You are in: eMedicine Specialties > Radiology > PEDIATRICS HepatoblastomaArticle Last Updated: Apr 9, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 12
  Author: Mary Elizabeth McCarville, MD, Associate Member, Department of Radiological Sciences, St Jude Children's Research Hospital Mary Elizabeth McCarville is a member of the following medical societies: American Association for Women Radiologists, American College of Radiology, American Institute of Ultrasound in Medicine, American Roentgen Ray Society, Radiological Society of North America, and Society for Pediatric Radiology Coauthor(s): Wayne L Furman, MD, Professor, Department of Pediatrics; Univ of Tennessee College of Medici, Department of Hematology-Oncology, Member; Dept Hem/Onc, St Jude Children's Res Hosp, St Jude Children's Research Hospital Editors: Fredric A Hoffer, MD, FAAP, FSIR, Section Chief Inteventional Radiology, Professor of Radiology, Department of Radiology, (Seattle) Children's Hosptial and Regional Medical Center; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; Marc S Keller, MD, Chairman, Professor, Departments of Radiology and Pediatrics, Department of Medical Imaging, Alfred I DuPont Hospital for Children; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; John Karani, MBBS, FRCR, Consulting Staff, Department of Radiology, King's College Hospital, London Author and Editor Disclosure Synonyms and related keywords: malignant hepatoblastoma, epithelial and mesenchymal hepatoblastoma, hepatic mixed tumor of childhood INTRODUCTIONSection 2 of 12
  BackgroundHepatoblastoma is the most common malignant liver tumor in early childhood. Most patients present younger than age 3 years with an enlarging asymptomatic abdominal mass. Some patients have fever, pain, anorexia, and weight loss. The two most important genetic conditions associated with hepatoblastoma are Beckwith-Wiedemann syndrome and familial adenomatous polyposis. The incidence of hepatoblastoma in familial adenomatous polyposis kindreds is 200-800 times greater than in the general population. Evidence also exists of an association between hepatoblastoma and maternal exposure to metals, paints, and oil products. A significant number of patients with hepatoblastoma (10%) have a history of prematurity with prolonged hospitalization. Unlike hepatocellular carcinoma, hepatoblastoma has no association with cirrhosis. PathophysiologySeveral histologic subtypes of hepatoblastoma exist. Approximately 56% of tumors are of the epithelial type, which is subclassified further as pure fetal (31%), embryonal (19%), macrotrabecular (3%), and small-cell undifferentiated (anaplastic; 3%). Approximately 44% of tumors contain both mixed epithelial and mesenchymal components. Mesenchymal elements may consist of osteoid, cartilage, or other spindle cells. Evidence is growing that pure fetal histology is associated with a better prognosis and that anaplasia is associated with a poor prognosis. Serum alpha-fetoprotein (AFP) level is elevated in approximately 80% of patients with hepatoblastoma. Although AFP normally is high in infancy, in children with hepatoblastoma the level is exceptionally elevated. Patients with normal or low levels of AFP and those with extremely high levels have a poor prognosis, in contrast to those with intermediate values. In one study, patients with low levels had the small-cell variant, which often does not produce AFP, grows rapidly, and usually does not respond to chemotherapy. Extremely high levels of AFP were associated with extensive and/or metastatic tumors, thus an unfavorable outcome. AFP also is used to monitor response to therapy and to detect tumor recurrence after treatment. In one study of 31 children with primary unresectable hepatoblastoma, a large, early fall in AFP level (defined as greater than or equal to 2 logs) in response to chemotherapy was the strongest independent predictor of outcome. Patients with recurrent disease may demonstrate an elevated AFP level long before observing imaging evidence of tumor recurrence. Metastatic spread most commonly affects the lungs, with pulmonary metastases present in 10% of children at diagnosis (see Image 10). The porta hepatis also may be involved, with invasion of the portal vein (see Image 3). Bone metastases occur rarely (see Image 11). FrequencyUnited StatesThe incidence of hepatoblastoma is 0.7-1 case per 1 million population per year in children in Western countries. In the United States, approximately 100 new patients present per year. Mortality/MorbidityCure of hepatoblastoma is possible only when complete surgical excision is achieved. Typically, tumors are considered unresectable for the following reasons:
Prior to the use of preoperative chemotherapy, approximately 50% of newly diagnosed hepatoblastomas were considered resectable; however, determination of resectability may be subjective and may vary among surgeons. More recently, approximately 30% of tumors have been considered resectable at diagnosis, since those tumors likely to result in significant surgical morbidity are treated initially with chemotherapy. In addition, recent success with orthotopic liver transplantation in patients with hepatoblastoma may influence the surgeon's decision of whether to attempt resection or proceed to transplantation. For children with resectable tumors, survival rates greater than 90% can be seen with the addition of contemporary postoperative chemotherapy. For children with initially unresectable tumors, preoperative chemotherapy converts approximately 75% to a resectable condition (see Image 1). Outcomes for children in whom the tumor recurs or progresses while on treatment are poor, with a 2-year survival rate of less than 20%. RaceHepatoblastoma occurs 4-5 times more frequently in white children than in black children. SexMale-to-female predominance, which varies from 1.4-2:1, is more apparent in younger children. In children older than 5 years, the sex difference disappears. AgeHepatoblastoma typically presents in infants and children younger than 5 years, with most occurrences prior to age 2 years. AnatomyHepatoblastoma has an average diameter of 10-12 cm at diagnosis. The tumor most often is a unifocal, well-circumscribed mass, but it may be multinodular. When presenting as a solitary mass, the right lobe more commonly is affected. If the tumor is multinodular, both lobes may be involved. On gross inspection, the epithelial type tends to be homogenous, while mixed epithelial-mesenchymal tumors demonstrate a more variegated appearance with areas of osteoid, cartilage, calcification, fibrosis, necrosis, and hemorrhage. The anaplastic variant frequently contains a large focus of central necrosis. Microscopic vascular invasion may be seen beyond an apparently encapsulated tumor. Clinical DetailsPostsurgical extent of the disease has been the criterion used to stage hepatoblastoma in most North American clinical trials. Hepatoblastoma staging, with stage and resection margins, is as follows:
In North America, the standard approach has been to attempt initial complete resection before initiating chemotherapy. If the tumor cannot be resected completely, the abdomen is closed and the child is started on a chemotherapy regimen designed to shrink the tumor and make it resectable. In children in whom the tumor remains unresectable, alternative therapies offer promise. Intra-arterial chemoembolization of the tumor with chemotherapeutic and vascular occlusive agents has resulted in reduced tumor bulk. In selected patients, orthotopic liver transplantation may achieve local control when other measures fail to remove the entire gross tumor. For children with disseminated disease, cure is possible only when both local and systemic disease are controlled. Preferred ExaminationFor evaluation of the primary tumor, MRI is the preferred imaging modality. Because of the orthogonal-imaging capability of MRI, it is superior to CT in defining tumor margins and determining tumor resectability. However, 3-dimensional CT-reconstructed images may compare favorably to MRI. Magnetic resonance angiography (MRA) can evaluate the tumor blood supply, which is valuable information for surgical planning. Postoperatively, MRI is superior to CT in detecting residual or recurrent tumor in the surgical bed. CT is the imaging modality of choice for detecting pulmonary metastases. Limitations of TechniquesOne limitation of MRI is that patients with hepatoblastoma typically require sedation for the procedure because they are young. The value of MRI also may be limited by breathing motion. However diagnostic-quality, standard-sequence MRI now can be performed in breathing-sedated patients. Rapid-scanning techniques allow diagnostic quality MRI and MRA in breathing-sedated patients and in those capable of only limited cooperation. Conversely, helical CT imaging of both the chest and abdomen can be performed quickly, easily, and usually without sedation. However, CT may not be as accurate as MRI in defining tumor margins, evaluating the portal vein, or in detecting residual or recurrent tumor following surgery. DIFFERENTIALSSection 3 of 12
Hepatic Adenoma Hepatocellular Carcinoma Hepatocellular Carcinoma, Fibrolamellar Other Problems to Be ConsideredEmbryonal sarcoma
RADIOGRAPHSection 4 of 12
FindingsAbdominal radiography may show hepatomegaly as evidenced by elevation of the right hemidiaphragm and displacement of bowel gas. Although they are not diagnostically specific, hepatic calcifications may be present. Chest radiography may demonstrate pulmonary metastases and can aid in the differential diagnosis. Degree of ConfidenceDegree of confidence is low. Plain films cannot localize the tumor to the liver definitively, distinguish between the solid or cystic nature of a neoplasm, or provide information regarding tumor vascularity. False Positives/NegativesA normal abdominal plain film cannot exclude hepatoblastoma. CT SCANSection 5 of 12
FindingsAppearance of hepatoblastoma on CT varies greatly. Prior to contrast administration, an epithelial-type tumor appears as a homogeneous hypodense mass, while a mixed mesenchymal-epithelial tumor demonstrates a more heterogeneous appearance. Calcifications may be present in either type; small and fine in the epithelial type and coarse and extensive in the mixed type. Following the injection of IV contrast, some enhancement of the tumor is seen, usually less than in normal liver tissue (see Image 8). The enhancement pattern typically is inhomogeneous, and a peripheral rim of enhancement may be observed if imaging is performed during the early arterial phase. If peripheral enhancement is seen, perform delayed serial scans at a single level of the tumor to distinguish hepatoblastoma from hemangioendothelioma. The tumor may involve one, two, or three segments or may diffusely involve the entire liver. Degree of ConfidenceDegree of confidence is moderate. Tumor margins and segmental involvement may be difficult to determine. The status of the portal vein may be difficult to assess, and the selective use of ultrasonography (US), Doppler US, MRI, or MRA may be necessary. False Positives/NegativesCT cannot differentiate hepatoblastoma from hepatocellular carcinoma. The patient's age is the most important criteria for differentiating these tumors; patients younger than 5 years are more likely to have hepatoblastoma; those older than 5 years are more likely to have hepatocellular carcinoma. False-negative images for tumor recurrence may be observed following tumor resection. In addition, CT of both the abdomen and chest may fail to recognize neoplasm when rising serum AFP levels are seen until a sufficient volume of disease is present. In these patients, recurrent tumor usually becomes evident on follow-up imaging. MRISection 6 of 12
FindingsSimilar to CT, the MRI appearance of hepatoblastoma varies with its histologic nature.
Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. As of late December 2006, the FDA had received reports of 90 such cases. Worldwide, over 200 cases have been reported, according to the FDA. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble movingor straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape. Degree of ConfidenceDegree of confidence is high. MRI appearance of hepatoblastoma is unlike common infantile hemangioma (the other primary liver tumor in this age group), because hepatoblastoma usually lacks enlarged feeding hepatic arteries and draining veins. The infantile hemangioma, if extensive, may exhibit multiple lesions in the liver and soft tissues. The child may exhibit cardiomegaly and overcirculation or even congestive heart failure. The Kaposiform hemangioendothelioma that produces a consumptive coagulopathy may be a single lesion and is more difficult to distinguish from hepatoblastoma because no arteriovenous (AV) shunting may be present. MRI is superior to CT in determining tumor margins and portal vein invasion. However, MRI cannot detect pulmonary nodules with confidence. CT remains the most sensitive imaging screening test for this purpose. False Positives/NegativesMRI appearance of hepatoblastoma may mimic embryonal sarcoma and fibrolamellar hepatocellular carcinoma. These latter two lesions are more likely to occur in older teenagers. The embryonal sarcoma may have a distinctive pattern of central necrosis and hemorrhage with a rim of viable tissue of varying thickness. Fibrolamellar hepatocellular carcinoma may have a fibrous center, benign regional reactive lymphadenopathy, and an indolent course. ULTRASOUNDSection 7 of 12
FindingsOn US, hepatoblastoma may appear as a solitary mass, a dominant mass with smaller satellite lesions, or multiple nodules throughout the liver. Rarely, hepatoblastoma may infiltrate throughout the entire liver. Most tumors have some hyperechoic areas relative to normal liver, often with some inhomogeneity resulting from the presence of mesenchymal elements. Calcifications may be present and appear as brightly echogenic punctate or linear foci with acoustic shadowing. Portal vein invasion is seen as echogenic intraluminal thrombus. Areas of necrosis and hemorrhage appear as anechoic foci. Doppler sonography may detect neovascularity around the rim of the neoplasm with high velocity and low-resistance vasculature. Degree of ConfidenceDegree of confidence is low. Findings on US are nonspecific and may be seen with other primary malignant neoplasms, metastatic disease, abscesses, and benign vascular lesions. However, US is useful as a preliminary imaging study and usually determines the tumor's organ of origin. This is aided by watching the tumor in real time with normal respirations and detecting motion between the tumor and the noninvolved organs. US can be performed quickly, does not require sedation, is relatively inexpensive, and does not involve ionizing radiation. The presence of high-velocity Doppler signals within a mass and invasion of the portal vein strongly support the diagnosis of malignant neoplasm. Common infantile hemangioma may be distinguished from hepatoblastoma by the presence of enlargement of the hepatic artery and a tapering of the aortic dimension distal to the celiac axis. Often, it is difficult to assess tumor margins accurately by US, although in the future, this limitation may be overcome by US contrast agents (see Image 9). False Positives/NegativesAs with other imaging modalities, US appearance of hepatoblastoma is nonspecific and may be similar to other benign or malignant neoplasms. The patient's age helps narrow the differential diagnosis. NUCLEAR MEDICINESection 8 of 12
FindingsOn technetium Tc 99m sulfur-colloid liver scintigraphy, hepatoblastomas usually demonstrate hypervascularity, with prominent tracer avidity at the site of the tumor within a few seconds of the appearance of the bolus in the abdominal aorta. This increased activity persists into the venous phase. Delayed images typically demonstrate a photopenic defect at the tumor site from replacement of Kupffer cells by the tumor. Less commonly, in tumors containing large foci of necrosis, a photopenic defect is seen on both the static and dynamic portions of the examination. Rarely, hepatoblastomas may demonstrate increased uptake on delayed imaging. Degree of ConfidenceDegree of confidence is low. Findings seen with hepatoblastoma usually are indistinguishable from those observed with hepatocellular carcinoma, embryonal sarcoma, and other malignant liver tumors. False Positives/NegativesA liver lesion must be at least 1.5-2.0 cm to be detected by planar scintigraphy. Detection of smaller lesions with single photon emission computed tomography (SPECT) is possible but not practical in this entity. ANGIOGRAPHYSection 9 of 12
FindingsHistorically, the role of angiography has been to demonstrate normal and variant vascular anatomy (eg, a replaced right hepatic artery), tumor vascularity, segmental and lobar extent of tumor, and potential for surgical resection. Venous-phase arteriography also has demonstrated the portal vein and defined tumor thrombus. These questions usually can be answered accurately with MRI and 3-dimensional contrast-enhanced MRA or at times by CT or US. Therefore, hepatic angiography is now reserved for patients in whom noninvasive cross sectional images fail to demonstrate crucial anatomy prior to resection or transplantation. Degree of ConfidenceDegree of confidence is high for demonstrating vascular anatomy and segmental involvement by tumor. False Positives/NegativesNo known false positives or false negatives exist in evaluating the major vessels. INTERVENTIONSection 10 of 12
Cure of hepatoblastoma can be achieved only by surgical resection of the primary tumor and control of metastatic disease with adjuvant chemotherapy. Hepatoblastomas are considered resectable at presentation in approximately 30% of patients. The most important advance in treatment has been the discovery of effective chemotherapeutic agents that can convert extensive unresectable tumors into resectable ones. This advance has increased the cure rate for hepatoblastoma dramatically. While in North America, resection is often attempted prior to initiating chemotherapy, some have advocated preoperative chemotherapy to reduce tumor bulk, even for resectable tumors. In Japan, investigators have successfully used preoperative transarterial chemoembolization (TACE) to treat both resectable and unresectable hepatoblastoma. This approach exposes tumor cells to high concentrations of antitumor drugs that cannot be achieved by systemic administration of the same dose.
TACE has resulted in tumor necrosis of 25-95% and tumor shrinkage of approximately 26%. While most patients receiving TACE experienced fever (>38°C) and transient elevations in liver enzymes, other toxicities encountered with systemic chemotherapy (eg, alopecia, vomiting, anorexia) were not observed. Investigators concluded that TACE was an effective and safe initial treatment for resectable and unresectable hepatoblastoma. However, no randomized trials have been performed that compare outcome for patients who receive TACE versus standard chemotherapy. The complications of TACE (hemorrhage, pain) and its inability to treat metastatic disease may be detrimental limitations. In addition, TACE requires the significant expertise of an experienced, pediatric interventional radiologist. Currently, in the United States, consider TACE when an unresectable tumor fails to respond to standard chemotherapy. Another approach to unresectable hepatoblastoma is orthotopic liver transplantation. Selection criteria for transplantation are based on establishing the extent of the tumor either by CT or MRI to confirm both the resectability and the absence of extrahepatic metastases. Angiography may be needed to confirm patency of the portal-venous system and to define vascular anatomy when this is not seen clearly on MRA, CT, or US. When a patient presents with metastatic disease, transplantation remains a suitable treatment option if metastatic disease is controlled before surgery. When chemotherapy can reduce unresectable tumors to a resectable state, orthotopic liver transplantation may provide a cure. Careful patient selection to exclude the presence of metastatic disease before transplant and early referral to a transplant center are crucial to achieve good results. Medical/Legal Pitfalls
MULTIMEDIASection 11 of 12
REFERENCESSection 12 of 12
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