidates for upfront surgical resection (PRETEXT I and II) and those who were good candidates for early referral for liver transplant (PRETEXT IV) [26]. The current COG AHEP0731 study will investigate the feasibility of early referral of PRETEXT IV patients for liver transplant, and the reliability of institutional assignment of PRETEXT stage by comparing it to PRETEXT stage assigned by an expert panel of surgeons, radiologists, and oncologists.

POST-OPERATIVE IMAGING
Most relapses occur within three years of diagnosis, and surveillance imaging after this time is probably unhelpful. Furthermore, there is no evidence that early detection of relapsed hepatoblastoma improves prognosis. Hepatoblastoma is unusual among pediatric malignancies because serum AFP is a sensitive tumor marker. This limits the need for surveillance imaging to detect relapse or residual disease, but makes identication of the site of relapse more difcult because the AFP often rises before there is imaging evidence of recurrent tumor or clinical signs to guide the imaging workup. Almost all relapses occur in the lung, the liver or both.

Fig. 7. Sagittal T2-weighted MR images shows a very large liver tumor (asterisk). There are insufciency fractures of the vertebral endplates (arrows), with loss of height but no signal abnormality in several of the vertebral bodies. This is a paraneoplastic phenomenon (see text).
Pediatr Blood Cancer DOI 10.1002/pbc

Diagnosis, Staging Hepatoblastoma

Although follow-up abdominal imaging with CT or MRI has been recommended following resection [7], ultrasound is cheaper and safer, and combined with AFP assuming this was elevated before treatment, is likely to detect relapse as early as the other techniques. PET may prove to be useful in detecting local recurrences [27], but false-positive ndings due to FDG uptake in regenerating liver tissue and areas of inammation can occur [25,28]. When AFP levels are only slightly or moderately elevated PET imaging ndings should be interpreted with caution. In children with no lung metastases at diagnosis, follow-up with chest radiographs every 3 months is probably adequate [7]. When metastases were present at diagnosis, CT is preferred [7]. PET alone should not be used for pulmonary surveillance imaging, because it may fail to detect even large (10 mm) pulmonary metastases [27]. There may, however, be a role for PET to detect relapse in children with rising AFP and normal CT and abdominal conventional imaging [27]. In one patient, relapse was suspected because of elevated AFP and a suspected brain metastasis on CT. MRI of this patient suggested hemorrhage, but was inconclusive for metastatic tumor. PET imaging showed a focus of FDG avidity within the brain lesion that was proven by biopsy to be tumor recurrence [25].

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REFERENCES
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CONCLUSION
Diagnostic imaging of the child with a liver mass provides crucial information for diagnosis. In the case of malignancy it is essential for staging, monitoring treatment effect and detecting recurrences. We have reviewed the clinical and imaging features that aid in the diagnosis and management of children with hepatoblastoma. As imaging technologies evolve their role in the assessment of these patients will undoubtedly change. Newer techniques, such as diffusion weighted MRI, novel liver-specic MR contrast agents and PET-CT may provide additional information that will aid patient management. Large, prospective, multiinstitutional trials are necessary to fully understand the biology of this rare tumor and to better dene the role of imaging in patient management. Differences in the approach to children with hepatoblastoma currently exist between the major European and North American cooperative groups. However, efforts are underway to develop international collaboration in order to unify treatment strategies, increase patient accrual into therapeutic research protocols and ultimately improve patient outcome.

Pediatr Blood Cancer DOI 10.1002/pbc