Hepatic tumors make up only 1% to 4% of pediatric solid tumors, and most of these are metastatic lesions from an extrahepatic site. The symptoms leading to their diagnosis are usually nonspecific and may be erroneously attributed to a chronic underlying gastrointestinal condition. Awareness of these associated conditions is important; however, most encountered neoplasms will be unanticipated and the ability to arrive at a prompt and correct diagnosis can be crucial to the survival of the patient. This chapter reviews the most common hepatic neoplasms encountered in childhood, with a complete list detailed in Table 48-1 .
| Tumor | Most Common Age at Presentation |
|---|---|
| Infantile hemangioma | <6 months |
| Hepatoblastoma | <5 years, most <2 years |
| Hepatocellular carcinoma | >5 years |
| Fibrolamellar variant of hepatocellular carcinoma | Second decade |
| Mesenchymal hamartoma | Most <2 years |
| Focal nodular hyperplasia | Second decade in adults, 2 to 5 years in children |
| Hepatocellular adenoma | >10 years |
| Nodular regenerative hyperplasia | All ages |
| Undifferentiated embryonal sarcoma | 5 to 10 years |
| Angiosarcoma | All ages |
| Embryonal rhabdomyosarcoma | <5 years |
| Teratoma | <1 year |
Hepatic tumors can be classified as benign or malignant. The most common pediatric benign neoplasms of the liver include hepatic hemangiomas, mesenchymal hamartomas, focal nodular hyperplasia, and hepatic adenomas. The malignant hepatic tumors include hepatoblastoma, hepatocellular carcinoma, undifferentiated embryonal sarcoma, and embryonal rhabdomyosarcoma of the biliary system. Two of these tumors account for roughly 80% of liver neoplasms in children younger than the age of 2 years; hepatic hemangiomas usually occur in the first 6 months of life and 90% of hepatoblastomas present in the first 5 years of life (68% in the first 2 years). In contrast, undifferentiated embryonal sarcomas are most commonly encountered in school-aged children.
Benign Masses
Hepatic Hemangioma
Like their cutaneous counterparts, hepatic vascular lesions have been plagued with the overlapping nondiscriminatory use of various terms such as hepatic hemangioma, cellular, cavernous or capillary hemangioma, infantile hemangioendothelioma, and arteriovenous malformations. The unfortunate use of the widely accepted term “infantile hemangioendothelioma” should be avoided to prevent confusion with “epithelioid hemangioendothelioma,” a malignant tumor with metastatic potential. Hepatic hemangiomas are the most common benign liver tumors that occur in children, and based on more recent analysis, they can be classified into three subtypes—focal, multifocal, and diffuse. Approximately 30% of them occur in the first month of life, with the majority of the remainder being diagnosed in the first 6 months of life; focal lesions are often asymptomatic but may be detected antenatally on routine ultrasound, after which they undergo rapid spontaneous involution.
Given the vascular nature of these lesions, anemia is common (50%). Most patients have recognizable abdominal enlargement, and 10% to 15% of patients have congestive heart failure at presentation, particularly those with diffuse lesions. Diffuse lesions are extensive and may nearly replace the liver parenchyma; children with the lesions often have serious clinical complications of massive hepatomegaly that may result in respiratory compromise, abdominal compartment syndrome, and multiorgan system failure. Severe hypothyroidism has been reported rarely and is attributed to increased activity of type 3 iodothyronine deiodinase within the hemangioma. Less common signs and symptoms include jaundice (20%), thrombocytopenia, including Kasabach-Merritt syndrome, failure to gain adequate weight, fever, and intra-abdominal/intrahepatic hemorrhage. Although extrahepatic anomalies or syndromes such as Beckwith-Wiedemann have been associated with hepatic hemangiomas, the most frequent extrahepatic finding is cutaneous hemangiomas, which are seen mostly in patients with multifocal or diffuse hepatic lesions.
The diagnosis is usually suggested by radiographic evaluations. Ultrasound reveals hypoechoic, hyperechoic, or complex lesions as well as multifocality. Computed tomography (CT) and magnetic resonance imaging (MRI) can better delineate the lesions and detect extrahepatic foci. Selective angiography can then identify the major feeding vessels. Biopsies are generally avoided given the vascularity of the lesion.
Approximately one-third of lesions are solitary and range from less than 1 cm to 13 cm in greatest diameter. Multifocal lesions may number from 2 to more than 25, and frequently involve large portions of both liver lobes. Discovery of “hemangioma specific markers” has led to new concepts about the nature of hepatic vascular lesions. Glut-1, is an erythrocyte-type glucose transporter protein that consistently marks the endothelium of hemangiomas and has proven utility in classifying hepatic hemangiomas Focal hemangiomas typically have extensive central hemorrhage or infarction with focal calcifications and a peripheral spongy appearance. Histologically, the central zones contain large, tortuous thin-walled channels with dense fibrous stroma. The outer portion is characterized by capillary-sized vessels lined by plump endothelium that is nonreactive to GLUT1; entrapped hepatocytes and bile ducts are common and neighboring hepatic sinusoids may be dilated ( Figure 48-1 ). Although some observers have regarded these lesions as vascular malformations, many believe they represent the hepatic counterpart of the so-called cutaneous “rapidly involuting congenital hemangiomas.” By contrast, the multifocal and diffuse lesions extensively involve the liver, with reddish nodules ranging from a few millimeters to 3 cm. The cellular nodules contain closely packed capillaries with plump endothelium surrounded by pericytes; the capillary endothelium is immunoreactive for Glut-1. Mitotic activity can be prominent in regions of greatest cellularity and diminishes in areas of regression as vascular channels become more obvious.
Treatment depends on the severity of extrahepatic symptoms. Asymptomatic patients with focal or multifocal disease, who lack significant shunting, should be observed and undergo serial ultrasonography to document regression. Hypothyroidism should be excluded. Recently, to hasten spontaneous regression, propranolol has been proposed as the first-line agent in treatment of not only hepatic hemangiomas but also cutaneous forms of hemangiomas. Other medical treatment with diuretics alone or in combination with α interferon or steroids has been used in patients with hemodynamically significant shunting. Patients in congestive heart failure or with large shunts should be considered for early embolization or undergo surgery when the lesion is resectable. Historically, infants with diffuse hepatic hemangiomas have had a poor response to pharmacologic therapy alone and have commonly progressed to require orthotopic liver transplantation. However, recent studies have suggested excellent response to propranolol, even in diffuse hepatic hemangiomas with cardiovascular instability.
The survival of infants is excellent, with rates of 70% to 92% to at least 2 years using surgery or other treatments. Most deaths that occur are in young infants with diffuse lesions, who present with congestive heart failure and jaundice.
Mesenchymal Hamartoma
Mesenchymal hamartomas of the liver are benign tumors that usually present with an enlarged abdomen from ascites accumulation in the first 2 years of life.
Ultrasonography CT, or MRI imaging can define the location of the mass and can generally distinguish this tumor by its fluid-filled multicystic parenchyma ( Figure 48-2 ) from hepatoblastomas or infantile hemangiomas, the other liver tumors that commonly occur in this age group. The well-circumscribed tumor comprises a variably dominant mixture of loose mesenchyme, irregular bile ducts and ductules, and peripherally placed hepatocyte cords and blood vessels ( Figure 48-3 ). Proposed etiologies have included developmental anomalies, biliary obstruction, and segmental ischemia, but recurring abnormalities involving chromosome band 19q13 corroborate a neoplastic origin. Androgenetic/biparental mosaicism has been demonstrated in hamartomas from patients who have associated disorders (i.e., placental mesenchymal dysplasia or Beckwith-Weidemann syndrome) as well as in those without suspected somatic mosaicism. These findings support heterogeneous genetic causes, including dysregulated imprinting, for tumor development.
Hamartomas typically enlarge quickly in the first few months of life. Some then stabilize while others continue to grow; spontaneous partial regression has been reported rarely in highly vascular lesions. Surgical resection is the treatment of choice, with an excellent expected prognosis. Few have been associated with undifferentiated embryonal sarcomas.
Focal Nodular Hyperplasia
Focal nodular hyperplasia (FNH) is a benign hepatic neoplasm, representing roughly 2% of pediatric liver tumors, that is typically diagnosed in school-aged children. The well-circumscribed, unencapsulated, lobulated lesion is typically paler than the adjacent liver. It is characterized by disorganized hepatocyte hyperplasia, separated into nodules by fibrous septa that coalesce into a central stellate scar that contains proliferated ductules. Dysplastic vessels course through the septa and scar ( Figure 48-4, A, B ). Its etiology is unknown but theories have suggested that FNH is a reactive hyperplasia that occurs after a vascular event within the parenchyma. There is an increased incidence in children after exposure to chemotherapy and radiation therapy for malignancies, and in those with surgical or congenital portosystemic shunts.
Although typically asymptomatic, children are more likely than adults to have associated abdominal pain and rarely present with weight loss and fatigue. The diagnosis can be made using radiographic imaging. Ultrasound with Doppler shows a solid, lobulated mass with a feeder artery that has stellate branches within the tumor. CT and MRI show a homogenous mass with a central vessel and no calcifications. Rarely is liver biopsy needed for diagnosis.
The treatment of FNH is often conservative observation. Surgical management is indicated for very large lesions with compressive symptoms, or when the diagnosis is in question. If the tumor is associated with portosystemic shunts, closure of the shunt may lead to shrinkage of the tumor.
Hepatocellular Adenoma
Hepatocellular or hepatic adenoma is a benign entity that occurs rarely in childhood, but can arise in adolescents with a history of oral contraceptive use or anabolic androgenic steroid therapy. Fifty-two percent and 25% of patients with Glycogen Storage Disease (GSD) types 1 and 3, respectively, develop hepatic adenomas. These lesions are also detected in patients with galactosemia, familial diabetes mellitus, and congenital vascular malformations, and in association with hypervascular hepatic neoplasms such as focal nodular hyperplasia and hemangiomas. Hepatic adenomas have also been linked to familial adenomatous polyposis. Hepatocellular adenomas have recently been divided into four subtypes including those with (1) β-catenin mutations, (2) Hepatic Nuclear Factor 1 alpha (HNF1-α-mutations), (3) inflammation and no mutations, and (4) no inflammation or mutations. The roles of β-catenin activation and HNF1-α inactivation have not been completely investigated in children.
Hepatic adenomas are well-circumscribed soft tumors composed of sheets and thick cords of hepatocytes that lack an acinar arrangement and may contain an increased amount of fat and glycogen. Hepatic adenomas are typically solitary and unencapsulated, with large feeding arteries that can be associated with an increased risk of intratumoral hemorrhage. Imaging is needed to evaluate the composition of the lesion. Ultrasonography can show hyperechoic areas high in lipid content or hemorrhage, whereas CT and MRI may demonstrate areas of calcification or hemorrhage.
Usually hepatic adenomas are incidental findings, but patients can develop abdominal pain with or without a palpable mass. Two main complications of hepatic adenomas are hemorrhage in up to 10%, and malignant transformation into hepatocellular carcinoma, especially in the setting of glycogen storage disease and in adenomas harboring β-catenin–activating mutations. In children with glycogen storage disorders, it is prudent to monitor α-fetoprotein (AFP) levels, obtain yearly hepatic ultrasound studies, and maintain good metabolic control. Discontinuation of estrogen-containing medication is also recommended. Surgical resection is the definitive treatment, especially in those patients with the β-catenin mutation who are at an increased risk of transformation; however, radiofrequency ablation has been proposed as an alternative treatment.
Malignant Masses
Hepatoblastoma
The first case of hepatoblastoma was described in 1898, and this tumor is now known to be the most common pediatric liver malignancy. Hepatoblastomas account for 1% of all pediatric malignancies, with an incidence of 0.5 to 1.5 cases per million children younger than the age of 15 years in developed countries, and 50-70 new cases per year in the United States diagnosed mostly prior to 2 years of age.
Classically, the presentation is a palpable non-tender abdominal mass or enlarging abdomen that is often discovered by family members. Accompanying anorexia, weight loss, nausea, vomiting, or abdominal pain are less commonly observed and jaundice is uncommon (5%).
Initial diagnostic workup includes a combination of radiographic and laboratory tests but confirmation requires a liver biopsy with histologic diagnosis. CT or MRI can be helpful in defining the size and distribution of the mass and can identify features that distinguish it from other liver tumors. The finding of speckled calcifications is well described and found in roughly 50% of cases. At diagnosis, approximately 20% of tumors have metastasized, most commonly to the lungs. The most diagnostically useful laboratory finding seen with hepatoblastomas is a significant elevation in serum AFP, present in approximately 90% of the cases. The extent of AFP elevation correlates with tumor size or presence of metastases and its decrease reflects tumor clearance after therapy. AFP levels are helpful in monitoring recurrence. The 10% of hepatoblastomas that do not have elevated AFP levels tend to be of small-cell undifferentiated histology and carry a poor prognosis.
Multiple preoperative and postoperative scoring systems have been developed over the years to predict prognosis and two methods of risk stratification are in current use. The Children’s Oncology Group (COG) system is based on postoperative extent of disease and histologic classification and has a highly significant predictive value for survival ( p = 0.0009) ( Table 48-2 ). The PRETEXT (pretreatment extent of disease), developed by the International Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology Group (SIOPEL), defines four sections based on Couinaud’s system of liver segmentation, and assesses radiographic tumor extent before therapy ( Table 48-3 ).
| Stage | Description |
|---|---|
| I | Complete resection of tumor |
| II | Microscopic residual tumor |
| III | Macroscopic residual tumor or lymph node involvement |
| IV | Distant metastases |
| Stage | Description |
|---|---|
| 1 | 1 sector, 3 adjoining sectors free |
| 2 | 2 sectors involved, 2 sectors free |
| 3 | 3 sectors involved, no adjoining sectors free |
| 4 | All 4 sectors involved |
Hepatoblastomas are derived from undifferentiated embryonal tissue and do not have a characteristic chromosomal anomaly, although trisomies of chromosomes 20, 2, and 8 are frequent. Most cases are sporadic, but associations with some familial conditions such as Beckwith-Wiedemann syndrome and familial adenomatous polyposis are well known. Other risk factors implicated in the development of this tumor include postnatal tobacco smoke exposure and low birth weight. Hepatoblastomas are typically a single mass and involve the right lobe in slightly more than half of the cases. Their gross appearance varies tremendously and is dependent on the proportion of mesenchymal elements. There are two main histologic types of hepatoblastoma: epithelial and mixed epithelial and mesenchymal. The tumor is believed to arise from a hepatocyte precursor and often recapitulates stages of liver development, most commonly an embryonal pattern, that resembles liver at 6 to 8 weeks of gestation. Embryonal cells are approximately 10 to 15 microns with high nuclear-to-cytoplasmic ratios and grow in sheets or often cluster into pseudorosettes or tubules. The cells in fetal hepatoblastomas are uniform, cuboidal, small to medium (10 to 20 microns), and arranged in sheets or trabeculae. A bi-phasic pattern produced by the mixture of fetal and embryonal epithelial cells is a pathognomonic feature of hepatoblastoma and helps to distinguish it from hepatocellular carcinoma ( Figure 48-5 ). When fetal and embryonal cells form cellular plates stacking at least five cells thick, the growth pattern is termed macrotrabecular. A rare “small cell undifferentiated” variant comprises tumor cells that are indistinguishable from other “small round blue cell” tumors of childhood, and are characterized by small, noncohesive, undifferentiated cells with minimal cytoplasm, round nuclei that lack conspicuous nucleoli, and do not form acini. Some of these tumors have been shown to lack expression of the Integrase Interactor 1 (INI-1) protein, a characteristic feature of the malignant rhabdoid tumor. Even a minor component of tumor with small cell undifferentiated histology, confers an adverse outcome. Twenty percent to 30% of hepatoblastomas have mesenchymal elements, notably osteoid-like and cartilaginous tissues. Hepatoblastomas are designated as “teratoid” when heterologous tissues are abundant and include muscle, melanin pigment, and squamous or mucinous epithelium.
