from the archives of the afip - imagenologia...

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801AFIP ARCHIVES

Ellen M. Chung, COL, MC, USA • Regino Cube, CPT, MC, USA • Rachel B. Lewis, LCDR, MC, USN • Richard M. Conran, COL, MC, USA

Benign hepatic tumors in children include lesions that are unique to the pediatric age group and others that are more common in adults. Infantile hemangioendothelioma, or infantile hepatic hemangioma, is a benign vas-cular tumor that may cause serious clinical complications. It is composed of vascular channels lined by endothelial cells. At imaging, large feeding arteries and draining veins and early, intense, peripheral nodular enhance-ment with centripetal filling on delayed images are characteristic features. Mesenchymal hamartoma of the liver occurs in young children and is char-acterized pathologically by mesenchymal proliferation with fluid-containing cysts of varying size and number. The mesenchymal component or cystic component may predominate; this predominance determines the imag-ing appearance of the tumor. Benign epithelial tumors that are common in adults may infrequently occur in childhood. These include focal nodular hyperplasia (FNH), hepatocellular adenoma, and nodular regenerative hyperplasia. All are composed of hyperplastic hepatocytes similar to sur-rounding liver parenchyma and may be difficult to discern at imaging. Preferential hepatic arterial phase enhancement helps distinguish FNH and hepatic adenoma from uninvolved liver. Hepatic adenoma often has intracellular fat and a propensity for intratumoral hemorrhage, neither of which are seen in FNH. Unlike adenoma, FNH often contains enough Kupffer cells to show uptake at sulfur colloid scintigraphy. Nodular regen-erative hyperplasia is often associated with portal hypertension, which may be evident at imaging. Knowledge of how the pathologic features of these tumors affect their imaging appearances helps radiologists offer an appro-priate differential diagnosis and management plan.

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From the Archives of the AFIPPediatric Liver Masses: Radiologic-Pathologic Correlation Part 1. Benign Tumors1

Abbreviations: AFP = α-fetoprotein, CHF = congestive heart failure, FNH = focal nodular hyperplasia, GLUT1 = glucose transporter protein 1, H-E = hematoxylin-eosin, NRH = nodular regenerative hyperplasia, UES = undifferentiated (embryonal) sarcoma

RadioGraphics 2010; 30:801–826 • Published online 10.1148/rg.303095173 • Content Codes: 1From the Department of Radiology and Radiological Sciences (E.M.C.) and Department of Pathology (R.M.C.), Edward F. Hebert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814; Department of Radiologic Pathology, Armed Forces Institute of Pathology, Washington, DC (E.M.C., R.B.L.); Department of Radiology, Madigan Army Medical Center, Tacoma, Wash (R.C.); and Department of Radiology, National Naval Medical Center, Bethesda, Md (R.B.L.). Received September 15, 2009; revision requested December 8 and received January 15, 2010; accepted January 19. For this CME activity, the authors, editors, and reviewers have no relevant relation-ships to disclose. Address correspondence to E.M.C. (e-mail: [email protected]).

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official nor as reflecting the views of the Departments of the Army, Navy, or Defense.

LEARNING OBJECTIVES FOR TEST 6After reading this article and taking the test, the reader

will be able to:

Describe an age- ■

appropriate differ-ential diagnosis for a liver mass in a child.

List the clinical, ■

pathologic, and imaging features of common benign liver tumors in children.

Discuss how to ■

distinguish benign liver tumors from other hepatic tu-mors on the basis of clinical and imaging data.

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TEACHING POINTS

802 May-June 2010 radiographics.rsna.org

IntroductionAlthough primary hepatic neoplasms represent only a small percentage of solid tumors that oc-cur in children, the finding of focal hepatic le-sions in a child is not an uncommon event in a busy radiology practice. The most common neoplasm involving the liver in children, as in adults, is metastatic disease. Most primary liver tumors in children are malignant, but one-third are benign; benign lesions may be of mesenchy-mal or epithelial origin. In a series of 716 hepatic tumors in patients under the age of 21 years from the Armed Forces Institute of Pathology (1), the most common benign tumors were, in decreasing order of frequency, infantile hemangioendothelio-ma, focal nodular hyperplasia (FNH), mesenchy-mal hamartoma, nodular regenerative hyperplasia (NRH), and hepatocellular adenoma. In this ar-ticle, we focus on benign liver tumors in children. The clinical, pathologic, and imaging features of these tumors are reviewed and correlated.

Infantile HemangioendotheliomaInfantile hemangioendothelioma, or infantile hepatic hemangioma, is a vascular neoplasm and the most common benign hepatic tumor of in-fancy. About one-half of cases occur as solitary masses and one-half are multifocal. The biologic behavior is benign, but serious clinical complica-tions may develop.

NomenclatureOur understanding of vascular lesions in infants is markedly hampered by widely varied terminology. The term infantile hemangioendothelioma is gener-ally preferred in the pathology literature to differ-entiate this neoplasm of infancy from the common benign liver lesion of young adult women widely known as hemangioma (1–3). Others assert that the term hemangioendothelioma leads to confusion with epithelioid hemangioendothelioma, a distinct tu-mor of adults with borderline malignant potential (4,5). The terms capillary hemangioma, which is often applied to the lesion in infants, and cavernous hemangioma, which is often applied to the lesion in adults, are less favored because both capillary- and cavernous-sized vascular spaces are encountered in infantile hemangioendothelioma (3,6). The name adopted by the International Society for the Study of Vascular Anomalies and based on the classifi-cation of Mulliken and Glowacki (7) is infantile hepatic hemangioma. This term emphasizes the similarity of the hepatic lesion to the most com-mon neoplasm of infancy, which, when it occurs in the skin and other organs, is known as infantile hemangioma (4,8,9).

Epidemiology and Clinical FeaturesNearly 90% of infantile hemangioendotheliomas are diagnosed in the first 6 months of life, and one-third are diagnosed within the first month (3,10). They are rarely discovered after 1 year of age, and biopsy is indicated for older patients to exclude malignant tumors (8,9,11). There is a slight female predominance but no racial predilection. There is an increased prevalence in patients with hemihypertrophy and Beckwith-Wiedemann syndrome (2).

Most infantile hemangioendotheliomas mani-fest as an asymptomatic abdominal mass, but life-threatening complications may occur (3). Hemangiomas involving other sites, such as the skin, trachea, thorax, adrenal gland, and dura mater, have been reported to occur in up to 68% of patients with multifocal liver tumors, but larger series suggest that the prevalence is lower (10%–15%) (3). Patients with multiple liver le-sions should be evaluated with chest radiography and brain imaging to exclude additional lesions (11). Serious complications include high-output congestive heart failure (CHF) due to associated large arteriovenous shunts and the Kasabach-Merritt syndrome of coagulopathy due to intra-tumoral platelet sequestration. CHF may accom-pany both solitary and multifocal lesions and is associated with a poorer prognosis. In addition, severe hypothyroidism may be caused by high levels of type 3 iodothyronine deiodinase activity produced by the tumor; the hypothyroidism may lead to cardiac dysfunction and mental retarda-tion (5,12). Rarely, patients may present acutely with hemoperitoneum due to tumor rupture (3).

Laboratory tests frequently show anemia and occasionally show hyperbilirubinemia. Serum α-fetoprotein (AFP) levels are rarely elevated above the normal reference range for age (adult levels are not reached until age 6 months). If el-evated, the serum AFP level is much lower than is typical with hepatoblastoma (1,3,13).

Classification of Vascular Lesions of the LiverVascular anomalies in children are now under-stood to represent a range of pathologic entities that can be divided, according to the classifica-tion of Mulliken and Glowacki (7), into two broad categories: high-flow and low-flow lesions. High-flow lesions include arteriovenous malfor-mations and the true vasoproliferative neoplasm, infantile hemangioma. Low-flow lesions include vascular malformations composed of venous, lymphatic, and capillary components. It is likely that the vascular lesions occurring in the liver in children also represent a heterogeneous group of malformations and neoplasms, giving rise to the confusion in the nomenclature.

RG • Volume 30 Number 3 Chung et al 803

Common cutaneous infantile hemangiomas are now pathologically differentiated from other vascular lesions on the basis of positive immu-noreactivity to erythrocyte-type glucose trans-porter protein 1 (GLUT1) in the former (14,15). Similarly, in a study of 19 pediatric vascular le-sions of the liver in the pathology literature, Mo et al (9) were able to distinguish two groups of lesions on the basis of their immunoreactivity to GLUT1. Group 1 consisted of tumors that showed positive immunostaining for GLUT1. The tumors were usually multifocal without ne-crosis or large vessels, and most underwent invo-lution. The authors called these tumors hepatic infantile hemangiomas and believed that these represented the hepatic counterpart of infantile (or juvenile) cutaneous hemangiomas (9). Group 2 consisted of GLUT1-negative lesions (9), which were usually solitary with central necrosis and large peripheral vessels. These did not regress or respond to medical therapy. The authors des-ignated these GLUT1-negative lesions as hepatic vascular malformations with capillary prolifera-tion (9). Other authors have described additional GLUT1-negative vascular hepatic lesions that do involute (16); thus, GLUT1-negative lesions rep-resent a heterogeneous group of anomalies.

Clinical investigators from two large North American referral centers for vascular anomalies divide hepatic vascular lesions into three categories with distinctive clinical presentations, features, and outcomes (5,8) (Table). The first category consists of multifocal lesions. These stain positive for GLUT1, do not have central necrosis, and may or may not have associated arteriovenous shunts or cutaneous hemangiomas. They exhibit a natural history of proliferation followed by invo-lution, similar to the natural history of common

cutaneous infantile hemangiomas. Many patients are asymptomatic, but some are symptomatic with CHF due to arteriovenous shunting. These are the same as the group 1 lesions of Mo et al (9) and represent typical infantile hepatic hemangiomas or hemangioendotheliomas.

The second category is made up of focal le-sions, which do not stain for GLUT1 and often contain central areas of hemorrhage, necrosis, or thrombosis. These lesions variably demonstrate arteriovenous shunts, are usually symptomatic, and are often diagnosed at birth or at antenatal ultrasonography (US). They are rarely associated with cutaneous hemangiomas. The authors con-sider these the hepatic counterpart of the cutane-ous rapidly involuting congenital hemangioma, which is also GLUT1 negative and completely involutes by age 12–14 months (5,8).

The third category is diffuse disease with the liver largely replaced by growing tumors, which cause massive hepatomegaly and secondary respiratory distress, inferior vena cava compres-sion, and abdominal compartment syndrome. These patients frequently also have severe hy-pothyroidism. Although arteriovenous shunts may be present, these patients do not have high-output CHF (5,8).

Pathologic FeaturesSolitary tumor size varies from 0.5 to 14 cm in maximum dimension. Multifocal lesions are usu-ally around 1 cm in diameter (Fig 1). On cut sec-tions, the mass varies from red-brown and spongy to tan-white and firm. Central areas of hemor-rhage, necrosis, thrombosis, or fibrosis and gritty calcifications are frequent in large solitary tumors (Fig 2) (2,3).

Three Clinical Categories of Hepatic Vascular Malformations*

Type of Malformation Clinical Presentation GLUT1 Reactivity

Pathologic Features Outcome

Multifocal Patients are usually asympto-matic, but some have CHF; manifests in first few months of life

GLUT1 positive Small with no cen-tral necrosis

Proliferation followed by involution

Focal Patients are usually symptomatic and may have CHF; manifests in perinatal period

GLUT1 negative Large with central necrosis, hemor-rhage, or fibrosis

Involute by age 12–14 months

Diffuse Manifests with mass effect; pa-tients may develop abdominal compartment syndrome or severe hypothyroidism; no CHF

Not yet established Liver enlarged and replaced by masses

Complicated clinical course

Source.—Reference 5. *As proposed by two large North American referral centers for vascular anomalies. The malformations differ in clinical presentation, pathologic appearance, and prognosis.


Figure 1. Multifocal infantile hemangioendothelioma in a 6-month-old girl. (a) Intraoperative photograph obtained in another patient shows multiple small, purplish masses bulging out from the surface of the liver. (Reprinted, with permission, from reference 1.) (b) Transverse US image shows several small, well-demarcated, homogeneous hypoechoic lesions (arrowheads) in the liver. (c) Color Doppler image shows peripheral flow around some of the lesions. (d) Computed tomographic (CT) image obtained without intravenous contrast material shows that the lesions (arrowheads) are hypoattenuating relative to the liver. (e) Contrast material–enhanced CT image shows that the nodules enhance intensely and uniformly (arrowheads). (f) Coronal fat-saturated T2-weighted magnetic resonance (MR) image shows numerous well-defined hyperintense nodules in the liver. Arrow = gallbladder. (g) Coronal T1-weighted MR image shows that the nodules (arrowheads) are hypointense relative to the liver. (h) Coronal gadolinium-enhanced fat-saturated T1-weighted MR image shows uniform enhancement of the nodules (arrowheads).


Figure 2. Hepatic vascular lesion (GLUT1 immuno-reactivity unknown) in a 12-week-old boy. (a) Photograph of the cut specimen shows a tan mass with a cystic space (*) and large blood vessel (arrowhead). (b) Photomi-crograph (original magnification, ×100; hematoxylin-eosin [H-E] stain) shows interconnecting vas-cular spaces (*) lined by endothelial cells and surrounded by fibrous stroma (S). (c) Longitudinal US image shows a mark-edly enlarged right hepatic vein (arrow-head). (d) Longitu-dinal US image shows a large celiac axis (ar-rowhead) and taper-ing of the aorta distal to its origin. (e) On a duplex US image, the spectral waveform of the artery supplying the mass shows little variation in flow between systole and diastole. (f ) Nonen-hanced CT image shows tiny calcifica-tions (arrowheads) in the tumor, which has mixed attenuation and replaces the right hepatic lobe. (g) Arterial phase CT image shows an enlarged hepatic artery (ar-rowhead) and intense, nodular, pe-ripheral enhancement of the mass (arrows). (h) Equilibrium phase CT image shows peripheral fill-in of contrast enhancement but persistent low attenuation in the tumor center.


cular spaces lined by a single layer of flattened endothelial cells, usually in the center of the tumor. Thrombosis in these spaces may lead to infarction, fibrosis, and dystrophic calcification. As involution continues, cellularity is replaced by loose fibrofatty stroma (3,17,18).

Figure 3. Congenital hepatic vascular le-sion (GLUT1 immunoreactivity unknown) in a 12-day-old girl who was premature (born at 31 weeks gestation). (a) Plain radio-graph of the chest and abdomen shows an enlarged cardiac silhouette, paucity of bowel gas with lateral deviation of the stomach, and body wall edema. (b) Axial T2-weighted MR image shows a predominantly hyperintense mass (arrow) with a central hypointense area and adjacent flow voids (arrowhead), which represent enlarged hepatic veins. (c) Axial nonenhanced T1-weighted spoiled gradient-echo MR image shows that the mass (T) is hypointense relative to the liver. (d) Arterial phase gadolinium-enhanced T1-weighted MR image shows intense, peripheral, papil-lary enhancement (arrowheads) of the mass. (e) Delayed phase gadolinium-enhanced T1- weighted MR image shows centripetal en-hancement of the mass with a persistent hypointense area (arrowhead).

At histologic examination, the tumor is com-posed of thin vascular channels lined by a single layer of plump endothelial cells within a scanty fibrous stroma (Fig 2). The vascular channels vary in size from small (capillary) to large (cav-ernous), as described by Dehner and Ishak (17) as a type 1 infantile hemangioendothelioma. The type 2 lesion of Dehner and Ishak (17) is now believed to represent an angiosarcoma (3). Areas of involutional or regressive change are frequently seen, including cavernous vas-


Imaging FeaturesThe imaging features of infantile hemangio-endotheliomas depend on whether the lesions are focal, multifocal, or diffuse and reflect their vascular nature (8,18). Multifocal lesions are small and uniform in appearance (5,8). Large focal lesions often demonstrate findings related to central hemorrhage, necrosis, fibrosis, and cal-cification (5,8,18). In diffuse disease, the liver is massively enlarged and replaced by multiple large masses, causing mass effect on adjacent organs and compression of the inferior vena cava (5,8). Typically, evidence of high flow is apparent, as manifest by enlargement of the hepatic arteries and veins and possibly tapering of the abdomi-nal aorta below the origin of the celiac axis (Fig 2) (8,18). Owing to the risk of bleeding, biopsy of these masses is avoided, and the diagnosis is made on the basis of typical imaging findings and the demonstration of involution at follow-up.

Figure 4. Congenital hepatic vascular malfor-mation (GLUT1 negative) in a 3-month-old girl. (a) Prenatal MR image shows a large hyperintense mass (straight arrow) in the left hepatic lobe (the fetus is in cephalic presentation) with a large adjacent flow void (arrowhead). Curved arrow = right kidney. (b) Transverse US image shows a well-demarcated heterogeneous mass (arrowheads) in the left hepatic lobe. (c) Transverse color Doppler image shows flow within and adjacent to the tumor. (d) Coronal gadolinium-enhanced MR angiogram shows many large vessels, including a very large draining vein (*).

Plain radiographs of the abdomen often show hepatomegaly or an abdominal mass (Fig 3). Fine calcifications are seen in about 16% of cases (18). In infants with CHF, chest radiography demon-strates cardiomegaly and pulmonary edema (Fig 3).

At prenatal US, polyhydramnios and a hy-poechoic liver mass may be detected. Findings of fetal hydrops, including anasarca, ascites, pleural effusion, and cardiomegaly, should be sought because these have prognostic import (18). At postnatal US, infantile hemangioendotheliomas appear as well-demarcated masses that are gener-ally hypoechoic or of mixed echogenicity relative to adjacent liver (Figs 1, 4) (18). The typical


hyperechoic appearance of adult hemangioma is uncommon in infantile hemangioendothelioma (8,18). Tiny echogenic foci with posterior acous-tic shadowing representing calcifications are seen in up to 36% of cases (8,18). Small multifocal le-sions are homogeneous, whereas the echotexture is more often heterogeneous in large focal lesions with central hemorrhage, necrosis, or fibrosis (8,18). Diffuse disease may appear as an enlarged liver without discrete masses, or the liver may be replaced by large predominantly hypoechoic masses (Fig 5) (8).

Color and spectral Doppler analysis demon-strates a variety of flow patterns: arteries with waveforms with little systolic-diastolic variation, a finding indicative of arteriovenous shunting; arte-rial and venous waveforms with high-frequency shifts; and arteries and veins with low-frequency signals (Fig 2) (6). The hepatic arteries and veins generally appear enlarged, and large feeding and draining vessels are seen surrounding and within the tumors (Figs 1, 4). Direct arteriovenous or portovenous shunts may be visualized (Fig 5) (8). Some anechoic areas may show venous flow (6,18). Follow-up of treated or observed lesions

Figure 5. Diffuse form of hemangioendothe-lioma in a 10-week-old girl with severe hypothyroidism. (a, b) Transverse (a) and longi-tudinal (b) US images show numerous large masses (* in a) replacing the liver and com-pressing the inferior vena cava (arrow in a). AO in a = aorta. (c) Longitudinal color Dop- pler image shows a direct portal vein–to–hepatic vein shunt. (d) Contrast-enhanced CT image, obtained in the early portal venous phase, shows peripheral corrugated enhancement of the masses (arrowheads) and compression of the inferior vena cava (arrow). (e) Delayed phase CT image shows centripetal enhancement of the masses.


demonstrates a decrease in flow velocity in the feeding arteries and resolution of arteriovenous shunts, with a decrease in the size of the masses (5,6). Sonographic and Doppler features are sug-gestive of hemangioendothelioma but not diag-nostic. The main role of US is in detection and localization of lesions and in follow-up (6,8).

Findings at dynamic contrast-enhanced CT are often diagnostic. Precontrast images show well-defined masses that are hypoattenuat-ing to the adjacent uninvolved liver (Figs 1, 2) (8,18,19). Speckled calcifications are noted in up to 50% of cases, usually in the large focal tumors (Fig 2) (8,18,19). The enhancement pattern of infantile hemangioendothelioma is similar to that of adult hemangioma. On arterial phase images, there is generally intense peripheral nodular or corrugated enhancement. On portal venous and delayed phase images, there is progressive cen-tripetal fill-in of the enhancement of the tumor (Figs 2, 5). Small multifocal tumors enhance in-tensely and uniformly, whereas large focal tumors with central hemorrhage, necrosis, or fibrosis enhance centripetally and may never completely enhance in the center, in contradistinction to the typical adult hemangioma (Figs 1, 2) (8,18,19). Patients with diffuse disease demonstrate near total replacement of the liver by innumerable le-sions with centripetal enhancement (Fig 5) (5,8).

MR imaging is the preferred modality for evaluating infantile hemangioendothelioma, as characteristic findings at T2-weighted and gradi-ent-echo imaging as well as dynamic gadolinium-enhanced imaging allow confident diagnosis (8,11,20). On precontrast T1-weighted images, infantile hemangioendotheliomas are generally hypointense to surrounding normal parenchyma, although occasionally hyperintense foci reflect-ing hemorrhage may be encountered (Figs 1, 3) (18). On T2-weighted images, infantile heman-gioendotheliomas are markedly hyperintense owing to their vascular nature, similar to adult hemangiomas (Figs 1, 3) (5,8,18). Small multi-focal lesions are almost always homogeneous in signal intensity, whereas larger focal lesions may demonstrate heterogeneous signal intensity due to central thrombosis, necrosis, or fibrosis (Figs 1, 3) (8). Flow voids are commonly seen in or adjacent to some of the lesions (Figs 3, 4) (8). At dynamic gadolinium-enhanced imaging, the pat-tern of enhancement is intense peripheral nodu-lar enhancement with centripetal fill-in, similar to that seen at dynamic contrast-enhanced CT (Fig 3) (5,8,21). Central varices, if present, also enhance (8,11).

Angiography was the mainstay of diagnosis in the past but has been largely supplanted by dy-namic contrast-enhanced MR imaging and CT. Angiography is now reserved for patients with intractable complications from arteriovenous shunts in whom use of embolotherapy is contem-plated (11,18). Arteriography frequently shows dilated tortuous feeding arteries including the hepatic arteries and adjacent systemic arteries. Early draining veins due to arteriovenous shunts are seen (11,18). Focal lesions may have large ve-nous varices with anomalous draining veins (Fig 4) (8,11).

Infantile hemangioendotheliomas have been studied with both technetium 99m (99mTc)–labeled sulfur colloid and 99mTc-tagged red blood cells. Blood flow images show early uptake with both studies, in contrast to findings in adult he-mangioma, which does not show early increased flow. Delayed sulfur colloid images show a pho-topenic defect at the site of the tumor, whereas delayed images from tagged red blood cell stud-ies reveal increased radiotracer accumulation, although a central photopenic defect may be encountered in large tumors with hemorrhage, necrosis, or fibrosis (18,22).

Differential DiagnosisThe principal diagnostic considerations are soli-tary and multifocal hepatic tumors that occur in the same age group. Hepatoblastoma rarely occurs in the newborn but can be seen in young infants (3). This tumor is distinguished by a heterogeneous rather than intense centripetal en-hancement pattern and markedly elevated levels of AFP in 90% of patients (3,18). AFP level is rarely elevated in infantile hemangioendothe-lioma (13).

Mesenchymal hamartoma of the liver, like infantile hemangioendothelioma, may also be found in the perinatal period. This benign tumor differs in imaging appearance from infantile he-mangioendothelioma in that it usually appears as a multicystic, multilocular mass with enhance-ment of only the septa and solid portions. Less commonly, mesenchymal hamartoma may be predominantly solid, but it differs from infantile hemangioendothelioma in that it is hypovascular at dynamic contrast-enhanced imaging (18).

Metastatic neuroblastoma can mimic the appearance of multifocal infantile hemangioen-dothelioma, but neuroblastoma is associated with elevated levels of urinary catecholamines. At CT,


Figure 6. Mesenchymal hamartoma in a 16-month-old girl. (a) Photograph of the resected specimen shows a partly cystic (arrowheads) and partly solid (T) tumor. * = normal liver. (b) Photomi-crograph (original magnification, ×100; H-E stain) shows compressed, branching ductules (arrow-heads) surrounded by loose mesenchyme. * = normal liver. (c) Photomicrograph (original magni-fication, ×40; H-E stain) shows fibrils of collagen within loose mesenchyme; these separate to form early cysts (*). (d) Transverse US image shows cystic (arrowheads) and solid (T) portions of the tu-mor and adjacent normal liver (*). (e) Longitudinal color Doppler image shows no flow to the cystic component, which contains low-level echoes (arrowhead). Minimal flow is seen in the solid compo-nent (arrows). (f) Coronal CT image obtained with intravenous and oral contrast material shows the mixed cystic (arrowheads) and solid (T) tumor replacing the left hepatic lobe. * = normal liver.

neuroblastoma metastases in the liver generally enhance less instead of more than the adjacent liver (18). Further, imaging findings of additional sites of metastases or the primary tumor in the

adrenal gland, retroperitoneum, or posterior me-diastinum suggest the proper diagnosis.

Angiosarcoma should also be considered, as there are reports of angiosarcomas arising in preexisting hemangioendotheliomas (3,8,23). Presentation after age 1 year or lack of response


to treatment should prompt further evaluation with biopsy. Atypical imaging features, such as heterogeneous signal intensity in multifocal le-sions on T2-weighted images, lack of flow voids, and central or only mild peripheral enhancement, should also lead one to consider biopsy (8).

Treatment and PrognosisMost infantile hemangioendotheliomas are asymptomatic and spontaneously involute, but a minority cause serious complications. Overall survival is about 90% in series with selection bias for complicated cases, so the actual survival rate is likely higher (3,8,18). Most deaths are second-ary to CHF (18). Both GLUT1-positive infantile hemangioendotheliomas and GLUT1-negative focal lesions may exhibit arteriovenous shunting and cause CHF. Kassarjian et al (8) found that diffuse disease with massive replacement of the liver by tumors is associated with hypothyroid-ism, respiratory distress, abdominal compartment syndrome, and a complicated clinical course (5).

A diagnosis and treatment algorithm proposed by authors from two North American vascular anomalies centers provides a rational approach to infantile hemangioendotheliomas based on the imaging appearance of the lesions and the pres-ence or absence of complications (5). Patients with focal or multifocal disease and symptoms related to tumor size or arteriovenous shunting are initially treated with corticosteroids followed by interferon-α-2a or vincristine, if necessary. Cardiac failure is managed with diuretics and digoxin. Patients with shunts who fail medical therapy benefit from embolotherapy. Those with diffuse disease replacing most of the liver benefit from medical therapy, including treatment of as-sociated hypothyroidism, but may require trans-plantation. These patients do not have CHF and do not benefit from embolotherapy (5).

Mesenchymal HamartomaMesenchymal hamartoma of the liver is the sec-ond most common benign liver mass in children after infantile hemangioendothelioma (1,3,24). The gross appearance, which ranges from pre-dominantly cystic to predominantly solid, deter-mines the imaging features. The vast majority of mesenchymal hamartomas contain cysts.

Epidemiology and Clinical FeaturesMesenchymal hamartoma is most commonly dis-covered in children younger than 2 years of age, with nearly all lesions (95%) discovered by age 5 years (3,24). There is a slight male predominance (3:2), with no known racial predilection (3,24).

The most common presentation is painless abdominal distention. The abdominal enlarge-ment is usually gradual, although distention can develop fairly rapidly due to fluid accumulation within the cysts (3,24,25). Mesenchymal hamar-toma has been diagnosed prenatally and has been associated with hydrops (25–27).

There is no specific laboratory marker for mesenchymal hamartoma. Serum AFP levels are typically normal, although mild elevation above the age-adjusted reference range occasionally oc-curs; this elevation presumably originates from the peripheral hepatocyte component of the le-sion (28–32).

Pathologic FeaturesThe gross pathologic appearance of mesenchymal hamartoma is typically a large, well-marginated, solitary mass measuring up to 30 cm (24). Most lesions (85%) contain cysts of varying sizes, rang-ing from a few millimeters to more than 15 cm (Fig 6) (1). In the series of 30 cases described by Stocker and Ishak (24), 83% of tumors contained gross cysts. Those without cysts tend to be found in younger patients (24). The cystic areas of the mass contain a clear amber fluid or gelatinous material. The mass arises in the right lobe in 75% of cases and may be pedunculated with a thin or thick pedicle (1,3,24). The appearance of the mass ranges from predominantly cystic to pre-dominantly stromal (mesenchymal).

At histologic analysis, mesenchymal hamarto-ma is characterized by mesenchymal proliferation containing variably sized cysts, bile ducts, and hepatocyte cords. The mesenchymal component consists of stellate cells in a loose mucopolysac-charide-rich matrix surrounding interspersed vessels and bile ducts (Fig 6). Loose areas of mesenchyme may contain fibrils of collagen that separate to form the cystic spaces. The cysts typi-cally have no discrete endothelial lining and are delimited only by slightly more dense mesenchy-mal tissue (3,24). In addition to the stromal ele-ment, interspersed bile ducts and hepatocytes are seen. The single or branching bile ducts appear to constitute an active proliferating component, whereas the hepatocytes, which are compressed into thin strips at the periphery of the mass, likely represent an inactive component (Fig 6) (1). Cytologic sampling limited to the peripheral hepatocyte component may lead to an erroneous diagnosis of hepatoblastoma (32). Hemorrhage and necrosis are infrequently seen and are fea-tures that suggest a malignant tumor (3).


Figure 7. Mesenchymal hamartoma of the liver in a 2-year-old boy. * = normal liver. (a) Trans- verse US image shows a well-defined cystic mass with multiple septa in the liver. (b) Axial T2- weighted MR image shows the markedly hyperintense mass containing thin septa (arrows). (c) Co-ronal nonenhanced T1-weighted MR image shows that the mass (arrows) is homogeneously hypoin-tense relative to the liver. (d) Coronal contrast-enhanced T1-weighted MR image obtained at the same level shows that enhancement is limited to the septa (arrows).

PathogenesisMesenchymal hamartoma is characterized by uncoordinated proliferation of primitive mesenchyme in the periportal tracts (3,24). Mesenchymal hamartoma has generally been considered to represent a congenital lesion, which has been attributed to a multiplicity of factors including developmental anomaly of the ductal plate, bile duct obstruction, hepatic lobe ischemia or degeneration, and lymphatic duct obstruction (1,3). The finding of expanded portal areas in satellite lesions at the periphery suggests that the mass proliferates by extending

along the portal tracts, causing compression of adjacent parenchyma. Fluid accumulation and cyst formation then develop in the resulting ar-eas of atrophy and degeneration (3,24). More recently, a few reports of cytogenetic analysis and flow cytometry studies of mesenchymal hamartomas have demonstrated balanced trans-locations at 19q13.4 and aneuploidy, findings that suggest that the lesion may in fact represent a true neoplasm (3,26,31,33,34).

Although mesenchymal hamartoma is general-ly regarded as a benign lesion with no malignant potential, whereas undifferentiated (embryonal) sarcoma (UES) is an aggressive malignant tumor, there are several common histopathologic, immu-nohistochemical, and cytogenetic features of mes-


enchymal hamartoma and UES that suggest a relationship between the two (1,3). Furthermore, recent reports in the literature identify recurring chromosomal abnormalities for cytogenetically characterized mesenchymal hamartomas involv-ing alterations of 19q with a breakpoint at band 13.4, suggesting that alteration in this location may serve as a genetic marker for mesenchymal hamartoma (33–35). Alterations at the same lo-cus have also been described in UES (26,35). In addition, several reports in the literature describe cases of UES arising in a background of mesen-chymal hamartoma (1,3,26,35,36). These raise the question of whether the UES arose within a preexisting mesenchymal hamartoma or simply represents a malignant entity with areas resem-bling the histologic appearance of mesenchymal hamartoma (1,3).

Imaging FeaturesAt imaging evaluation, the appearance of mesen-chymal hamartoma depends on its gross patho-logic appearance, which constitutes a spectrum from a predominantly cystic mass with thin or thick septa to a predominantly solid (stromal or mesenchymal) mass containing a few small cysts. Cystic portions are avascular, and stromal por-tions are relatively hypovascular (37).

At sonography, the cystic portions of the mass are anechoic or nearly anechoic with thin or thick echogenic septa. The solid portions appear echo-genic. Portions with very small cysts may appear completely solid at US (Figs 6, 7). Low-level echoes may be seen within the fluid, presumably reflecting gelatinous contents (Fig 6) (38). Color Doppler imaging shows relatively little blood flow, which is limited to solid portions and septa (Fig 6). Intraoperative US may also be used to guide resection and define vascular anatomy (31).

At CT, mesenchymal hamartoma appears as a complex cystic mass. The cystic components show water attenuation, whereas the stromal components are hypoattenuating to surrounding liver. After administration of iodinated intrave-nous contrast material, enhancement of the septa and solid (stromal) elements is observed (Fig 6) (21,37,39). Hemorrhage is not typical in mesen-chymal hamartoma (39).

At MR imaging, the appearance of mesen-chymal hamartoma depends on the cystic versus stromal (mesenchymal) composition of the mass, as well as the protein content of the fluid in the cysts (21,39,40). Solid portions may appear hypointense to adjacent liver on both T1- and

T2-weighted images owing to fibrosis (21,37,41). The cystic portions are generally close to water signal intensity on T2-weighted images and dem-onstrate variable signal intensity on T1-weighted images, depending on the protein content of the cyst fluid (Fig 7) (21,40,41). After intravenous administration of gadolinium contrast material, enhancement is mild and limited to the septa and stromal components (Fig 7) (21).

Differential DiagnosisSeveral diagnostic considerations remain for a hepatic mass in a young child. Hepatoblastoma is a malignant tumor that occurs in the same age group; it is generally distinguished from mesen-chymal hamartoma by marked elevation of the serum AFP level and the solid appearance of and finding of calcification in hepatoblastoma; however, occasionally, the AFP may be low in hepatoblastoma or mildly elevated in mesenchy-mal hamartoma, and mesenchymal hamartoma may appear predominantly solid (stromal), lead-ing to diagnostic difficulty. Even biopsy results may be misleading, as mesenchymal hamartoma may histopathologically resemble hepatoblasto-ma if sampling is limited to the peripheral hepa-tocyte-rich component of the lesion (30,32,42). In such instances, the uncertainty is resolved only at surgery.

The focal form of infantile hemangioendothe-lioma with myxoid change of the stroma can also resemble mesenchymal hamartoma and oc-curs in the same age group (3). One-half of he-mangioendotheliomas show calcification at CT, whereas mesenchymal hamartoma does not con-tain calcifications. In addition, the markedly vas-cular nature of infantile hemangioendothelioma, with enlarged vessels and peripheral nodular en-hancement with centripetal fill-in, distinguishes this tumor from the hypovascular mesenchymal hamartoma. Rarely, initial peripheral enhance-ment with progressive filling has been described in mesenchymal hamartoma; however, the pe-ripheral enhancement is slower and much less intense than that seen in vascular tumors (28).

UES shares many imaging and pathologic features with mesenchymal hamartoma but is seen in an older age group (6–10 years of age). At pathologic analysis, UES is distinguished by the frequent finding of hemorrhage and necrosis and by frankly malignant stroma.


Figure 8. FNH in a 6-year-old girl. (a) Photograph of the sectioned gross specimen shows a nodular mass with a stellate scar (arrowhead). Note the adjacent vessel (arrow). * = normal liver. (b) Photomicrograph (original magnification, ×40; H-E stain) shows the vascular central scar (arrow) with radiating septa (arrowheads) that separate the hyperplastic hepatocytes into nodules. (c) Transverse US image shows the well-circumscribed, ho-mogeneous, slightly hypoechoic mass (arrows) in the liver. (d) Color Doppler image shows flow in vessels radiat-ing outward from the central scar. (e) On a duplex US image, the Doppler spectrum of the intratumoral vessels shows an arterial waveform. (f) Arterial phase coronal CT image shows the tumor (arrow) enhancing more than the adjacent liver and lack of enhancement of the central scar (arrowhead). (g) Coronal CT image obtained pos-terior to f shows intensely enhancing vessels (arrow) adjacent to the tumor.


For predominantly cystic mesenchymal hamartomas, differential diagnostic consid-erations include simple cyst, hydatid disease, and abscess if the mass is intrahepatic and choledochal cyst, enteric duplication cyst, and mesenteric lymphangioma if the mass is pedun-culated. Simple cysts can be distinguished from mesenchymal hamartoma by the lack of any internal enhancement (43). Hydatid disease and abscess may be suggested by a history of travel or of fever or immunocompromise. Choledochal cyst is located in the porta hepatis and can be shown with nuclear scintigraphy to communi-cate with the biliary tree. Enteric duplication cysts demonstrate gut signature in their walls and peristalsis at US. The mesenteric origin of lymphangioma may be demonstrated with mul-tiplanar imaging, although intrahepatic lymph-angiomas rarely occur.

Treatment and PrognosisThe natural history of mesenchymal hamarto-ma is to enlarge during the first several months of life and then stabilize or continue to grow. Spontaneous partial regression has been reported (1,26,44). The definitive treatment, if possible, is complete surgical excision with hepatic lobec-tomy or nonanatomic resection (3,31). Partial resection and drainage with marsupialization have been used for unresectable lesions, although disease recurrence may follow (1,3). Orthotopic liver transplantation has also been reported (1), but the benign nature of the mass and reports of spontaneous regression support a conserva-tive surgical approach in lesions that involve vital structures (44). Observation of mesenchymal hamartoma is discouraged due to the potential for rapid growth, as well as the rare reports of malignant transformation to UES (26,35,36). The long-term survival rate is high (90%), even with incomplete resection (1,24).

Focal Nodular HyperplasiaFNH is most often seen in adult women but uncommonly occurs in young children and ado-lescents. FNH is a benign epithelial liver tumor arising from a polyclonal proliferation of hepato-cytes, Kupffer cells, vascular structures, and bil-iary ductules. The lesion demonstrates a complex architecture, with well-differentiated hepatocytes forming nodules subdivided by fibrous septa, which coalesce to form a characteristic central vascular stellate scar (45).

PathogenesisAlthough the exact pathogenesis of the lesion re-mains uncertain, it is generally accepted that FNH is the result of a vascular abnormality and most likely represents a hyperplastic response to a pre-existing vascular malformation within the central scar (45,46). Some authors have suggested that the mass arises from a focal injury or circulatory disturbance within the hepatic parenchyma lead-ing to vascular thrombosis, subsequent recanaliza-tion, and reperfusion with resultant hepatocyte proliferation (45). Several studies in children show an increased prevalence of FNH many years after antineoplastic and radiation therapy for solid ma-lignancies, suggesting that chemotherapy-induced vascular injury, including veno-occlusive disease, leads to development of FNH (47). Oral contra-ceptive use and pregnancy, once considered risk factors for the development of FNH, are no longer considered etiologic factors (45).

Epidemiology and Clinical FeaturesFNH represents 2% of all primary hepatic tu-mors in children from birth to age 20 years (1). In the pediatric population, the lesion is typically diagnosed between the ages of 2 and 5 years (48). Although generally regarded as the result of a congenital vascular malformation, FNH has not been reported in a newborn or stillborn, to our knowledge. A marked female predominance of the lesion is reported (45).

As a benign mass with nonaggressive features, FNH is most commonly an incidental finding at imaging, in surgical specimens, or at autopsy. Symptoms of a mass lesion are described in 20% of cases (45). Abdominal pain is another com-mon symptom. Tumor rupture and hemorrhage are rare (45). AFP levels are not elevated (45).

Pathologic FeaturesAt gross inspection, FNH appears as a solitary mass or, less commonly, multiple lesions that may bulge from the surface of the liver. The mass is well-circumscribed, lobulated, and unencap-sulated, although it may be surrounded by a rim of fibrous tissue of variable thickness. Most arise in the right lobe (1,40,45). A central fibrous scar can be seen macroscopically within the light red–brown-tan mass in most cases (Figs 8, 9) (4,7). Foci of hemorrhage, necrosis, or infarction are rare, in contradistinction to the findings of hepa-tocellular adenoma (45).


At histologic examination, the lesion paren-chyma consists predominantly of hyperplastic hepatocytes. Normal acinar architecture, portal

tracts, and interlobular bile ducts are absent (Fig 8). The hyperplastic hepatocytes are similar to normal hepatocytes but may be larger and paler. In addition to the hepatocyte proliferation, there is proliferation of biliary epithelium, which forms

Figure 9. FNH in a 14-year-old girl. (a) Photograph of the resected specimen shows a nodular mass with a central stellate scar (arrowhead) and an adjacent large vessel (arrow). * = normal liv-er. (b) Axial T2-weighted MR image shows that the mass (curved arrow) is homogeneously isoin-tense except for the hyperintense central scar (arrowhead) and a large flow void (straight arrow) at the periphery. (c) Nonenhanced axial T1-weighted MR image shows that the mass (curved arrows) is minimally hyperintense relative to adjacent liver and that the central scar (arrowhead) is hypointense. Straight arrow = adjacent artery. (d) Arterial phase axial T1-weighted MR image shows that the mass (arrow) uniformly enhances more than the liver. The central scar does not en-hance (arrowhead). (e) Delayed phase axial MR image shows that the mass (arrow) is isointense relative to the liver; there is some enhancement of the central scar (arrowhead). (f) Coronal image from hepatobiliary scintigraphy shows focal increased activity in the mass (arrow) compared with that in the adjacent liver. * = biliary tree.


ductules but no bile ducts, so that there is no connection to the biliary tree. Kupffer cells are typically present (45).

The vascular central stellate scar is also char-acteristic of FNH. Composed predominantly of large arteries and smaller venous structures in a myxomatous stroma, the vascular component is present throughout the septa that radiate from the central scar (Fig 8) (45).

Imaging FeaturesThe appearance of FNH at imaging reflects its pathologic features. Because the mass is com-posed predominantly of hepatocytes, it appears similar to normal liver, and the lesion may be inapparent except for mass effect on adjacent structures. The presence of the central scar may aid identification of the mass on nonenhanced scans (49). The vascular supply from the hepatic artery causes early contrast enhancement relative to the adjacent parenchyma. The scar often dem-onstrates delayed enhancement as contrast mate-rial diffuses into the myxomatous stroma (21). Atypical imaging features are fairly common, and multiple imaging studies may be required to ob-tain a specific diagnosis.

At US, FNH appears as a homogeneous, well-circumscribed mass that may be iso-, hypo-, or hyperechoic (Fig 8) (50). The central scar ap-pears hyperechoic relative to the remainder of the mass (48,50). Calcification is rare. Color and power Doppler evaluation of the mass reveals increased blood flow in the central scar extending to the periphery in a spoke-wheel pattern (Fig 8) (21,51,52). Spectral analysis of intratumoral flow reveals arterial waveforms, a finding that distin-guishes FNH from hepatocellular adenoma, in which intratumoral flow is venous (51).

At unenhanced CT, FNH is typically well cir-cumscribed and iso- to slightly hypoattenuating to uninvolved liver, and the scar is hypoattenuat-ing (49,50,52–54). FNH typically demonstrates early, uniform enhancement after intravenous administration of iodinated contrast material. The mass enhances more than the adjacent liver in the arterial and early portal venous phases and becomes isoattenuating to the liver in the late portal venous and delayed phases (49,50,53,54). Enlarged feeding arteries may be apparent on arterial phase images (Fig 8) (49,53). The stel-late scar is typically hypoattenuating on early contrast-enhanced images and demonstrates enhancement on delayed images (Fig 8) (49). An enhancing artery may be seen within the hypoat-tenuating scar on arterial phase images (49,53).

Atypical features may be observed including lack of the central scar, rapid washout of contrast ma-terial in the portal venous phase, lack of enhance-ment of the central scar on delayed images, early draining veins, and partial peripheral rim-like enhancement on delayed images (49,53).

At MR imaging, FNH typically appears ho-mogeneous and iso- to slightly hypointense to the liver on T1-weighted images and iso- to slightly hyperintense on T2-weighted images (Fig 9) (50,55,56). The scar is usually hypointense to un-involved liver on T1-weighted images and hyper-intense on T2-weighted images owing to edema within the myxomatous tissue of the scar (Fig 9) (50,55,56). Dynamic imaging after intravenous administration of gadolinium contrast material shows uniform enhancement of the mass, which is hyperintense to the liver on arterial phase im-ages and isointense to slightly hyperintense on portal venous phase images (Fig 9) (21,52,55). In general, delayed images demonstrate enhance-ment of the central scar (Fig 9) (56). In surgical series, which have a selection bias for cases with difficult imaging diagnoses, up to one-half of le-sions display an atypical appearance at MR imag-ing (56). Atypical features include lack of a scar, a scar that is hypointense on T2-weighted images, a T1-hypointense enhancing pseudocapsule due to compression of surrounding parenchyma with mild fibrosis, and a strongly hyperintense lesion on T2-weighted images or diffusely hyperintense lesion on T1-weighted images (56).

FNH demonstrates a characteristic appearance at scintigraphy that correlates with its histologic features. 99mTc sulfur colloid imaging typically exhibits normal uptake in 60%–75% of lesions owing to the presence of Kupffer cells (Fig 10) (48,57). The abundance of Kupffer cells is variable in FNH, and the remainder of the lesions show either increased or, less commonly, decreased ra-diotracer accumulation relative to normal liver pa-renchyma. Normal or increased uptake of colloid by the mass distinguishes FNH from hepatic ad-enoma and malignant tumors (50,52). For smaller lesions, SPECT is particularly useful in localizing the region of radiopharmaceutical uptake. At cholescintigraphy, increased uptake with delayed excretion is shown in 90% of cases, presumably due to uptake by functional hepatocytes within the lesion and abnormal excretion by the biliary ductules, which do not communicate with the bil-iary tree (Fig 9) (57).


Figure 10. FNH in a 15-year-old girl. (a) Arterial phase coronal T1-weighted MR image shows a ho-mogeneously enhancing mass with hypointense eccentric scars (arrowhead). (b) Coronal single-photon-emission computed tomographic (SPECT) image from a sulfur colloid study shows slightly increased uptake in the mass (arrow) relative to the adjacent liver.

Differential DiagnosisDifferential diagnostic considerations for FNH include other solid tumors that occur in children. The typical homogeneous, nearly isoattenuating appearance distinguishes FNH from the malig-nant tumors hepatoblastoma and hepatocellular carcinoma, which are more likely to appear het-erogeneous due to hemorrhage, necrosis, and calcification. In addition, both are associated with elevated levels of serum AFP, which is absent in FNH. On the other hand, atypical features of FNH overlap with imaging findings in malignant tumors. In such cases, biopsy may be necessary.

Fibrolamellar carcinoma may also occur in adolescents and demonstrate a central scar. Unlike the vascular myxomatous scar of FNH, the scar of fibrolamellar carcinoma is collagenous and consequently is hypointense, rather than hyperintense, on T2-weighted images and does not enhance on delayed images. Hepatocellular adenoma may also occur in adolescents, espe-cially girls taking oral contraceptives. FNH may be differentiated from hepatic adenoma on the basis of imaging features, as described in the “Hepatocellular Adenoma” section.

Treatment and PrognosisFNH has no known malignant potential, grows very slowly, rarely causes complications such as hemorrhage or rupture, and may be managed conservatively in asymptomatic patients (48). Symptomatic patients should undergo surgical resection, if possible, or, alternatively, ablative therapy or embolization (48).

Hepatocellular AdenomaHepatocellular adenoma, or hepatic adenoma, is a rare benign hepatic neoplasm that is etiologi-cally associated with the use of steroids, especially oral contraceptives. Imaging findings reflect its histologic composition of sheets of hepatocytes containing intracellular fat and glycogen and its propensity for intratumoral hemorrhage.

Clinical FeaturesMost cases of hepatocellular adenoma occur in women in their reproductive years with a mean age of 30 years. Pediatric patients mainly con-sist of girls over 10 years old, most of whom have a history of oral contraceptive use (24,58). Androgenic steroid therapy is also associated with an increased prevalence of hepatic adenoma and accounts for the occurrence of these neoplasms in pediatric patients with Fanconi anemia (59). Hepatocellular adenomas have been reported in association with several diseases, particularly gly-cogen storage disease types I and III, and also galactosemia and familial diabetes mellitus. There is also an association with congenital and ac-quired abnormalities of the hepatic vasculature, such as portal vein absence or occlusion, and other hypervascular hepatic neoplasms, including adult hemangioma and FNH (60,61).

The main clinical concern is intratumoral hemorrhage, which occurs in approximately 10% of patients, or, in rare instances, rupture with in-traperitoneal hemorrhage and hypovolemic shock (60). More commonly, patients are asymptomatic or present with an abdominal mass. Chronic and acute abdominal pain are other reported symp-toms. Results of liver function tests are usually normal with no elevation of AFP level.


Figure 11. Multiple hepatocellular adenomas in a gravida 1, para 1 16-year-old girl. (a) Photograph of the sectioned explanted liver shows multiple well-demarcated, yellow-tan masses. (b) In-phase axial T1-weighted gradient-echo MR image shows a heterogeneous, predominantly hypointense mass (arrow-heads) with a small hyperintense focus consistent with hemorrhage. In addition, there is also an isoin-tense mass (arrow). (c) Out-of-phase axial MR image shows a decrease in the signal intensity of both masses (arrowheads, arrow), a finding indicative of intralesion fat. (d) Nonenhanced axial T1-weighted spoiled gradient-echo MR image shows the well-defined masses (T). One is slightly hypointense rela-tive to the liver; the other is isointense. (e) Arterial phase axial T1-weighted MR image shows that both masses (T) enhance slightly more than the liver. An additional smaller lesion is visible (arrow). (f) Portal venous phase MR image shows that the masses (T) are isointense to slightly hypointense relative to the liver. Straight arrow = additional smaller lesion, curved arrow = adjacent enlarged vein.

Pathologic FeaturesAt macroscopic examination, approximately 70%–80% of hepatocellular adenomas are soli-tary. They are more often multiple in the setting of anabolic androgen therapy or glycogen storage disease (45). Liver adenomatosis has been de-

fined as a separate entity consisting of over 10 ad-enomas per patient without underlying glycogen storage disease or steroid use (Fig 11) (62,63).


Kupffer cells are present, although they dem-onstrate reduced numbers and function com-pared with those in normal liver, so that little uptake is seen after 99mTc sulfur colloid admin-istration (61). Bile ducts are absent. Large peri-

Figure 12. Hepatocellular adenoma in a 19-year-old woman. (a) Photograph of the sectioned gross specimen shows a heterogeneous mass with a pseudocapsule (arrowhead) and intratumoral hemorrhage (arrow). (b) Photomicrograph (original magnification, ×400; H-E stain) of a specimen from an 8-week-old patient shows hepatocytes arranged in sheets without normal acinar archi-tecture. Some cells contain clear lipid vacuoles. (c) Axial contrast-enhanced CT image shows the heterogeneous mass with its pseudocapsule (arrowheads). The mass has a layered appearance with the dependent portion being relatively hyperattenuating, a finding that corresponds to the hemor-rhage seen in a. (d) Axial nonenhanced T1-weighted MR image shows the mass in the left lobe (arrowheads) and the dependent area of high signal intensity representing hemorrhage (arrow). (e) Axial T2-weighted MR image shows that the mass is heterogeneous, with the area of hemor-rhage being markedly hypointense (arrow).

Hepatocellular adenomas are spherical or ovoid well-circumscribed masses (45). Most are 1–15 cm in diameter and yellow to tan-brown (Fig 11). Heterogeneity is frequent due to areas of necrosis, hemorrhage, myxoid stroma, or calci-fication (Fig 12) (61). They are usually unencap-sulated, although a pseudocapsule of compressed adjacent hepatic parenchyma may be present.

At histologic examination, hepatocellular ad-enomas are composed of benign-appearing hepa-tocytes in sheets or cords rather than the normal acinar pattern (Fig 12). The cells usually contain increased amounts of fat and glycogen compared with the hepatocytes in the surrounding normal liver, except in the glycogenoses, in which the op-posite is true (45).


Figure 13. Hepatocellular adenoma in a 21-year-old woman. * = normal liver. (a) Photograph of the gross specimen shows hemorrhage (arrowheads) within the mass. (b) Nonenhanced CT image shows the heterogeneous mass replacing the right hepatic lobe. The hyperattenuating focus (arrowhead) is indicative of acute hemorrhage.

tumoral arteries feed the sinusoids; in combina-tion with poor connective tissue support, this feature is thought to predispose these neoplasms to hemorrhage.

Imaging FeaturesThe appearance of hepatocellular adenoma varies depending on its pathologic composition. Those without hemorrhage are homogeneous and simi-lar in appearance to adjacent normal liver. The presence of intratumoral hemorrhage or intracel-lular fat produces distinguishing imaging features.

The US appearance of hepatocellular ad-enomas depends both on the composition of the lesion and that of the surrounding liver. Lesions with a high lipid content or hemorrhage may be hyperechoic to the normal liver; however, in the background of diffuse fatty infiltration or glycogen storage disease, adenomas may be hypoechoic compared with the remainder of the liver (64). Color Doppler evaluation may demonstrate cen-tral vessels with a triphasic pattern or a continuous flat venous waveform with no central arterial flow (65), in contrast to FNH, which has predominant central arterial flow. Peripheral peritumoral arterial and venous waveforms may be seen.

At CT, hepatocellular adenomas are typically sharply marginated, with a pseudocapsule seen in 25%–30% (Fig 12) (61,66). On unenhanced im-ages, most lesions are hypoattenuating compared with normal liver, although areas of hyperattenu-ation are seen with recent hemorrhage in approxi-mately 15%–43% (Fig 13) (61,66–68). They may be heterogeneous with areas of lipid or fat seen at CT in 7%–10% and calcification in 5%–15% (61,64,66). Smaller lesions, less than 4 cm, are typically homogeneously enhancing, whereas larger lesions heterogeneously enhance because of necrosis, fat, hemorrhage, and calcification (Fig 12). Hepatocellular adenomas demonstrate prefer-

entially hepatic arterial enhancement after admin-istration of iodinated contrast material, with most being hyperattenuating compared with the normal liver in the arterial phase and isoattenuating in the portal venous and delayed phases.

At MR imaging, most hepatocellular ad-enomas are predominantly hyperintense to the normal liver on T1-weighted and T2-weighted images (35%–77% and 47%–74%, respectively) (61,69–71). T1 hyperintensity from intracellular glycogen or lipid demonstrates signal dropout on opposed-phase or fat-suppressed images in 36%–77% of cases (Fig 11) (61). However, this finding is not specific for adenoma, as 40% of hepatocellular carcinomas also histologically contain fat. T1 hyperintensity can also be due to hemorrhage in 52%–93% of cases (Fig 12) (61). T2 hyperintense areas may represent hemorrhage or areas of peliosis-like changes at patholog-ic analysis (60,69). A peripheral pseudocapsule may be seen that is hypointense on T1-weighted images, is variable on T2-weighted images, and may enhance (Fig 12). According to a study of 51 adenomas by Arrive et al (69), 88% of hepatic adenomas demonstrated one of the following findings: tumor heterogeneity, a peripheral rim, or hyperintense T1 signal. As with CT, hepatic adenomas usually demonstrate early arterial enhancement on MR images after intravenous administration of gadolinium contrast material, becoming isointense to the liver on portal venous and delayed phase images (Fig 11).

Nuclear medicine studies show nonspecific findings. A focal photopenic defect is seen on 99mTc sulfur colloid scans. At hepatobiliary scintigraphy, because of the lack of bile ducts, hepatocellular adenomas demonstrate increased uptake or retention of the radiotracer (72).


Figure 14. NRH. (a) Photograph of the sectioned resected specimen from a 10-year-old girl shows replace-ment of part of the liver by a cluster of yellow-brown nodules. * = normal liver. (b) Photomicrograph (original magnification, ×40; H-E stain) shows coalescing relatively pale nodules surrounded by darker intervening pa-renchyma. (c) US image obtained in a 21-year-old man shows a well-circumscribed, homogeneous, hypoecho-ic hepatic mass (arrow). (d) On a contrast-enhanced CT image, the mass (arrow) diffusely enhances more than adjacent liver. (e) Axial T1-weighted MR image shows that the mass (arrow) is ill defined and slightly hypoin-tense relative to the liver with a slightly hyperintense partial rim. (f) Axial T2-weighted MR image shows the ill-defined hyperintense mass (arrow).

Differential DiagnosisOther liver lesions that are hyperattenuating in the arterial phase of contrast-enhanced studies include FNH, hepatocellular carcinoma, and

fibrolamellar carcinoma. FNH frequently has a stellate scar and is homogeneous, whereas hepatic adenoma does not have a scar and may be quite heterogeneous in appearance due to intratumoral hemorrhage or fat. Also, FNH lacks the intrale-


sion fat and glycogen evident in hepatic adenoma on opposed-phase T1-weighted gradient-echo or fat-suppressed images. Doppler US evaluation of intratumoral flow can also be used to differentiate the two benign tumors, as FNH has arterial flow in a spoke-wheel pattern whereas adenoma has venous flow (51). In addition, 99mTc sulfur colloid scans usually demonstrate normal or increased uptake of radiopharmaceutical in FNH, whereas a photopenic defect is seen with hepatic adeno-ma, which lacks Kupffer cells (60,61,66).

Hepatocellular carcinoma may have imaging characteristics similar to those of hepatocellular adenoma, but most hepatocellular carcinomas occur in the setting of cirrhosis with findings of portal hypertension or other signs of malignancy, such as vascular invasion or metastatic disease. Fibrolamellar carcinoma arises in a normal liver, but adenopathy and an eccentric scar with calcifi-cation are common findings in fibrolamellar car-cinoma that are not seen in hepatic adenoma.

Treatment and PrognosisWith the discontinuation of oral contraceptives or the institution of dietary therapy for glycogen storage disease, some hepatocellular adenomas spontaneously regress; however, others remain stable or enlarge. Some authors advocate surgical excision of all hepatocellular adenomas because of the risk of rupture and hemorrhage. There ap-pears to be an increased risk of bleeding with in-creasing size of the neoplasm and duration of oral contraceptive use (72). There are also reported cases of hepatocellular carcinoma arising in both solitary and multiple adenomas (45), particularly those greater than 4 cm in size (73). Alternatives to surgical resection include percutaneous proce-dures such as radiofrequency ablation (74).

Nodular Regenerative HyperplasiaNRH may occur in patients of any age and has infrequently been reported in children (45,75,76). NRH is characterized by regenerative nodules sur-rounded by atrophic liver in the absence of fibro-sis. The nodules vary in size from a few millimeters to several centimeters.

Epidemiology and Clinical FeaturesThe pathogenesis of NRH is not fully under-stood, but a small-vessel etiology is suspected. It is hypothesized that decreased flow to some acini causes atrophy, while adjacent acini with pre-served flow undergo compensatory hyperplasia. Causes of these blood flow alterations are likely varied (45). NRH is often seen in association with a plethora of underlying diseases, such as myelo- and lymphoproliferative disorders, au-toimmune disorders, collagen vascular disease,

and Budd-Chiari syndrome (45,77). In addition, there is an association with use of certain drugs, including steroids, immunosuppressive drugs, and antineoplastic agents. There is no gender predilection.

One-half of cases are found incidentally dur-ing studies performed for other indications, but one-half have signs and symptoms of portal hy-pertension (45). NRH should be considered in young patients with portal hypertension and no evidence of portal vein thrombosis.

Pathologic FeaturesAt macroscopic examination, unencapsulated yellow-tan nodules of varying sizes are seen dif-fusely within atrophic liver parenchyma (Fig 14). Evidence of central hemorrhage or infarction may be noted in larger lesions (45).

At histologic analysis, these monoacinar nod-ules are composed of hyperplastic hepatocytes resembling normal hepatocytes. Smaller nodules appear to coalesce to form larger ones. In larger nodules, the hepatocytes are often larger and paler than normal hepatocytes (Fig 14). They may demonstrate vacuolated cytoplasm due to increased intracellular glycogen or lipid, similar to cells composing hepatocellular adenomas. The nodules contain Kupffer cells. The surrounding parenchyma demonstrates acinar atrophy but no fibrosis. Small nodules are difficult to detect, es-pecially in needle biopsy specimens (45).

Imaging FeaturesThe appearance of NRH at imaging is variable and depends in part on the size of the nod-ules. Diffuse tiny nodules are not detected, and the imaging appearance of the liver is normal. Nodules have a propensity to coalesce and may then become evident at imaging; however, the masses are composed of hepatocytes like the sur-rounding liver, and even large nodules may be difficult to distinguish from the adjacent paren-chyma. Findings related to portal hypertension, including esophagogastric varices, ascites, and splenomegaly, may be observed (76).

At US, the nodules may be inapparent or le-sions may manifest only as heterogeneous echo-texture or distortion of normal architecture. If visible, the nodules are generally well-circum-scribed, homogeneous, and hypoechoic but may be hyperechoic compared with normal liver (Fig 14) (75,76,78). Occasionally, they may appear hyperechoic with hypoechoic centers, a finding possibly related to prior hemorrhage (75,76).

At CT, the masses are usually hypoattenuating to normal liver on precontrast images, although


they may be isoattenuating (75,76). After intrave-nous administration of iodinated contrast material, they usually do not enhance and appear hypoat-tenuating to normal liver (75,76). Occasionally, they may enhance diffusely (77) or demonstrate peripheral rim-like enhancement (Fig 14) (78).

At MR imaging, the nodules that are visible are most commonly homogeneous and slightly hyperintense to uninvolved liver on T1-weighted images and variable on T2-weighted images, al-though a T1 hyper- or hypointense or T2 hyper-intense rim may be noted (Fig 14) (75,77–79). Decreased signal intensity on fat-suppressed T1-weighted images may be observed due to intra-cellular fat, similar to findings in hepatic adenoma (79). After intravenous injection of gadolinium contrast material, the nodules may enhance pref-erentially in the portal venous phase like normal liver parenchyma (75).

Differential DiagnosisNRH is difficult to diagnose at imaging owing to its variable, nonspecific findings and similarity to other hepatocellular lesions, including FNH and hepatocellular adenoma. The nodules are fre-quently multiple, a finding suggestive of metastatic disease. Most of these lesions differ from NRH in that they demonstrate arterial phase enhance-ment, which NRH does not. There is an increased prevalence of NRH in patients previously treated for solid tumors; this increased prevalence causes a diagnostic dilemma (47). In most cases, the di-agnosis must be confirmed pathologically (45). A large specimen from an open biopsy may be neces-sary to obtain a proper diagnosis (45,76,79).

Treatment and PrognosisThere is no specific treatment outside of dis-continuation of any associated drugs; such dis-continuation can bring about lesion regression. Nodules that continue to grow may coalesce and form large nodules, which can develop hemorrhage or even rupture, like hepatocellular adenomas (45). Malignant transformation to he-patocellular carcinoma may occur (45). Patients with portal hypertension may benefit from surgi-cal portocaval shunts, and their prognosis is far better than that of patients with portal hyperten-sion due to cirrhosis (45).

ConclusionsBenign hepatic masses in children include tu-mors that are unique to children and others that are more common in adults. Knowledge of

the pathologic spectrum of hepatic lesions in children and how their pathologic features are represented at imaging helps the radiologist di-rect proper evaluation and treatment of children with focal liver masses.

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This article meets the criteria for 1.0 AMA PRA Category 1 CreditTM. To obtain credit, see the questionnaire on pp 838–844.

Teaching Points May-June Issue 2010

From the Archives of the AFIP Pediatric Liver Masses: Radiologic-Pathologic Correlation Part 1. Benign TumorsEllen M. Chung, COL, MC, USA • Regino Cube, CPT, MC, USA • Rachel B. Lewis, LCDR, MC, USN • Rich-ard M. Conran, COL, MC, USA

RadioGraphics 2010; 30:801–826 • Published online 10.1148/rg.303095173 • Content Codes:

Page 802Infantile hemangioendothelioma, or infantile hepatic hemangioma, is a vascular neoplasm and the most common benign hepatic tumor of infancy.

Page 807Typically, evidence of high flow is apparent, as manifest by enlargement of the hepatic arteries and veins and possibly tapering of the abdominal aorta below the origin of the celiac axis (Fig 2) (8,18). Owing to the risk of bleeding, biopsy of these masses is avoided, and the diagnosis is made on the basis of typical imaging findings and the demonstration of involution at follow-up.

Page 811Mesenchymal hamartoma of the liver is the second most common benign liver mass in children after in-fantile hemangioendothelioma (1,3,24). The gross appearance, which ranges from predominantly cystic to predominantly solid, determines the imaging features. The vast majority of mesenchymal hamartomas contain cysts.

Page 817The appearance of FNH at imaging reflects its pathologic features. Because the mass is composed pre-dominantly of hepatocytes, it appears similar to normal liver, and the lesion may be inapparent except for mass effect on adjacent structures. The presence of the central scar may aid identification of the mass on nonenhanced scans (49). The vascular supply from the hepatic artery causes early contrast enhancement relative to the adjacent parenchyma. The scar often demonstrates delayed enhancement as contrast mate-rial diffuses into the myxomatous stroma (21). Atypical imaging features are fairly common, and multiple imaging studies may be required to obtain a specific diagnosis.

Page 818Hepatocellular adenoma, or hepatic adenoma, is a rare benign hepatic neoplasm that is etiologically associated with the use of steroids, especially oral contraceptives. Imaging findings reflect its histologic composition of sheets of hepatocytes containing intracellular fat and glycogen and its propensity for intratumoral hemorrhage.

from the archives of the afip - imagenologia...

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