Congenital hemangiomas (CH) are rare, develop in utero (allowing prenatal detection) and are fully formed at birth. Typically, these lesions are not clinically symptomatic, but giant fetal hepatic hemangiomas– defined as those larger than 4 cm in diameter– can present with complications in-utero, including high-output CHF, nonimmune hydrops, severe anemia, consumptive thrombocytopenic coagulopathy, or tumor rupture. More commonly, CH are focal, asymptomatic, and less frequently associated with cutaneous hemangiomas. CH are classified by the clinical pattern of postnatal involution: rapid involution by 24 months of age (RICH), partially involuting (PICH), or noninvoluting (NICH).

In patients with a congenital hemangioma, a complete blood count, coagulation parameters, fibrinogen level, and liver function tests should be obtained since a minority of patients demonstrate anemia, thrombocytopenia, and hypofibrinogenemia related to intralesional thrombosis. Anemia and thrombocytopenia are typically self-limited and resolve. As discussed above, AFP should also be quantified. A static or rising AFP would not be indicative of hemangioma.

Doppler ultrasound of the liver is the usual radiologic study performed at presentation and is often sufficient to make the diagnosis. CHs demonstrate high velocity flow through arterial feeding vessels that may directly shunt to the hepatic veins. If shunting is noted and/or the patient presents with CHF, the patient should also undergo an echocardiogram. These lesions may also demonstrate central hypodensity if hemorrhage and thrombosis occur. Both RICH and NICH demonstrate calcification and cystic change, but intratumoral shunting is more likely to appear in a NICH on ultrasound. As mentioned, the diagnosis of congenital hemangioma can be made prenatally on a maternal ultrasound. These patients should then undergo fetal MRI as well as fetal echocardiography to rule out high output cardiac failure. Focal infantile hemangiomas may appear similar to CHH on ultrasound, but they typically do not demonstrate calcification.

In the rare case that the history and ultrasound are not definitive, an MRI with a gadolinium-based contrast agent should be performed. Focal lesions on MRI are well-defined and hypointense to the liver on T1 images and hyperintense on T2-weighted images. These lesions demonstrate rapid filling but slow excretion of contrast as well as peripheral enhancement with variable central enhancement (related to the amount of hemorrhage or thrombosis present). On delayed imaging, hemangiomas often become hypointense compared to the surrounding parenchyma after a hepatocyte-specific contrast agent such as Eovist.

Given the diagnostic accuracy of clinical presentation and imaging, biopsy to rule out hemangioma is rare. A positive Glut-1 immunohistochemical stain is diagnostic of infantile hepatic hemangiomas (IHH), whereas CHH (such as RICH or NICH) do not express this marker. ^, Microscopically, the histologic pattern of IHH has been divided into Type 1 and Type 2 lesions. In Type 2 lesions (20% of cases), the endothelial cells are pleomorphic, larger, and more hyperchromatic (characteristic of a rapidly proliferating process) than those seen in Type 1 tumors.

A management algorithm for HH has been defined ( Fig. 64.3 ). ^, All asymptomatic lesions should be monitored with US until resolution. Focal HH are usually RICH and undergo rapid involution over the first 12–14 months of life, decreasing in size to approximately 20% of their original size. Calcification of the residual mass typically occurs and can be expected to remain stable throughout life. Serial ultrasounds should be performed until the lesion is stable in size and vascular distribution on two consecutive studies, or until at least the patient is 1 year of age. Noninvoluting focal hemangiomas will require ablation either via embolization or surgical resection.

Algorithm for management of pediatric hepatic hemangioma. TFT, Thyroid function tests; US, ultrasound.

Infantile hepatic hemangiomas are the most common liver tumors in the first year of life, and most are multifocal (discrete and nodular) or diffuse (replacing normal hepatic parenchyma). Almost all children with multifocal hemangiomas are initially seen before the age of 6 months, with most presenting in the first 2 months of life. However, they can appear up to 6–12 months of age. ^, They are not present at birth but become apparent within days to a few weeks after birth. Like their cutaneous counterpart, the progression of IHH is divided into three stages: (1) proliferation characterized by rapid growth that lasts about 9–12 months, (2) early involution that can take anywhere from 5 to 7 years, (3) late involution, in which the hemangioma is permanently replaced by fibrofatty tissue.

At-risk populations include premature infants, females, and Caucasians. A significant incidence of placental abnormalities has recently been reported in infants with very low birth weight (<1500 g) who present with infantile hemangiomas. IHH can occur with other congenital anomalies such as renal agenesis, diaphragmatic hernia, hemihypertrophy, and Cornelia de Lange, but these associations are sporadic. Extrahepatic hemangiomas can also occur at other sites, including lung (10%), pancreas, lymph nodes, and bone. ^,

As many as 25% of infants who present with multiple cutaneous hemangiomas (more than five) also have a hepatic hemangioma, and therefore they should be screened with a Doppler liver ultrasound. One study demonstrated that early diagnosis allowed for mitigation of complications related to the multifocal hepatic hemangiomas through early intervention.

Most multifocal and diffuse hemangiomas are either asymptomatic or present only as an abdominal mass or with abdominal distention. However, more dramatic presentations may occur including hepatomegaly leading to compartment syndrome, high-output heart failure, respiratory distress, hypothyroidism, and anemia. Cardiac symptoms and hepatomegaly can progress as systemic arteriovenous shunting increases since multifocal hemangiomas can proliferate after birth. Severe hypothyroidism can result from increased degradation of thyroid hormones (acquired consumptive hypothyroidism) by type III iodothyronine deiodinase ; it is nearly universal with diffuse disease and less common in multifocal IHH. The hypothyroidism can be severe enough to cause low-output cardiac failure or significant developmental delay. Correction can require very large doses of thyroid hormone replacement, and the hypothyroidism resolves with the involution of the IHH.

Other symptoms in patients with IHH can include jaundice, failure to thrive, respiratory difficulties, or poor feeding. In patients with IHH, the hepatic transaminase levels and occasionally the α-fetoprotein (AFP) level can be elevated. The source of the AFP is not the tumor but rather the hepatocytes that are surrounding the IHH. ^, When there is a significant elevation of the AFP level, other hepatic malignancies must be ruled out.

Further evaluation should include complete blood count, coagulation studies, fibrinogen level, liver function tests, thyroid studies, and AFP. Multifocal HHs appear on ultrasound as multiple, well defined hypoechoic masses. Contrast-enhanced ultrasound may also discriminate between types of HHs, as one study demonstrated that CHH showed hyperenhancement in the portal venous phase while IHH showed isoenhancement. In late phase, IHH seemed to washout contrast material while CHH did not.

The ultrasound appearance may vary depending on the size of the hemangioma(s), with smaller, focal lesions appearing homogeneous while larger hemangiomas may demonstrate calcifications, cysts, and areas of fibrosis. IHH can closely resemble other primary liver lesions such as hypervascular HB, focal nodular hyperplasia (FNH), and mesenchymal hamartoma (MH). If the clinical presentation is unclear and/or the ultrasound findings are indeterminate, MRI with hepatocyte specific contrast agent administration is recommended ( Fig. 64.4 ).

Infantile hepatic hemangioma: diffuse form. (A) An MRI in the arterial phase showing rim enhancement of the hemangiomas after injection with gadoxetate disodium (Eovist). (B) The T2-weighted image showing the same liver that is filled with hemangiomas.

Infants with cardiac symptoms should also undergo echocardiography. In the (rare) cases where multifocal or diffuse hemangiomas are biopsied, they will stain Glut-1 positive on immunohistochemistry.

Therapy for IHH depends on the severity and type of presenting symptoms and these correlate with the size of the mass(es). A few asymptomatic multifocal lesions can be monitored, and no specific therapy is instituted until symptoms develop. However, some reports suggest that multifocal IHH and diffuse IHH are part of a continuous spectrum. If there is evidence that a multifocal IHH may be progressing, treatment with propranolol should be initiated to try to prevent progression to the diffuse type, even though the patient is asymptomatic. ^, Patients who present with high output cardiac failure, very large or enlarging masses, hypothyroidism, or with a diffuse subtype should also be started on propranolol. This drug has become the first line treatment for infantile hemangiomas, regardless of their anatomic location. This meta-analysis determined that the efficacy of propranolol was almost 10 times greater than other therapies in IHH. In these complicated presentations, propranolol reduces the size of infantile hemangiomas thereby mitigating the symptoms. Dosing is typically 1–3 mg/kg/day, and treatment typically lasts several months (it can be stopped when the lesion is fully involuted) or continued until at least 1 year of age, when the propranolol is weaned. ^, Complications of propranolol treatment are unusual, but they can include hypotension, hypoglycemia, bronchial reactivity, and bradycardia. Prior to starting therapy, an echocardiogram and an electrocardiogram should be obtained. In some cases, infantile hemangiomas are refractory to beta-blockade or severe enough that a combination of propranolol and steroids is used. Sirolimus has also proven effective, both in conjunction with steroids, or as monotherapy in the treatment of diffuse hemangioma.

As mentioned above, the medical sequelae of symptomatic hemangiomas must be addressed as well. Hypothyroidism can not only precipitate long term neurologic consequences but may contribute to concurrent heart failure as well. CHF should be medically managed while awaiting regression of hemangiomas. If abdominal compartment syndrome occurs, decompressive laparotomy may become necessary.

Endovascular embolization is often the next step when medical therapy is not effective in controlling symptoms, and it is important that both the arterial and portal vascular supply to the IHH are occluded as distally as possible to decrease recurrence. ^, Embolization should be considered early in the treatment course in infants who are in significant cardiac failure. After successful embolization, a rapid improvement in the clinical course usually occurs within 5 days, despite the absence of any change in the size of the hemangioma. Embolization can still be used as a temporizing measure in conjunction with medical therapy if the response is less pronounced.

Resection can be considered if the hemangioma is confined to a single lobe, but with the efficacy of propranolol, surgery has become rare. Liver transplantation has been used successfully for severe CHF and/or unremitting coagulopathy in whom other modes of treatment have failed. However, infants who experience rapid clinical deterioration secondary to CHF are very unstable and have a high mortality after liver transplantation. Careful consideration needs to be given to these children’s transplant candidacy, since many patients may be too ill to survive a transplant.

Malignant transformation of an IHH to an angiosarcoma is rare but has been reported in older children, ^, and 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. In addition, the possibility of malignant transformation should be considered in a multifocal or diffuse IHH patient who is unresponsive to treatment.

MH can be seen on prenatal ultrasound. Unfortunately, the prognosis for these antenatally diagnosed neonates is often poor, with a reported mortality rate of about 30% in one study. Thus, in some rare settings it may be best to deliver these fetuses via cesarean section before fetal hydrops develops. Intrauterine aspiration of monocystic MHs has been performed to provide decompression until the infant can be delivered and definitive treatment initiated. However, this may not provide the same temporizing benefit in multicystic lesions since the individual cysts do not communicate with one another.

Postnatally these lesions can have a varying presentation. A recent review of the literature ( n = 95 cases) determined that median age of diagnosis was 1 year, with most presenting with either abdominal distension (80%) or an enlarging mass palpable on physical exam. Occasionally, the associated symptoms of nausea and vomiting can occur secondary to the compression of the stomach and intestine by the expanding mass. Median tumor size in this series was 12 cm, and over half reflected the predilection for the right hepatic lobe only. High-output cardiac failure, pulmonary hypertension, and disseminated intravascular coagulopathy can occur with highly vascular MHs. Respiratory distress can also result secondary to the large mass.

Laboratory studies, including liver function studies, are almost always normal. AFP was elevated in about a quarter of patients in the above series. As a cautionary note, patients have been treated with chemotherapy for HB until a tumor biopsy was performed and an MH found to be the true pathology.

MH usually has both cystic and solid components. On US, the cystic portions will be anechoic (fluid) or have low level echoes indicating gelatinous material. Occasionally the mass is pedunculated ( Fig. 64.5 ). The presence of calcifications within a tumor does not exclude an MH, although they are not common. On MRI, the cystic components will be T2 hyperintense with variable T1 signal intensity depending on protein content. The solid components will be hypointense on T1 and T2 sequences. MR angiography has proven useful in both diagnosis and planning of resection.

This young child presented with a palpable right upper abdominal mass. (A) CT scan shows an anechoic mass ( asterisk ) in the periphery of the liver. (B) At operation, the mass ( asterisk ) was found to be pedunculated and emanating from the right lobe of the liver. This hamartoma was easily removed.

MH typically are large, well-circumscribed tumors with multiple cysts measuring from a few millimeters to as much as 15 cm in diameter. These cysts are filled with either serous or viscous fluid separated by loose fibrous and myxoid tissue ( Fig. 64.6 ). The surrounding tissue is yellow-tan to brown and is loose to moderately dense.

Cut surface of a mesenchymal hamartoma showing multiple cysts.

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. Elongated or tortuous bile ducts surrounded by connective tissue are unevenly distributed throughout the mesenchyme. Typically, hepatocytes appear normal and are not a predominant part of the pathologic process. The bile ducts in the periphery of the lesion seem to be undergoing active proliferation. Despite most of these tumors being localized, there have been reports of multifocality, which may account for the occasional recurrences that are seen after resection.

Various management strategies have been used for these lesions, from enucleation for small lesions to marsupialization into the peritoneal cavity for larger lesions (but with a significant recurrence rate). Spontaneous involution of these lesions has been reported but is unusual. However, complete excision of the lesion with a margin of normal liver is curative and is the recommended therapy because of the potential for a coexistent undifferentiated embryonal sarcoma. ^, One group reported the use of US-guided, intraoperative aspiration for massive or multiple cysts, to substantially reduce the size of the mass and facilitate resection. Liver transplantation may even be required for large, bilobar lesions.

There is strong evidence that an UESL can develop within a preexisting MH, either synchronously or metachronously. The evidence for a direct link between an MH and UESL 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 MH and an UESL. ^,

FNH accounts for about 2% of the hepatic tumors in school age children and adolescents and is the second most common benign hepatic lesion after hemangioma. Median age at presentation is 8.7 years, and there is a 2:1 female:male predominance. Unlike hepatocellular adenoma (HCA), oral contraceptive/female sex hormone use do not appear to influence development or growth of FNH. ^,

FNH is a regenerative nodule of hyperplastic, polyclonal hepatocytes surrounding the classically described central scar containing abnormal arteries and bile ducts. ^, It may result from hepatic hyperplasia secondary to anomalous vascularization including thrombosis, vascular hyperplasia, or elevated hepatic sinusoidal pressure. Classical FNH is characterized by transforming growth factor beta activation in the central scar while the periphery demonstrates activation of the Wnt-beta-catenin pathway. These lesions occur in otherwise normal livers.

In contrast, “ FNH-like lesions ” can occur in (1) children with congenital portosystemic shunts (CPSS) and (2) long-term survivors of pediatric malignancy, including Wilms’ tumor and neuroblastoma, who received chemotherapy and/or radiation and those who have undergone hematopoietic stem cell transplant. ^, These FNH appear pathologically similar but lack beta catenin pathway activation. In the case of patients with CPSS, intestinal blood is diverted to the systemic circulation, and the liver is left with arterial flow through an anomalous artery, which results in hepatocyte injury. In oncology and bone-marrow transplant patients, high dose alkylating agents, hepatic radiotherapy, or venoocclusive disease may disrupt the normal hepatic circulation and lead to hepatic hyperplasia. Retrospective series demonstrated 11%–28% of pediatric FNH cases occurred in children with previous malignancy. ^, Awareness of these associations may impact the approach to diagnosis and therapy for this subset of patients when FNH is part of the differential diagnosis.

FNH are typically asymptomatic at diagnosis. About half did not have a history of prior malignancy in one series. Of those with a malignancy history, 80% were asymptomatic at time of diagnosis, likely due to routine posttherapy imaging in this group. The most common symptom is abdominal pain but decreased appetite, abdominal mass, weight loss, or a combination of symptoms can be present. Hepatomegaly may occur, but liver enzymes are often normal.

The diagnosis of FNH may be made on the basis of imaging alone. As with other liver lesions, US is typically the initial radiologic study, but results are typically nonspecific. On CT, FNH appears as a well-circumscribed, homogeneously hyperenhancing lesion distinct from the surrounding parenchyma when IV contrast is administered. Classically, a central scar is described which represents retention of contrast in the myxoid component of the tumor, but this central scar is only seen in 50%–70% of lesions ( Fig. 64.7A ). ^, Historically, single-photon emission radionuclide scans with radiolabeled Technetium-99m sulfur colloid were used to distinguish between FNH and a hepatic adenoma. FNH lesions take up radiotracer because the Kupffer cells are present in FNH but not in hepatic adenomas. MRI enhanced with a hepatocyte-specific agent demonstrates uptake of this contrast with abnormal biliary excretion and retention on delayed phase such that FNH appears somewhat hyperintense compared to the surrounding parenchyma ( Fig. 64.7B ). Other MR characteristics of FNH include iso- or hypointensity on T1 weighted images and iso- or slightly hyperintensity on T2, intense and transient enhancement in the arterial phase without washout, and a central stellate area that is hypointense on T1 and very hyperintense on T2.

CT scan after intravenous administration of contrast agent (A) and MRI with hepatocyte phase contrast (Eovist, T1, fat saturated) (B) show an early enhancing lesion in the right lobe with a hypodense central scar ( arrows ) consistent with focal nodular hyperplasia.

The most common histological features of pediatric FNH include central scar with fibrous septa, dystrophic vessels and unpaired arteries, lymphocytic septal inflammation, and biliary ductular reaction. There are significant histologic differences between pediatric and adult FNH: larger size at time of resection, absence of dystrophic vessels which were present in all of the adult specimens, absence of sinusoidal dilation, and pseudoacini formation.

A diagnostic algorithm has been proposed that considers patient age and the presence of liver disease as well as increasingly sensitive radiologic findings, with the aim of minimizing the need for invasive tissue biopsy ^, ( Fig. 64.8 ). This schema proposes that if MRI indicates FNH, biopsy can be avoided. This population of patients includes children of all ages with a history of a condition that involves abnormal liver circulation, those with a history of nonliver cancer treated with chemotherapy, and adolescent females. All other patients are recommended to undergo biopsy to confirm the diagnosis. These investigators also highlight children under 6 years of age as a population that deserves more nuanced consideration, given the risk of invasive procedures and general anesthesia. However, there is limited data to suggest that if children in this age group have no underlying liver disease and no history of malignancy, observation without tissue diagnosis may be possible if imaging is strongly suggestive of FNH.

Proposed diagnostic and surveillance algorithm for focal nodular hyperplasia. ∗MRI is the preferred axial imaging modality for the evaluation of FNH given the specificity of the test, recognizing the need for general anesthesia in young patients. AFP, Alpha fetoprotein; LFT, liver function tests; US, ultrasound.

Adapted from Ma IT, et al. Focal nodular hyperplasia in children: an institutional experience with review of the literature. J Pediatr Surg. 2005;50:382–87.

Surgical resection should be considered when the patient is symptomatic, the lesion increases in size, or if malignancy cannot be eliminated by imaging and/or biopsy. Up to 60%–80% of children undergo liver resection for these reasons. Since an FNH is a benign lesion, segmental, subsegmental, or nonanatomic resections are appropriate to save as much liver parenchyma as possible. Surgical excision can be performed safely with minimal morbidity. After surgery, most patients become asymptomatic and their postoperative quality of life substantially improves. If the FNH is in an area difficult to resect, arterial embolization with Lipiodol and absorbable gelatin foam (Gelfoam), iodinated oil and polyvinyl alcohol, or bleomycin and iodinated oil can result in significant regression or complete disappearance of the FNH.

HCA is a very rare hepatic tumor in children, comprising only about 4% of all solid liver tumors. HCA is divided into four distinct histopathologic subtypes: inflammatory (40%–50%, IHCA), HNF1A-mutated (30%–40%, H-HCA), β-catenin activated (10%–15%, β-HCA), and unclassified (10%–25%, UHCA) ( Table 64.5 ). Patients with IHCA have both serum and intralesional markers of inflammation, including C-reactive protein. These patients tend to be overweight. The H-HCA subtype is characterized by the downregulation of LFABP (liver fatty acid binding protein), and this phenotype rarely leads to malignant degeneration. However, it has the highest risk of spontaneous bleeding. Subtype β-HCA has an activating mutation of β-catenin that resists downregulation by the APC gene and this plays a significant role in the progression of an HCA to HCC. This subtype also has an overproduction of glutamine synthase, which can be used as a sensitive biomarker for this type of HCA. UHCA subtype does not have a particular genetic mutation and is instead classified by histologic criteria that are unusual in the other subtypes.

HCAs were extremely rare prior to 1960, which corresponds to the year in which oral contraceptives were first introduced. 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 5–7 years carries a 5-fold increased risk and use for 9 or more years has a 25-fold increased risk. ^,

HCAs in children more often occur in abnormal livers associated with such disorders as galactosemia, glycogen storage disease (GSD), hypothyroidism, polycythemia, diabetes, Fanconi anemia, polycystic ovary syndrome, and the use of anabolic steroids ( Table 64.6 ). There also are an increasing number of reports of IHCA in patients with obesity and metabolic syndrome.

HCAs are a significant complication in patients with Type 1A GSD, from their teenage years into adulthood. ^, The estimated prevalence of adenomas in these patients is close to 50%. The pathogenesis of adenoma development is poorly understood in this group but may be related in part to the tightness of the metabolic control. These adenomas are often multiple rather than solitary lesions. Unfortunately, in this patient population, Hepatocellular carcinoma (HCC) can occur in association with the HCA. The youngest reported patient with HCC with a history of GSD was 6 years of age, and HCC has been found to develop in up to 20% of GSD patients. ^, Direct evidence for malignant transformation of an HCA into a carcinoma has been confirmed with the reporting of an HCC within an HCA in patients with GSD. Abnormalities in chromosome 6 also have been identified in Type 1A GSD adenomas, and similar chromosome 6 alterations have been identified in HCCs, suggesting a possible genetic link between these two diagnoses.

Adenomatosis (the occurrence of more than 10 simultaneous adenomas) is a rare disorder with a heterogenous clinical phenotype and natural history. ^, There is a massive form, characterized by multiple nodules measuring 2–10 cm, and a multifocal form, in which most lesions are smaller than 1 cm, with only a few larger than 4 cm. Oral contraceptive use has been seen in about half of the female patients. Interestingly, diabetes, GSD, and hepatic steatosis have been noted in these patients, but it is not clear if there is a causative relation.

In children, HCAs are often asymptomatic and are discovered during evaluation for other problems. Intralesional hemorrhage with possible intraabdominal rupture and acute volume depletion has an overall incidence of about 15%–18%. In general, the larger the lesion the greater the chance of hemorrhage, with HCAs larger than 5 cm being at highest risk. Malignant transformation is a rare (4%) complication that has been reported in HCAs. Risk factors for malignant degeneration include male sex, size greater than 5 cm, and the β-HCA and IHCA subtypes. When these conditions are present, resection of the lesion must be considered.

Hepatic adenomas are solitary lesions in most cases, but occasionally two to three adenomas can be seen in one patient. They have a variable ultrasound appearance: 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.

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. 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.

HCAs are MRI hypointense to hyperintense on T1-weighted images, often due to hemorrhage. On T2 images, the lesions are isointense to slightly hyperintense and gadolinium enhancement is maximal during the arterial phase with rapid fading ( Fig. 64.9 ). Subtypes of HCAs also can demonstrate specific findings on MRI, making this modality the gold standard for imaging. IHCAs are hyperintense in the periphery on T2 images and demonstrate significant enhancement during the arterial phase, which continues through the portal venous and delayed phases. In contrast, β-HCAs demonstrate similar arterial enhancement but washout on subsequent phases.

Hepatic adenoma seen on MRI with T2 weighting with Eovist contrast. There is a 4.1-cm mass located in segment 2 of the left hepatic lobe (A, white arrow ) with characteristic portal venous phase washout resulting in a hypointense mass (B).

The primary differential diagnosis for HCA is an FNH. MRI with hepatobiliary contrast can be helpful in making this distinction. If the lesion is isointense to hyperintense, the differential is FNH or, rarely, HCC. If the lesion is hypointense, that is consistent with HCA. This differential can be made with a sensitivity of 91%–100% and a specificity of 87%–100% (rarely an IHCA can be isointense). Finally, HCAs typically lack the central scar characteristic of FNH.

HCAs 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, accounting for their hypervascular nature. 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 HCA from FNH. Lipid accumulation is responsible for the characteristic yellow appearance on the cut surface.

The exact reason for their development is unclear. Mutations in the Wnt/β-catenin pathway have been found in patients with an HCA. This pathway mutation has been identified in many hepatocellular neoplasms, although its direct contribution to the development of an HCA 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.

The treatment approach depends on a variety of factors including preexisting medical diagnosis, symptoms, size and number of adenomas, and their subtype. In patients who are receiving oral contraceptives or androgenic steroid therapy, the first step should be withdrawal of these medications. There are multiple reports that document regression of an adenoma after the withdrawal of hormonal treatments. ^, However, this response is not universal. Biopsy of an HCA should be done if it is not possible to differentiate between it and an FNH by imaging techniques, or if there is the concern that there could be a β-catenin mutation.

Considering the above factors, surgical or endoarterial therapy is preferred for HCAs >5 cm, as well as I-HCAs, given higher risk of bleeding and rupture. If the HCA is <5 cm, it can be monitored annually with MRI, but US is an option with reduced cost and ease to obtain. Duration of follow up is unclear; however, one study demonstrated that 90% of patients with a single HCA and 71% with multiple HCAs demonstrated stability or regression with a median follow up of 5 years. If the HCA is greater than 5 cm, surgical excision or hepatic artery embolization of the dominant feeding vessel is recommended. Additionally, male patients may require a more aggressive approach as there is a higher risk of malignant transformation.

For patients with ruptured HCAs who are hemodynamically stable, monitoring and hemodynamic support is the initial treatment. Once the hemorrhage has resolved and the patient has recovered, elective resection can be performed. In patients who continue to actively bleed, selective embolization should be performed. This not only stops the hemorrhage but also can decrease the size of the adenoma. After resolution of the hemorrhage, resection is indicated. This stepwise management plan both decreases the size of the lesion and allows for a more limited hepatic resection under controlled conditions.

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 HCC. Liver transplantation not only corrects the potential hemorrhagic problem, but also removes the potential for cancer. Similarly, other conditions may precipitate advanced chronic liver disease which results in adenoma formation. These lesions should be biopsied to determine whether they are β-HCA as this is an indication for liver transplantation as well.

Most HBs present before the age of 3 years, with a median age at diagnosis of 18 months. ^, HBs can arise in utero (congenital) with an estimated incidence of 4% of the HBs. Conversely, only 3% of cases are found in children older than 15 years of age. There is a male predominance of 1.7:1. Based upon the U.S. Surveillance, Epidemiology, and End Results (SEER) database, the rate of HB from 2002 to 2008 was 10.5 cases per million in children younger than one year old and 5.2 cases per million in those 1–4 years old. ^,

HBs are associated with a variety of clinical conditions, syndromes, and malformations ( Box 64.1 ). Beckwith–Wiedemann syndrome (BWS) is an overgrowth syndrome resulting in gigantism, macroglossia, omphalocele, hemihypertrophy, and neonatal hypoglycemia. Though BWS is associated with Wilms tumor, it is also linked to other tumors such as HBs, gonadoblastomas, and adrenal carcinomas. For children with BWS under 5 years of age, the rate of HB is elevated, and some protocols advocate serial AFP levels and an abdominal US every 3 months until the age of 4 years. An association between HB and the APC gene was noted in patients with familial adenomatous polyposis (FAP) and Gardner syndrome. Though HB occurs rarely in patients with FAP, its incidence in children under 5 years of age was 847 times higher than that in the general population of the same age in one report. Chromosomal abnormalities also have been documented in patients with HB. The most common defects are trisomy of chromosomes 2, 8, 18, or 20, individually or in combination.

Epidemiologic studies have revealed several other factors associated with an increased risk for the development of neonatal HB, including birth weight less than 1000 g, maternal age younger than 20 years, use of infertility treatment, maternal smoking, and a higher prepregnancy body mass index (BMI of 25–29). In the Japanese Children’s Cancer Registry (JCCR), it was noted that HB accounted for 58% of the malignancies diagnosed in children with extremely low birth weight. The tumors that occurred in this group grew rapidly and had an unfavorable biologic behavior.

HB is thought to arise from unregulated proliferation of primary hepatoblasts and hepatic stem cells or human fetal liver multipotent progenitor cells. ^, There is a spectrum of histologic subtypes in HBs because they arise from progenitor cells. Wnt pathway mutations are found in 90% of tumors. The Wnt/β-catenin signaling plays a critical role in embryonic development, including cell proliferation, migration, and fate determination, as well as body axis determination and organ system development. Most mutations associated with HB are the result of deletions or missense point mutations in exon 3 of CTNNB1 which changes the serine/threonine phosphorylation site such that β-catenin cannot be phosphorylated and marked for degradation. It has been demonstrated that large deletions of exon 3 of CTNNB1 are associated with fetal histology HB, whereas those with point mutations in exon 3 of CTNNB1 are more frequent in embryonal and small cell undifferentiated subtypes.

The neoplastic transformation that occurs in HB is thought to occur at multiple points in the hepatocyte differentiation pathway, thereby leading to a diversity of histologic patterns and clinical behaviors. Individual HB tumors are typically made up of multiple cell types and histologic patterns ( Fig. 64.10 ). Well-differentiated fetal histology is an established histologic category with the appearance of fetal hepatocytes with low levels of mitotic activity. It accounts for 7% of all HB tumors, and is associated with better outcomes, and those without multifocal or metastatic disease can be treated with resection alone. Intermediate-risk tumors demonstrate epithelial and mixed histology ( Fig. 64.11 ). In contrast, high-risk HB tumors most commonly demonstrate embryonal histology and demonstrate high-risk histologic features such as anaplasia, a macrotrabecular pattern, and cytologic features similar to those of HCC. The small cell undifferentiated histologic subtype was thought to be high-risk but results from the AHEP 0731 study found this not to be the case. Hepatocellular neoplasm–not otherwise specified is a tumor that occurs in older children and has the features of both HCC and HB, and is now recognized as a more aggressive subtype.

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