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A Pictorial Review of Hepatobiliary Magnetic Resonance Imaging With Hepatocyte-Specific Contrast Agents: Uses, Findings, and Pitfalls of Gadoxetate Disodium and Gadobenate Dimeglumine
Canadian Association of Radiologists Journal xx (2017) 1e15 www.carjonline.org
Abdominal Imaging / Imagerie abdominale
A Pictorial Review of Hepatobiliary Magnetic Resonance Imaging With Hepatocyte-Specific Contrast Agents: Uses, Findings, and Pitfalls of Gadoxetate Disodium and Gadobenate Dimeglumine Elena P. Scali, MDa,*, Triona Walshe, MBBCha, Hina Arif Tiwari, MDb, Alison C. Harris, MDa, Silvia D. Chang, MDa a
Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada b Department of Radiology, University of Arizona, Tuscon, Arizona, USA
Abstract Magnetic resonance imaging (MRI) has a well-established role as a highly specific and accurate modality for characterizing benign and malignant focal liver lesions. In particular, contrast-enhanced MRI using hepatocyte-specific contrast agents (HSCAs) improves lesion detection and characterization compared to other imaging modalities and MRI techniques. In this pictorial review, the mechanism of action of gadoliniumbased MRI contrast agents, with a focus on HSCAs, is described. The clinical indications, protocols, and emerging uses of the 2 commercially available combined contrast agents available in the United States, gadoxetate disodium and gadobenate dimeglumine, are discussed. The MRI features of these agents are compared with examples of focal hepatic masses, many of which have been obtained within the same patient therefore allowing direct lesion comparison. Finally, the pitfalls in the use of combined contrast agents in liver MRI are highlighted. Resume L’imagerie par resonance magnetique (IRM) est reconnue pour sa grande specificite et sa grande precision lorsqu’il s’agit de caracteriser les lesions hepatiques focales benignes et malignes. C’est particulierement le cas de l’IRM avec injection de produits de contraste specifique aux hepatocytes, qui detecte et caracterise les lesions plus efficacement que toute autre modalite d’imagerie ou technique d’IRM. La presente analyse d’images decrit le mecanisme d’action des produits de contraste a base de gadolinium utilises en IRM, en particulier les produits de contraste specifiques aux hepatocytes. Elle presente les indications cliniques, les protocoles et les nouvelles utilisations de deux produits de contraste mixtes commercialises aux Etats-Unis: le gadoxetate disodique et le gadobenate de dimeglumine. Elle compare aussi les images d’IRM realisees a l’aide de ces produits aux images de tumeurs hepatiques focales. Ces images proviennent bien souvent du m^eme patient, ce qui permet une comparaison directe des lesions. Enfin, l’analyse aborde les pieges associes au recours a des produits de contraste mixtes lors d’une IRM du foie. Ó 2016 Canadian Association of Radiologists. All rights reserved. Key Words: Focal liver lesions; Gadobenate dimeglumine; Gadoxetate disodium; Hepatocyte-specific contrast agents; Magnetic resonance imaging
Magnetic resonance imaging (MRI) of the liver routinely employs the use of gadolinium-based contrast agents in order to increase conspicuity and facilitate characterization of focal lesions. Each category of contrast agent offers different properties, which may be tailored to answer a specific clinical question. * Address for correspondence: Elena P. Scali, MD, Department of Radiology, University of British Columbia, 3350-950 West 10th Avenue, Vancouver, British Columbia V5Z 4E3, Canada. E-mail address: [email protected] (E. P. Scali).
Extracellular gadolinium-containing agents consist of gadolinium chelated to an organic compound. Gadolinium shortens the T1 and T2 relaxation times, leading to increased T1 signal intensity. They demonstrate vascular perfusion by distributing into the extracellular fluid compartment and are predominantly renally excreted. Differential vascular perfusion between normal liver parenchyma and focal hepatic lesions enables characterization. In the cirrhotic liver, however, heterogeneous background enhancement may obscure focal lesions [1]. Hepatocyte-specific contrast agents (HSCAs) distribute initially into the extracellular fluid compartment, are
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Table 1 Pharmacologic characteristics of gadobenate dimeglumine and gadoxetate disodium [1,4]
Agent
Gadobenate dimeglumine (MultiHance)
Bolus IV injection Excretion
2 mL/s of 0.1 mmol/kg 3%-5% biliary 95%-97% renal Recommended timing Same as extracellular of dynamic imaging agents Recommended timing 1-2 hours of hepatocyte phase
Gadoxetate disodium (Primovist) 2 mL/s of 0.025 mmol/kg 50% biliary 50% renal Same as extracellular agents 10 minutes to hours, 20 minutes commonly used
Table 2 Magnetic resonance imaging protocol for assessment of focal liver lesions T1-weighted in-phase and opposed-phase imaging T2-weighted fast spin echo magnetic resonance cholangiopancreatography (optional) Unenhanced T1-weighted fat-saturated GRE (optional) T1-weighted fat-saturated hepatic arterial phase or triple arterial phase GRE T1-weighted fat-saturated portal venous phase GRE T1-weighted fat-saturated late venous phase GRE Diffusion-weighted imaging (optional) T2-weighted fast spin echo (with or without fat saturation) T1-weighted fat-saturated hepatocellular phase GRE GRE ¼ gradient recalled echo.
subsequently taken up by functioning hepatocytes and then excreted into biliary canaliculi along the same pathway as bilirubin [2]. Based on gadolinium, these agents cause T1 shortening of the liver and biliary tree and enable comprehensive noninvasive imaging in both the dynamic and hepatocyte phases [3]. As a result of these properties, HSCAs enable differentiation of hepatocellular and nonhepatocellular lesions, the latter of which demonstrate increased conspicuity on delayed T1 images compared to background parenchyma [1]. The pharmacologic characteristics of the 2 commercially available HSCAs in the United States, gadobenate dimeglumine (MultiHance; Bracco, Milan, Italy) and gadoxetate disodium (Eovist or Primovist; Bayer Schering Pharma, Berlin, Germany) are outlined in Table 1. A suggested protocol for performing MRI of focal hepatic lesions with HSCAs is included in Table 2. Gadoxetate disodium possesses slightly different properties than both extracellular contrast agents and gadobenate dimeglumine. The arterial phase appears less intense than with conventional extracellular agents [2]. Strategies to optimize the arterial phase of gadoxetate disodium include injection strategies, such as reducing the injection flow rate and diluting the contrast agent, and fluoroscopic or bolus triggering techniques [4]. Of note, a subset of patients may experience acute transient dyspnea following intravenous injection of gadoxetate disodium, which results in more severely motion degraded images than with gadobenate dimeglumine [5].
Table 3 Typical magnetic resonance imaging findings of common focal liver lesions using hepatocyte-specific contrast agents [1,2,16] Dynamic contrast enhancement
Hepatocyte phase
T1 and T2
Focal nodular hyperplasia
Hypervascular, isointense to background liver on delayed phases
Iso- to hyperintense
Hepatic adenoma
Hypervascular, iso- to slightly hypointense to background liver on delayed phases Inflammatory subtype: hypervascular with persistent enhancement on delayed phases
Gadobenate dimeglumine: variable, isoto hyperintense Gadoxetate disodium: hypointense Inflammatory subtype: iso- to hyperintense
Hemangioma
Discontinuous peripheral nodular enhancement with centripetal progression Hypervascular: hyperintense, iso- or hypointense on delayed phases Hypovascular: hypointense Hypervascular (80%), hypovascular (20%), iso- to hypointense in delayed phases Irregular peripheral rim enhancement, variable central enhancement Iso- to hyperintense in portal venous phase Iso- to hyperintense in portal venous phase May enhance in arterial phase
Hypointense
T1: iso- to hypointense T2: iso- to hyperintense with hyperintense central scar T1: variable, heterogeneously Hyperintense with presence of fat or hemorrhage T2: moderately hyperintense Inflammatory subtype: T1: iso- to mildly hyperintense T2: hyperintense ‘‘Atoll sign’’ in w50% T1: hypointense T2: hyperintense
Metastases
Hepatocellular carcinoma
Cholangiocarcinoma Regenerative nodule Dysplastic nodule, well differentiated Dysplastic nodule, poorly differentiated
Hypointense, targetoid central high signal
T1: hypointense T2: variable, hyperintense
Hypointense (80%), iso- to hyperintense in moderately to well differentiated (20%) Hypointense
T1: variable, heterogeneous T2: iso- to hyperintense
Iso- to hyperintense Iso- to hyperintense Variable, may be hypointense
T1: T2: T1: T2: T1: T2: T1: T2:
hypointense mildly to moderately hyperintense iso- to hyperintense iso- to hypointense variable hyperintense variable, heterogeneous mildly hyperintense
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Hepatocyte uptake occurs rapidly and liver parenchymal enhancement may be seen as early as 90 seconds following injection; due to greater hepatic uptake, there is more intense hepatocyte phase enhancement compared to gadobenate dimeglumine [6,7]. Similarly, rapid hepatocyte clearance of gadoxetate disodium causes the vessels to become hypointense compared to liver parenchyma as soon as 10 minutes postinjection [6]. Hepatocyte phase imaging is generally performed following a 20-minute delay, compared to 12 hours with gadobenate dimeglumine. Impaired gadoxetate disodium uptake in the cirrhotic liver reduces hepatocyte phase enhancement and therefore protocol adjustments may be needed to improve image quality [7e9]. Indeed, peak hepatocyte phase enhancement may be delayed beyond the conventional 20 minutes and may take 40 minutes or more [10]. Significantly higher enhancement ratio has been reported in patients with Child-Pugh class A
3
disease compared to Child-Pugh class C disease [4]. Moreover, initial studies suggest improved lesion-to-liver contrast ratio in the cirrhotic liver with a dose increase from the standard 0.025 mmol/kg to an off-label dose of 0.05 mmol/ kg [11]. MRI Findings in Focal Hepatic Lesions Using HSCAs The typical MRI findings of focal liver lesions using HSCAs are summarized in Table 3. Liver MRI is often used to distinguish 2 benign focal hepatic lesions, nodular hyperplasia (FNH) and adenoma. Although FNH is often managed conservatively, adenomas require more frequent monitoring or resection due to risk of rupture, hemorrhage or malignant transformation. In the absence of typical features, however, FNH and adenoma may be challenging to distinguish using extracellular contrast
Figure 1. Focal nodular hyperplasia in a 40-year-old woman. Gadoxetate disodium magnetic resonance imaging demonstrates iso- to hypointensity on T1-weighted imaging, isointensity on T2-weighted imaging, intense arterial phase enhancement, hyperintensity of the portal venous and transitional phases, and iso- to mild hyperintensity on the hepatocyte phase (arrows).
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Figure 2. Focal nodular hyperplasia in a 34-year-old woman. Gadobenate dimeglumine (top row) and gadoxetate disodium (bottom row) enhanced magnetic resonance imaging in the same patient demonstrates intense enhancement the arterial phase, isointensity to liver parenchyma in the portal venous and transitional phases, and predominately iso- to hyperintense in the hepatocyte phase (arrows).
agents: for example, only approximately half of FNHs demonstrate the classic T2 hyperintense scar and a similar proportion of adenomas contain intratumoural fat [12]. Moreover, a minority of adenoma demonstrates a central enhancing scar, a finding more typically observed in FNH [13].
Focal Nodular Hyperplasia FNH is a benign neoplasm characterized histopathologically by increased density of normal functioning hepatocytes and abnormal blind-ending biliary ductules, which
Figure 3. Hepatic adenoma in a 37-year-old woman. Gadobenate dimeglumine (top row) and gadoxetate disodium (bottom row) magnetic resonance imaging in the same patient demonstrates intense enhancement in the arterial phase, isointensity to liver parenchyma in the portal venous and transitional phases, and hypointensity of the hepatocyte phase (arrows).
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Figure 4. Hepatic adenoma in a 43-year-old woman. Gadobenate dimeglumine (top row) and gadoxetate disodium (bottom row) magnetic resonance imaging in the same patient demonstrates intense enhancement in the arterial phase, fading of enhancement on subsequent phases to isointensity to liver parenchyma in the portal venous and transitional phases, and hypointensity in the hepatocyte phase (arrows).
Figure 5. Inflammatory adenoma in a 46-year-old woman. Gadoxetate disodiumeenhanced magnetic resonance imaging demonstrates the classic ‘‘atoll sign’’ with a band of peripheral hyperintense signal surrounding central isointensity compared to surrounding liver parenchyma on T2-weighted images. Homogeneous arterial phase enhancement, mild peripheral portal venous phase enhancement, and iso- to mildly hypointensity on the hepatocyte phase are seen (arrows).
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Figure 6. Cavernous hemangioma in a 44-year-old woman. Gadobenate dimeglumine (top row) and gadoxetate disodium (bottom row) enhanced magnetic resonance imaging in the same patient demonstrates unique features of gadoxetate disodium with comparatively less intense arterial enhancement, early hepatocyte uptake that may obscure characteristic puddling, hypointensity (‘‘pseudo-washout’’) on the transitional phase, and hypointensity on the hepatocyte phase (arrows).
demonstrate delayed biliary excretion compared to normal liver parenchyma. Risk of rupture and hemorrhage is small and no malignant potential has been reported [14]. FNH is typically iso- to hypointense to background liver parenchyma on T1; iso- to slightly hyperintense on T2-weighted images and hypervascular and fade to isointensity on the portal venous and late dynamic phases (Figures 1 and 2). Hepatocyte phase enhancement is commonly homogeneously iso- to hyperintense due to contrast retention within hepatocytes (Figures 1 and 2); less common patterns include iso- or hypointense and heterogeneous or peripheral enhancement [12]. Slower uptake is seen in the central scar, which remains hypointense on hepatocyte phase using gadoxetate disodium compared to hyperintense with extracellular agents [3]. Gadobenate dimeglumine enables discrimination of adenoma from FNH with a high degree of confidence: lack of uptake in adenomas leads to hepatocyte phase hypointensity while uptake in FNHs leads to iso- or hyperintensity (Figure 2) [12,15]. Hepatic Adenoma Hepatic adenoma is a less common benign neoplasm characterized histopathologically by cords of hepatocytes separated by sinusoids. Adenomas lack portal and central veins as well as biliary ductules and normal biliary excretion is therefore impaired. Adenomas may demonstrate heterogeneous hyperintensity on T1-weighted images due to the presence of
hemorrhage or intralesional fat. Dynamic phase enhancement of adenomas with HSCAs is similar to extracellular agents and typically demonstrates hypervascularity with isointensity observed on the portal venous and transitional (late dynamic) phases (Figures 3 and 4) [16]. With the exception of inflammatory adenomas, discussed subsequently, no hepatocyte phase enhancement is observed using gadobenate dimeglumine, whereas variable enhancement may occur with gadoxetate disodium [12,15]. Recent advances in molecular studies have led to the reclassification of the telangiectatic focal nodular hyperplasia as inflammatory subtype of hepatic adenoma [17,18]. They represent the most common adenoma subtype, accounting for approximately 40%-50%, a subset of which may demonstrate imaging features that overlap with FNH [18]. Inflammatory adenomas are hypervascular masses that demonstrate persistent enhancement on portal venous and delayed phases and are typically iso- to mildly T1 hyperintense and T2 hyperintense [19]. Hepatocyte phase enhancement using gadoxetate disodium demonstrates iso- to hyperintense compared to background parenchyma [18]. A distinguishing feature identified in approximately half of cases is a band of peripheral T2 hyperintense signal with central isointensity, the so-called atoll sign, with small T2 hyperintense lesions often seen at the centre of the lesion (Figure 5), a finding not clearly demonstrated in the remaining adenoma subtypes [20].
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Figure 7. Cavernous hemangioma in a 47-year-old woman. Gadoxetate disodium enhanced magnetic resonance imaging demonstrates unique subtle arterial enhancement, early contrast uptake by surrounding hepatocyte uptake that may obscure characteristic puddling, hypointensity (‘‘pseudo-washout’’) of the hemangioma on the transitional phase, and hypointensity on the hepatocyte phase (arrows).
Cavernous Hemangioma Histopathologically, cavernous hemangiomas are characterized by large vascular channels separated by thin septations. Hemangiomas are typically T1 hypointense and T2 hyperintense; dynamic phase imaging demonstrates discontinuous peripheral hyperintensity with centripetal progression. Because they lack hepatocytes, hemangiomas typically appear hypointense to normal hepatic parenchyma in the hepatocyte phase; however, subtle central hyperintensity may be observed beyond the dynamic phase due to progressive centripetal contrast accumulation. Caution is advised when using gadoxetate disodium in known or suspected hemangiomas: the arterial phase is typically less intense and the characteristic peripheral contrast puddling observed with extracellular contrast agents may be obscured due to intense hepatocyte uptake, which may be seen as early as the portal venous and transitional phase (Figures 6
and 7). As a result, hemangiomas may demonstrate avid arterial enhancement and subsequently appear hypointense to normal liver parenchyma as early as 3 minutes following injection due to rapid progressive hepatic parenchymal enhancement [2]. This leads to a ‘‘pseudo-washout’’ phenomenon, which may cause high flow hemangiomas to mimic hypervascular tumours (Figures 6 and 7) [21]. To distinguish these entities, the characteristic high T2 signal intensity, arterial phase enhancement, and pseudo-washout sign during the transitional phase have been suggested to favor a diagnosis of hemangioma [21]. Hepatic Metastases Hepatic metastases from extrahepatic malignancies are typically T1 hypointense and T2 hyperintense and may be hypo- or hypervascular on dynamic phase imaging (Figures 8 and 9). Histopathologically, hepatic metastases lack
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Figure 8. Hepatic metastases from a colorectal primary in a 62-year-old man. Contrast-enhanced liver magnetic resonance imaging using an extracellular contrast agent demonstrates moderately T2 hyperintense signal intensity. Dynamic phase images demonstrate heterogeneous or rim enhancement (arrows).
functioning hepatocytes or bile ducts and therefore remain uniformly hypointense compared to normal enhancing liver during the hepatocyte phase (Figure 9) [2,3]. A ‘‘target sign’’ of central round enhancement with peripheral low signal rim may also be observed in the hepatocyte phase [22,23]. A thin, hyperintense rim may be seen at the interface between the metastasis and normal liver, which may represent compressed normal liver, biliary reaction, or both [2]. Both gadobenate dimeglumine and gadoxetate disodium reliably detect small, subcentimeter hepatic metastases compared to computed tomography (CT), which enables more accurate preoperative assessment of candidates for curative liver resection [24e26]. Indeed, a recent metaanalysis of the diagnostic performance of gadoxetate disodium in the detection of hepatic metastases from colorectal carcinoma demonstrated an overall sensitivity of 93% and sensitivity of 95% [27]. Gadobenate dimeglumine has also shown a statistically significant improvement in the detection rate and positive predictive value of identifying colorectal metastases compared unenhanced or conventional contrastenhanced MRI [25]. In the postchemotherapy patient, MRI demonstrates superior diagnostic performance over CT, positron emission tomography, and positron emission tomography/CT in the detection of metastases [28]; moreover, gadoxetate disodium-enhanced MRI demonstrated superior performance to CT in detecting subcentimeter colorectal hepatic metastases in the preoperative evaluation of patients with hepatic steatosis [29]. Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) typically demonstrates arterial enhancement with portal venous and transitional
phase washout. Due to the reduced expression of membrane cotransporters necessary for enhancement, HCCs usually remain hypointense relative to background parenchyma in the hepatocyte phase [2] (Figures 10 and 11). A diagnostic pitfall with the use of gadoxetate disodium in a minority of HCCs is paradoxical uptake, whereby the lesion appears isoor hyperintense compared to liver parenchyma, attributable to increased expression of membrane transporters in moderately or well-differentiated lesions [10,30e32]. As a result of this paradoxical uptake, these hyperintense HCCs may be difficult to detect or be mistaken for benign cirrhosisassociated nodules (Figure 12) [15,33]. Identification of small HCCs remains a diagnostic challenge, particularly given the less intense arterial phase and respiratory motion artifact observed in some patients following injection of gadoxetate disodium. Advantages of using gadoxetate disodium include significantly greater diagnostic performance over both contrast-enhanced CT and conventional dynamic MRI in evaluating small early HCCs [34e36]. In addition, 4 statistically significant findings associated with small HCCs have been demonstrated using gadobenate dimeglumine: hyperintensity during the arterial phase, hypointensity during the portal venous and hepatocytes phases, and hyperintensity on T2-weighted images [37]. Cholangiocarcinoma Cholangiocarcinoma originates from the biliary epithelium as adenocarcinoma, papillary carcinoma, or mucinous carcinoma and may arise within the intra- or extrahepatic bile ducts. Mass-forming cholangiocarcinoma is typically T1 hypointense and mild to moderately T2 hyperintense, depending on the amount of fibrous tissue and mucin, with delayed washout observed with extracellular agents.
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Figure 9. Treated hepatic metastases in a 59-year-old woman with history of pancreatic neuroendocrine tumour. Gadoxetate disodium enhanced dynamic imaging demonstrates numerous arterially enhancing lesions, 1 of which is demonstrated within segment VI, which fades to hypointensity by the portal phase and remains hypointense on the hepatocyte phase (arrows). The lesion also shows mild T2 hyperintensity and evidence of restricted diffusion (arrows). Given the background history of pancreatic neuroendocrine tumour, the findings of multiple hyperenhancing lesions favor a diagnosis of hypervascular metastatic lesions. The differential includes multifocal hepatocellular carcinoma, but is less likely in the absence of underlying cirrhosis. DWI ¼ diffusion-weighted imaging.
Additional findings include biliary duct dilatation and atrophy and capsular retraction of the involved segment. Arterial phase imaging with gadoxetate disodium may demonstrate irregular peripheral rim enhancement [3]. Due to hepatic uptake using HSCAs, cholangiocarcinoma appears hypointense to background liver in the transitional and hepatobiliary phases (Figure 13) [4]. As a result, gadoxetate
acid-enhanced MRI has been shown to be a reliable method to assess bile duct tumour resectability, with accuracy in a retrospective review of up to 84% [38]. Hepatic epithelioid hemangioendothelioma Hepatic epithelioid hemangioendothelioma is a rare vascular tumour characterized histopathologically by
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Figure 10. Hepatocellular carcinoma in a 70-year-old man with known cirrhosis. Gadoxetate disodium enhanced T1 dynamic imaging demonstrates a focal 2 cm arterially enhancing lesion in segment VI, which fades to hypointensity by the portal phase and remains hypointense on the hepatocyte phase (yellow arrows). The lesion shows mild T2 hyperintensity and evidence of restricted diffusion (yellow arrows). The findings are diagnostic of hepatocellular carcinoma in this patient with a background of cirrhosis. Note the large portocaval shunt on the medial aspect of the lesion, demonstrating flow void on T2 sequence (red arrow). DWI ¼ diffusion-weighted imaging.
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Figure 11. Infiltrative hepatocellular carcinoma in a 64-year-old man with chronic hepatitis (B) Gadoxetate disodium enhance magnetic resonance imaging demonstrates an expansile mass lesion occupying the left hepatic lobe (arrows), which demonstrates T1 hypointensity and T2 hyperintensity compared to background liver parenchyma. There is mild, heterogeneous arterial enhancement with washout in the portal venous and transitional phases. The mass remains hypointense to background liver on the hepatocyte phase.
epithelioid and dendritic cells with central fibrotic stroma. Lesions may be single or multiple, typically peripheral in location with associated capsular retraction. Hepatic epithelioid hemangioendothelioma lesions are typically T1 hypointense and T2 hyperintense with ring or target-like enhancement following extracellular contrast administration [39,40]. Progressive centripetal fill-in on dynamic postcontrast sequences has been observed (Figure 14) [40]. Hepatobiliary phase imaging using gadoxetate acid demonstrates homogeneous or target-shaped hypointensity [40]. Nodules in the cirrhotic liver A spectrum of nodules may be seen in the cirrhotic liver. Hemodynamic changes and fibrosis may cause heterogeneous enhancement, making differentiation of
benign regenerative nodules and premalignant dysplastic nodules from HCC challenging [41,42]. Furthermore, impaired hepatocyte function may limit contrast uptake, leading to decreased distinction between the focal lesion and background parenchyma. Regenerative and dysplastic nodules typically demonstrate portal venous phase enhancement to become iso- or hyperintense to background liver parenchyma. Iso- to hyperintense hepatocyte phase enhancement is observed due to preserved hepatocellular function and intact ion transporters [28,29]. With increasing atypia, as with poorly differentiated dysplastic nodules, there is decreased expression of ion transporters and reduced ability to take up gadoxetate disodium, with subsequent hypointensity observed on the hepatocyte phase [10].
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Figure 12. Well-differentiated hepatocellular carcinoma versus highly dysplastic nodule in a 59-year-old woman with known cirrhosis. The lesion shows mild T2 hypointensity and is isointense on precontrast T1 imaging. Gadoxetate disodium enhanced T1 dynamic imaging demonstrates arterial enhancement, which fades to hypointensity by the portal phase and becomes slightly hyperintense to surrounding hepatocytes on transitional phase (arrows). The lesion is hyperintense on the hepatocyte phase (arrow). Uptake of gadoxetate disodium in the hepatocyte phase can occur in a small percentage of well-differentiated hepatocellular carcinoma. Short interval follow-up imaging was recommended.
A retrospective study of 34 patients with 29 surgically resected HCCs and 31 benign nodules using gadoxetate disodium suggested the following imaging criteria to differentiate HCC from premalignant nodules: size 1.5 cm, hypointense on T1-weighted images, hyperintense on T2and diffusion-weighted images, hyperenhancement on the arterial phase, and hypointensity on the portal venous and
hepatocyte phases [43]. Lesions were considered malignant if they satisfied 3 or more of these criteria; sensitivity was higher than arterial enhancement and washout alone. In addition, a retrospective study of hypervascular hepatic lesions using gadobenate dimeglumine demonstrated that all 82 regenerative nodules were iso- or hyperintense on the hepatocyte phase, which suggests this may be used as a
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Figure 13. Cholangiocarcinoma in a 59-year-old woman. Gadoxetate disodium enhanced magnetic resonance imaging demonstrates an ill-defined mass in the region of the left porta hepatis (arrows), which is T1 hypointense compared to liver parenchyma. There is mild arterial and portal venous phase postgadolinium enhancement, with hypointensity to background liver parenchyma on the hepatocyte phase. Biliary ductal dilatation is noted adjacent to the mass.
Figure 14. A 22-year-old woman with hepatic epithelioid hemangioendothelioma. Gadoxetate-disodium enhanced magnetic resonance imaging demonstrates multiple hepatic lesions, some of which coalesce peripherally (arrows), primarily involving the right hepatic lobe. These lesions are moderately T2 hyperintense and T1 hypointense with no postgadolinium enhancement. The lesions remain hypointense on the hepatocyte phase.
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Figure 15. Dysplastic nodules in a 73-year-old man with known cirrhosis. Gadobenate dimeglumine (top row) and gadoxetate disodium (bottom row) enhanced magnetic resonance imaging in the same patient demonstrates multifocal lesions that do not demonstrate arterial enhancement but become apparent as hyperintense foci on the portal venous phase and become even more hyperintense during the hepatocyte phase (arrows).
feature of lesion benignity (Figure 15) [44]. Finally, the combination of dynamic and hepatocyte phase gadoxetate disodium-enhanced MRI has been shown to provide incremental value over conventional dynamic phase MRI alone in characterizing focal liver lesions in the cirrhotic liver [45]. Conclusions Owing to their unique pharmacologic properties, MRI using HSCAs enables comprehensive evaluation of focal liver lesions in both the dynamic and hepatocyte phases. This offers improved lesion conspicuity and characterization over other imaging modalities and conventional extracellular gadolinium-based contrast agents. In particular, HSCA offer unique advantages in differentiation of hepatocellular from nonhepatocellular lesions, detection of hepatic metastases and distinction between hepatic adenoma and focal nodular hyperplasia. Familiarity with the uses, findings and pitfalls of the 2 commercially available HSCAs, gadoxetate disodium and gadobenate dimeglumine, is essential to image interpretation and patient management. References [1] Seale MK, Catalano OA, Saini S, Hahn PF, Sahani DV. Hepatobiliaryspecific MR contrast agents: role in imaging the liver and biliary tree. Radiographics 2009;29:1725e48. [2] Goodwin MD, Dobson JE, Sirlin CB, Lim BG, Stella DL. Diagnostic challenges and pitfalls in MR imaging with hepatocyte-specific contrast agents. Radiographics 2011;31:1547e68. [3] Ringe KI, Husarik DB, Sirlin CB, Merkle EM. Gadoxetate disodiumenhanced MRI of the liver: part 1, protocol optimization and lesion appearance in the noncirrhotic liver. AJR Am J Roentgenol 2010;195: 13e28. [4] Jhaveri K, Cleary S, Audet P, et al. Consensus statements from a multidisciplinary expert panel on the utilization and application of a liver-specific MRI contrast agent (gadoxetic acid). AJR Am J Roentgenol 2015;204:498e509.
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focal nodular hyperplasias of the liver. Gastroenterology 2005;128: 1211e8. Agarwal S, Fuentes-Orrego JM, Arnason T, et al. Inflammatory hepatocellular adenomas can mimic focal nodular hyperplasia on gadoxetic acid-enhanced MRI. AJR Am J Roentgenol 2014;203: W408e14. Khanna M, Ramanathan S, Fasih N, Schieda N, Virmani V, McInnes MDF. Current updates on the molecular genetics and magnetic resonance imaging of focal nodular hyperplasia and hepatocellular adenoma. Insights Imaging 2015;6:347e62. van Aalten SM, Thomeer MGJ, Terkivatan T, et al. Hepatocellular adenomas: correlation of MR imaging findings with pathologic subtype classification. Radiology 2011;261:172e81. Doo KW, Lee CH, Choi JW, Lee J, Kim KA, Park CM. ‘‘Pseudo washout’’ sign in high-flow hepatic hemangioma on gadoxetic acid contrast-enhanced MRI mimicking hypervascular tumor. AJR Am J Roentgenol 2009;193:W490e6. Fu G-L, Du Y, Zee C-S, et al. Gadobenate dimeglumine-enhanced liver magnetic resonance imaging: value of hepatobiliary phase for the detection of focal liver lesions. J Comput Assist Tomogr 2012;36: 14e9. Ha S, Lee CH, Kim BH, et al. Paradoxical uptake of Gd-EOB-DTPA on the hepatobiliary phase in the evaluation of hepatic metastasis from breast cancer: is the ‘‘target sign’’ a common finding? Magn Reson Imaging 2012;30:1083e90. Hammerstingl R, Huppertz A, Breuer J, et al. Diagnostic efficacy of gadoxetic acid (Primovist)-enhanced MRI and spiral CT for a therapeutic strategy: comparison with intraoperative and histopathologic findings in focal liver lesions. Eur Radiol 2008;18:457e67. Choi J-Y, Choi J-S, Kim M-J, et al. Detection of hepatic hypovascular metastases: 3D gradient echo MRI using a hepatobiliary contrast agent. J Magn Reson Imaging 2010;31:571e8. Zech CJ, Herrmann KA, Reiser MF, Schoenberg SO. MR imaging in patients with suspected liver metastases: value of liver-specific contrast agent Gd-EOB-DTPA. Magn Reson Med Sci 2007;6:43e52. Chen L, Zhang J, Zhang L, et al. Meta-analysis of gadoxetic acid disodium (Gd-EOB-DTPA)-enhanced magnetic resonance imaging for the detection of liver metastases. PloS One 2012;7:e48681. van Kessel CS, Buckens CFM, van den Bosch MAAJ, van Leeuwen MS, van Hillegersberg R, Verkooijen HM. Preoperative imaging of colorectal liver metastases after neoadjuvant chemotherapy: a meta-analysis. Ann Surg Oncol 2012;19:2805e13. Berger-Kulemann V, Schima W, Baroud S, et al. Gadoxetic acidenhanced 3.0 T MR imaging versus multidetector-row CT in the detection of colorectal metastases in fatty liver using intraoperative ultrasound and histopathology as a standard of reference. Eur J Surg Oncol 2012;38:670e6. Narita M, Hatano E, Arizono S, et al. Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma. J Gastroenterol 2009;44:793e8.
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[31] Lee SA, Lee CH, Jung WY, et al. Paradoxical high signal intensity of hepatocellular carcinoma in the hepatobiliary phase of Gd-EOB-DTPA enhanced MRI: initial experience. Magn Reson Imaging 2011;29:83e90. [32] Kitao A, Zen Y, Matsui O, et al. Hepatocellular carcinoma: signal intensity at gadoxetic acid-enhanced MR imagingecorrelation with molecular transporters and histopathologic features. Radiology 2010; 256:817e26. [33] Saito K, Kotake F, Ito N, et al. Gd-EOB-DTPA enhanced MRI for hepatocellular carcinoma: quantitative evaluation of tumor enhancement in hepatobiliary phase. Magn Reson Med Sci 2005;4:1e9. [34] Sano K, Ichikawa T, Motosugi U, et al. Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid-enhanced MR imaging. Radiology 2011;261:834e44. [35] Bashir MR, Gupta RT, Davenport MS, et al. Hepatocellular carcinoma in a North American population: does hepatobiliary MR imaging with Gd-EOB-DTPA improve sensitivity and confidence for diagnosis? J Magn Reson Imaging 2013;37:398e406. [36] Baek C-K, Choi J-Y, Kim K-A, et al. Hepatocellular carcinoma in patients with chronic liver disease: a comparison of gadoxetic acidenhanced MRI and multiphasic MDCT. Clin Radiol 2012;67:148e56. [37] Kim TK, Lee KH, Jang H-J, et al. Analysis of gadobenate dimeglumine-enhanced MR findings for characterizing small (1-2-cm) hepatic nodules in patients at high risk for hepatocellular carcinoma. Radiology 2011;259:730e8. [38] Sun HY, Lee JM, Park HS, et al. Gadoxetic acid-enhanced MRI with MR cholangiography for the preoperative evaluation of bile duct cancer. J Magn Reson Imaging 2013;38:138e47. [39] Paolantonio P, Laghi A, Vanzulli A, et al. MRI of hepatic epithelioid hemangioendothelioma (HEH). J Magn Reson Imaging 2014;40:552e8. [40] Kim EH, Rha SE, Lee YJ, Yoo IR, Jung ES, Byun JY. CT and MR imaging findings of hepatic epithelioid hemangioendotheliomas: emphasis on single nodular type. Abdom Imaging 2015;40:500e9. [41] Willatt JM, Hussain HK, Adusumilli S, Marrero JA. MR Imaging of hepatocellular carcinoma in the cirrhotic liver: challenges and controversies. Radiology 2008;247:311e30. [42] Hanna RF, Aguirre DA, Kased N, Emery SC, Peterson MR, Sirlin CB. Cirrhosis-associated hepatocellular nodules: correlation of histopathologic and MR imaging features. Radiographics 2008; 28:747e69. [43] Rhee H, Kim M-J, Park M-S, Kim KA. Differentiation of early hepatocellular carcinoma from benign hepatocellular nodules on gadoxetic acid-enhanced MRI. Br J Radiol 2012;85:e837e44. [44] Morana G, Grazioli L, Kirchin MA, et al. Solid hypervascular liver lesions: accurate identification of true benign lesions on enhanced dynamic and hepatobiliary phase magnetic resonance imaging after gadobenate dimeglumine administration. Invest Radiol 2011;46:225e39. [45] Chou C-T, Chen Y-L, Su W-W, Wu H-K, Chen R-C. Characterization of cirrhotic nodules with gadoxetic acid-enhanced magnetic resonance imaging: the efficacy of hepatocyte-phase imaging. J Magn Reson Imaging 2010;32:895e902.
Abdominal Imaging / Imagerie abdominale
A Pictorial Review of Hepatobiliary Magnetic Resonance Imaging With Hepatocyte-Specific Contrast Agents: Uses, Findings, and Pitfalls of Gadoxetate Disodium and Gadobenate Dimeglumine Elena P. Scali, MDa,*, Triona Walshe, MBBCha, Hina Arif Tiwari, MDb, Alison C. Harris, MDa, Silvia D. Chang, MDa a
Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada b Department of Radiology, University of Arizona, Tuscon, Arizona, USA
Abstract Magnetic resonance imaging (MRI) has a well-established role as a highly specific and accurate modality for characterizing benign and malignant focal liver lesions. In particular, contrast-enhanced MRI using hepatocyte-specific contrast agents (HSCAs) improves lesion detection and characterization compared to other imaging modalities and MRI techniques. In this pictorial review, the mechanism of action of gadoliniumbased MRI contrast agents, with a focus on HSCAs, is described. The clinical indications, protocols, and emerging uses of the 2 commercially available combined contrast agents available in the United States, gadoxetate disodium and gadobenate dimeglumine, are discussed. The MRI features of these agents are compared with examples of focal hepatic masses, many of which have been obtained within the same patient therefore allowing direct lesion comparison. Finally, the pitfalls in the use of combined contrast agents in liver MRI are highlighted. Resume L’imagerie par resonance magnetique (IRM) est reconnue pour sa grande specificite et sa grande precision lorsqu’il s’agit de caracteriser les lesions hepatiques focales benignes et malignes. C’est particulierement le cas de l’IRM avec injection de produits de contraste specifique aux hepatocytes, qui detecte et caracterise les lesions plus efficacement que toute autre modalite d’imagerie ou technique d’IRM. La presente analyse d’images decrit le mecanisme d’action des produits de contraste a base de gadolinium utilises en IRM, en particulier les produits de contraste specifiques aux hepatocytes. Elle presente les indications cliniques, les protocoles et les nouvelles utilisations de deux produits de contraste mixtes commercialises aux Etats-Unis: le gadoxetate disodique et le gadobenate de dimeglumine. Elle compare aussi les images d’IRM realisees a l’aide de ces produits aux images de tumeurs hepatiques focales. Ces images proviennent bien souvent du m^eme patient, ce qui permet une comparaison directe des lesions. Enfin, l’analyse aborde les pieges associes au recours a des produits de contraste mixtes lors d’une IRM du foie. Ó 2016 Canadian Association of Radiologists. All rights reserved. Key Words: Focal liver lesions; Gadobenate dimeglumine; Gadoxetate disodium; Hepatocyte-specific contrast agents; Magnetic resonance imaging
Magnetic resonance imaging (MRI) of the liver routinely employs the use of gadolinium-based contrast agents in order to increase conspicuity and facilitate characterization of focal lesions. Each category of contrast agent offers different properties, which may be tailored to answer a specific clinical question. * Address for correspondence: Elena P. Scali, MD, Department of Radiology, University of British Columbia, 3350-950 West 10th Avenue, Vancouver, British Columbia V5Z 4E3, Canada. E-mail address: [email protected] (E. P. Scali).
Extracellular gadolinium-containing agents consist of gadolinium chelated to an organic compound. Gadolinium shortens the T1 and T2 relaxation times, leading to increased T1 signal intensity. They demonstrate vascular perfusion by distributing into the extracellular fluid compartment and are predominantly renally excreted. Differential vascular perfusion between normal liver parenchyma and focal hepatic lesions enables characterization. In the cirrhotic liver, however, heterogeneous background enhancement may obscure focal lesions [1]. Hepatocyte-specific contrast agents (HSCAs) distribute initially into the extracellular fluid compartment, are
0846-5371/$ - see front matter Ó 2016 Canadian Association of Radiologists. All rights reserved. http://dx.doi.org/10.1016/j.carj.2016.10.008
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Table 1 Pharmacologic characteristics of gadobenate dimeglumine and gadoxetate disodium [1,4]
Agent
Gadobenate dimeglumine (MultiHance)
Bolus IV injection Excretion
2 mL/s of 0.1 mmol/kg 3%-5% biliary 95%-97% renal Recommended timing Same as extracellular of dynamic imaging agents Recommended timing 1-2 hours of hepatocyte phase
Gadoxetate disodium (Primovist) 2 mL/s of 0.025 mmol/kg 50% biliary 50% renal Same as extracellular agents 10 minutes to hours, 20 minutes commonly used
Table 2 Magnetic resonance imaging protocol for assessment of focal liver lesions T1-weighted in-phase and opposed-phase imaging T2-weighted fast spin echo magnetic resonance cholangiopancreatography (optional) Unenhanced T1-weighted fat-saturated GRE (optional) T1-weighted fat-saturated hepatic arterial phase or triple arterial phase GRE T1-weighted fat-saturated portal venous phase GRE T1-weighted fat-saturated late venous phase GRE Diffusion-weighted imaging (optional) T2-weighted fast spin echo (with or without fat saturation) T1-weighted fat-saturated hepatocellular phase GRE GRE ¼ gradient recalled echo.
subsequently taken up by functioning hepatocytes and then excreted into biliary canaliculi along the same pathway as bilirubin [2]. Based on gadolinium, these agents cause T1 shortening of the liver and biliary tree and enable comprehensive noninvasive imaging in both the dynamic and hepatocyte phases [3]. As a result of these properties, HSCAs enable differentiation of hepatocellular and nonhepatocellular lesions, the latter of which demonstrate increased conspicuity on delayed T1 images compared to background parenchyma [1]. The pharmacologic characteristics of the 2 commercially available HSCAs in the United States, gadobenate dimeglumine (MultiHance; Bracco, Milan, Italy) and gadoxetate disodium (Eovist or Primovist; Bayer Schering Pharma, Berlin, Germany) are outlined in Table 1. A suggested protocol for performing MRI of focal hepatic lesions with HSCAs is included in Table 2. Gadoxetate disodium possesses slightly different properties than both extracellular contrast agents and gadobenate dimeglumine. The arterial phase appears less intense than with conventional extracellular agents [2]. Strategies to optimize the arterial phase of gadoxetate disodium include injection strategies, such as reducing the injection flow rate and diluting the contrast agent, and fluoroscopic or bolus triggering techniques [4]. Of note, a subset of patients may experience acute transient dyspnea following intravenous injection of gadoxetate disodium, which results in more severely motion degraded images than with gadobenate dimeglumine [5].
Table 3 Typical magnetic resonance imaging findings of common focal liver lesions using hepatocyte-specific contrast agents [1,2,16] Dynamic contrast enhancement
Hepatocyte phase
T1 and T2
Focal nodular hyperplasia
Hypervascular, isointense to background liver on delayed phases
Iso- to hyperintense
Hepatic adenoma
Hypervascular, iso- to slightly hypointense to background liver on delayed phases Inflammatory subtype: hypervascular with persistent enhancement on delayed phases
Gadobenate dimeglumine: variable, isoto hyperintense Gadoxetate disodium: hypointense Inflammatory subtype: iso- to hyperintense
Hemangioma
Discontinuous peripheral nodular enhancement with centripetal progression Hypervascular: hyperintense, iso- or hypointense on delayed phases Hypovascular: hypointense Hypervascular (80%), hypovascular (20%), iso- to hypointense in delayed phases Irregular peripheral rim enhancement, variable central enhancement Iso- to hyperintense in portal venous phase Iso- to hyperintense in portal venous phase May enhance in arterial phase
Hypointense
T1: iso- to hypointense T2: iso- to hyperintense with hyperintense central scar T1: variable, heterogeneously Hyperintense with presence of fat or hemorrhage T2: moderately hyperintense Inflammatory subtype: T1: iso- to mildly hyperintense T2: hyperintense ‘‘Atoll sign’’ in w50% T1: hypointense T2: hyperintense
Metastases
Hepatocellular carcinoma
Cholangiocarcinoma Regenerative nodule Dysplastic nodule, well differentiated Dysplastic nodule, poorly differentiated
Hypointense, targetoid central high signal
T1: hypointense T2: variable, hyperintense
Hypointense (80%), iso- to hyperintense in moderately to well differentiated (20%) Hypointense
T1: variable, heterogeneous T2: iso- to hyperintense
Iso- to hyperintense Iso- to hyperintense Variable, may be hypointense
T1: T2: T1: T2: T1: T2: T1: T2:
hypointense mildly to moderately hyperintense iso- to hyperintense iso- to hypointense variable hyperintense variable, heterogeneous mildly hyperintense
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Hepatocyte uptake occurs rapidly and liver parenchymal enhancement may be seen as early as 90 seconds following injection; due to greater hepatic uptake, there is more intense hepatocyte phase enhancement compared to gadobenate dimeglumine [6,7]. Similarly, rapid hepatocyte clearance of gadoxetate disodium causes the vessels to become hypointense compared to liver parenchyma as soon as 10 minutes postinjection [6]. Hepatocyte phase imaging is generally performed following a 20-minute delay, compared to 12 hours with gadobenate dimeglumine. Impaired gadoxetate disodium uptake in the cirrhotic liver reduces hepatocyte phase enhancement and therefore protocol adjustments may be needed to improve image quality [7e9]. Indeed, peak hepatocyte phase enhancement may be delayed beyond the conventional 20 minutes and may take 40 minutes or more [10]. Significantly higher enhancement ratio has been reported in patients with Child-Pugh class A
3
disease compared to Child-Pugh class C disease [4]. Moreover, initial studies suggest improved lesion-to-liver contrast ratio in the cirrhotic liver with a dose increase from the standard 0.025 mmol/kg to an off-label dose of 0.05 mmol/ kg [11]. MRI Findings in Focal Hepatic Lesions Using HSCAs The typical MRI findings of focal liver lesions using HSCAs are summarized in Table 3. Liver MRI is often used to distinguish 2 benign focal hepatic lesions, nodular hyperplasia (FNH) and adenoma. Although FNH is often managed conservatively, adenomas require more frequent monitoring or resection due to risk of rupture, hemorrhage or malignant transformation. In the absence of typical features, however, FNH and adenoma may be challenging to distinguish using extracellular contrast
Figure 1. Focal nodular hyperplasia in a 40-year-old woman. Gadoxetate disodium magnetic resonance imaging demonstrates iso- to hypointensity on T1-weighted imaging, isointensity on T2-weighted imaging, intense arterial phase enhancement, hyperintensity of the portal venous and transitional phases, and iso- to mild hyperintensity on the hepatocyte phase (arrows).
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Figure 2. Focal nodular hyperplasia in a 34-year-old woman. Gadobenate dimeglumine (top row) and gadoxetate disodium (bottom row) enhanced magnetic resonance imaging in the same patient demonstrates intense enhancement the arterial phase, isointensity to liver parenchyma in the portal venous and transitional phases, and predominately iso- to hyperintense in the hepatocyte phase (arrows).
agents: for example, only approximately half of FNHs demonstrate the classic T2 hyperintense scar and a similar proportion of adenomas contain intratumoural fat [12]. Moreover, a minority of adenoma demonstrates a central enhancing scar, a finding more typically observed in FNH [13].
Focal Nodular Hyperplasia FNH is a benign neoplasm characterized histopathologically by increased density of normal functioning hepatocytes and abnormal blind-ending biliary ductules, which
Figure 3. Hepatic adenoma in a 37-year-old woman. Gadobenate dimeglumine (top row) and gadoxetate disodium (bottom row) magnetic resonance imaging in the same patient demonstrates intense enhancement in the arterial phase, isointensity to liver parenchyma in the portal venous and transitional phases, and hypointensity of the hepatocyte phase (arrows).
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Figure 4. Hepatic adenoma in a 43-year-old woman. Gadobenate dimeglumine (top row) and gadoxetate disodium (bottom row) magnetic resonance imaging in the same patient demonstrates intense enhancement in the arterial phase, fading of enhancement on subsequent phases to isointensity to liver parenchyma in the portal venous and transitional phases, and hypointensity in the hepatocyte phase (arrows).
Figure 5. Inflammatory adenoma in a 46-year-old woman. Gadoxetate disodiumeenhanced magnetic resonance imaging demonstrates the classic ‘‘atoll sign’’ with a band of peripheral hyperintense signal surrounding central isointensity compared to surrounding liver parenchyma on T2-weighted images. Homogeneous arterial phase enhancement, mild peripheral portal venous phase enhancement, and iso- to mildly hypointensity on the hepatocyte phase are seen (arrows).
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Figure 6. Cavernous hemangioma in a 44-year-old woman. Gadobenate dimeglumine (top row) and gadoxetate disodium (bottom row) enhanced magnetic resonance imaging in the same patient demonstrates unique features of gadoxetate disodium with comparatively less intense arterial enhancement, early hepatocyte uptake that may obscure characteristic puddling, hypointensity (‘‘pseudo-washout’’) on the transitional phase, and hypointensity on the hepatocyte phase (arrows).
demonstrate delayed biliary excretion compared to normal liver parenchyma. Risk of rupture and hemorrhage is small and no malignant potential has been reported [14]. FNH is typically iso- to hypointense to background liver parenchyma on T1; iso- to slightly hyperintense on T2-weighted images and hypervascular and fade to isointensity on the portal venous and late dynamic phases (Figures 1 and 2). Hepatocyte phase enhancement is commonly homogeneously iso- to hyperintense due to contrast retention within hepatocytes (Figures 1 and 2); less common patterns include iso- or hypointense and heterogeneous or peripheral enhancement [12]. Slower uptake is seen in the central scar, which remains hypointense on hepatocyte phase using gadoxetate disodium compared to hyperintense with extracellular agents [3]. Gadobenate dimeglumine enables discrimination of adenoma from FNH with a high degree of confidence: lack of uptake in adenomas leads to hepatocyte phase hypointensity while uptake in FNHs leads to iso- or hyperintensity (Figure 2) [12,15]. Hepatic Adenoma Hepatic adenoma is a less common benign neoplasm characterized histopathologically by cords of hepatocytes separated by sinusoids. Adenomas lack portal and central veins as well as biliary ductules and normal biliary excretion is therefore impaired. Adenomas may demonstrate heterogeneous hyperintensity on T1-weighted images due to the presence of
hemorrhage or intralesional fat. Dynamic phase enhancement of adenomas with HSCAs is similar to extracellular agents and typically demonstrates hypervascularity with isointensity observed on the portal venous and transitional (late dynamic) phases (Figures 3 and 4) [16]. With the exception of inflammatory adenomas, discussed subsequently, no hepatocyte phase enhancement is observed using gadobenate dimeglumine, whereas variable enhancement may occur with gadoxetate disodium [12,15]. Recent advances in molecular studies have led to the reclassification of the telangiectatic focal nodular hyperplasia as inflammatory subtype of hepatic adenoma [17,18]. They represent the most common adenoma subtype, accounting for approximately 40%-50%, a subset of which may demonstrate imaging features that overlap with FNH [18]. Inflammatory adenomas are hypervascular masses that demonstrate persistent enhancement on portal venous and delayed phases and are typically iso- to mildly T1 hyperintense and T2 hyperintense [19]. Hepatocyte phase enhancement using gadoxetate disodium demonstrates iso- to hyperintense compared to background parenchyma [18]. A distinguishing feature identified in approximately half of cases is a band of peripheral T2 hyperintense signal with central isointensity, the so-called atoll sign, with small T2 hyperintense lesions often seen at the centre of the lesion (Figure 5), a finding not clearly demonstrated in the remaining adenoma subtypes [20].
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Figure 7. Cavernous hemangioma in a 47-year-old woman. Gadoxetate disodium enhanced magnetic resonance imaging demonstrates unique subtle arterial enhancement, early contrast uptake by surrounding hepatocyte uptake that may obscure characteristic puddling, hypointensity (‘‘pseudo-washout’’) of the hemangioma on the transitional phase, and hypointensity on the hepatocyte phase (arrows).
Cavernous Hemangioma Histopathologically, cavernous hemangiomas are characterized by large vascular channels separated by thin septations. Hemangiomas are typically T1 hypointense and T2 hyperintense; dynamic phase imaging demonstrates discontinuous peripheral hyperintensity with centripetal progression. Because they lack hepatocytes, hemangiomas typically appear hypointense to normal hepatic parenchyma in the hepatocyte phase; however, subtle central hyperintensity may be observed beyond the dynamic phase due to progressive centripetal contrast accumulation. Caution is advised when using gadoxetate disodium in known or suspected hemangiomas: the arterial phase is typically less intense and the characteristic peripheral contrast puddling observed with extracellular contrast agents may be obscured due to intense hepatocyte uptake, which may be seen as early as the portal venous and transitional phase (Figures 6
and 7). As a result, hemangiomas may demonstrate avid arterial enhancement and subsequently appear hypointense to normal liver parenchyma as early as 3 minutes following injection due to rapid progressive hepatic parenchymal enhancement [2]. This leads to a ‘‘pseudo-washout’’ phenomenon, which may cause high flow hemangiomas to mimic hypervascular tumours (Figures 6 and 7) [21]. To distinguish these entities, the characteristic high T2 signal intensity, arterial phase enhancement, and pseudo-washout sign during the transitional phase have been suggested to favor a diagnosis of hemangioma [21]. Hepatic Metastases Hepatic metastases from extrahepatic malignancies are typically T1 hypointense and T2 hyperintense and may be hypo- or hypervascular on dynamic phase imaging (Figures 8 and 9). Histopathologically, hepatic metastases lack
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Figure 8. Hepatic metastases from a colorectal primary in a 62-year-old man. Contrast-enhanced liver magnetic resonance imaging using an extracellular contrast agent demonstrates moderately T2 hyperintense signal intensity. Dynamic phase images demonstrate heterogeneous or rim enhancement (arrows).
functioning hepatocytes or bile ducts and therefore remain uniformly hypointense compared to normal enhancing liver during the hepatocyte phase (Figure 9) [2,3]. A ‘‘target sign’’ of central round enhancement with peripheral low signal rim may also be observed in the hepatocyte phase [22,23]. A thin, hyperintense rim may be seen at the interface between the metastasis and normal liver, which may represent compressed normal liver, biliary reaction, or both [2]. Both gadobenate dimeglumine and gadoxetate disodium reliably detect small, subcentimeter hepatic metastases compared to computed tomography (CT), which enables more accurate preoperative assessment of candidates for curative liver resection [24e26]. Indeed, a recent metaanalysis of the diagnostic performance of gadoxetate disodium in the detection of hepatic metastases from colorectal carcinoma demonstrated an overall sensitivity of 93% and sensitivity of 95% [27]. Gadobenate dimeglumine has also shown a statistically significant improvement in the detection rate and positive predictive value of identifying colorectal metastases compared unenhanced or conventional contrastenhanced MRI [25]. In the postchemotherapy patient, MRI demonstrates superior diagnostic performance over CT, positron emission tomography, and positron emission tomography/CT in the detection of metastases [28]; moreover, gadoxetate disodium-enhanced MRI demonstrated superior performance to CT in detecting subcentimeter colorectal hepatic metastases in the preoperative evaluation of patients with hepatic steatosis [29]. Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) typically demonstrates arterial enhancement with portal venous and transitional
phase washout. Due to the reduced expression of membrane cotransporters necessary for enhancement, HCCs usually remain hypointense relative to background parenchyma in the hepatocyte phase [2] (Figures 10 and 11). A diagnostic pitfall with the use of gadoxetate disodium in a minority of HCCs is paradoxical uptake, whereby the lesion appears isoor hyperintense compared to liver parenchyma, attributable to increased expression of membrane transporters in moderately or well-differentiated lesions [10,30e32]. As a result of this paradoxical uptake, these hyperintense HCCs may be difficult to detect or be mistaken for benign cirrhosisassociated nodules (Figure 12) [15,33]. Identification of small HCCs remains a diagnostic challenge, particularly given the less intense arterial phase and respiratory motion artifact observed in some patients following injection of gadoxetate disodium. Advantages of using gadoxetate disodium include significantly greater diagnostic performance over both contrast-enhanced CT and conventional dynamic MRI in evaluating small early HCCs [34e36]. In addition, 4 statistically significant findings associated with small HCCs have been demonstrated using gadobenate dimeglumine: hyperintensity during the arterial phase, hypointensity during the portal venous and hepatocytes phases, and hyperintensity on T2-weighted images [37]. Cholangiocarcinoma Cholangiocarcinoma originates from the biliary epithelium as adenocarcinoma, papillary carcinoma, or mucinous carcinoma and may arise within the intra- or extrahepatic bile ducts. Mass-forming cholangiocarcinoma is typically T1 hypointense and mild to moderately T2 hyperintense, depending on the amount of fibrous tissue and mucin, with delayed washout observed with extracellular agents.
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Figure 9. Treated hepatic metastases in a 59-year-old woman with history of pancreatic neuroendocrine tumour. Gadoxetate disodium enhanced dynamic imaging demonstrates numerous arterially enhancing lesions, 1 of which is demonstrated within segment VI, which fades to hypointensity by the portal phase and remains hypointense on the hepatocyte phase (arrows). The lesion also shows mild T2 hyperintensity and evidence of restricted diffusion (arrows). Given the background history of pancreatic neuroendocrine tumour, the findings of multiple hyperenhancing lesions favor a diagnosis of hypervascular metastatic lesions. The differential includes multifocal hepatocellular carcinoma, but is less likely in the absence of underlying cirrhosis. DWI ¼ diffusion-weighted imaging.
Additional findings include biliary duct dilatation and atrophy and capsular retraction of the involved segment. Arterial phase imaging with gadoxetate disodium may demonstrate irregular peripheral rim enhancement [3]. Due to hepatic uptake using HSCAs, cholangiocarcinoma appears hypointense to background liver in the transitional and hepatobiliary phases (Figure 13) [4]. As a result, gadoxetate
acid-enhanced MRI has been shown to be a reliable method to assess bile duct tumour resectability, with accuracy in a retrospective review of up to 84% [38]. Hepatic epithelioid hemangioendothelioma Hepatic epithelioid hemangioendothelioma is a rare vascular tumour characterized histopathologically by
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Figure 10. Hepatocellular carcinoma in a 70-year-old man with known cirrhosis. Gadoxetate disodium enhanced T1 dynamic imaging demonstrates a focal 2 cm arterially enhancing lesion in segment VI, which fades to hypointensity by the portal phase and remains hypointense on the hepatocyte phase (yellow arrows). The lesion shows mild T2 hyperintensity and evidence of restricted diffusion (yellow arrows). The findings are diagnostic of hepatocellular carcinoma in this patient with a background of cirrhosis. Note the large portocaval shunt on the medial aspect of the lesion, demonstrating flow void on T2 sequence (red arrow). DWI ¼ diffusion-weighted imaging.
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Figure 11. Infiltrative hepatocellular carcinoma in a 64-year-old man with chronic hepatitis (B) Gadoxetate disodium enhance magnetic resonance imaging demonstrates an expansile mass lesion occupying the left hepatic lobe (arrows), which demonstrates T1 hypointensity and T2 hyperintensity compared to background liver parenchyma. There is mild, heterogeneous arterial enhancement with washout in the portal venous and transitional phases. The mass remains hypointense to background liver on the hepatocyte phase.
epithelioid and dendritic cells with central fibrotic stroma. Lesions may be single or multiple, typically peripheral in location with associated capsular retraction. Hepatic epithelioid hemangioendothelioma lesions are typically T1 hypointense and T2 hyperintense with ring or target-like enhancement following extracellular contrast administration [39,40]. Progressive centripetal fill-in on dynamic postcontrast sequences has been observed (Figure 14) [40]. Hepatobiliary phase imaging using gadoxetate acid demonstrates homogeneous or target-shaped hypointensity [40]. Nodules in the cirrhotic liver A spectrum of nodules may be seen in the cirrhotic liver. Hemodynamic changes and fibrosis may cause heterogeneous enhancement, making differentiation of
benign regenerative nodules and premalignant dysplastic nodules from HCC challenging [41,42]. Furthermore, impaired hepatocyte function may limit contrast uptake, leading to decreased distinction between the focal lesion and background parenchyma. Regenerative and dysplastic nodules typically demonstrate portal venous phase enhancement to become iso- or hyperintense to background liver parenchyma. Iso- to hyperintense hepatocyte phase enhancement is observed due to preserved hepatocellular function and intact ion transporters [28,29]. With increasing atypia, as with poorly differentiated dysplastic nodules, there is decreased expression of ion transporters and reduced ability to take up gadoxetate disodium, with subsequent hypointensity observed on the hepatocyte phase [10].
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Figure 12. Well-differentiated hepatocellular carcinoma versus highly dysplastic nodule in a 59-year-old woman with known cirrhosis. The lesion shows mild T2 hypointensity and is isointense on precontrast T1 imaging. Gadoxetate disodium enhanced T1 dynamic imaging demonstrates arterial enhancement, which fades to hypointensity by the portal phase and becomes slightly hyperintense to surrounding hepatocytes on transitional phase (arrows). The lesion is hyperintense on the hepatocyte phase (arrow). Uptake of gadoxetate disodium in the hepatocyte phase can occur in a small percentage of well-differentiated hepatocellular carcinoma. Short interval follow-up imaging was recommended.
A retrospective study of 34 patients with 29 surgically resected HCCs and 31 benign nodules using gadoxetate disodium suggested the following imaging criteria to differentiate HCC from premalignant nodules: size 1.5 cm, hypointense on T1-weighted images, hyperintense on T2and diffusion-weighted images, hyperenhancement on the arterial phase, and hypointensity on the portal venous and
hepatocyte phases [43]. Lesions were considered malignant if they satisfied 3 or more of these criteria; sensitivity was higher than arterial enhancement and washout alone. In addition, a retrospective study of hypervascular hepatic lesions using gadobenate dimeglumine demonstrated that all 82 regenerative nodules were iso- or hyperintense on the hepatocyte phase, which suggests this may be used as a
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Figure 13. Cholangiocarcinoma in a 59-year-old woman. Gadoxetate disodium enhanced magnetic resonance imaging demonstrates an ill-defined mass in the region of the left porta hepatis (arrows), which is T1 hypointense compared to liver parenchyma. There is mild arterial and portal venous phase postgadolinium enhancement, with hypointensity to background liver parenchyma on the hepatocyte phase. Biliary ductal dilatation is noted adjacent to the mass.
Figure 14. A 22-year-old woman with hepatic epithelioid hemangioendothelioma. Gadoxetate-disodium enhanced magnetic resonance imaging demonstrates multiple hepatic lesions, some of which coalesce peripherally (arrows), primarily involving the right hepatic lobe. These lesions are moderately T2 hyperintense and T1 hypointense with no postgadolinium enhancement. The lesions remain hypointense on the hepatocyte phase.
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Figure 15. Dysplastic nodules in a 73-year-old man with known cirrhosis. Gadobenate dimeglumine (top row) and gadoxetate disodium (bottom row) enhanced magnetic resonance imaging in the same patient demonstrates multifocal lesions that do not demonstrate arterial enhancement but become apparent as hyperintense foci on the portal venous phase and become even more hyperintense during the hepatocyte phase (arrows).
feature of lesion benignity (Figure 15) [44]. Finally, the combination of dynamic and hepatocyte phase gadoxetate disodium-enhanced MRI has been shown to provide incremental value over conventional dynamic phase MRI alone in characterizing focal liver lesions in the cirrhotic liver [45]. Conclusions Owing to their unique pharmacologic properties, MRI using HSCAs enables comprehensive evaluation of focal liver lesions in both the dynamic and hepatocyte phases. This offers improved lesion conspicuity and characterization over other imaging modalities and conventional extracellular gadolinium-based contrast agents. In particular, HSCA offer unique advantages in differentiation of hepatocellular from nonhepatocellular lesions, detection of hepatic metastases and distinction between hepatic adenoma and focal nodular hyperplasia. Familiarity with the uses, findings and pitfalls of the 2 commercially available HSCAs, gadoxetate disodium and gadobenate dimeglumine, is essential to image interpretation and patient management. References [1] Seale MK, Catalano OA, Saini S, Hahn PF, Sahani DV. Hepatobiliaryspecific MR contrast agents: role in imaging the liver and biliary tree. Radiographics 2009;29:1725e48. [2] Goodwin MD, Dobson JE, Sirlin CB, Lim BG, Stella DL. Diagnostic challenges and pitfalls in MR imaging with hepatocyte-specific contrast agents. Radiographics 2011;31:1547e68. [3] Ringe KI, Husarik DB, Sirlin CB, Merkle EM. Gadoxetate disodiumenhanced MRI of the liver: part 1, protocol optimization and lesion appearance in the noncirrhotic liver. AJR Am J Roentgenol 2010;195: 13e28. [4] Jhaveri K, Cleary S, Audet P, et al. Consensus statements from a multidisciplinary expert panel on the utilization and application of a liver-specific MRI contrast agent (gadoxetic acid). AJR Am J Roentgenol 2015;204:498e509.
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