Diagnosis and Prognostic Profiles for the Genotype/
Phenotype Subgroups of Hepatocellular Adenomas Using
Contrast-Enhanced MRI with Histopathological Correlation
Poster No.:
C-1242
Congress:
ECR 2013
Type:
Educational Exhibit
Authors:
N. Bastati , D. S. Feier , C. Balassy , L. Grazioli , F. Caseiro
1
4
2
1
1 1
3
2
3
Alves , A. Ba-Ssalamah ; Vienna/AT, Cluj napoca/RO, Brescia/
4
IT, Coimbra/PT
Keywords:
Molecular, genomics and proteomics, Cancer, Diagnostic
procedure, Contrast agent-intravenous, MR-Functional imaging,
MR, Molecular imaging, Management, Liver
DOI:
10.1594/ecr2013/C-1242
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Learning objectives
To review the recent genotype/phenotype classification of hepatocellular adenomas
based on principles of the cytogenetics and molecular biologic properties.
To highlight the ability of MRI, to classify the most majority of these different subgroups
based on specific features such as signal intensity and fat content.
To discuss the role of MRI using different contrast agents, to distinguish between
hepatocellular Adenoma and other focal liver lesions.
Background
Although Hepatocellular Adenoma (HCA) is classified as a benign liver lesion, clinically,
it is considered as a borderline tumor, especially if it reaches a certain (#5cm) size,
due to the risk of hemorrhage, growth, rupture and even malignant transformation.
Therefore, the management of this lesion varies, depending on the size, histological
subtype and clinical presentation. Recently, HCAs have been divided into four genotype/
phenotype subgroups: (1) hepatocyte nuclear factor 1a(HNF-1a)-inactivated, (2) bcatenin-activated, (3) inflammatory, and (4) an unclassified or mixed type. These
genotype/phenotype subgroups are associated with different prognostic profiles. The
recent literature has reported a close correlation between pathological classification of
HCAs and imaging features on magnetic resonance imaging (MRI). In this educational
exhibition, we demonstrate the correlation between the MRI features of HCAs and
their genotype/phenotype sub-classification. We highlight the diagnostic value of MRI
after administration of different contrast agents to distinguish HCA accurately and noninvasively from other benign or malignant liver tumors.
Imaging findings OR Procedure details
1) Inflammatory HCA (I-HCA)
I-HCA is the most common subtype and accounts for up to 40-55% of all HCAs. The
majority of affected patients are obese women or women with a history of longstanding
oral contraceptive (OC) use; I-HCA is rarely seen in men.
Histology: I-HCAs are characterized by marked sinusoidal dilatation, polymorphous
inflammatory infiltrates, and thickened tortuous arteries.
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Clinical presentation: Patients with I-HCAs may manifest a systemic inflammatory
syndrome with fever, leukocytosis, and elevated serum C-reactive protein (CRP).
MR imaging features: I-HCAs are markedly hyperintense on T2-w images, with a higher
signal intensity at the periphery of the lesion, correlating with dilated sinusoids, the socalled "atoll sign." On T1-w images,
I-HCAs are isointense or mildly hyperintense, with minimal or no signal drop-off using
chemical shift sequences due to the lack of significant fat content. After administration
of extracellular gadolinium-chelates contrast material, I-HCAs usually show intense
enhancement during the arterial phase, which persists in the portal venous and delayed
phases. A T2-hyperintense region typically enhances in the late vascular phase, possibly
corresponding to dilated sinusoids within inflammatory HCA.
After injection of a gadolinium-based "bimodal" contrast agent, either Gd-EOB-DTPA,
(Primovist® / Eovist®; Bayer Healthcare Berlin, Germany) or Gd-BOPTA, (Multihance®;
Bracco Imaging, Milan, Italy), I-HCAs show an enhancement pattern similar to that of
extracellular gadolinium-chelates contrast material in the dynamic imaging. However,
I-HCAs demonstrate wash-out in the hepatobiliary phase, 20 or 60 min. after i.v.
administration of Gd-EOB-DTPA or Gd-BOPTA, respectively. This wash-out may be
related to the expression and function of hepatic transporter proteins located either on
the sinusoidal (OATP) or canalicular side (MPR) of the cell membrane that regulate the
hepatocellular uptake and secretion of these contrast agents.
After administration of mangafodipir trisodium or Mn-DPDP (sold under the brand name
Teslascan®, but no longer available for clinical use) as a hepato-specific contrast agent, IHCAs have demonstrated uptake in a manner contrary to the other bimodal hepatobiliary
contrast agents, due to a different uptake mechanism via vitamin B6 receptors on
hepatocytes.
After the administration of a superparamagnetic iron oxide (SPIO) contrast agent,
(sold under the brand names Resovist® or Endorem® no longer available for clinical
use either),I-HCAs demonstrate a signal loss on T2/T2*-w sequences due to the
susceptibility effects of the iron oxide core through uptake by phagocytic Kupffer cells in
the reticuloendothelial system (RES). I-HCAs showed a variable uptake depending on
the variable content of Kupffer cells.
Management
I-HCAs are more prone to bleeding and about 10% of HCAs may show an increased risk
for malignancy. Therefore, surgical resection or close follow-up, depending on the lesion
size, is recommended.
2) HCA with HNF-1a Gene Mutation (Steatotic Adenoma)
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HNF-1a -mutated, or steatotic HCAs are the second most common type of HCAs and
constitute about 30 to 35% of all HCAs.
Histology: HNF-HCAs are characterized by markedly diffuse intralesional fat content due
to increased fatty acid synthesis and impaired transport of fatty acids, which results in
excessive intratumoral lipid accumulation.
Clinical presentation: HNF-1a-mutated HCAs occur almost exclusively in women with a
history of OC use. Germ line mutations of the TCF1 gene result in maturity-onset diabetes
of the young type 3 and familial adenomatosis.
MR imaging features: On T1-w images, steatotic HCAs are typically hyperintense due
to the presence of diffuse fat or glycogen. Fat content leads to diffuse signal loss on
T1 out-of-phase, compared to in-phase, images. On T2-w images, HCAs appear as
homogenous masses that may be hypointense or hyperintense to the surrounding liver.
After administration of an extracellular gadolinium chelate, moderate enhancement is
seen in the arterial phase without persistent enhancement in the portal venous and
delayed phases. However, after injection of a bimodal contrast agent, either Gd-EOBDTPA or Gd-BOPTA, a wash-out is observed in the hepatobiliary phase. In contrast, an
uptake was seen after the administration of mangafodipir trisodium (Teslascan®).
After the administration of superparamagnetic iron oxide (SPIO) contrast agents,
steatotic-HCAs showed variable uptake, depending on the amount of Kupffer cells within
the lesion.
Management: Among all hepatocellular adenomas, the HNF-1a-mutated HCAs are the
least aggressive subtype: tumors less than 5 cm in maximum dimension present a
minimal risk of bleeding and subsequent rupture, and carry minimal or no risk for the
development of malignancy; therefore, conservative follow-up is indicated as long as the
lesion does not exceed 5 cm in diameter.
3) HCA with b-Catenin Activation
These tumors constitute up to 10% of adenomas and primarily more frequently affect
male patients with glycogen storage disease or those under hormone therapy. This type
of adenoma has a greater potential than the other subtypes of HCAs to undergo malignant
transformation to hepatocellular carcinomas (HCCs).
Histology: HCAs with b-catenin activation show cytologic abnormalities and
pseudoglandular formation similar to that of HCC.
Clinical presentation: The majority of people with glycogen storage disease develop HCA
with b-catenin activation by the second or third decade of life.
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MR imaging features: No specific MR imaging patterns have yet been determined for the
identification of b-catenin-mutated HCA.
This subtype of HCAs may appear as homogeneous or heterogeneous hypervascular
masses with intense arterial enhancement, which may or may not persist into the delayed
phase. They lack intratumoral fat.
Again, wash-out is seen after the administration of bimodal contrast agents in the
hepatobiliary phase.
b-catenin-mutated HCAs showed uptake after the administration of mangafodipir.
Superparamagnetic iron oxide (SPIO) uptake was expected, as the lesion contains
Kupffer cells of variable content, which leads to a relative loss of signal intensity on SPIOenhanced T2-w images, based on the amount of Kupffer cells.
Management: Of all the HCAs, b-catenin-mutated HCAs carry the highest risk of
malignancy. Therefore, close-interval imaging follow-up, biopsy, and / or surgical
resection may be indicated in this subset of patients.
4) Unclassified Hepatocellular Adenoma
This group includes the remaining approximately 10% of all HCAs.
Histology: This type has none of the distinct genetic alternations and is without specific
pathologic abnormalities.
MR imaging features: This atypical group does not have any imaging features considered
to be specifically associated with it.
These HCAs may appear as homogeneous or heterogeneous isovascular or
hypervascular masses, which may or may not persist into the portal venous or delayed
phases. They lack significant intratumoral fat.
However, wash-out is seen after the administration of bimodal contrast agents in the
hepatobiliary phase.
Unclassified HCAs showed uptake after administration of mangafodipir.
After the administration of SPIO contrast agents, variable signal loss on T2/T2*-w images
was seen, based on the amount of Kupffer cells.
Management: Observation should be the first treatment choice for lesions smaller than 5
cm, or for lesions that demonstrate regression during radiological follow-up.
Differential Diagnosis based on contrast-enhanced MRI
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FNH: Unlike HCAs that show wash-out in the hepatobiliary phase, 20 or 60 minutes after
injection of Gd-EO-DTPA or Gd-BOPTA, respectively, FNHs show uptake and remain
isointense or become even hyperintense on hepatobiliary phase imaging. An exception
is FNH with steatosis, which may mimic wash-out in a HCA.
Lymphoma, Cholangiocarcinoma and Metastases: These malignant focal liver lesions
may show, in particular cases, MRI features similar to that of HCAs. In addition, on
contrast-enhanced MRI, using extracellular or even bimodal contrast agents, it is not
possible to clearly distinguish these malignant lesions from HCAs, due to the overlapping
enhancement pattern. However using mangafodipir-enhanced MRI, in which HCAs
always demonstrate uptake, it was possible to noninvasively discriminate these malignant
lesions from HCAs. Mangafodipir is not commercially available any longer, and thus,
biopsy is now necessary.
HCC in Non-cirrhotic Liver Lesions: Hepatocellular carcinomas (HCCs) may have an
imaging appearance similar to that of HCAs; HCCs may have a variable proportion of fat,
hemorrhage, and necrosis and commonly appear as heterogeneously enhancing solid
masses that show arterial phase enhancement and wash-out during the portal venous
phase. Furthermore, they show the same enhancement pattern after the administration
of all hepato-specific contrast agents. Therefore, HCCs may be indistinguishable from
HCAs. However, the presence of an infiltrative growth pattern, portal or hepatic venous
thrombosis, lymph nodes, and/or distant metastases helps discriminate HCCs from
HCAs. Accurate differentiation may warrant biopsy and histopathologic evaluation.
Images for this section:
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Fig. 1: Fig. 1 Inflammatory hepatocellular adenoma in a 45-year-old woman with longterm use of OC. T2-w image shows a hyperintense lesion 3 cm in diameter in segment
VI of the liver (arrow).
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Fig. 2: Fig. 2 Inflammatory hepatocellular adenoma in a 45-year-old woman with longterm use of OC. On T1-w image, the lesion is slightly hypointense (arrow).
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Fig. 3: Fig. 3 Inflammatory hepatocellular adenoma in a 45-year-old woman with longterm use of OC. On the T1-w opposed phase image, there is no significant signal drop
(arrow).
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Fig. 4: Fig. 4 Inflammatory hepatocellular adenoma in a 45-year-old woman with longterm use of OC. Hypervascular adenoma in the contrast-enhanced T1-w image after
injection of Gd-EOB-DTPA obtained in the arterial phase (arrow).
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Fig. 5: Fig. 5 Inflammatory hepatocellular adenoma in a 45-year-old woman with longterm use of OC. The portal venous (PV) phase shows the lesion with persistent
enhancement in the PV phase (arrow).
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Fig. 6: Fig. 6 Inflammatory hepatocellular adenoma in a 45-year-old woman with longterm use of OC. On the hepatobiliary phase (HBP), the lesion shows wash out (arrow).
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Fig. 7: Fig. 7 Follow-up of the same patient with I-HCA in segment VI, using mangafodipirenhanced MRI. On T1-w image, the lesion is slightly hypointense (arrow).
Fig. 8: Fig. 8 Follow-up of the same patient with I-HCA in segment VI, using mangafodipirenhanced MRI. On the HBP after injection of mangafodipir, the lesion appears isointense
due to the uptake of this group of hepatobiliary contrast agents (arrow).
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Fig. 9: Fig.9 I-HCA in a 38-year-old woman with long-term use of OC. The axial T2w image shows a hyperintense lesion 1.5 cm in diameter in segment VII of the liver
subcapsularly (arrow).
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Fig. 10: Fig. 10 I-HCA in a 38-year-old woman with long-term use of OC. On SPIOenhanced T2-w image after injection of (Resovist®), the lesion shows a slight signal
intensity loss, while the liver shows significant signal intensity loss due to the uptake
through the Kupffer cells (arrow).
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Fig. 11: Fig. 11 I-HCA in a 38-year-old woman with long-term use of OC. On the follow-up
of the same patient (Fig 9,10) after two years, the lesion showed significant growth. Due
to the risk of rupture and malignant transformation, the mass was surgically removed.
Histopathologic examination of the specimen confirmed the diagnosis of I-HCA (arrow).
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Fig. 12: Fig. 12 HNF-1#-mutated (steatotic) hepatocellular adenoma in a 26-year-old
woman with a history of elevated liver function parameters. Axial T1-w in-phase, depicts
a large mass that is mildly, inhomogeneously hyperintense on the T1-w image in-phase
(arrow).
Fig. 13: Fig. 13. HNF-1#-mutated (steatotic) hepatocellular adenoma in a 26-year-old
woman with a history of elevated liver function parameters. Axial T1-w-out-of-phase
image depicts a large mass that is mildly, inhomogeneously with significant signal loss
on the out-of-phase image (arrow).
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Fig. 14: Fig. 14 HNF-1#-mutated (steatotic) hepatocellular adenoma in a 26-year-old
woman with a history of elevated liver function parameters. Axial T2-w-image depict a
large mass that is mildly, inhomogeneous hyperintense on the T2-w image (arrow).
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Fig. 15: Fig. 15 HNF-1#-mutated (steatotic) hepatocellular adenoma in a 26-year-old
woman with a history of elevated liver function parameters. Axial unenhanced image
shows a large inhomogeneous hypointense adenoma (arrow).
Fig. 16: Fig. 16 HNF-1#-mutated (steatotic) hepatocellular adenoma in a 26-yearold woman with a history of elevated liver function parameters. Axial Gd-EOB-DTPAenhanced dynamic T1-w image obtained in the arterial phase shows that the lesion has
mild enhancement in the arterial phase, which does not persist into the PV phase(arrow).
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Fig. 17: Fig. 17 HNF-1#-mutated (steatotic) hepatocellular adenoma in a 26-year-old
woman with a history of elevated liver function parameters. Again, in the HBP, the mass
showed wash-out. Histopathologic examination of the specimen after resection confirmed
the diagnosis of steatotic HCA (arrow).
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Conclusion
Contrast-enhanced (CE)-MRI can reliably measure the size and determine the specific
features of at least the two major subtypes of HCAs, namely I-HCA and HNF-HCA, which
make up more than 80% of all HCAs, thus providing the required information for patient
management based on the putative subtype and HCA-size.
CE-MR imaging is the non-invasive modality of choice for the differentiation of
hepatocellular adenoma from other benign and malignant liver lesions.
This is helpful in establishing a correct diagnosis and also give new insights into the
pathogenesis of these lesions and may stimulate the development of molecular imaging
contrast agents.
References
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Personal Information
Nina Bastati-Huber, M.D.
Medical University of Vienna
Department of Radiology
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