Incidence

Infantile hepatic hemangioma (IHH) is the most common benign solid hepatic tumor in children, comprising about 16% of all pediatric liver tumors.¹ It also is the most common liver tumor in the first year of life. Almost all children with IHH are seen initially before age 6 months, and the majority are encountered in the first 2 months.^6,7 Historically, a slight female predominance has been found, but this finding has not been uniformly seen.⁸

Clinical Presentation

IHHs can be either single lesions that can expand to a massive size or a multinodular infiltrative mass. Occasionally these lesions are asymptomatic and present as an abdominal mass or abdominal distention. Hepatic hemangiomas can also be found in association with congenital syndromes such as Osler–Weber–Rendu, Klippel–Trénaunay–Weber, and Ehlers–Danlos. IHH has also been reported in association with Beckwith–Wiedemann syndrome, diaphragmatic hernia, trisomy 21, transposition of the great arteries, and extranumerary digits.9,10

Infants with IHH can present with significant symptoms including hepatomegaly, high-output congestive heart failure, respiratory distress, and anemia. Occasionally these infants present with the Kasabach–Merritt syndrome that is characterized by acute thrombocytopenia, a microangiopathic hemolytic anemia, and a consumptive coagulopathy.¹¹ This syndrome can be life threatening and requires aggressive supportive treatment, as well as treatment of the hemangioma itself. Fortunately, the Kasabach–Merritt syndrome occurs infrequently and is usually associated with IHH that have rapid growth to a diameter of 5 cm or more. No cases have been reported in association with smaller tumors.¹²

The Boston Children’s Hospital Vascular Anomalies Center has recently made a proposal to classify IHH as either focal, multifocal, or diffuse.¹³ Focal lesions tend to be asymptomatic, are rarely associated with cutaneous hemangiomas, and often are identified on prenatal ultrasound (US). Focal lesions can have high-flow shunts and can have an associated low grade anemia or thrombocytopenia. Multifocal lesions also can be asymptomatic. They are often found on visceral imaging that is performed when evaluating patients with multiple cutaneous hemangiomas. These extrahepatic hemangiomas can occur at multiple distant sites including the skin (45%), lung (10%), pancreas, lymph nodes, and bone.^14,15 Some of these multifocal IHH lesions, however, are associated with high-output cardiac failure from either intralesional or portovenous shunting. The diffuse lesions present with near total replacement of the hepatic parenchyma with multiple hemangiomas which can result in massive hepatomegaly, abdominal compartment syndrome, or significant respiratory compromise. This lesion is often associated with severe hypothyroidism due to the overproduction of type III iodothronine deiodinase.^16,17 The hypothyroidism can be severe enough to cause low-output cardiac failure or significant mental retardation. Interestingly, there has not been a patient reported with diffuse IHH who has developed high-output cardiac failure. Other symptoms that can occur in patients with IHH include jaundice, failure to thrive, respiratory difficulties, or poor feeding. Historically, as many as 50–60% of infants with IHH have symptoms of congestive heart failure that seems to be age related.^18,19 Neonates with a focal hemangioma tend to present with high-output heart failure at birth, whereas infants with multifocal lesions tend to present with heart failure between the ages of 1 and 16 weeks.

In patients with IHH, the hepatic transaminase levels and occasionally the α-fetoprotein (AFP) level can be elevated. The cause of this AFP elevation is unclear. Moreover, an elevated AFP level in neonates must be interpreted with some caution. The AFP level is normally elevated in neonates and it does not decrease to adult levels until about 6 months of age.¹⁵ When there is a significant elevation of the AFP level, however, hepatoblastoma must be excluded by either imaging studies or biopsy of the lesion.²⁰

A significant incidence of placental abnormalities has recently been reported in very low birth weight infants (<1500 g) who present with infantile hemangiomas.²¹ These researchers discovered a variety of anomalies that could potentially lead to the shedding of placental cells into the fetal circulation. If fetal hypoxic stress is also present, these placental cells could be exposed to an increased level of angiogenic factors that could then lead to increased endothelial cell or placental cell proliferation in the postnatal period with the subsequent development of an IHH.

Imaging

The ultrasound evaluation of IHH can be highly variable. Solitary lesions can have a heterogeneous echogenicity, and the Doppler spectral analysis can show a variety of flow patterns. Multifocal lesions, however, tend to be more uniform in their appearance and are seen as echolucent nodules associated with a high-flow vessel.²² On computed tomography (CT) with intravenous contrast, classically the lesions either enhance diffusely or show rim enhancement that is followed by gradual filling of the center of the lesion (Fig. 67-2).^19,23,24 In one series, the CT enhancement pattern was correlated to the size of the lesions. Lesions less than 1 cm enhanced homogeneously in the arterial phase. Lesions greater than 2 cm demonstrated peripheral rim enhancement and those in between 1–2 cm showed a mixed enhancement pattern in the arterial phase (Fig. 67-3).²⁵ Unfortunately, this ‘classic’ enhancement pattern is not always present in IHH which can make the radiologic diagnosis difficult.

Magnetic resonance imaging (MRI) is emerging as the single most useful modality to show both the location of the hemangioma and its flow pattern and structure.26,27 The addition of intravenous gadolinium and a gradient-recalled-echo sequence to the MRI enhances its utility.

Focal lesions on MRI are well defined and hypointense to the liver on T₁ images and hyperintense on T₂-weighted images. Gadolinium demonstrates peripheral enhancement with variable central enhancement that is related to the amount of hemorrhage or thrombosis that is present in the lesion. Multifocal and diffuse lesions tend to show similar MRI findings except that there are multiple lesions present. Recently, however, there has been a case report of a hypervascular hepatoblastoma that had an MRI pattern that was identical to a hemangioendothelioma.²⁸ Therefore, again, radiology alone cannot reliably distinguish between benign and malignant lesions.

IHH also has been seen in conjunction with both focal nodular hyperplasia and hepatic mesenchymal hamartoma.29,30 These associations are important to remember during the radiologic evaluation of a child with multiple hepatic masses.

Histology

Microscopically, the histologic pattern has been divided into type 1 and type 2 lesions. A type 1 lesion consists of a single layer or, occasionally, several layers of flat endothelial cells on a supporting fibrous stroma.³¹ In a type 2 lesion (20% of cases), the endothelial cells are pleomorphic, larger, and more hyperchromatic than those seen in type 1 tumors. Also, there are poorly formed vascular spaces that often show tufting or branching. It is thought that the histologic picture of the type 2 lesion is more characteristic of a rapidly proliferating process. The histological differentiation between a type 2 lesion and an angiosarcoma can be difficult.^14,32 The addition of a histologic stain for the marker Glut 1 can be helpful in making the diagnosis of IHH.⁹ Focal lesions do not stain positive for Glut 1, while multifocal lesions will be positive for this marker.^33,34 Well-preserved bile ducts can frequently be seen near the periphery of a type 1 lesion, whereas bile ducts are absent in a type 2 lesion.

Treatment

The life cycle of infantile cutaneous hemangiomas is divided into three stages. The first starts usually after birth and is a characterized by a rapid growth phase that lasts about 9 to 12 months. In the second phase, the hemangioma begins the process of involution. This process can take anywhere between 5 and 7 years. The last phase is the involuted phase where the hemangioma is permanently replaced by fibrofatty tissue.¹³ Hepatic hemangiomas also tend to follow a similar life cycle. The therapy for IHH depends on the severity of the presenting symptoms and the size of the mass(es).

Asymptomatic lesions are monitored, and no specific therapy is instituted until symptoms occur.11,35 As part of the evaluation of the asymptomatic patient with multifocal hemangiomas, imaging studies of the brain and chest should also be performed to make sure there are no associated intracranial or pulmonary lesions. In addition, all patients with multifocal lesions should be screened for hypothyroidism. Focal IHH are felt to follow a unique clinical course that is similar to the clinical course of a cutaneous rapidly involuting congenital hemangioma where involution is seen by 12 to 14 months of age.³⁶

Infants who present with congestive heart failure, coagulopathy, or respiratory compromise require intervention. Mortality rates in these patients have been reported to range from 17–35%, with some reports of death in as many as 90% of those who are severely symptomatic.37–39 Risk factors for death include congestive heart failure, jaundice, multiple tumor nodules, and the histologic absence of cavernous differentiation.

In patients with congestive heart failure, stabilization is initiated with digoxin and diuretics. Supportive measures may be necessary in patients with respiratory compromise either from the high-output cardiac failure or from restriction of diaphragmatic movement by the abdominal mass. Coagulation factors can be administered if a coagulopathy is present.

If there is hemodynamic instability, respiratory compromise, or coagulopathy, then therapy directed toward the hemangioma is needed. The usual initial treatment for a symptomatic lesion is prednisone or prednisolone at a dose of 2–3 mg/kg/day. The symptomatic response rate to corticosteroids is reported to be about 45%.40,41 If steroids are ineffective, then some IHHs have shown a response to vincristine at a weekly dose of 1–2 mg/m² for two weeks.¹² Labreze et al. have reported on the use of propranolol (2 mg/kg/day) for the treatment of severe infantile capillary hemangiomas with excellent results.⁴² Marsciani et al. have successfully used the combination of propranolol (1 mg/kg/day followed by 2 mg/kg/day) and steroids in the treatment of a 2-month-old child with diffuse IHH.⁴³ They noted a dramatic decrease in liver size only one week after the addition of the propranolol. Another agent that has been reported to be possibly effective in IHH is curcumin, which is derived from the spice tumeric. Curcumin has antiangiogenic activity and has been tested with some success in a variety of tumors.⁴⁴ Hassell et al. described its apparent successful use in a 6 month old with a multifocal IHH.⁴⁵

Resection should be considered if the hemangioma is confined to a single lobe. In this situation, a survival rate of 92% has been reported, even if the clinical situation is complicated by congestive heart failure.32,46 However, some authors feel that resection is rarely needed if both pharmacotherapy and embolization are aggressively pursued.¹³

Embolization is an important part of the therapy of symptomatic hemangiomas.47,48 In order to decrease the chance of the IHH recurring, it is important that both the arterial and portal vascular supply to the IHH are occluded as distally as possible.^11,19 After successful embolization, a rapid improvement in the clinical course usually occurs within five days. However, there may not be any associated change in the size of the hemangioma itself.^47,48 Embolization should be considered early in the treatment course in those infants who are in significant cardiac failure. Unfortunately, embolization has not been helpful in infants with diffuse disease because of the absence of significant shunting.

Finally, in infants in whom other modes of treatment have failed, liver transplantation has been used successfully for severe congestive heart failure or unremitting coagulopathy (or both).⁴⁹ The infants that will most commonly need to be considered for a liver transplant will be those who have the diffuse IHH subtype. Infants who experience rapid clinical deterioration in the postnatal period have a high mortality after liver transplantation so careful consideration needs to be given to their candidacy.⁵⁰

The Vascular Anomalies Center at Boston Children’s Hospital has suggested a treatment algorithm for IHH.¹³ All asymptomatic lesions should be monitored with ultrasound until resolution. Symptomatic lesions should be treated with steroids. If there is no response, then the hemangioma should be embolized. Infants with diffuse disease should have a TSH checked and be started on steroids. If abdominal compartment syndrome is present, then the infant needs to be evaluated for a liver transplant in case there is no response to steroids.

Malignant transformation of an IHH to an angiosarcoma has been reported in older children.18,51 For this reason, patients who are asymptomatic or who become asymptomatic after therapy must be monitored for complete anatomic resolution of their hemangioma. Resection of any residual lesion should be strongly considered.

Incidence

Mesenchymal hamartoma is reported to be the third most common hepatic tumor and the second most common benign tumor in children.¹ Of all benign hepatic lesions, mesenchymal hamartomas account for between 18–29% of these tumors.^52,53

Epidemiology

The reasons for the development of a mesenchymal hamartoma are unclear. One theory is that it results from abnormal development of the primitive mesenchyme, which appears to occur at the level of the hepatic ductal plate, causing abnormal bile ducts.⁵⁴ This concept is supported by the histologic finding of a combination of cystic, anaplastic, and proliferating bile ducts, as well as the presence of multiple portal vein branches, within the tumor. It is postulated that the tumor then develops a cystic component as a result of obstruction and dilatation of lymphatics or from occluded bile ducts (or both). The tumor enlarges during infancy as the cystic areas increase in size. Most of the proliferative growth appears to occur before or just after birth because no observable mesenchymal mitotic activity is visible on histologic sections of the tumor.⁵⁵

A second theory is that the lesions are reactive rather than developmental.⁵⁶ It is hypothesized that an abnormal blood supply to an otherwise normal hepatic parenchyma causes ischemic necrosis, leading to reactive cystic changes within that portion of the liver. This theory is supported by the findings that hamartomas often have a necrotic center, are often attached to the liver by only a thin pedicle, and rarely are found centrally in the liver.

The third theory suggests that a mesenchymal hamartoma is a proliferative lesion. This theory is supported by several findings. Increased fibroblast growth factor-2 (FGF-2) staining has been noted in the proliferating hepatic stellate cells adjacent to the mesenchymal hamartoma.⁵⁷ Both the stellate cells in the liver and the spindle cells in the mesenchymal hamartoma tissue strongly express molecules of the FGF-receptor family. It is speculated that a local increase of FGF-2 secretion could stimulate the growth of the spindle cells to form the mesenchymal hamartoma. FGF-2 also is a potent angiogenic factor that could contribute to the intense vascularization seen within some of these lesions. A recent study has identified that the spindle cells that make up the predominant cell line in a mesenchymal hamartoma appear to be derived from hepatic stellate cells.⁵⁸ A possible genetic cause for these abnormalities has been proposed as well. Cytogenetic studies of these tumors have documented several abnormalities including translocation/deletion of chromosome19q13 or the loss of heterozygosity due to multiple monosomies. The resulting dysregulated imprinting may be an additional cause for a mesenchymal hamartoma.^59–63

Clinical Presentation

The widespread use of prenatal imaging has led to the detection of hepatic masses before birth.¹⁵ Cases of hepatic mesenchymal hamartoma that were diagnosed prenatally have been described.^64,65 One of the unique characteristics of a prenatal mesenchymal hamartoma is that it can be solid as well as cystic. Unfortunately, the prognosis for these antenatally diagnosed neonates is often poor with a reported mortality rate of 29%.⁶⁶ This mortality is related to: (1) the development of congestive heart failure from compression of the inferior vena cava or the umbilical vein by the tumor mass; or (2) the development of hydrops that can occur from fluid losses into cysts or decreased albumin production by the liver. Thus, it may be best to deliver these fetuses before fetal hydrops develops.⁶⁵ Another series reported the use of repeated intrauterine aspiration of the cysts until the infants could be delivered and definitive treatment initiated.⁶⁷ While this therapy is appealing, there currently is insufficient evidence to recommend its widespread use.⁶⁶

In the neonate, these lesions can have a varying presentation. High-output cardiac failure, pulmonary hypertension, and disseminated intravascular coagulopathy have been reported in neonates with highly vascular mesenchymal hamartomas.68–70 Respiratory distress secondary to a large hepatic mass impinging on the diaphragm has also been described.⁶⁵ Unfortunately, the prognosis for infants with a perinatal diagnosis is also poor with a reported mortality of 35%.⁶⁶

The presentation of a mesenchymal hamartoma in the older child is usually that of progressive abdominal distention or an abdominal mass (or both). There is a significant right-sided predilection for these masses, and they tend to be somewhat more common in males.¹ Occasionally, the associated symptoms of nausea and vomiting can occur that are secondary to the compression of the stomach and intestine by the expanding mass.

On physical examination, abdominal distention or a palpable abdominal mass is most common. The mass tends to be nontender and fixed. Laboratory studies almost always are normal, including liver function studies. The AFP level can be moderately elevated and it returns to normal after resection. However, it is important to remember that patients have been treated with chemotherapy for hepatoblastoma until a tumor biopsy was performed and a mesenchymal hamartoma was subsequently diagnosed.71,72

Imaging

CT, ultrasound, and MRI have all been used for diagnosis. On CT and ultrasound, a multiseptated, multicystic, anechoic mass is usually located either in the periphery or scattered throughout the liver.73,74 Occasionally the mass is pedunculated. Calcification within the tumor is unusual, but has been reported so the presence of calcifications within a tumor does not exclude a mesenchymal hamartoma.^75,76 MR angiography has proven useful both in the diagnosis and planning of resection.^77,78 The finding of a small round hyperechoic parietal nodule on ultrasound is usually highly sensitive for making the diagnosis.⁷⁹

Histology

Mesenchymal hamartomas typically are large, well-circumscribed tumors that measure at least 8–10 cm in diameter (Fig. 67-4). Seventy-five per cent of these tumors occur in the right lobe of the liver, and only 3% are seen in both lobes of the liver. On cut section, multiple cysts can measure from a few millimeters to 15 cm in diameter. These cysts are filled with either serous or viscous fluid separated by loose fibrous and myxoid tissue (Fig. 67-5). The surrounding tissue is yellow-tan to brown and is loose to moderately dense.

Microscopically, the tissue consists of a mixture of bile ducts, liver cell cysts, and mesenchyme. The cysts may be dilated bile ducts, dilated lymphatics, or amorphous cysts surrounded by mesenchyme. In older patients, the cysts may be lined with cuboidal epithelium (Fig. 67-6). Elongated or tortuous bile ducts surrounded by connective tissue are unevenly distributed throughout the mesenchyme. Typically the hepatocytes appear normal, and they are not a predominant part of the pathologic process. The bile ducts in the periphery of the lesion seem to be undergoing active proliferation.¹

Despite the fact that the majority of these tumors are localized, there have been reports of these tumors being multifocal.⁶³ This may account for the occasional recurrences that are seen after resection of the primary tumor.

Treatment

Various management strategies have been used for these lesions. Because they are sometimes encapsulated, enucleation may be possible. Very large, bilobar tumors that are not amenable to resection can be marsupialized into the peritoneal cavity, but recurrence after marsupialization can occur. If marsupialization is performed or the resection is incomplete, careful, long-term follow-up is important because of the risk of recurrence or the development of undifferentiated embryonal sarcoma.⁸⁰ Complete excision of the lesion with a margin of normal liver is curative (including the use of liver transplantation for large, bilobar lesions) and is the recommended therapy.^81,82 For massive lesions with multiple cysts, one group reported the use of ultrasound-guided, intraoperative aspiration of the cysts.⁸³ This technique substantially reduced the size of the mass and made the resection much easier. Spontaneous involution of these lesions has been reported, but is unusual.⁸⁴

There is now strong evidence that an undifferentiated embryonal sarcoma of the liver can develop within a preexisting mesenchymal hamartoma.63,85–88 This association has occurred both synchronously and metachronously. The evidence for a direct link between a mesenchymal hamartoma and an undifferentiated embryonal hepatic sarcoma comes from the simultaneous finding of both tumors arising within the same mass. Moreover, aneuploidy and similar chromosomal abnormalities involving chromosome 19q13 have been reported in both a hepatic mesenchymal hamartoma and an undifferentiated embryonal sarcoma.^60,61,89,90

Incidence

Focal nodular hyperplasia (FNH) accounts for about 10% of the hepatic tumors in children.¹ The reported age range is between 7 months and 16 years, with a mean of 7 years, and there is a slight female predominance.⁹¹ The majority of these tumors are discovered incidentally.^91,92 The most common symptom is abdominal pain, but some patients describe decreased appetite, an abdominal mass, weight loss, or a combination. Hepatomegaly is a common finding, and liver function abnormalities are often present.

FNH has been seen in association with a variety of different conditions and situations, including previous liver trauma, other liver tumors, hemochromatosis, Klinefelter syndrome, the use of itraconazole, after a successful Kasai procedure, after liver transplantation, and with cigarette smoking.93–100

The etiology of FNH is not certain, but the evidence suggests that it may be a congenital vascular abnormality. These lesions have a single feeding artery and there is an absence of bile ducts or veins in the lesion. The large artery causes a hyperperfused area of the parenchyma with subsequent growth of the liver tissue around the artery.¹⁰¹ In addition, FNH has been associated with other vascular lesions such as hemangiomas, arteriovenous malformations, and hereditary hemorrhagic telangiectasia.^102,103 Further evidence that FNH is a reactive lesion secondary to vascular anomalies comes from a study in which an increase in the angiopoietin ratio (ANGPT1/ANGPT2) was seen.¹⁰⁴ The ANGPT1 and ANGPT2 genes are necessary for normal vascular development. In FNH, an overexpression of the ANGPT1 gene and an absence of the antagonistic ANGPT2 gene lead to uncontrolled and disorganized vascular development. Although it is not clear that this is the exact pathogenesis of FNH, it certainly suggests that this genetic imbalance may play a causative role. FNH can also develop from an acquired abnormality of the hepatic vasculature. Thrombosis of either a hepatic artery or portal venous branch can initially cause ischemia of a portion of the liver followed by recannulation and reperfusion, which leads to hepatocyte proliferation.¹⁰⁵

Controversy exists about the relation between oral contraceptive use and the development of FNH. In a case–control study, it was noted that neither menstrual nor reproductive factors correlated with FNH risk. However, oral contraceptive use was a significant risk factor in the development of FNH.⁹⁹ As the use of oral contraceptives also appears to be associated with hepatocellular adenomas, a history of oral contraceptive use does not help in distinguishing between these two entities.⁹⁹

In children, an association has been noted between the congenital absence of the portal vein (Abernathy syndrome) and FNH.106–108 In addition, these patients have an increased incidence of other solid tumors such as hepatoblastoma, hepatocellular carcinoma, and hepatocellular adenoma.^109,110 FNH also has been seen, albeit less frequently than hepatocellular adenoma, in patients with glycogen storage disease (GSD) type 1.¹⁰⁸

Over the last six years there has been an increasing awareness of the occurrence of FNH in oncologic patients who have completed their therapy. The reported incidence of FNH in the general pediatric population is 0.02% but is 0.45% in the postoncology treatment population.¹¹¹ As opposed to nononcologic patients where the FNH is usually solitary, post-treatment oncologic patients frequently have multiple FNHs. The cause of these post oncologic FNHs is not known, but is felt to be secondary to alterations in liver perfusion that occur as the result of the chemotherapy or radiation that these patients receive.^105,112 The development of hepatic mass(es) in an oncology patient leads to a diagnostic dilemma between an FNH or a recurrent tumor. One of the higher risk groups for developing an FNH after therapy are patients who were treated for neruoblastoma.^111–116 There also seems to be an increase in the development of FNHs in children who have received a hematopoietic stem cell transplant.^117–119 Therefore, a liver lesion that occurs after treatment of a previous cancer does not always mean that there has been a recurrence of the primary tumor. A biopsy of the lesion should always be done before the initiation of further therapy.¹²⁰

Imaging

The diagnosis of FNH often requires the use of multiple different imaging modalities. On CT, the classic findings are early enhancement of the lesion and the presence of a central scar (Fig. 67-7).¹²¹ Unfortunately, this pathognomonic association is not often seen.^122,123 Additional imaging modalities include single-photon emission radionuclide scans with either radiolabeled sulfur colloid or hepatobiliary iminodiacetic acid (HIDA) imaging. These studies usually demonstrate hypervascularization, increased tumor tracer uptake, and a central cold area.^124–126 Technetium-99m sulfur colloid scanning can also be useful in distinguishing between FNH and a hepatic adenoma. FNH lesions take up the tracer because the Kupffer cells in the FNH take up the colloid but hepatic adenomas do not take up tracer because they lack Kupffer cells.¹²⁷ MRI also has been useful when coupled with either gadolinium enhancement or the use of liver-specific contrast agents such as mangafodipir trisodium or iron oxide. During the arterial phase of dynamic contrast enhancement, an FNH will demonstrate distinct hypervascularity.¹²⁸ These contrast agents can also help diagnose an FNH by allowing better identification of the central scar.^129,130

Histology

FNH classically is characterized by nodular architecture, a central or eccentric scar containing malformed vessels that resemble an arteriovenous malformation, and a variable amount of bile duct proliferation (Figs 67-8 and 67-9).^131,132 FNHs always occur in the setting of a noncirrhotic liver.

Histologically, the classic form of FNH with a central scar accounts for about 80% of the lesions. Twenty per cent are nonclassic where the FNH lacks either the nodular architecture or the presence of the malformed blood vessels. These nonclassic lesions are subdivided into three histologic categories: the telangiectatic form, the mixed hyperplastic form, and the adenomatous form.¹³³ These nonclassic categories always lack a macroscopic scar and all three forms can be difficult to distinguish from and may be related to a hepatocellular adenoma.¹³⁴ Immunohistochemical staining for cytokeratins 7 and 19 along with staining for neuronal cell adhesion molecule (CD56) has shown to be very helpful in distinguishing between FNH and hepatocellular adenoma.¹³⁴ Hepatocellular adenomas have been reported to be present in association with FNH in about 4% of the cases.¹³¹

Recently, there has been a case report of what appears to be malignant transformation of an FNH to a fibrolamellar hepatocellular carcinoma.¹³⁵ Also, FNH has been reported to occur in association with a well-differentiated fibrolamellar hepatocellular carcinoma.^135,136 This observation is important to remember in patients who have multiple hepatic nodules.^137,138

Treatment

The treatment of FNH depends on the clinical situation. If the diagnosis is certain, and the patient is asymptomatic, the consensus is that these patients can be followed with serial ultrasound to ensure that no progression of the lesion occurs.91,122 Percutaneous biopsy can be helpful in the diagnosis.¹³⁹ However, if the patient is symptomatic, if the lesion is greater than 5 cm, if progression of the mass is seen, or if the diagnosis is unclear, then a biopsy or a resection of the lesion is recommended.^140–143 Due to the association of FNH with hepatocellular carcinoma, patients who are expectantly managed must have serial evaluations to ensure that no progression occurs. Moreover, they need to be monitored for the development of other hepatic lesions.

Several reports have noted a 40–50% regression rate in cases of FNH that have been monitored.144,145 In the pediatric population, the true incidence of regression is not known due to the lack of long-term follow-up studies; however, it may be much lower than in the adult population.¹⁴³ Regression of FNH is more likely if the use of oral contraceptives ceases.^146,147

In two symptomatic patients in whom the FNH was in an area that was thought to be difficult for resection, arterial embolization either with Lipiodol and absorbable gelatin foam (Gelfoam) or iodized oil and polyvinyl alcohol resulted in a significant regression in the size of the mass.148–150

Incidence

Hepatocellular adenoma is a very rare hepatic tumor in children, comprising only about 4% of all solid liver tumors.¹ It is most commonly seen in women in their 20s and is associated with the use of oral contraceptives.

Clinical Presentation

In children, these lesions are often asymptomatic and are discovered during evaluation for other problems. Occasionally, they can produce intermittent abdominal pain and rarely can spontaneously rupture resulting in hemoperitoneum and the clinical signs of acute volume depletion.

Imaging

Hepatic adenomas are solitary lesions in most cases, but occasionally two to three adenomas can be seen in one patient.149,151,152 On ultrasound, these lesions can have a variable appearance, depending on the tumor composition. They can have a hyperechoic, hypoechoic, or a mixed echoic pattern depending on whether it is a simple adenoma, an adenoma with fatty metamorphosis, or an adenoma with hemorrhagic necrosis.¹⁴⁹

On CT, the adenoma can either be isoattenuating relative to the normal liver or hyperattenuating (due to the presence of fat). They are usually sharply marginated and nonlobular, but can be encapsulated or calcified in some patients.¹⁵³ Hyperattenuated areas often correspond to areas of recent hemorrhage. On CT scan with intravenous contrast, a hypodense discrete lesion will show either arterial-phase enhancement or peripheral enhancement secondary to large subcapsular feeding vessels.¹⁵⁴

On MRI, these lesions are either hypo- to hyperintense on T₁-weighted images with uniform signal loss on out of phase T₁-weighted views. On T₂ images, the lesions are isointense to slightly hyperintense and gadolinium enhancement is maximal during the arterial phase with rapid fading.¹⁵⁴ The finding of central hemorrhage or necrosis on CT scan helps differentiate hepatocellular adenoma from FNH.

Associated Conditions

Hepatocellular adenomas were extremely rare prior to 1960, which corresponds to the year in which oral contraceptives were first introduced.¹⁵⁵ In women who have never used oral contraceptives, the annual incidence of hepatic adenoma is estimated to be about one per million. The duration of oral contraceptive use is directly related to the risk of developing a hepatic adenoma. The use of contraceptives for 5 to 7 years carries a fivefold increased risk, and use for 9 or more years has a 25-fold increased risk.^156–158

Hepatocellular adenomas also have been associated with galactosemia, hypothyroidism, polycythemia, diabetes, Fanconi anemia, polycystic ovary syndrome, and the use of anabolic steroids.159–162

Hepatocellular adenomas are a significant complication in patients with type 1A GSD from their teenage years into adulthood.163,164 The estimated prevalence of adenomas in these patients is close to 50%.^165,166 The pathogenesis of adenoma development is poorly understood in this group, but may be related in part to the tightness of the metabolic control.¹⁶⁷ These adenomas are often multiple rather than solitary lesions. Unfortunately, in this patient population, hepatocellular carcinoma can occur in association with hepatocellular adenomas. The youngest reported patient with GSD was 6 years old at the time of the diagnosis of hepatocellular carcinoma.¹⁶⁸ In several series, hepatocellular carcinoma has been found to develop in up to 18% of patients with a hepatocellular adenoma.^169–173 Direct evidence for malignant transformation of a hepatocellular adenoma into a carcinoma has been confirmed with the reporting of a hepatocellular carcinoma within a hepatic adenoma in patients with GSD.¹⁷⁴ Abnormalities in chromosome 6 have been also been identified in type 1A GSD adenomas and similar chromosome 6 alterations have been identified in hepatocellular carcinomas, suggesting a possible genetic link between these two diagnoses.¹⁷⁵

Adenomatosis (the occurrence of more than ten simultaneous adenomas) is a rare disorder, with 38 cases reported in the literature through 2000.¹⁷⁶ There is a massive form, characterized by multiple nodules measuring between 2–10 cm, and the multifocal form, in which most lesions are smaller than 1 cm, with only a few larger than 4 cm.¹⁷⁷ Oral contraceptive use has been seen in about half of the female patients. Interestingly, diabetes and hepatic steatosis has been noted in these patients, but it is not clear if there is a causative relation.^177,178 Adenomatosis has also been reported in patients seven to nine years after a Fontan procedure.¹⁷⁹

Histology

Hepatocellular adenomas histologically consist of large plates or cords of cells that resemble normal hepatocytes. These plates are separated by dilated vascular sinusoids, which are equivalent to thin-walled capillaries perfused by arterial pressure. Adenomas do not have a portal venous supply and are fed solely by peripheral arterial vessels that account for the hypervascular nature of these lesions. Kupffer cells are found in reduced numbers and have little or no function. The absence of bile ducts serves as a key histologic feature that helps distinguish the hepatocellular adenoma from FNH. Lipid accumulation is responsible for the characteristic yellow appearance on the cut surface.¹

The exact reason for their development is unclear. Two reports have cited the mutations of the Wnt/β-catenin pathway in patients with hepatocellular adenoma.180,181 This pathway mutation has been identified in many hepatocellular neoplasms, although its direct contribution to carcinogenesis is not completely understood. A second mutation has been found in the HNF1A gene that leads to the downregulation of hepatocyte nuclear factor-1α. This downregulation has been linked to the development of hepatic steatosis and hepatic adenomas.¹⁸² The significance of these findings in hepatocellular adenoma is also unknown.

Hepatocellular adenomas may be asymptomatic, but also can be the site of hemorrhage. Larger lesions are more likely to bleed than are smaller lesions. Contained hemorrhage may result in rapid enlargement of the adenoma, but rupture with intraperitoneal hemorrhage can occur if the lesion is near the liver surfaces. The patient may show signs of blood loss and/or peritonitis.

Treatment

The treatment approach for these lesions depends on a variety of factors. In patients who are receiving oral contraceptives or androgenic steroid therapy, the first step should be withdrawal of these medications. Multiple case reports mention regression of the adenomas after withdrawal of these compounds. However, in other multiple reports, withdrawal of these agents has resulted in persistence of the adenoma.183–185 If discontinuation is not effective, then the adenoma should be resected. This removes the potential for future hemorrhage or malignant degeneration (10% of lesions).¹⁸⁶ If the adenoma is larger than 5 cm or if the diagnosis of the hepatic lesion is uncertain, then excision is recommended.^187,188

For patients with ruptured hepatocellular adenomas, the current suggested therapy in the hemodynamically stable patient is nonoperative monitoring and hemodynamic support. Once the hemorrhage has resolved and the patient has recovered, elective resection can be performed. In patients who continue to bleed actively, hepatic arterial embolization should be performed. This not only stops the hemorrhage but also can decrease the size of the adenoma.¹⁸⁹ After resolution of the hemorrhage, resection is indicated. This management plan results in a decrease in size of the lesion and allows a more limited hepatic resection under controlled conditions.^190,191

In patients with type 1 GSD in whom multiple adenomas develop, hepatic transplantation should be considered because of the significant probability of the development of a concurrent hepatocellular carcinoma. Liver transplantation not only corrects the potential hemorrhagic problem, but also removes the potential for cancer development.

Epidemiology

Hepatoblastomas are associated with a variety of clinical conditions, syndromes, and malformations (Box 67-1). Beckwith–Wiedemann syndrome is associated most commonly with Wilms tumor, but other tumors such as hepatoblastomas, gonadoblastomas, and adrenal carcinomas are also seen.^194,195 The association with hepatoblastoma is so strong that patients with Beckwith–Wiedemann syndrome must be monitored with serial AFP levels every three months until the age of 4 years and an abdominal ultrasound every three months until they reach age 8 years.^195–197 Screening studies for hepatoblastoma are also recommended in patients with familial adenomatous polyposis. These patients should be screened for the APC tumor/suppressor gene. If this gene is present, then these patients are at increased risk for developing hepatoblastoma.^198,199

Another interesting association exists between hepatoblastoma and extreme prematurity (<1000 g). In the Japanese Children’s Cancer Registry (JCCR), it was noted that hepatoblastomas accounted for 58% of the malignancies diagnosed in extremely low birth weight children.²⁰⁰ In recent epidemiologic studies, several factors were associated with an increased risk for the development of neonatal hepatoblastoma, including birth weight less than 1000 g, maternal age younger than 20 years, use of infertility treatment, maternal smoking, and a higher pre-pregnancy body mass index (BMI of 25–29).^201,202 The time from birth to onset of hepatoblastoma in this population ranges from six months to six years.²⁰³ Unfortunately, the tumors that occurred in this group grew rapidly and had an unfavorable biologic behavior.²⁰⁴ Although the etiology for the predilection of hepatoblastomas to develop in very low birth weight infants is not known, oxygen therapy, furosemide use, and failure of the infant to grow appropriately were noted to be risk factors.²⁰⁴ The highest correlation was with the duration of oxygen therapy. The risk of hepatoblastoma increased by 20% if oxygen therapy was continued for 30 days, and the risk increased by 100% in children who were treated with oxygen for four months.

Cysteine has also been implicated as a contributing factor. Cysteine is an amino acid that is necessary for the production of glutathione and taurine, both of which are intracellular antioxidants. In premature infant livers, there appears to be impaired production of cysteine.²⁰⁵ Due to the complexities in treating ‘micropremies’ through their first few months, multiple other interventions could influence the development of a hepatoblastoma.

Histology

Hepatoblastomas tend to be unifocal lesions in most cases. Fifty per cent are isolated to the right lobe, 15% are in the left lobe, and 27% are centrally located to involve both lobes (Fig. 67-10).

Histologically, the tumor can be divided into six different subtypes (Figs 67-11 and 67-12) based on light microscopy (Box 67-2). A correlation between clinical outcome and the histologic subtypes has been suggested. The pure fetal subtype appears to be associated with the better prognosis, whereas the small cell undifferentiated subtype appears to have a very poor prognosis.^206–209 In several other studies, chemotherapy was initiated before surgical intervention and likely altered the accuracy of histologic definition of the resected tumor, making it difficult to correlate histology and outcome.²¹⁰

Biology and Cytogenetics

Thrombocytosis is common in patients with hepatoblastoma. This may be related to increased thrombopoietin levels, which have been reported in hepatoblastoma cell extracts.²¹⁰ Elevated interleukin-1b levels also have been noted in hepatoblastoma cell lines.²¹¹ This results in an increased production of interleukin-6, which is known to stimulate thrombopoiesis and thrombocytosis.²¹²

Chromosomal abnormalities have been documented in patients with hepatoblastoma.²¹³ The most common defects have been trisomy of chromosomes 20, 2, or 8, or a combination of these. Trisomy 18 also has been found.²¹⁴ However, to date, no correlation has been noted between these cytogenetic abnormalities and either clinical outcome or tumor biology.

An association between hepatoblastoma and the APC gene was noted in patients with familial adenomatous polyposis and Gardner syndrome.212,215 A recent study found an association between the activation of the Wnt/β-catenin signaling pathway and the development of carcinogenesis in hepatoblastoma and hepatocellular carcinoma.²¹⁶

Clinical Presentation

Patients with hepatoblastoma are most commonly seen with an asymptomatic right upper abdominal mass that is noted incidentally by either a parent or the pediatrician. Rarely these patients have tumor rupture, followed by significant hemorrhage and hypovolemia. Sexual precocity may be a presenting feature with hepatoblastoma, secondary to the tumor producing human chorionic gonadotropin. With large tumors, it is not unusual to see anorexia and failure to thrive. These lesions can become very large (15 cm) and can extend across the midline or down into the pelvis.

Imaging

The first diagnostic test is usually an ultrasound. This usually differentiates between a renal and hepatic mass. An abdominal CT scan is then usually performed. In half of patients, calcification is noted within the mass.²¹⁷ Spiral CT with an intravenous bolus of a contrast agent not only is helpful in the diagnosis, but also is useful in the staging of the tumor and in determining its resectability. With three-dimensional reconstruction, the location of the mass with respect to the vena cava, the hepatic veins, and the portal venous system can often be precisely delineated (Fig. 67-13). MRI is becoming an increasingly helpful modality for determining the relation of the tumor to the hepatic anatomy and in differentiating hepatoblastomas from other childhood hepatic tumors.²¹⁸ However, no current noninvasive study can always differentiate between a benign or malignant liver lesion.²⁸ If there is any concern about the diagnosis, a biopsy should be performed.

Laboratory Studies

Anemia and thrombocytosis (platelet count >500,000/mm³) are often found in patients with hepatoblastoma.²¹⁹ However, the hallmark of hepatoblastoma is an elevated AFP level, which occurs in up to 90% of patients.²²⁰ The serum levels of AFP can sometimes exceed 1 million ng/mL. This can lead to the ‘hook’ effect in which the initially reported AFP level can be low despite the actual level being very high. If the lesion is suspicious for hepatoblastoma, a request should be made to dilute the AFP sample before retesting.²²¹ Serum AFP has a half-life of between 4 and 9 days, and the levels usually decrease to normal by 4 to 8 weeks after complete removal of the tumor.²²² It is important to remember that neonates normally have an elevated AFP level (25–50,000 ng/mL) at birth that does not decrease to ‘adult’ levels until age 6 months.¹⁵ This becomes important when evaluating a neonate with a hepatic mass or when monitoring the AFP after liver resection in a neonate or infant.

AFP also has been useful for monitoring purposes. In one case report, a radioimmunodetection method was used (technetium-labeled mouse antihuman monoclonal antibody to AFP).²²³ After an initial decline in the AFP following liver resection, it began to increase, and an anti-AFP nuclear medicine study accurately located an active tumor in the remaining liver.

Recently, a new marker has been found for hepatoblastoma. Glypican 3 (GPC3) has been detected in hepatic stem cells and has been identified as being expressed by fetal, embryonal, and small cell undifferentiated hepatoblastomas. This marker is also shed by the tumor cells and has the potential to be used as a serum marker for hepatoblastoma.²²⁴

Staging

Two staging systems are currently used. In the USA, a combined histologic and surgical staging system is used by the Children’s Oncology Group (COG) (Table 67-3).²²⁵ This tumor staging system is self-explanatory and is based on information gathered before any chemotherapy is started. The second staging system, used by the International Society of Pediatric Oncology (SIOP), is based on the radiologic location of the tumor before treatment and is called the PRETEXT (Pretreatment Extent of Disease) Grouping System (Fig. 67-14).²²⁶ Both of these staging systems are currently being used in ongoing studies so patient groups can be compared across different study groups.

In the PRETEXT system, the liver is divided into four sections: the anterior and posterior sectors on the right, and the medial and lateral sectors on the left. Therefore, based on the extent of the tumor, the patient is classified as follows: PRETEXT 1, with three adjoining sectors free (tumor in only one sector); PRETEXT 2, with two adjoining sectors free (two sectors involved); PRETEXT 3, in which only one sector is free or a total of three nonadjoining sectors are involved (tumor involves two or three sectors); and PRETEXT 4, in which no sector is free (tumor in all four sectors). It also takes into account hepatic vein or portal vein involvement, if extrahepatic spread has occurred (enlargement of the hilar lymph nodes), or if metastases are found. Both staging systems have been shown to have direct correlations with patient survival (Table 67-4).

In addition to the staging systems, in upcoming protocols, the patients will also be stratified according to risk. In the COG staging system, low-risk patients will be stage I/II without unfavorable biologic features, intermediate-risk patients will be stage III or stage I/II with small cell undifferentiated histology, and high-risk patients will be stage IV or stage I, II, III with an AFP less than 100 ng/mL at diagnosis. In the SIOPEL studies, the patients are stratified into standard risk (PRETEXT I, II, III) or high risk (PRETEXT IV or any tumor with metastases, vena cava or portal vein invasion, contiguous extrahepatic disease, or tumors with an AFP <100 ng/mL at presentation).²²⁷

Treatment

The treatment of hepatoblastoma requires a multidisciplinary approach. Except on very rare occasions, chemotherapy alone is unable to eradicate the tumor. The only chance for a long-term cure is complete resection of the primary tumor. This goal can be achieved by the use of either traditional hepatic resections (right lobectomy: segments 5–8; left lobectomy: segments 2–4; or left lateral segmentectomy: segments 2–3) or extended resections (right trisegmentectomy: segments 4–8; or left trisegmentectomies: segments 2–4, 5, 8). The resection can be performed using either open or laparoscopic techniques. There have been several case reports and two large series of laparoscopic liver resections in adults for both benign and malignant disease.228–231 The outcomes of these laparoscopic series have been identical to the results of resections by an open approach.

The resection should be planned so that there is an anticipated margin of normal liver around the tumor. Fortunately, this margin does not need to be large (2–3 mm).²³² If it is doubtful that the tumor can be resected with a clear margin, then the patient should undergo preoperative chemotherapy to try to reduce the size of the tumor to the point where complete resection is possible. In several studies, only between 30% and 50% of the patients were able to undergo either a complete or gross total resection of the tumor at the initial procedure.^233,234 In the COG trials, only 23% of the patients initially presented with stage I or stage II disease.²³⁵

If a difficult liver resection is elected, the conundrum exists as to what to do if the resection is unsuccessful and microscopic residual disease is left after a resection. The data from the COG studies, SIOPEL-1 and SIOPEL-2, indicate that microscopic residual disease after resection can be successfully treated with additional chemotherapy.208,236,237 On the other hand, several series have reported that the most common reason for tumor recurrence is either a gross or microscopically incomplete resection.^238–241 If local recurrence of the tumor occurs, the prognosis is poor.^222,242,243 ‘Rescue’ transplantation for local recurrence results in a survival rate of only 30%.²⁴⁴ This would suggest that there must be multiple, yet to be defined, variables that determine if microscopic disease can be eradicated or if it will result in recurrent disease. In any case, there must be careful thought before undertaking a ‘difficult’ liver resection when the possibility exists of leaving residual disease versus referring the patient directly for liver transplant evaluation.

If chemotherapy is necessary, it should be noted that there are two distinct approaches to its utilization in the treatment of hepatoblastoma. The COG approach is based on the premise that all patients who present with hepatoblastoma should be evaluated for a primary resection. If this is not possible, then the patient receives chemotherapy with the goal of shrinking the tumor to the point where it is resectable. The intent of this approach is to limit the patient’s exposure to chemotherapeutic drugs that carry significant side effects including renal, cardiac, and ototoxicity. The SIOP approach is fundamentally different in that all their patients receive chemotherapy before any consideration for resection. The logic behind this approach is that chemotherapy will provide multiple benefits, such as shrinking the tumor, thereby potentially decreasing the size and risks of hepatic resection, decreasing the viability of the tumor prior to surgical manipulation, and decreasing the vascularity of the tumor. The SIOP group uses the PRETEXT staging system, but the correlation between survival and PRETEXT stage is based on the fact that all PRETEXT staged tumors (regardless of stage) have received chemotherapy. It should be noted that neither approach has been proved to be superior to the other in multiple, multicenter trials.

Multiple chemotherapy regimens have been evaluated for hepatoblastoma.225,245 The most active chemotherapy agent for hepatoblastoma is cisplatin. This drug is then combined with either vincristine, doxorubicin, or 5-fluorouracil, and used in either an adjuvant or neoadjuvant fashion. The current recommended COG chemotherapy regimen for initially unresectable hepatoblastoma is doxorubicin, cisplatin, 5-fluorouracil, and vincristine.²⁴⁶ In the patients who have had complete resection of their tumor (without preoperative chemotherapy), either four to six postoperative courses of chemotherapy are given. In those children in whom the liver tumor was deemed unresectable at the initial operation (stage III disease), two rounds of chemotherapy are initially given, followed by repeat imaging.

If the tumor appears resectable, then resection should be done at this time. If the tumor is not resectable, then the patient undergoes an additional two rounds of chemotherapy. In addition, the patient also needs to be referred to a center where there is the option for transplantation. If after the additional two rounds of chemotherapy the tumor is resectable (total of four rounds), then resection is performed (Fig. 67-15). With chemotherapy and delayed or second-look surgery, the resection rate has been reported to increase to between 69% and 98% (Fig. 67-16).^5,247–249 In patients with stage IV disease (initially unresectable), only 40% of these tumors were rendered resectable after four rounds of chemotherapy. If the tumor is still unresectable, the patient needs to be evaluated and listed for a liver transplant.

Current United Network Organ Sharing (UNOS) policy allows hepatoblastoma patients to be listed as status 1B in order to maximize their chance of being transplanted within one month of listing. Preferably the time between the last round of chemotherapy and transplantation should be less than four weeks because it is now known that up to 80% of hepatoblastomas will develop drug resistance after four to five courses of chemotherapy.248,250 After transplant, the patient receives a final two rounds of chemotherapy.

Some newer chemotherapy agents have been investigated for hepatoblastoma. Topotecan inhibits growth and neovascularization in a mouse model.²⁵¹ In addition, the suppressive effects of the topotecan lasted several weeks after discontinuation of the agent. Irinotecan appears to have some promise in salvaging patients who have recurrent disease. This drug could potentially be added to front-line chemotherapy regimens.²⁵² High-dose chemotherapy with stem cell rescue has been attempted but has not been successful.

Another approach to the unresectable hepatoblastoma is the use of preoperative chemoembolization. In one study, transarterial catheterization with selective tumor chemoembolization was able to shrink the tumor by an average of 26%, which allowed subsequent complete tumor resection in every case.²⁵³ Interestingly, the surgical specimens showed only minimally viable or no viable tumor. It was postulated that this technique may be useful not only as a therapeutic modality for unresectable hepatoblastomas but also potentially for resectable tumors that could be made minimally viable to nonviable before surgical intervention.²⁵⁴

Another therapeutic dilemma occurs in the child first seen with a ruptured tumor. In one review, all three patients who survived the initial rupture had no evidence of recurrent disease, with a mean survival of 36 months.²⁵⁵ Even though tumor rupture and peritoneal soiling occurred, no peritoneal growths were subsequently identified in any patient.

Outcome

Patient-outcome studies have been based on histologic type, the extent of the original tumor, or tumor response to chemotherapy.²⁰⁶ Several studies have shown a good outcome with fetal histology and with complete resection of the tumor.^{51,194,209,256,257} All the studies that have consistently shown a good outcome based on fetal histology have limited this diagnosis to tumors with a mitotic activity less than two per ten high-power fields. Conversely, several studies have consistently reported a poor outcome for those patients who have small cell undifferentiated hepatoblastoma.²⁰⁷ Except for these data, no consistent correlation has been found with any of the other histologic patterns and patient outcomes.

The AFP level also has been found to have both prognostic and therapeutic implications. Patients with an AFP level less than 100 ng/mL or greater than 1 million ng/mL have a worse prognosis.²⁵⁸ The low AFP group comprised patients with small cell undifferentiated tumors, suggesting that a low AFP level could be related to a very primitive and poorly differentiated tumor that was unable to make AFP.²⁵⁹ Patients who had a slow decline in their AFP levels, either after resection or chemotherapy, had a worse long-term prognosis than did those who had an early, very rapid decline (>99% drop in AFP levels).²⁶⁰

The best survival rate in patients with hepatoblastoma is for those tumors with pure fetal histology. A recent COG study demonstrated that after complete surgical resection of a stage I tumor with pure fetal histology, the patient can be carefully monitored with no further therapy.²⁶¹ However, if an area of undifferentiated small cell histology is noted within an otherwise pure fetal histology tumor, then aggressive chemotherapy should be instituted.²⁰⁷

In another COG study, the 3-year event free survival (EFS) was 90% for stage I/II tumors, 50% for stage III tumors, and only 20% for stage IV tumors.²⁶² The European SIOPEL-2 study reported that the 3-year survival for standard risk tumors was 90% and was 50% for high-risk tumors. These data compare favorably with those of a large German series that noted an EFS of 100% for stage I, 80% for stage II, and 68% for stage III disease.²⁴⁹ None of the patients with stage IV disease in the German trial survived. In another prospective study, the German group showed that the important prognostic factors for survival appeared to be the tumor growth pattern, vascular invasion, and serum AFP levels.257,263

As the patients in the high-risk PRETEXT or COG trials have poor outcomes despite a complete surgical resection, additional or different chemotherapy regimens are necessary to improve patient survival in these groups.²⁵⁷ Currently there are ongoing studies that are evaluating the possibility of modifying different cellular or gene targets in hepatoblastoma cells that will make them more susceptible to chemotherapy.²⁶⁴

There are several treatment options currently under clinical evaluation by COG. For more information on ongoing studies, please check the COG website (www.childrensoncologygroup.org).

Transplantation

Once a patient has completed four rounds of chemotherapy, a decision is made to either perform a resection with the goal of complete tumor excision or to refer the patient for liver transplantation. Several characteristics of hepatoblastoma have recently been reported as indicators of unresectability. Patients with these indicators are possible candidates for liver transplantation. Patients who were younger than 3 years of age at presentation tend to respond better to chemotherapy with greater reductions in tumor size when compared with older children.²⁶⁵ Bilobar, multifocal tumors at presentation are candidates for transplantation because, despite apparent radiologic clearing of a lobe after chemotherapy, microscopic disease can persist in the liver leading to later recurrent disease.^236,266,267 Patients who present with low AFP levels (<100 ng/mL) tend not to respond to chemotherapy, so they should be considered for either upfront resection or transplantation. Patients who have tumor extension into the inferior vena cava, all three hepatic veins, or the bifurcation of the portal vein are unlikely to sufficiently shrink their tumor with chemotherapy to allow a complete resection and therefore should be considered as possible candidates for transplantation.²⁴⁴

Orthotopic liver transplantation is a successful treatment for unresectable hepatoblastoma.²⁶⁸ A recurrence-free survival rate of between 79% and 92% has been reported.^244,269,270 In several series, an important prognostic factor that predicted good results after transplantation was a good initial response to chemotherapy. In one series, only 60% of the patients who were poor responders are currently alive, with a follow-up of less than 1 year.²⁶⁹ As mentioned previously, liver transplantation for local tumor recurrence after resection is associated with a post-transplant recurrence rate of 30%.

Although two post-transplant rounds of chemotherapy are currently utilized, one multicenter review noted no significant difference in survival rates between those patients who received chemotherapy (77%) versus those who did not (70%).241,271–273

Patients with extrahepatic metastases found on initial evaluation can be successfully treated with liver transplantation if the metastatic disease is eradicated before the transplant. Hepatoblastoma commonly metastasizes to the lungs, and lung metastases are often present at diagnosis. Because this tumor tends to be chemoresponsive, these metastases will often disappear after the first several rounds of chemotherapy. If the pulmonary metastases do not resolve, then current data would suggest that these patients should undergo a metastasectomy for any remaining disease, either before or shortly after hepatic resection, and before consideration for transplantation. This approach has been successful in increasing patient survival.274,275 Unfortunately the data on resection of pulmonary recurrences are less optimistic. There may be a role for resection of late pulmonary metastasis in patients who presented with stage I disease. However, pulmonary relapse in stage III and IV disease portends a poor prognosis that is not changed by lung resection.

Incidence

Undifferentiated embryonal sarcoma of the liver makes up about 7% of the solid liver tumors in children.¹ Unfortunately, this is a very malignant tumor with a poor outcome.

Clinical Presentation

Undifferentiated embryonal sarcoma most commonly affects children between the ages of 6 and 10 years, but has been reported in a child as young as 19 months.²⁷⁶ A slight male predominance has been noted. The most common clinical presentation is either right upper quadrant or epigastric pain with or without a palpable abdominal mass. Occasionally, marked hepatomegaly is seen without a definite mass. Rarely, this tumor can even masquerade as a hepatic abscess or infection.²⁷⁷ Other nonspecific presenting complaints can include vomiting, anorexia, and lethargy. Laboratory studies, including AFP level, are usually normal.

Imaging

On ultrasound examination, the lesion appears predominantly solid.²⁷⁸ However, on CT and MRI, the lesion appears cystic without any significant solid component (Fig. 67-17). This same type of disparity has been reported only in Wilms’ tumor metastatic to the liver. Thus, it appears that such a discrepancy between the two imaging techniques would be highly suggestive of an undifferentiated embryonal sarcoma.

Histology

Undifferentiated embryonal sarcoma is a neoplasm with a very primitive mesenchymal phenotype. These tumors tend to occur predominantly in the right lobe of the liver and to be large, with an average diameter of 14–21 cm.²⁷⁸ In cross section, the tumors are often variegated, with white mucoid or gelatinous areas alternating with other areas of tumor necrosis and hemorrhage (Fig. 67-18). The tumor typically is well demarcated from the adjacent liver by a compressed, fibrous pseudocapsule.²⁷⁶

On microscopic section, these tumors are composed of medium to large spindle- to stellate-type cells in a variable amount of myxoid stroma (Fig. 67-19). The cells are usually densely arranged in a myxomatous background. In the periphery, entrapped bile ducts or hepatic cords have been noted.^4,276 Mitoses are frequent and usually bizarre.

No characteristic immunohistochemical stain pattern has been identified for embryonal sarcoma.²⁷⁹ The only consistent cell markers have been vimentin and the ‘histiocytic’ determinants α1-antitrypsin and α-antichymotrypsin.^280,281

In a cytogenetic study, extensive chromosomal rearrangements were noted to be very similar to other soft tissue sarcomas such as leiomyosarcoma, osteosarcoma, and malignant fibrous histiocytoma.²⁸² In only a few cytometric studies, the tumors have ranged from diploid to tetraploid to aneuploid.^283,284

Treatment

In addition to the highly suggestive radiologic findings, these patients can be diagnosed by fine needle aspiration. Two separate reports have noted that the cytologic features of undifferentiated embryonal sarcoma are distinctive and different from other childhood tumors.285,286

The initial experience with undifferentiated embryonal sarcoma of the liver was poor. In a review of patients treated from 1950 to 1988, only 37% of the patients were noted to survive.²⁸⁴ This tumor usually proves fatal because of massive upper abdominal growth with secondary involvement of the diaphragm, stomach, abdominal wall, ribs, or pancreas rather than by metastases. Occasionally, intra-abdominal dissemination of the tumor can occur, causing diffuse matting of the small bowel. Pulmonary and pleural metastases have been noted but are much less common than the secondary involvement of the extrahepatic tissue by direct extension.²⁷⁶

The only chance for cure is radical excision.287,288 Unfortunately, despite complete resection of the tumor, many patients have recurrent disease, which suggests the need for postoperative chemotherapy.²⁸⁹

The chemotherapy regimens that have been used are based on nonrhabdomyosarcomatous soft tissue sarcoma-type protocols.²⁹⁰ With these regimens, survival rates have improved to 66%, because these tumors are very chemotherapy sensitive.^291,292 This finding has led to the use of preoperative chemotherapy to shrink an unresectable tumor to a size at which a radical hepatic resection is possible.²⁹³ This is similar to the approach used to manage an initially nonresectable hepatoblastoma.

With the ongoing improvement in chemotherapy regimens for sarcomas, the previously bleak outlook for this tumor is now much more optimistic. The use of an aggressive chemotherapy regimen, along with complete resection of the primary tumor, has resulted in a 37% survival rate in patients whose tumors initially presented as free intraperitoneal rupture.²⁹²

Moreover, a prospective series from the Italian and German Soft Tissue Sarcoma Cooperative Groups reported a protocol that included surgery or biopsy followed by neoadjuvant chemotherapy for four cycles. This was followed by second-look surgery to try to remove residual tumor followed by additional chemotherapy. In their series, ten of 17 patients survived with complete remission.²⁹⁴

In patients in whom complete resection of the tumor is not possible despite chemotherapy, liver transplantation has been advocated as another possible means for complete excision.295,296 This aggressive approach is reasonable because these tumors are sensitive to chemotherapy.

Clinical Presentation

Most patients are initially seen with either an abdominal mass or abdominal pain. Other associated symptoms include nausea and vomiting, anorexia, malaise, and a significant weight loss. As many as 10% are seen initially with tumor rupture and hemoperitoneum.³¹⁸ More than one-third of HCCs appear as multiple nodules rather than a single tumor.³¹⁹

Laboratory studies can show mild elevations in the serum glutamic oxaloacetic transaminase (SGOT) and lactic dehydrogenase (LDH) levels. The AFP is elevated in about 85% of patients but can be normal or only mildly elevated with the fibrolamellar variant. ^{318, 320} An elevated AFP is associated with an increased risk for recurrence after resection and therefore reflects a worse prognosis.321,322

Imaging

CT and MRI are both helpful for delineating the mass and for determining resectability. With the advent of spiral CT with intravenous bolus contrast administration, the hepatic veins and portal venous system can be well delineated, and any tumor involvement can be adequately assessed. The American Association for the Study of Liver Diseases has published criteria for the noninvasive diagnosis of HCC. In nodules less than 2 cm in diameter in cirrhotic livers, the diagnosis of HCC can be made without biopsy of the lesion if two coincidental dynamic imaging studies (e.g., CT/MRI) reveal arterial-phase hypervascularity followed by wash-out in the portal venous phase.³²³ The fibrolamellar variant is notable as a hypodense, single or multilobed mass on CT that tends to be hypervascular as well as sometimes showing a central scar.³²⁴ This appearance could easily be confused with FNH, and care must be taken to distinguish between these two lesions.

Histology

HCC can vary in size from 2–25 cm, and the surrounding liver can exhibit either micro- or macronodular cirrhosis in up to 60% of cases (Figs 67-20 and 67-21).¹ Microscopically, trabeculae that are two to ten cell layers in thickness are seen with the larger trabeculae sometimes displaying central necrosis. The individual cells are usually larger than normal hepatocytes, with nuclear hypochromasia and frequent and bizarre mitosis (Fig. 67-22). Vascular invasion may be prominent. Tumors less than 2 cm generally are well differentiated. Over time, as the tumor grows, the original tumor cells are replaced by poorly differentiated cell clones.³²⁵ Moreover, as the tumor enlarges, its blood supply becomes more dependent on newly formed arterial vessels and less dependent on the portal circulation. This imbalance between the hepatic arterial and portal venous supply leads to the hypervascular pattern that is the radiologic hallmark for HCC.

In the fibrolamellar variant, the hepatocytes are large, deeply eosinophilic, and embedded within a lamellar fibrosis. Clusters of cells are often separated by broad bands of laminated collagen.1,326 The presence of large amounts of fibrosis alone is not sufficient in itself for the diagnosis of fibrolamellar carcinoma.³²⁷

Treatment

The treatment of HCC for stages I and II is complete surgical resection followed by chemotherapy. A COG study in 2002 reported that seven of eight patients with stage I disease survived after adjuvant cisplatin-based chemotherapy.³²⁸ Moreover, it has been postulated that routine use of chemotherapy with cisplatin and doxorubicin may benefit children with completely resected HCC.^5,329

Unfortunately, primary resection is not always possible because either the tumor is bilobar or the tumor is associated with cirrhosis. Because of the cirrhosis, concern may exist that the hepatic resection might leave the patient with insufficient functioning parenchyma.

In one pediatric report of 49 children, resection was possible in only 10%. Only two patients lived for more than 2 years.³¹² If a complete, microscopically free, radical resection is possible, the prognosis can be good, with an 80–90% survival.³³⁰ Unfortunately, the overall cure rate for this tumor in children is a dismal 15%. In the adult population, 3-year survival rates between 34–57% have been reported.^331,332 Multiple studies have looked at prognostic factors that influence outcome and recurrence after resection for HCC. Multiple staging systems have been proposed based on multivariant analyses of various prognostic factors. Three factors that have been repeatedly associated with improved survival and decreased recurrence rates are small tumor size (<2 cm), the number of tumor nodules, and a histologic increase in tumor microvascular density. These findings are highly predictive of tumor relapse after resection.³³³ Unfortunately, it is rare to see patients initially with all three favorable variables. In most series, the tumors are usually larger than 5 cm in diameter at presentation.^331,334

An important variant that should be mentioned is the fibrolamellar type. Only in the 1980s did this variant become established as a histologic and clinically distinct entity.³³⁵ This lesion is characterized by relatively slow growth and occurs almost exclusively in a noncirrhotic liver.³²⁶ The fibrolamellar variant usually occurs in adolescents and young adults, with a peak incidence in the second decade of life.^336,337 It accounts for between 16–50% of HCC diagnosed in patients younger than 21 years of age.³³⁸ In contrast to conventional HCC, fibrolamellar carcinoma is not associated with risk factors such as cirrhosis or chronic hepatitis B infection.^339,340 However, an association does exist between FNH and the fibrolamellar variant.

Radiologically, the fibrolamellar variant is often hypodense on noncontrast CT and can show variable perfusion, including hypervascularity, on contrast CT. In addition, a central hypodense or hypervascular area can be seen that can mimic a central scar.³⁴¹ This can create confusion between the diagnosis of the fibrolamellar variant and FNH. MRI may be helpful in distinguishing between these two diagnoses.³⁴² The results after resection for fibrolamellar carcinoma in adults are very good, with 50% 5-year survivals. However, after apparent curative resections, recurrences or metastases can occur after very long disease-free intervals.^343,344 Unfortunately when the fibrolamellar variant was examined in children, there was no survival benefit to this diagnosis.²⁶²

Transplantation for Hepatocellular Carcinoma

Liver transplantation has been used as curative therapy for HCC.272,345 The early experience of liver transplantation in adults for HCC was discouraging.³⁴⁶ However, in a review of 344 patients who underwent liver transplantation for HCC (excluding the fibrolamellar type), three factors were associated with tumor-free survival: a unilobar tumor, a tumor smaller than 2 cm, and the absence of vascular invasion.³⁴⁷ Two different pretransplant selection criteria are currently being utilized in adults (Table 67-5).

The Milan criteria are widely recognized as excellent predictors of a low recurrence rate after transplantation.³⁴⁸ These criteria, however, have not been verified in the pediatric population, and their applicability in children is unclear.³⁴⁹ As HCC can be a rapidly growing tumor, it is common for the tumor to exceed these criteria by the time an organ becomes available and the patient is no longer a candidate for transplant. The University of California at San Francisco criteria are an attempt to allow an increased pretransplant tumor burden and still have a low post-transplant recurrence rate. Several studies have supported this hypothesis.^350,351

Two absolute contraindications to transplantation for HCC in children are extrahepatic spread and macroscopic vascular invasion.²⁷² The SIOPEL-1 study reported no long-term survivors among those who failed to respond to chemotherapy.³⁵² Therefore, the lack of response to preoperative chemotherapy is a relative contraindication to transplantation. Despite these possible limitations, liver transplantation in children for HCC has a very good five-year survival rate between 63–89%.^272,353 Both adult and child patients are given additional points in the UNOS matching system so they can be transplanted before the tumor progresses.

Interestingly, in contrast to patients with hepatoblastoma, several studies have shown that liver transplantation is an appropriate salvage procedure for patients with HCC who experience a recurrence after a resection. Their post-transplant survival is comparable to that of patients who underwent primary transplantation for HCC.354,355

Postresection chemotherapy has been uniformly ineffective in preventing or treating recurrences in the Pediatric Oncology Group (POG), SIOPEL, and German studies.328,352,356,357 New chemotherapeutic approaches are needed for this tumor, and currently studies are planned that will combine chemotherapeutic agents with antiangiogenic agents. However, in two small series, chemotherapy was given to children with unresectable HCC before transplant. Eighty per cent of these children had a dramatic decrease in their tumor size.^297,358 At the time of transplant, all tumors still had viable cells but only one patient after transplant had a recurrence and subsequently died.

Patients who are not surgical or transplant candidates, patients who demonstrate recurrences, or patients who are on the transplant list and their tumors have grown to the point that they exceed the Milan criteria can potentially benefit from several nonsurgical strategies, including percutaneous ethanol injection, radiofrequency ablation, or chemoembolization of the tumor.³⁵⁹ All of these therapies have proved efficacious in decreasing or eradicating localized tumors, treating recurrent tumors, or shrinking tumors so that the patient again falls within the transplant criteria.³⁶⁰ These therapies also improved survival with this tumor, but unfortunately, none has been proved to be curative.²⁹⁹

A catastrophic presentation of HCC is spontaneous rupture. These patients present with acute right upper quadrant pain and hypovolemic shock. The diagnosis can be made with ultrasound or abdominal CT. In the hemodynamically stable patient, the treatment is conservative with correction of volume status and correction of any coagulopathy. Then a careful assessment of the tumor needs to be made with the goal of primary resection of the tumor. If the patient is unstable, then transarterial embolization of the tumor should be performed to control the hemorrhage. After the patient’s condition has stabilized, he or she needs to be evaluated for a resection.³⁶¹

The outcome for patients with HCC, regardless of the treatment modality, is still not as good as the outcome for hepatoblastoma. Further improvements in survival for HCC will come from advances in chemotherapy regimens that will prevent tumor recurrences.

Incidence and Clinical Presentation

Even though rhabdomyosarcoma is the most common sarcoma in children, it accounts for only 1% of all liver tumors and only 0.8% of all rhabdomyosarcomas in children.1,362 Hepatobiliary rhabdomyosarcoma tends to be a disease of the young, with a median age of 3 years. It is rarely seen in children older than 15 years.^363,364 This tumor most commonly arises in the intrahepatic biliary system and then extends into the liver parenchyma. It also has been reported to arise from a variety of other sites, including an intrahepatic cyst, the gallbladder, the cystic duct, the ampulla of Vater, a choledochal cyst, and the hepatic parenchyma itself.^363–369

As it arises most commonly from the bile ducts, the most common presenting symptom is jaundice. The median tumor diameter at diagnosis is 8 cm. Therefore an abdominal mass is a common finding.³⁶²

Laboratory Findings and Differential Diagnosis

As jaundice is a common presenting symptom, elevated direct bilirubin, alkaline phosphatase, and γ-glutamyltransferase (GGT) levels are common. The differential diagnosis for an intraductal lesion in a child includes either an inflammatory pseudotumor or a cholangiocarcinoma, but these are extraordinarily rare.³⁷⁰ If the rhabdomyosarcoma is a predominantly hepatic mass with minimal bile duct involvement, then the differential diagnosis would be more dependent on the patient’s age, as noted in previous sections.

The pathology of the intraductal lesions is similar to that of rhabdomyosarcoma at extrabiliary sites. The intraductal tumor is usually either the botryoid or embryonal subtype, unless the lesion involves predominantly the hepatic parenchyma, in which the alveolar subtype predominates.³⁷¹

Imaging

Multiple imaging modalities have been useful for diagnosis. Ultrasound typically reveals biliary dilatation and possibly a mass in the biliary system. Larger lesions may have cystic areas within them, possibly reflecting areas of partial tumor necrosis (Fig. 67-23).²¹⁷ CT will often show an intraductal mass in association with areas of low attenuation within the tumor. MRI may have an advantage over CT in that not only can it show the anatomic source and location of the mass but, with the advent of MR cholangiography, also can evaluate the bile ducts by demonstrating biliary dilatation and intraductal irregularity.³⁷² Percutaneous transhepatic cholangiography (PTC) also can be useful in patients who have a dilated biliary system. PTC can demonstrate multiple filling defects that correspond to the intraductal tumor.³⁷³ PTC also has the advantage of providing external drainage of the biliary system in those patients with obstructive jaundice.

Treatment and Prognosis

The best treatment for biliary rhabdomyosarcoma is a multidisciplinary approach using operation, chemotherapy, and, potentially, radiation therapy. Unfortunately, resection alone is not usually possible because of spread of the tumor into the liver parenchyma or direct local extension into the duodenum, stomach, or pancreas. It is common to find lymphatic spread at the initial operation. Because of these problems, adequate resection is usually possible in only 20–40% of the patients.362–364 In patients in whom primary resection is not possible, the initial approach should be biopsy and lymph node sampling, followed by standard rhabdomyosarcoma chemotherapy protocols and a second-look procedure. In a study of biliary rhabdomyosarcoma that used this multimodality approach, four of ten children remained disease free after a mean of four years.³⁶²