malignant.

Acute abdominal pain may be caused by bleeding

into the mass or into the peritoneum,2 particularly in hepato-
cellular adenomas, although this problem is rarely seen in
children. Children may present with congestive heart failure
(CHF) and thrombocytopenia, which is known as Kasabach-
Merritt syndrome when associated with a vascular anomaly
such as a liver hemangioma.3 Cutaneous hemangiomas are
seen in about half the children with a liver hemangioma,4,5
and the rapid enlargement of the liver with a diffuse liver
hemangioma can cause abdominal compartment syndrome
and respiratory distress.4 CHF without significant throm-
bocytopenia can also be seen with liver arteriovenous
malformation (AVM)6 or mesenchymal hamartoma.7 Fetal
hydrops has been identified by prenatal ultrasonography
in some fetuses with liver hemangiomas8 or mesenchymal
hamartoma.9

Diagnosis
------------------------------------------------------------------------------------------------------------------------------------------------

LABORATORY TESTS
Serum alpha fetoprotein (AFP) is present in very high con-
CHAPTER 32 centrations at birth (48,000  35,000 ng/mL) and rapidly
declines to adult levels of less than 10 ng/mL by 8 months of
age (Table 32-1).10 Thus in infants younger than 8 months,

Nonmalignant
AFP levels must be interpreted in the context of this dramatic
change. Markedly elevated AFP levels in a child with a liver
mass almost certainly means that the mass is malignant,

Tumors of the Liver

although milder elevation may be encountered with some
benign lesions, such as mesenchymal hamartoma11 or tera-
toma.12 As mentioned previously, significant thrombocytopenia
associated with a liver mass is usually part of the Kasabach-
Wolfgang Stehr and Philip C. Guzzetta, Jr. Merritt syndrome resulting from a liver hemangioma. Hypothy-
roidism may also occur in multiple or diffuse forms of liver
hemangioma13; thyroid function tests should be done routinely
in these children, because hypothyroidism significantly impacts
their management.14
Primary liver tumors constitute less than 3% of tumors seen in
the pediatric population, and only one third of those tumors
IMAGING TECHNIQUES
are benign.1 Benign tumors may be epithelial (focal nodular
hyperplasia, hepatocellular adenoma), mesenchymal (hepatic The initial imaging study in a child presenting with an
hemangioma, mesenchymal hamartoma), or other (teratoma, abdominal mass should be a supine radiograph of the abdo-
inflammatory pseudotumor). Nonparasitic cysts, although not men, looking for calcifications within the mass. The next im-
technically neoplasms, are also discussed in this chapter. One aging study should be an abdominal ultrasonogram with
of the more interesting aspects of benign liver tumors in Doppler spectral analysis, followed by computed tomogra-
children is their predilection to occur in patients with other phy (CT) with intravenous contrast (Fig. 32-1).15 Magnetic
conditions, and this phenomenon will be discussed with each resonance imaging (MRI) may be indicated, depending on
tumor type. the sonogram and CT scan results, especially when surgical
resection is planned and more detailed information about the
vascular anatomy relative to the tumor is desired or in infants
Clinical Presentation with hemangiomas in whom another diagnosis is being con-
------------------------------------------------------------------------------------------------------------------------------------------------
sidered because the MRI appearance may be diagnostic.
Most children with benign liver tumors present with a painless Arteriography is reserved for children with a liver hemangi-
right upper quadrant abdominal mass or hepatomegaly. oma, an AVM, or, rarely, a mesenchymal hamartoma with
Symptoms of gastrointestinal compression, such as constipa- CHF, when embolization of the blood supply to the tumor
tion, anorexia, or vomiting, may also be present. If the mass is is needed for treatment. The use of percutaneous biopsy
painful, the pain is usually dull and aching and is caused by under sonogram or CT guidance in children with benign tu-
expansion of the liver capsule or compression of the normal mors is generally discouraged, unless excision of the tumor
surrounding structures. Jaundice and weight loss are uncom- would pose a major risk to the child, because establishing a
mon except in infants with symptomatic hemangiomas, and diagnosis on the basis of a small sample may be problematic
those signs should raise the suspicion that the lesion is for the pathologist and because resection is the proper
459
460 PART III MAJOR TUMORS OF CHILDHOOD

TABLE 32-1 FOCAL LIVER HEMANGIOMA

Normal Serum Alpha Fetoprotein (AFP) Levels of Infants by Age
Focal lesions vary in size but can be as large as 8 cm in diam-
Age No. of Patients AFP Level  SD (ng/mL) eter.5 They are usually asymptomatic. Some of the children
Premature 11 138,734  41,444 will have cutaneous hemangiomas as well. On MRI, there is
Newborn 55 48,406  34,718 a solitary liver lesion that is hypodense on T1-weighted
Newborn to 2 weeks 16 33,113  32,503 sequences and hyperintense on T2-weighted sequences
2 weeks to 1 month 43 9452  12,610 compared with normal liver. CT scan similarly shows contrast
1 month 12 2645  3080 enhancing in the periphery of the mass with little contrast
2 months 40 323  278 in the center (see Fig. 32-1). These lesions seldom need
3 months 5 88  87 treatment, may be a hepatic form of hemangioma similar to
4 months 31 74  56 the cutaneous rapidly involuting congenital hemangioma
5 months 6 46.5  19 (RICH), and have generally regressed spontaneously by 1 year
6 months 9 12.5  9.8 of age.4,5
7 months 5 9.7 ?7.1
8 months 3 8.5  5.5
MULTIFOCAL LIVER HEMANGIOMA
From Wu JT, Book L, Sudar K: Serum alpha fetoprotein (AFP) levels in normal Multifocal lesions are generally widely dispersed, spherical,
infants. Pediatr Res 1981;5:50.
and homogeneously enhancing lesions on MRI. Flow voids
may be present in the lesions and may indicate the presence
of arteriovenous shunts that may lead to congestive heart
failure (CHF).15 Cutaneous hemangiomas are almost always
present in these children.5 Treatment by corticosteroids of
patients with CHF is highly successful,4,5 but if steroids fail
to control CHF, embolization of the shunts may be neces-
sary.6,16 Children with this lesion may have evidence of hypo-
thyroidism, and thyroid function tests (TFT) should be
obtained in all children with multifocal lesions. Prognosis is
excellent with 100% survival in one series.5

DIFFUSE LESIONS
Diffuse lesions frequently replace nearly all of the liver with
lesions showing centripetal enhancement on MRI or CT.
The clinical course is more complicated and potentially lethal.
Massive hepatomegaly may lead to abdominal compartment
syndrome, multisystem organ failure, and death. Severe hypo-
thyroidism may develop because of overproduction of type III
iodothyronine deiodinase; therefore TFT must be obtained.13
Despite the large tumor burden, CHF is rare. If corticosteroid
therapy does not result in rapid improvement, then liver trans-
FIGURE 32-1 Contrast-enhanced abdominal computed tomography plantation should be considered early,17 because the progno-
scan of a 4-day-old infant with a large focal hemangioma of the left hepatic sis is otherwise poor.4 Medical therapy with vincristine has
lobe. Note the central area of necrosis. shown some success,18 but this option is often limited by
the rapid clinical deterioration of children with diffuse lesions.
therapy for most of these tumors, with the exception of liver Interferon therapy has been abandoned because of the risk of
hemangiomas. The findings on imaging studies are discussed spastic diplegia in infants.19 Survival for all children with the
in the sections on each individual tumor. diffuse form of liver hemangioma is approximately 75%.5,13

ARTERIOVENOUS MALFORMATION
Hepatic Hemangioma An AVM may occur within the liver parenchyma or outside the
------------------------------------------------------------------------------------------------------------------------------------------------
liver between the hepatic artery and the portal venous system.
Hepatic hemangiomas are the most common benign liver tu- Similar to patients with diffuse liver hemangiomas, patients with
mor in children and are more common than all other benign hepatoportal AVMs usually present before 6 months of age, many
liver tumors combined. Most of these lesions are identified in in the newborn period, with hepatomegaly, CHF, and a bruit over
the newborn period or during prenatal ultrasound screening.8 the liver.21 In older children and adults, hepatic AVM may occur
To facilitate discussion about treatment and prognosis, a as part of hereditary hemorrhagic telangiectasia, also known as
new subtype classification was delineated in 2007.4 This clas- Osler-Weber-Rendu disease.15,22 Angiography is diagnostic,
sification designates the hemangioma as either focal, multiple, and embolization is therapeutic in some patients, but it is neces-
or diffuse and eliminates confusing terms such as infantile sary to eliminate the extensive collaterals for successful closure of
hepatic hemangioendothelioma. the AVM.15,21 Fatal complications from the embolization of liver

AVMs have been reported in adults.23 Steroids have no place in
the management of these lesions, and AVMs not managed
successfully with embolization may be controlled with ligation
of the hepatic artery.24,25
MESENCHYMAL HAMARTOMA
Mesenchymal hamartoma (MH) usually presents as a painless
right upper quadrant abdominal mass in a child younger than
2 years.20,26,27 Some patients may have evidence of CHF,7 and,
similar to liver hemangiomas, MH has been diagnosed prena-
tally.20,9 Edmondson28 proposed that MH arises from a mes-
enchymal rest that becomes isolated from the normal portal
triad architecture and differentiates independently. The tumor
grows along bile ducts and may incorporate normal liver tis-
sue. Because the blood vessels and bile ducts are components
of the mesenchymal rest, the biologic behavior of the tumor
varies with the relative predominance of these tissues within
the loose connective tissue stroma (mesenchyma) that sur-
rounds them. Thus the tumor may present as a predominantly
cystic structure (Fig. 32-2) that enlarges rapidly because of
fluid accumulation,29 or it may be predominantly vascular
and present with CHF.7 Von Schweinitz and colleagues30 sug-
gested that fat-storing (Ito) cells of the immature liver may be
involved in the development of MH. There are reports of chro-
mosomal translocations within mesenchymal hamartomas.31
Serum AFP levels are usually normal in children with MH,
but they may be mildly elevated.20,11,32 The radiographic fea-
tures of these tumors are consistent and distinguishing; ab-
dominal sonography and CT demonstrate a single, usually
large, fluid-filled mass with fine internal septations and no
calcifications.33
Management must be tempered by the understanding that
MH usually follows a benign course,34 although there have
been reports of malignant transformation.35,36 In general,
complete operative resection is the procedure of choice, if it
can be accomplished safely. Huge lesions or those that involve
FIGURE 32-2 Cross section of a pathology specimen of a left hepatic
lobectomy for mesenchymal hamartoma in a 10-month-old male infant.
CHAPTER 32 NONMALIGNANT TUMORS OF THE LIVER 461
both lobes may be treated by unroofing and marsupializing the
cysts, although the lesion may recur after incomplete resection.
MH is an entity distinct from the liver hamartomas associ-
ated with tuberous sclerosis. The latter are smaller, multifocal
lesions that may be associated with angiomyolipomas in other
locations, such as the kidney; they are rarely symptomatic and
usually present in children older than 2 or 3 years. These
hamartomas have little clinical significance, but their presence
may be helpful in diagnosing tuberous sclerosis.37
HEPATOCELLULAR ADENOMA
Although isolated lesions are encountered in childhood, hepa-
tocellular adenoma (HCA) is most commonly observed in
adults in association with the use of anabolic corticosteroids
or estrogen. HCA has been described in children treated
with anabolic steroids and multiple blood transfusions for
chronic anemia,38 and it is expected in children with type I
glycogen storage disease.39 Bianchi40 proposed several mech-
anisms for the development of HCA in patients with type I
glycogen storage disease, including (1) regional imbalance
in insulin and glucagon metabolism, because these hormones
are important in the regulation of hepatocyte proliferation
and regeneration; (2) response to glycogen overload; and
(3) oncogene activation. A giant hepatocellular adenoma has
also been reported in a child treated with oxcarbazepine for
a seizure disorder.41
Microscopic examination of adenomas reveals hepatocytes
in sheets and cords oriented along sinusoids without a ductal
component. The cells have glycogen-filled cytoplasm and
small nuclei without mitoses. Adjacent liver and vessels are
compressed but not invaded. Children usually do not have
coexisting cirrhosis.38 The histologic pattern is similar to that
of a well-differentiated hepatocellular carcinoma, and devel-
opment of hepatocellular carcinoma within an unresected
HCA has been reported.42,43
In children, HCA generally presents as an asymptomatic
hepatic mass. The mass is solid on ultrasonography and CT.
Liver enzyme and AFP levels are normal. A feature unique
to this lesion is its propensity for intraperitoneal hemorrhage
from spontaneous rupture. In adults, intraperitoneal bleeding
is almost always seen in patients receiving estrogen therapy,
and tumor regression may occur with the cessation of hor-
mone administration. In patients with glycogen storage dis-
ease and HCA, tumor regression may occur with the
correction of metabolic disturbances.40 Because of the known
association between HCA and hepatocellular carcinoma,
resection of HCA is recommended when it occurs in a child
who is not receiving steroids and does not have glycogen stor-
age disease. If resection cannot be accomplished without sub-
stantial risk, observation of the lesion while monitoring the
serum AFP level may be appropriate. If the AFP level begins
to increase or the lesion is significantly symptomatic, and if
the risk of resection is unacceptably high, liver transplantation
may be the best alternative.
FOCAL NODULAR HYPERPLASIA
Focal nodular hyperplasia (FNH) in children presents as an
irregularly shaped, nontender liver mass. It is frequently found
incidentally at laparotomy for another cause or on radiographic
studies performed for another indication. The female-to-male
462 PART III MAJOR TUMORS OF CHILDHOOD
FIGURE 32-3 Surgical view of focal nodular hyperplasia within the left
lobe of the liver in a 2-year-old child treated by left lateral lobectomy.
ratio for FNH is approximately 4:1.44 FNH is occasionally seen
with vascular malformations and hemangiomas in the liver,45 as
well as in children with type 1 glycogen storage disease,46 and it
has been postulated that the lesions represent an unusual re-
sponse to injury or ischemia.28 On abdominal sonography,
the lesions may be isoechoic, hypoechoic, or hyperechoic com-
pared with normal liver parenchyma, and multiple lesions may
occur in 10% to 15% of patients. The classic central scar may
not be seen on ultrasonography. CT typically shows a hypervas-
cular lesion with a dense stellate central scar. Conventional ar-
teriography or magnetic resonance angiography show a
hypervascular mass with feeding arteries entering the periphery
and converging on the central portion of the tumor. Some cases
of fibrolamellar hepatocellular carcinoma are radiographically
indistinguishable from FNH, which is a cause for concern if
the diagnosis is being made without a biopsy.47 There are
reports of adult patients who have FNH and hepatocellular
carcinoma simultaneously.48
On gross examination, the lesions are nonencapsulated,
occasionally pedunculated, and quite firm (Fig. 32-3).
Microscopic examination shows proliferation of hepatocytes
and bile ducts and the pathognomonic central fibrosis. These
lesions rarely become malignant or hemorrhage. Therefore
expectant therapy is appropriate when removal might be asso-
ciated with significant morbidity, the child is asymptomatic,
and the diagnosis has been made conclusively by radiographic
studies, normal AFP levels, and biopsy.49
TERATOMA
There have been fewer than 25 case reports of hepatic tera-
toma in children invariably younger than 1 year.12,50 Calcifi-
cation is usually present within the teratoma, helping to
differentiate it from other tumors. Some have met the criteria
for an intrahepatic fetus in fetu.51 Serum AFP levels may be
elevated with a teratoma, but only mildly elevated in
comparison with the levels seen with hepatoblastoma. Resec-
tion is the procedure of choice for a teratoma because of the
risk of malignancy in any immature elements of the tumor.
INFLAMMATORY PSEUDOTUMOR
Inflammatory pseudotumor of the liver is rare and generally
seen in children older than 3 years but has been reported in
younger children as well. Because this lesion is predomi-
nantly solid, it is difficult to differentiate it from other
benign or malignant tumors by imaging studies. Invariably,
the serum AFP level is normal. Fever, leukocytosis, and high
C-reactive protein level in a child with a solid liver mass and
normal AFP level are suggestive of an inflammatory pseudo-
tumor of the liver thought to be an inflammatory reaction
to some insult, although the instigating cause is usually
unknown. It is difficult to diagnose this lesion without
a large biopsy. Most children undergo resection, which is
curative.52,53
NONPARASITIC CYSTS
Nonparasitic cysts of the liver are rare and occur more com-
monly in adults than in children. Although they may be pres-
ent and symptomatic at birth, most are asymptomatic and are
identified incidentally at autopsy or laparotomy. Symptoms
are related to abdominal distention or displacement of adja-
cent structures. Nonparasitic cysts occur with equal frequency
in males and females54 and are generally unilocular lined by
cuboidal or columnar epithelium characteristic of bile ducts.
The cyst fluid is typically clear or brown, and bile is rarely
present. Pathologic studies suggest that nonparasitic cysts
arise from congenital or secondary obstruction of peribiliary
glands. These glands normally arise from the ductal plate at
the hepatic hilum around the 7th week of gestation and con-
tinue to proliferate until adolescence.54 Symptomatic cysts can
be effectively treated by simple unroofing, marsupialization,55
or sclerotherapy.56 If biliary communication is suspected,
cholangiography may identify the source and allow the com-
municating ductule to be oversewn.
Cystic dilatation of the intrahepatic ducts may also present as
a mass, although jaundice and cholangitis are often associated
with this problem. Resection of the affected lobe is the preferred
therapy.57 If mesenchymal hamartoma appears to be completely
cystic on imaging, it may be misdiagnosed as a nonparasitic cyst.
Post-traumatic bile cysts result from ductal disruption and intra-
hepatic accumulation of bile. These lesions can be treated by
percutaneous drainage or, in some cases, by biliary sphincterot-
omy to reduce the bile duct pressure and lessen the biliary
leak.58 Resection is rarely necessary for post-traumatic cysts.
Multiple parenchymal cysts associated with hereditary polycys-
tic kidney disease are generally asymptomatic and so small that
they do not require intervention.
Epidermoid cysts differ from other nonparasitic cysts, in
that the lining epithelium is squamous rather than cuboidal.
This histologic characteristic has led to the theory that these
lesions may be foregut bud anomalies trapped in the hepatic
substance. Although they are rare, there has been a report of
malignant degeneration. Thus resection is the appropriate
management.59
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