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MRI Eovist, Saenz MRI of Benign Liver Lesions and Metastatic Disease Characterization with Gadoxetate Disodium

Rocky C. Saenz, D.O.

Department of Diagnostic Radiology, Botsford Hospital, Farmington Hills, MI

Introduction limitations. The same restrictions and precautions remain with gadoxetate disodium for nephrogenic Imaging characterization of liver lesions is of systemic fibrosis as with standard extracellular diagnostic importance with regard to its implications gadolinium products.2 on patient treatment. Utilization of dynamic MRI has Gadoxetate disodium is best utilized with dynamic, become a common practice as an adjunct to dynamic gradient echo (GRE) T1 fat saturation imaging. CT scanning. With the recent FDA approval of Optimally, arterial phase imaging, portal venous gadoxetic disodium, this provides another avenue for imaging, and delayed imaging at 20 minutes should be evaluation and characterization of indeterminate liver performed. Typically, liver lesions without lesions. Gadoxetic acid was approved for use in the will not accumulate gadoxetate disodium on delayed United States by the FDA in 2008 for detection and imaging. Therefore, they are hypointense relative to characterization of liver lesions in adults with known 1 the native liver parenchyma on the phase. or suspected focal liver disease The purpose of this Since nearly all lack functioning article is to review the imaging findings utilizing hepatocytes, they will typically be hypointense on the gadoxetic disodium with respect to benign liver lesions hepatocyte phase. The one exception to this rule is and metastatic disease. well-differentiated hepatocellular , which demonstrates enhancement on the hepatocyte phase Gadoxetate Disodium secondary to residual functioning hepatocytes.4-5 Pre- contrast imaging with T1-weighted, T2-weighted, and The advantage of utilizing gadoxetate disodium in-phase and out-of-phase imaging are also beneficial comes from its added hepatocyte phase intracellular in characterizing liver lesions. imaging. The prior standard gadolinium agents only provide extracellular information with regards to indeterminate liver lesions. Gadoxetic disodium with Hepatic its additional hepatocyte phase has the ability to Hepatic are seen routinely on diagnostic provide more specific information of the hepatocyte imaging studies and usually do not pose a diagnostic function/content of an indeterminate liver lesion. dilemma. Histologically, hepatic cysts are derived from Gadoxetic disodium has two routes of elimination: biliary endothelium and contain serous fluid lined by a 2 renal and hepatobiliary. The elimination pathways single layer of .6 These benign lesions are 2 are equally distributed. Given its increased T1 more commonly seen in women and may be multiple shortening compared to traditional extracellular in number. Entities such as autosomal dominant gadolinium products, a lower dose of contrast is polycystic kidney disease or tuberous sclerosis have 2 required (0.1 mL per kilogram of body weight). The been known to present with innumerable hepatic gadoxetate disodium is transported from the cysts. extracellular space to the intracellular space by ATP- CT and MRI imaging of hepatic cysts are dependent organic anion transporting polypeptide 1 3 complementary in that both modalities show similar (OATP1) and then excreted into the . The findings. Cysts on CT and MRI do not demonstrate intracellular imaging (hepatocyte phase) is obtained 20 contrast enhancement. In addition, T1 and T2- minutes after intravenous injection. This hepatocyte 2 weighted MR images show the cysts to follow fluid phase lasts up to 120 minutes, which allows for signal. Hepatocyte phase imaging is usually not repeat acquisitions on delayed phase imaging to needed in order to characterize these lesions; these correct for patient motion or other potential technical

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Figure 1. Hepatic Cyst. Multiple axial images demonstrate a Figure 2. Hemangioma. Multiple axial images demonstrate a small lesion in segment VII of the right lobe of the liver. The moderately-sized lesion in segment IVa of the liver. The T1 T1 (A) and T2 fat saturation (B) images show the lesion to be (A) and T2 fat saturation (B) images show the lesion to be well circumscribed and of homogeneous low and high signal, well circumscribed and of homogeneous low and high signal, respectively. The pre-contrast, fat saturation GRE (C) shows respectively. Notice that the T2 signal is “light bulb” bright. the lesion to follow fluid signal. The dynamic portion of the The pre-contrast, fat saturation GRE (C) shows the lesion to study shows no enhancement on the arterial phase (D), be of low signal. The dynamic portion of the study shows portal venous phase (E), or hepatocyte phase (F). Notice the peripheral enhancement of the lesion on the arterial phase signal of the lesion follows the signal of cerebrospinal fluid (D) with near total enhancement on the portal venous phase on all sequences. (E). Notice the lesion is slightly hyperintense to the liver on the portal venous phase (E). The hepatocyte phase (F) lesions are hypointense to the surrounding liver demonstrates a hypointense lesion. parenchyma on hepatocyte phase (Fig. 1). In the setting of atypical imaging features, such as mural Hemangioma nodules, debris, or thickened septa, then alternative diagnoses must be considered, including cystic Hemangiomas are the most common benign tumors metastasis.6 of the liver. They are also commonly seen in daily radiology practice and are more common in females than males. The incidence of these lesions is approximately 5 to 20% of the population.6 Histologically, hemangiomas are endothelial lined vascular channels separated by fibrous septa, which

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MRI Liver Eovist, Saenz accounts for their dynamic enhancement pattern.6 Unlike hepatic , it is accepted that these lesions are not associated with oral contraceptive use.3,6,7 Hemangiomas are rarely associated with complications, such as spontaneous rupture/ hemorrhage;6 therefore, they are usually asymptomatic. Symptomatic lesions are usually very large (>10cm usually termed giant hemangiomas) and rarely may be associated with platelet sequestration, resulting in thrombocytopenia, known as Kasabach- Merritt syndrome.8-9 Large hemangiomas may also have a central scar, which represents fibrosis secondary to an area of central necrosis produced when the tumor outgrows its blood supply. Since hemangiomas are commonly encountered, radiologists must recognize their imaging features in order to preclude unnecessary workup or invasive procedures. Many lesions are diagnosed via dynamic liver CT based upon their enhancement patterns. Three dominant enhancement patterns have been described in the literature. The most common pattern is centripetal, peripheral, nodular enhancement of the lesion on early phases (arterial and portal venous phases).3 The enhancement progressively fills the lesion, resulting in iso- to slightly hyperattenuating compared to liver parenchyma on delayed imaging. This enhancement pattern typically occurs in hemangiomas 2-5 cm in size. Once lesions become Figure 3. Hepatocellular . Multiple axial images and a single coronal image demonstrate a lesion in segment I of larger, a similar enhancement pattern is seen; the liver. The T1 (A) and T2 (B) images show the lesion to be however, centripetal, peripheral, nodular well circumscribed and hyperintense and intermediate in enhancement of the lesion remains discontinuous signal intensity, respectively. Notice the lesion has bright T1 centrally. This may occur secondary to the large size of signal secondary to its fat content, which corresponds with the lesion or be related to central scar formation. its loss of signal on the pre-contrast, fat saturation GRE Therefore, the lesion centrally remains image (C). The dynamic portion of the study shows minimal hypoattenuated compared to surrounding liver peripheral enhancement of the lesion on the arterial phase parenchyma on delayed imaging. The final (D) and the portal venous phase (E). The lesion overall enhancement pattern usually occurs in small lesions remains hypointense to the liver on the portal venous phase (<2 cm in size). This enhancement pattern has been (E). The hepatocyte phase (F) also demonstrates a termed "flash-filling".3 These lesions typically enhance hypointense lesion. Case courtesy of Ankit B. Patel, D.O. homogeneously between the arterial and early portal venous phases, resulting in increased attenuation T1 and hyperintense on T2 compared to liver compared to the surrounding liver parenchyma. These parenchyma. Classically, the lesions are hyperintense, smaller hemangiomas also characteristically become almost “light bulb” bright on T2-weighted imaging. iso-attenuated to liver on delayed imaging. This feature helps distinguish them from malignant The MRI characteristics of hemangiomas are well lesions, which are typically of intermediate signal on documented. The lesions typically are hypointense on

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T2 imaging. The dynamic enhancement pattern on MRI with gadolinium agents is similar to the CT pattern just described. By utilizing gadoxetate acid, hemangiomas are hypointense on the hepatocyte phase, since they do not contain hepatocytes (Fig 2).

Adenoma

Hepatocellular adenoma is an uncommon benign liver lesion which occurs predominantly in women of reproductive age.6 A direct association has been made with the use of oral contraceptives and steroids.3,6,7,10 Histologically, adenomas are made up of benign hepatocytes arranged in cords separated by dilated sinusoids.7 They lack bile ducts, which histologically distinguishes them from focal nodular (FNH).6,7 These histologic qualities are responsible for the dynamic enhancement pattern seen on imaging. Hepatocellular adenomas also lack portal tracks and hepatic veins, which predisposes them to development of necrosis and rupture with spontaneous hemorrhage.6 There is also the potential for malignant degeneration with approximately 5% of adenomas differentiating into .3 Since the severity of potential complications exists, adenomas are managed differently from other benign liver masses with the majority surgically removed. Therefore, it is important Figure 4. Focal Nodular Hyperplasia. Multiple axial images for radiologists to understand and recognize their demonstrate a moderately sized lesion in segment II of the imaging appearance. liver. On the T1 (A) and T2 fat saturation (B) images the le- The MRI characteristics of hepatocellular adenomas sion is very subtle and hypointense and slightly hyperintense in signal intensity, respectively. Notice the lesion has inter- may be variable. Typically, these lesions are mediate T2 signal when compared to the hepatic cyst and hypointense to liver parenchyma on T1 and hemangioma from Figures 1 and 2. The pre-contrast fat intermediate to hyperintense compared to liver saturation GRE (C) shows the lesion to be iso to hypointense parenchyma on T2 weighted images. On occasion, signal. The dynamic portion of the study demonstrates brisk macroscopic fat may be present, which results in areas enhancement of the lesion in the arterial phase (D) and of high T1 signal intensity (Fig. 3). The dynamic MRI slightly hyperintense signal on the portal venous phase (E). The hepatocyte phase (F) shows an iso-intense lesion. Table 1. DDx Hypervascular Liver Lesions enhancement pattern is variable as well; typically, Benign these lesions demonstrate homogeneous, Hepatocellular Adenoma hyperintense enhancement on arterial phase imaging, 10 Focal Nodular Hyperplasia similar to other hepatic lesions (Table 1). Hemangioma (Flash-fill) Hepatocellular adenomas demonstrate this enhancement pattern secondary to their vascular Malignant . They typically remain hyperintense to iso- Hepatocellular Carcinoma intense to liver parenchyma on portal venous imaging. Metastatic Disease The hepatocyte phase characteristics are a helpful

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Focal Nodular Hyperplasia

Focal nodular hyperplasia (FNH) is the second most common of the liver, and is also more common in females. The incidence is approximately 5% of the general population.3 The majority of these lesions are solitary and contain a central scar.3,6 It is controversial in the literature regarding the lesion’s association with oral contraceptive use, but most studies agree that no direct relationship exists.3,4 FNH is composed of hyperplastic liver parenchyma superimposed upon a pre-existing arterial spiderlike vascular malformation.7 Histologically, these lesions contain Kupffer cells, hepatocytes, and small bile ductules with surrounding radiating fibrous septa.7 On MRI, FNH is typically of low signal on T1- weighted imaging and intermediate signal on T2- weighted imaging. Greater than 50% of these lesions demonstrate a central scar, which classically is of high T2 signal. Morphologically, FNH can be differentiated from hepatocellular adenoma based upon the tumor margins. Hepatocellular adenoma is typically well circumscribed, whereas FNH has lobulated margins. Arterial phase imaging characteristically demonstrates marked uptake of gadolinium, making the lesion hyperintense to the surrounding liver parenchyma. On the portal venous phase, the lesion is typically hyperintense or iso-intense compared to liver Figure 5. Focal Nodular Hyperplasia. Multiple axial images parenchyma. The hepatocyte phase of the dynamic demonstrate a large lesion in the right lobe of the liver. On MR enhancement pattern is the most specific the T1 (A) and T2 fat saturation (B) images the lesion is very radiographic finding in diagnosing FNH.5 On delayed subtle and is hypointense and slightly hyperintense in signal 20 minute imaging, the hepatocyte phase usually intensity, respectively. Notice the lesion has a central scar demonstrates the lesion to be hyperintense to iso- which is of high T2 signal. The pre-contrast, fat saturation intense to the remaining liver parenchyma (Fig 4). The GRE image (C) shows the lesion to be hypointense. The dy- increased signal during the hepatocyte phase is due to namic portion of the study demonstrates enhancement of the presence of hyperplastic hepatocytes and small the lesion, resulting in a slightly hyperintense appearance on 7 the arterial phase (D) and the portal venous phase (E). The bile ductules. hepatocyte phase (F) shows the lesion to be iso-intense to Multiple liver lesions including focal nodular the remaining liver. hyperplasia may have a central scar (Table 2). The discriminator with regard to diagnosis of these lesions, as adenomas are usually hypointense compared to Table 2. DDx Liver Lesions with Central Scar liver parenchyma (Fig. 3). The gadoxetate acid hepatocyte phase is instrumental in differentiating Giant Hemangioma these lesions from focal nodular hyperplasia, which is Hepatocellular Adenoma typically hyperintense to iso-intense to liver Focal Nodular Hyperplasia parenchyma.10 Lastly, an additional potential Hepatocellular Carcinoma (Fibrolamellar) discriminating characteristic of adenomas is peripheral rim enhancement of the pseudocapsule.

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Table 3. Summary MRI Characteristics Table 4. DDx Hypervascular Liver Metastasis T1 T2 ART PV HC SPEC “MR. CT Craves Peanut Butter” Peripheral Melanoma Hemangioma D B V B/I D nodular CE Renal Cell Fat content, Choriocarcinoma Adenoma V I V V D pseudocapsule Thyroid Central scar T2 FNH D I B B/I B bright Breast Heterogeneous Metastatic V V B D D signal, erratic CE

Abbreviations: ART-Arterial Phase, PV-Portal venous Phase, HC- Hepatocyte Phase, SPEC-Special Characteristics, B-Bright, D-Dark, I-Intermediate, V-Variable, CE-Contrast Enhancement central scar in FNH is unlike the other lesions with benign liver lesions such as hemangiomas, the T2 respect to its bright T2 signal (Fig. 5). Delayed imaging signal intensity of metastatic lesions is typically less on CT and MRI with extracelluar, standard gadolinium intense. While hemangiomas have a very similar bright agents usually demonstrates enhancement of the T2 signal compared to hepatic cysts, metastatic lesions fibrous scar. Hepatocyte imaging with gadoxetate are slightly hyperintense compared to background disodium typically shows non-enhancement of the liver parenchyma on T2 sequences (Table 3). Rarely, central scar.5 metastatic lesions may be bright on T1-weighted In comparing FNH with hepatocellular adenoma, a imaging, as is seen with hepatic metastases from a recent study by Grazioli et al, demonstrated that pancreatic ; the increased T1 signal is thought to be related to the effects of insulin hepatocellular adenomas and FNH have different 11 imaging characteristics on hepatocyte phase imaging promoting hepatocyte triglyceride accumulation. greater than 90% of the time. 10 This study also The majority of metastases have their vascular highlighted the fact that a combination of marked supply from the hepatic arteries secondary to neo- enhancement on arterial phase imaging with angiogenesis; therefore, they demonstrate early corresponding hyperintense to iso-intense appearance enhancement on arterial phase imaging. This early on hepatocyte phase imaging differentiates FNH from enhancement, however, is nonspecific. The differential the moderate arterial phase enhancement and diagnoses of hypervascular metastatic lesions are hypointensity on hepatocyte imaging seen with listed in Table 4. Unlike some of the benign entities hepatocellular adenoma.10 previously discussed, metastases typically do not demonstrate homogeneous enhancement. Lesions from breast carcinoma and gastrointestinal Metastatic Disease may have a “target” enhancement Metastatic disease represents the most common pattern on arterial and early portal venous imaging malignant tumor of the liver. The most common (Fig. 6). Most metastatic lesions show “washout” on portal venous imaging (hypointense to liver primary tumors include lung, breast, colon, pancreas, 11 and melanoma.6 The majority are multiple and vary in parenchyma). Hepatocyte phase imaging size as well as appearance.11 Classically, metastatic demonstrates low signal intensity compared to lesions are poorly circumscribed with erratic behavior surrounding liver parenchyma. Metastatic lesions on dynamic CT and MR liver studies. demonstrate no enhancement on the intracellular 20 minute delayed phase, since they do not contain The majority of metastases are heterogeneous but functioning hepatocytes (Fig. 7). low in T1 signal intensity with corresponding intermediate to high T2 signal intensity. Compared to

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Figure 6. Metastatic Breast Adenocarcinoma. Multiple axial Figure 7. Metastatic . Multiple axial images demonstrate an irregular lesion in segment VIII of images demonstrate an irregular, poorly circumscribed the liver. On the T1 (A) and T2 fat saturation (B) images the lesion spanning segments V and VI of the liver. On the T1 lesion is heterogeneous but predominantly hypointense and (A) and T2 fat saturation (B) images the lesion is slightly hyperintense in signal intensity, respectively. Notice heterogeneous with mixed signal intensity. The pre- the lesion has intermediate T2 signal with central high signal contrast, fat saturation GRE image (C) also shows (B). The pre-contrast, fat saturation GRE (C) shows the heterogeneous signal. The dynamic portion of the study lesion to be hypointense. The dynamic portion of the study demonstrates irregular enhancement on the arterial phase demonstrates peripheral rim enhancement with an inner (D) and portal venous phase (E). The hepatocyte phase (F) ring of enhancement resulting in a “target” appearance on shows a predominantly hypointense lesion. the arterial phase (D) and demonstrates central enhancement remaining slightly hyperintense on the portal venous phase (E). The hepatocyte phase (F) shows a hypointense lesion. imaging can provide important information in the Summary characterization of indeterminate liver lesions. This additional information not only assists in making the It is imperative for the radiologist to be familiar with correct diagnosis, but also helps guide management, the different dynamic enhancement patterns of benign to include avoiding unnecessary follow-up or invasive and malignant liver lesions. With the advent of procedures in some cases. gadoxetate disodium, hepatocyte phase specific

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