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AJR Integrative Imaging LIFELONG LEARNING FOR RADIOLOGY |
1 Both authors: Department of Radiology, Children's Mercy Hospitals and Clinics and the University of Missouri–Kansas City, 2401 Gillham Rd., Kansas City, MO 64108.
Received April 19, 2007; accepted after revision June 11, 2007.
Address correspondence to D. C. Rivard
(dcrivard{at}cmh.edu).
Keywords: hepatic hemangioma • hepatic masses • neuroblastoma • pediatric imaging
OBJECTIVE
A 4.5-month-old boy was found to have hepatomegaly by his primary care pediatrician on a routine well-baby check and was referred for sonography. Innumerable hepatic lesions of varying echogenicity were found in an enlarged liver. Further characterization with multiphase CT, followed by contrast-enhanced MRI, showed innumerable hepatic masses of varying size with heterogeneous enhancement. The objective of this article is to discuss appropriate evaluation of multiple hepatic masses in infants and describe the major disease entities that are considered in the differential diagnosis.
CONCLUSION
Hepatic lesions in infants frequently are evaluated with multiple imaging techniques in an attempt to identify imaging findings that would suggest a specific diagnosis. Although various imaging features may suggest a particular pathologic diagnosis, correlation with patient's age and laboratory markers often is the most helpful factor in infants to suggest a particular disease process and formulate a management plan.
Case History
A 4.5-month-old boy was evaluated on a routine well-baby check by his
primary care physician, at which time the liver margin was palpated several
centimeters below the right costal margin. The child had no known medical
problems and was born full-term in an uncomplicated delivery. The patient had
elevated levels of 
-fetoprotein of 172 ng/mL (reference value,
0–7 ng/mL) and lactate dehydrogenase of 1,828 U/L (reference value,
425–975 U/L). Abdominal sonography was requested.
Sonography
Sonography showed hepatomegaly with diffuse discrete round hypoechoic and
isoechoic lesions throughout the liver nearly replacing the normal parenchyma
(Figs. 1A,
1B, and
1C). Doppler sonography
suggested the lesions had mildly increased flow. The portal veins, hepatic
veins, hepatic arteries, aorta, and inferior vena cava were normal, with
little mass effect by the extensive hepatic lesions.
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MRI
Multiplanar MR sequences were performed including T1-weighted,
fat-saturated T2-weighted, inversion recovery, and dynamic contrast-enhanced
T1-weighted images. Innumerable small round masses with overall increased T2
signal intensity and heterogeneous enhancement were present throughout an
enlarged liver. The dynamic contrast-enhanced T1-weighted MR images showed
varying heterogeneous peripheral and central enhancement in the lesions, with
some completely filling in after a short delay.
Expert Discussion (Dr. Lowe)
The incidental discovery of hepatomegaly or a palpable right upper quadrant
mass on physical examination, such as in this patient, should prompt
additional imaging and laboratory workup. Indeed, organomegaly is one of the
most common presentations of liver masses in infants
[1]. Sonography is the initial
imaging technique of choice because of its safety, expedience, and ability to
provide general hepatic and abdominal information. The sonographic findings
are extremely useful for planning an appropriate imaging evaluation. CT, MRI,
nuclear scintigraphy, or a combination of studies with specified protocols
appropriate to the suspected disorder can be suggested on the basis of the
sonographic findings.
The differential diagnosis of hepatomegaly in infants is extensive. Benign causes include congestive heart failure, hepatitis, infantile hemangioma (also termed "hemangiomatosis" when multiple), infantile hemangioendothelioma, and mesenchymal hamartoma [1, 2]. The most common malignant hepatic lesions in infants are hepatoblastoma, metastatic disease (especially neuroblastoma and Wilms' tumor), and lymphoproliferative disorders (lymphoma or leukemia). Hepato megaly may also be the result of infectious disorders such as cat-scratch disease, pyogenic abscesses, fungal infection, and granulomatous disease [3–5].
The differential diagnosis can be narrowed by correlation with patient history (age at presentation), physical examination, laboratory values, and the distribution of other involved organs. The history and physical examination can usually exclude infectious or cardiac causes. The age of the patient at presentation helps immensely to limit the differential possibilities. Specifically, multiple hepatic lesions in an infant younger than 3 months are most likely to be infantile hepatic hemangiomas, which nearly always present before 6 months of age [6, 7]. Multiple hepatic lesions found in an infant older than 6 months are more likely due to metastatic disease. The young age of the patient in this case and the multiplicity of lesions scattered throughout the liver strongly suggest metastatic neuroblastoma or multiple infantile hemangiomas (hemangiomatosis) as the most likely diagnoses.
Laboratory Values
The presence of abnormal laboratory values, including catecholamines and
elevated -fetoprotein, may be useful. Urine catecholamines are elevated
in more than 90% of neuroblastomas
[8]. Their measurement is so
pivotal in infants with multiple hepatic masses that catecholamine measurement
should precede any imaging evaluation beyond sonography. The primary
catecholamines excreted in patients with neuroblastoma are homovanillic acid
(HVA) and vanillylmandelic acid (VMA). The sensitivity and specificity of HVA
for detection of neuroblastoma are 72% and 98%, respectively
[9]. Corresponding statistics
for VMA are 80% sensitivity and 97% specificity
[9].
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Elevation of -fetoprotein, however, should be considered with
caution. Alpha-fetoprotein levels can vary greatly in neonates, with marked
elevation immediately after birth and a gradual decline to normal levels over
the first few months of life. As a general rule, -fetoprotein levels
decrease as gestation advances and birth weight increases
[10]. Finally, the number of
lesions and other associated organs involved can aid in narrowing the
differential diagnosis. Hepatic hemangiomas are multiple in 10–20% of
cases, and involvement of three or more organ systems is termed
"disseminated hemangiomatosis"
[11].
Differential Diagnosis
Vasoproliferative Disorders
Infantile hemangioma (or hemangiomatosis), the most common tumor in
infants, has undergone a continuing evolution of understanding and
reclassification over the past two to three decades (Figs.
2A and
2B). It is currently considered
to be part of a spectrum of vasoproliferative disorders, which range from the
benign infantile hemangioma to the intermediate lesion, hemangioendothelioma,
to the rare malignant angiosarcoma
[12]. Vasoproliferative
lesions are diagnosed definitively with pathology and classified according to
the binary system set forth by Mulliken
[13] and Mulliken and Glowacki
[14], which has gradually
gained acceptance.
Histologically, hemangiomas are characterized by a rapidly dividing single layer of endothelial cells with an increase in mast cells during the regression phase. Recently, strong expression of the immunohistochemical marker, glucose transporter protein isoform-1 (GLUT1), has been described in infantile hemangiomas and is useful for a more definitive diagnosis [15].
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Hemangioendothelioma occasionally has diffuse liver involvement, causing some overlap in the imaging appearance with infantile hemangiomas [21]. However, hemangioendotheliomas have a tendency toward a large single mass rather than the multiple small masses seen with infantile hemangiomas (Fig. 3). The distinction between these two vasoproliferative disorders is ultimately histologic, with hemangioendothelioma having slightly more aggressive features than hemangioma, including multiple layers of rapidly dividing endothelial cells with areas of hematopoiesis, hemorrhage, or necrosis [2, 21]. Both hemangioendotheliomas and hemangiomas have a favorable prognosis and typically regress without surgical or medical intervention [12]. Both have similar potential complications as well.
Angiosarcoma, a rare, highly malignant vasoproliferative hepatic lesion, may also present with multiple hepatic masses. It is diagnosed histologically on the basis of the presence of aggressive features [22, 23]. The imaging features of angiosarcomas are variable, but they tend to have multiple, large, well-defined masses with varying enhancement, central necrosis, and hemorrhage (Figs. 4A and 4B). The prognosis of angiosarcoma is extremely poor, with a 6- to 13-month median survival [24].
Hepatic Neoplasms
Pediatric hepatic masses account for 5–6% of all abdominal masses and
0.5–2% are malignant
[25,
26]. The two most common
malignant hepatic masses in children are metastases secondary to neuroblastoma
and Wilms' tumor, which occur in up to 15% and 12% of patients, respectively
[3,
4]. The most common primary
pediatric hepatic malignancy is hepatoblastoma, which usually has a large
single mass.
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Metastatic hepatic neuroblastoma has several imaging appearances depending on the type of involvement (multiple focal lesions vs diffuse infiltration or both). In the setting of multiple discrete focal masses, the sonographic echogenicity varies among lesions from hypo- to hyperechoic with varying color Doppler flow. On CT, multifocal liver lesions of low attenuation are identified, usually with diminished enhancement relative to the surrounding liver parenchyma. The liver also may become diffusely infiltrated with neuroblastoma, especially in stage 4s disease, which is defined as a primary tumor in an infant with dissemination to the liver, skin, or bone marrow [8]. Diffuse hepatic parenchymal infiltration may cause loss of normal hepatic architecture and often is associated with severe hepatomegaly. Diffuse heterogeneous hepatic echogenicity and contrast enhancement are seen on sonography and CT, respectively. On MRI, metastatic neuroblastoma typically appears hypointense on T1- and inhomogeneously hyperintense on T2-weighted sequences. Contrast-enhanced T1-weighted sequences show varying enhancement. Treatment involves lesion resection, chemotherapy, or both.
Wilms' Tumor
Wilms' tumor, together with neuroblastoma, is the most common hepatic
metastasis in children. Wilms' tumor metastases occur to the lung most often
(85% of cases), followed by the liver and lymph nodes
[3,
27,
28]. These lesions have a
variable appearance at imaging, with irregular complex mixed-density
components and varying enhancement on CT and MRI
(Fig. 5).
Lymphoproliferative Disorders
Lymphoproliferative disorders, such as leukemia and lymphoma, frequently
involve the liver, but often are not seen with imaging despite being detected
at autopsy [5,
29–31].
With many metastatic lesions, extrahepatic masses or nodes are often present
[32]. Multifocal disease is
common, and the overall hepatic enlargement usually is not as severe as is
seen in metastatic neuroblastoma
[33].
Hepatic Infection
Multifocal liver abnormalities also can be seen in the setting of
infectious processes such as cat-scratch disease or Mycobacterium
avium-intracellulare infection
[34–36].
The history and physical findings in these patients usually are helpful in
elucidating the cause. Infectious processes tend to be disseminated, and
adenopathy and other signs of systemic infection are frequently present
[37]. Extrahepatic lesions
involving the spleen and lymph nodes also are an important diagnostic clue to
the presence of infectious processes. Occasionally, a tissue specimen from a
liver lesion or lymph node is required for diagnosis.
Other infectious disorders that may involve the liver include pyogenic abscess, fungal infection, and granulomatous disease [36]. Pyogenic abscesses most commonly are associated with biliary obstruction or cholangitis, and Staphylococcus aureus is the most commonly isolated organism [37]. Catscratch disease is a self-limited disorder caused by Bartonella henselae that most often affects the lymph nodes, but may involve any part of the reticuloendothelial system (liver, spleen, bone marrow) or brain parenchyma [36]. Hepatic candidiasis is a common cause of multiple hepatic and splenic lesions in immunocompromised patients [36]. Mycobacterial infection of the liver and spleen is most common in disseminated miliary pulmonary tuberculosis (> 80% of cases at autopsy) [37]. Hepatomegaly, and less often, focal macronodular liver lesions with or without calcifications, may be seen on sonography or CT (Figs. 6A and 6B). Nonspecific findings are seen on MRI, including focal lesions of low attenuation on T1-weighted and of bright signal on T2-weighted sequences. Lymphadenopathy with central low attenuation and a rim of peripheral enhancement is common [37].
Commentary
In the case presented, 24-hour urine was strongly positive for
catecholamines, and a subsequent skin nodule biopsy confirmed the diagnosis of
metastatic neuroblastoma, accounting for the multiple liver masses.
Unfortunately, by the time the urine was checked, the patient already had
undergone multiple radiologic studies in an attempt to reach a diagnosis.
Astute clinicians will undertake a concurrent laboratory and imaging
evaluation in any child presenting with a liver mass. If the presence of
elevated urine catecholamines or serum -fetoprotein is detected,
confirming the presence of neuroblastoma or suggesting hepatoblastoma, then
further imaging can be selectively tailored to staging and surgical planning.
Pathologic diagnosis or strong suggestion of a specific imaging diagnosis is
important to determine treatment planning, which may be widely divergent
depending on the diagnosis. Specifically, vasoproliferative disorders
typically require no surgical or medical treatment, whereas neoplasms usually
warrant intensive medical or surgical treatment. Despite correlation of
clinical presentation, age, laboratory values, and imaging, biopsy is
ultimately required for a pathologic diagnosis in some patients.
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  C.-H. Liu, D. C. Rivard, A. C. Silva, K. J. Burkholz, and S. D. Beaty Imaging of Focal Hepatic Lesions: Self-Assessment Module Am. J. Roentgenol., June 1, 2008; 190(6_Supplement): S65 - S68. [Abstract] [Full Text] [PDF]
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