Consensus Report of the Fifth International Forum for Liver MRI

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1 Fifth International Forum for Liver MRI Gastrointestinal Imaging Commentary Gastrointestinal Imaging Commentary FOCUS ON: Christoph J. Zech 1,2 Carlo Bartolozzi 3 Paulette Bioulac-Sage 4 Pierce K. Chow 5 Alejandro Forner 6 Luigi Grazioli 7 Alexander Huppertz 8 Herve Laumonier 9 Jeong Min Lee 10 Takamichi Murakami 11 Jens Ricke 12 Claude B. Sirlin 13 Zech CJ, Bartolozzi C, Bioulac-Sage P, et al. Keywords: Eovist, gadoxetic acid enhanced MRI, hepatocellular adenoma, hepatocellular carcinoma, Liver Forum, Liver Imaging Reporting and Data System, liver lesions, Primovist DOI: /AJR Received June 21, 2012; accepted after revision November 21, The Fifth International Forum for Liver MRI was supported by Bayer Healthcare, and all authors received honoraria and travel expenses. C. B. Sirlin is a member of the Liver Advisory Board, Bayer Healthcare, a member of the Bayer Healthcare Speaker Bureau, and Principal Investigator, Investigator-Initiated Study, Bayer Healthcare. C. J. Zech is a member of the Liver Advisory Board, Bayer Healthcare and the Scientific Cooperation, Bayer Healthcare, and has received honoraria for lectures and travel costs from Bayer Healthcare and Bracco. L. Grazioli is a member of the Liver Advisory Board, Bayer Healthcare. A. Forner has received consultancy and lecture fees from Bayer Healthcare. P. K. Chow received research funding from Bayer Healthcare for an investigator-initiated clinical trial and was on the Bayer Hepatocellular Carcinoma Advisory Board. J. Ricke has received consultancy and lecture fees, funding for investigator-initiated clinical trials, and is a member of the Liver Advisory Board, Bayer Healthcare. J. M. Lee is a member of the Liver Advisory Board, Bayer Healthcare, and Principal Investigator, Investigator-Initiated Study, Bayer Healthcare, and has received honoraria for lectures and travel costs from Bayer Healthcare. 1 University Hospital Basel, Clinic of Radiology and Nuclear Medicine, Basel, Switzerland. 2 Department of Clinical Radiology, Munich University Hospitals Grosshadern, Munich, Germany. AJR 2013; 201: X/13/ American Roentgen Ray Society Consensus Report of the Fifth International Forum for Liver MRI OBJECTIVE. This article reviews topics discussed during the Fifth International Forum for Liver MRI (with a focus on gadoxetic acid enhanced MRI), which was held in Munich, Germany, in September CONCLUSION. Growing evidence shows that gadoxetic acid enhanced MRI has high sensitivity and specificity for diagnosing liver tumors. Hepatobiliary phase imaging adds new information for the characterization of borderline lesions. However, there is a need to develop standardized criteria for interpretation of gadoxetic acid enhanced MRI in patients with cirrhosis or other risk factors for hepatocellular carcinoma. O ptimization of the techniques and protocols for the use of MRI in patients with suspected liver lesions is essential for improving the diagnostic accuracy, management decisions, and costs associated with such patients and for future trial designs. Issues and the latest developments in MRI with a particular focus on gadoxetic acid enhanced liver MRI were discussed at the Fifth International Forum for Liver MRI, which was held in Munich, Germany, in September As summarized in this article, four topics were presented at the forum to an audience of around 100 abdominal radiologists, hepatologists, and surgeons from the United States, Europe, and Asia and were further discussed in small work groups: first, the diagnosis and management of hepatocellular carcinoma (HCC); second, HCC guidelines and optimized MRI techniques for patients with cirrhosis or other risk factors for HCC; third, update on MRI findings of hepatocellular adenoma (HCA); and fourth, update on MRI in colorectal cancer, including cost considerations Each work group generated and refined a number of consensus statements relating to key areas within each topic. The aim of these statements was to advance current thinking in controversial areas on the basis of experience and feedback from the participants. These statements were then presented to the entire group, who were asked to vote agree, disagree, or abstain using an electronic voting system (the numbers in parentheses represent the number of delegates who agreed with the statement). These statements, based on expert opinion, are summarized throughout this article. It is envisaged that some consensus statements will be useful for radiologists in their daily clinical routine, whereas others will help to identify areas in which further research is needed. 3 Universita die Pisa, Radiologia Diagnostica e Interventistica, Pisa, Italy. 4 University Hospital Bordeaux, Pathology Department Hôpital Pellegrin, Bordeaux, France. 5 Office of Clinical Sciences, Duke-NUS Graduate Medical School Singapore and Department of Surgery Singapore General Hospital, Singapore. 6 Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic Barcelona, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain. 7 Department of Radiology, Spedali Civili di Brescia, University of Brescia, Brescia, Italy. 8 Imaging Science Institute Charité-Siemens, Berlin, Germany. 9 Polyclinique Bordeaux Tondu, Bordeaux, France. 10 Department of Radiology, Seoul National University Hospital, Seoul, Korea. 11 Department of Radiology, Kinki University Faculty of Medicine, Osaka, Japan. 12 Klinik für Radiologie und Nuklearmedizin, Universitätsklinikum Magdeburg AöR, Magdeburg, Germany. 13 Liver Imaging Group, Department of Radiology, University of California San Diego, 408 Dickinson St, San Diego, CA Address correspondence to C. B. Sirlin (csirlin@ucsd.edu). AJR:201, July

2 Diagnosis and Management of HCC How Important Is Early Detection of HCC for Effective Treatment Strategies? HCC is a prevalent neoplasia, with a worldwide incidence of cases/100,000 population per year, depending on the global region [1]. HCC is still associated with a high mortality of up to 1 million global deaths per year [1] despite advancements in diagnosis and treatment. The only way to offer potentially curative therapies (e.g., surgical resection, ablation, and liver transplantation) is by diagnosing the disease at an asymptomatic early stage. For that reason, routine surveillance by frequent imaging is performed in patients at high risk of HCC development (patients with cirrhosis or patients with long-standing chronic hepatitis without cirrhosis) [2, 3]. Tumor burden has been shown to be a strong predictive factor for HCC mortality. This has been clearly shown by the different staging systems widely used for HCC management. For example, patients categorized as early stage by the Barcelona Clinic Liver Cancer system (asymptomatic patient with single lesion or up to three nodules < 3 cm without vascular invasion or extrahepatic spread) have a 5-year survival in the range 40 70% after curative treatment, and this survival is significantly superior to the median survival of 11 months in patients with advanced HCC, which is defined as vascular invasion or extrahepatic spread or the presence of symptoms [4, 5]. Moreover, in the scenario of liver transplantation, tumor burden, which is defined as tumor size and the number of nodules, has shown a strong predictive value for survival [6]. Although dynamic imaging techniques are recommended for diagnosis of HCC, such techniques have a number of diagnostic limitations related largely to tumor size [2], and the accurate detection and characterization of small hepatocellular nodules remains a challenge in imaging patients with chronic liver disease. In nodules larger than 1 cm detected by screening sonography in patients with chronic liver disease, the depiction on dynamic CT or MRI of a characteristic enhancement pattern (vascular profile) consisting of hyperenhancement during the late arterial phase (wash-in) and venous or delayed phase hypoenhancement (washout) is associated with nearly 100% specificity for HCC diagnosis. However, the sensitivity of this vascular profile for diagnosing HCCs smaller than 2 cm is limited, ranging from 44% to 62% for MRI and from 44% to 53% for CT. Because of the low sensitivity of the vascular profile for small HCCs, biopsy confirmation is required in many cases [7 9]. However, biopsy is associated with a number of limitations, including risks of needle tract seeding (2.7%) [10] or bleeding complications (0.5%) [11], high false-negative results in small (< 2 cm) lesions [7], and the challenge of sampling high-grade dysplastic nodules that contain HCC islets ( 35% of high-grade dysplastic nodules) [12]. Biopsy is also not suitable for evaluating multiple lesions concurrently or for staging the extent of disease, and ascites and coagulation disorders may prevent biopsy in a number of patients. Accordingly, there is a need to improve the sensitivity of imaging for the diagnosis of small HCCs while maintaining high specificity. Several cohort studies have shown that size is a critical prognostic factor, and this provides a rationale for diagnosing HCC as early as possible [6, 13 17]. Despite suggestions that nodules smaller than 2 cm not displaying hypervascularization have a low risk of malignancy, the balance of outcomes and costs in terms of early characterization and treatment versus potential tumor dissemination during follow-up are unclear [18]. One strategy for improving the sensitivity of imaging for such lesions is to incorporate additional image parameters. In that regard, a prospective analysis including 159 cirrhotic patients with newly detected solitary lesions 5 20 mm in size showed that the MRI depiction of tumor capsule in association with intralesional fat was highly specific for HCC diagnosis; however, the combination of tumor capsule and intralesional fat had sensitivity of only 9.7% for HCC diagnosis, and all nodules with this combination of MRI features also displayed the characteristic vascular profile. Thus, these imaging features did not increase the diagnostic accuracy of MRI for HCC [19]. In addition to structural imaging features, such as capsule and intralesional fat, another strategy is to add the information provided by functional MRI sequences, such as diffusion-weighted imaging (DWI). In a small single-center study [20], the authors showed that, compared with conventional MRI alone, the addition of DWI with a signal intensity (SI) ratio (defined as the ratio of the lesion SI to the adjacent liver SI at a given b value) greater than 1.23 at a b value of 600 s/mm 2 improved the per-lesion sensitivity (91.2% vs 67.6%) and negative predictive value (91.9% vs 69.4%) for differentiating malignant from benign lesions smaller than 2 cm. On the basis of emerging data, a promising strategy for improving the diagnostic accuracy of imaging techniques for early HCC diagnosis may be the use of tissue-specific contrast agents such as gadoxetic acid. This contrast agent has shown favorable results in several studies. In a comparison of 104 pseudolesions and 123 HCCs, the mean hepatocyte phase SI ratio (ratio of lesion to liver SI) was significantly lower in HCCs than in pseudolesions (0.65 vs 0.95; p < 0.01), and an optimal SI ratio cutoff value of less than 0.84 in conjunction with visibility on DWI provided high specificity for HCC [21]. A study of 102 histopathologically confirmed nodules from 34 cirrhotic patients who underwent gadoxetic acid enhanced MRI before orthotopic liver transplantation showed that 97.5% (39/40) of HCCs and 70% (21/30) of high-grade dysplastic nodules were hypointense during the hepatobiliary phase of gadoxetic acid enhanced MRI, whereas 96.9% (31/32) of low-grade dysplastic nodules were hyperintense during the dynamic and hepatobiliary phases [22]. Importantly, 27.5% (11/40) of hepatobiliary phase hypointense HCCs and 95.2% (20/21) of hepatobiliary phase hypointense high-grade dysplastic nodules lacked arterial phase hyperenhancement and showed venous phase hypoenhancement. Moreover, quantitative evaluation of lesion enhancement ratios showed no significant difference between hypovascular HCCs and high-grade dysplastic nodules on hepatobiliary phase imaging. These findings indicate that hypointensity on the hepatobiliary phase, even in the absence of arterial phase hyperenhancement, is suggestive of premalignancy or malignancy and could be a useful diagnostic marker for the identification of small arterial iso- or hypovascular premalignant or malignant lesions that otherwise would be undetected. Nodules in cirrhotic patients with such findings at MRI have a high likelihood of being high-grade dysplastic nodules or well-differentiated HCCs and should be considered high-risk lesions. Appropriate management, which should include close follow-up or percutaneous treatment or transplantation, must be selected on the basis of additional risk factors and clinical presentation. It should be emphasized that hypointensity on the hepatobiliary phase does not in isolation differentiate malignant from premalignant arterial iso- or hypovascular lesions. Such differentiation is important, because the prognosis and management of the two lesion types are not identical. HCCs generally should be treated and, depending on the size and number of HCC lesions, may give the patient priority for liver transplantation [23]. The clinical and biologic relevance of high-grade dysplastic 98 AJR:201, July 2013

3 Fifth International Forum for Liver MRI nodules is not as well understood. High-grade dysplastic nodules are premalignant lesions at the borderline between benign and malignant. Compared with cirrhotic nodules and lowgrade dysplastic nodules, high-grade dysplastic nodules have higher risk for transformation into overt HCC [24 26]. The optimal management of high-grade dysplastic nodules is not yet established and may depend on factors such as patient age, eligibility for transplantation, and degree of liver function impairment. These nodules probably warrant close monitoring, but they do not give patients priority for liver transplantation and aggressive treatment is probably not indicated. Because hypointensity on the hepatobiliary phase of gadoxetic acid enhanced MRI does not differentiate arterial hypo- or isovascular high-grade dysplastic nodules and early HCCs, further research is needed to define discriminatory imaging features. Until such features are identified and validated, biopsy may be necessary for further evaluation of such lesions, depending on lesion size and other factors. The diagnosis of HCC can be established by pathologic findings such as the presence of stromal invasion or immunohistochemical staining [27]. Another benefit of gadoxetic acid enhanced MRI is evident in the differentiation of HCCs and arterial enhancing pseudolesions 2 cm or smaller. Most HCCs (95.5% [42/44]) displayed low hypointensity during the hepatobiliary phase of gadoxetic acid enhanced MRI, whereas most arterial enhancing pseudolesions were isointense on the hepatobiliary phase (94.3% [50/53]); the sensitivity for gadoxetic acid enhanced MRI was significantly higher than that for multiphasic CT (93.9% and 90.9% [two MRI reviewers] vs 54.5% and 54.5% [two CT reviewers], respectively) in these patients [28]. However, a small proportion of HCCs are iso- or hyperintense during the hepatobiliary phase of gadoxetic acid enhanced MRI [29]. These lesions display differences in molecular markers and imaging characteristics, including a stronger expression of organic anion-transporting polypeptides and multidrug-resistant proteins compared with background liver (p < 0.001) [29]. The presence of a focal defect in contrast media uptake and hypointense rim could help to differentiate hyperintense HCC from benign lesions [21, 29 31] (Table 1). Understanding some of the limitations of gadoxetic acid enhanced MRI could help to avoid misdiagnosis; for example, strong enhancement of liver parenchyma, which develops over time, could mask intralesional enhancement, resulting in difficultly in diagnosing flash hemangioma or arterially enhancing cholangiocarcinoma. However, some of the additional features observed during the hepatobiliary phase of gadoxetic acid enhanced MRI still make this a valuable tool for characterization of early HCCs in the cirrhotic liver. Consensus Statement 1.1 Lesions without arterial phase hyperenhancement but with both venous phase hypoenhancement and hepatobiliary phase hypointensity at gadoxetic acid enhanced MRI have a high likelihood of being high-grade dysplastic nodules or well-differentiated HCCs and should be considered high-risk lesions (78% agreement [75/96]). Consensus Statement 1.2 High-grade dysplastic nodules represent the progression from benign to malignant lesions. The diagnosis of HCC should be determined by pathologic findings such as the presence of stromal invasion or immunohistochemical staining (87% agreement [85/98]). Consensus Statement 1.3 The optimal strategy after the diagnosis of high-grade dysplastic nodule is not well established and may depend on factors such as patient age, eligibility for transplantation, and degree of liver function impairment, but it is reasonable to monitor patients with highgrade dysplastic nodule every 3 6 months (78% agreement [79/101]). HCC Guidelines and Optimized MRI Techniques for Patients With Cirrhosis or Other Risk Factors for HCC A number of guidelines have been published in an attempt to optimize the diagnosis and management of liver lesions in patients with cirrhosis or other risk factors for HCC [2, 32 34]. In general, there is agreement on the imaging features of typical (classic) HCC (i.e., the presence of wash-in and washout) [2, 33]. However, in lesions with atypical presentation, the American Association for the Study of Liver Diseases guidelines recommend pathologic confirmation [2], whereas the Asian Pacific Association for the Study of the Liver guidelines focus on Kupffer cell density (a marker of benignity) with the use of Kupffer-specific superparamagnetic iron oxide or perflubutane injection (Sonazoid, Nycomed-Amersham) agents (where available) in contrast-enhanced ultrasound or MRI [33, 34]. The Japanese guidelines also include gadoxetic acid enhanced MRI for use in the detection of atypical lesions [34]. Gad oxetic acid enhanced MRI has a higher sensitivity for detecting HCC than does superparamagnetic iron oxide enhanced MRI (90.7% vs 84.7%, respectively; p < 0.05), and the hepatobiliary phase of gadoxetic acid enhanced MRI is 11% more sensitive and 7% more specific than dynamic MRI in identifying small ( 2 cm) atypical HCCs in cirrhotic liver [35, 36]. TABLE 1: Characteristic Findings for Hepatocellular Carcinomas (HCCs) That Appear Iso-, Hyper-, or Hypointense on the Hepatobiliary Phase of Gadoxetic Acid Enhanced MRI, and Pathologic and Imaging Findings That Allow Differentiation from Pseudolesions and Other Benign Entities Hepatobiliary Phase Image Frequency a (%) Pathologic and Imaging Findings Hypointense 90 Expression of gadoxetic acid transporters (organic anion-transporting polypeptide 8 and multidrugresistant protein 3) is weak; decreasing time signal intensity curve after the arterial phase Iso- or hyperintense 10 Expression of gadoxetic acid transporters (organic anion-transporting polypeptide 8 and multidrugresistant protein 3) is strong; increasing time signal intensity curve after the arterial phase; pseudoglandular proliferation pattern with bile plugs is common; focal defects in uptake (68.8% vs 3.1%; p < 0.001) a ; nodule-in-nodule appearance (75.0% vs 0%; p < 0.001) a ; absence of a central scar (100% vs 46.9%; p < 0.001) a ; internal septation (50.0% vs 3.1%; p < 0.001) a ; hypointense rim (75.0% vs 15.6%; p < 0.001) a ; significantly lower signal intensity ratio with HCC (p < 0.84) b ; visibility on diffusionweighted imaging b Note Pathologic and imaging findings were compiled from references [21, 29, 31, 75]. Signal intensity ratio is the ratio of lesion signal intensity to liver signal intensity. a Versus benign lesions. b Versus pseudolesions. AJR:201, July

4 Consensus Statement 2.1 Several studies have shown the usefulness of gadoxetic acid enhanced MRI for HCC diagnosis. In the future, gadoxetic acid enhanced MRI may become an accepted diagnostic tool by international guidelines for HCC diagnosis (85% agreement [67/79]). There are also differences in guideline recommendations on the surveillance of high-risk patients [3]. Biannual screening with α-fetoprotein and sonography has been shown to reduce HCC mortality by 37%, and recent studies indicate that an α-fetoprotein level of 200 ng/ml or more is the optimal cutoff for diagnosing HCC risk [37]. However, α-fetoprotein has been removed from the revised American Association for the Study of Liver Diseases guidelines mainly because of its low sensitivity for HCC detection, specifically in a low-prevalence population (positive predictive value, %) [38, 39]. Screening in these guidelines is limited to sonography every 6 months [2]. In the American Association for the Study of Liver Diseases and other clinical practice guidelines [2,3], CT and MRI are recommended as noninvasive methods to confirm HCC diagnosis in lesions larger than 1 cm, according to their perfusion characteristics. These characteristics comprise not only wash-in but also washout. The current diagnostic algorithm considers that a noninvasive diagnosis of HCC is feasible for nodules larger than 1 cm detected in patients with chronic liver disease if the nodules display the characteristic vascular profile described previously at dynamic MRI or CT (the current guidelines [2] no longer recommend the use of contrast-enhanced ultrasound as a diagnostic imaging technique for this purpose). A study by Forner et al. [7] found that these revised criteria lead to sensitivity of 48% and specificity of 100% in tumors 1 2 cm in size. The same range of HCC sizes tested in a cohort of 43 nodules (10 19 mm) by Leoni et al. [40] showed 70% sensitivity and 87% specificity. In essence, application of the revised American Association for the Study of Liver Diseases guidelines [2] reduces the need for biopsy even in small suspicious nodules, thus limiting the associated risks of biopsy. Standardization of Gadoxetic Acid Enhanced MRI Techniques and Protocols When considering future updates to clinical guidelines, awareness of measures to improve the optimization of contrast-enhanced MRI techniques is essential. Such measures are designed to enable greater accuracy for HCC detection by allowing the fine visualization of small anatomic structures and lesions. For gadoxetic acid enhanced MRI, dynamic studies with fat-suppressed high-spatial-resolution 3D T1-weighted sequences are recommended. Refinements to the protocol include an injection rate of 1 2 ml/s for the usual dose (0.1 ml/kg, mmol/kg), which should be followed by a saline chaser (e.g., 35 ml of 0.9% saline at 2 ml/s) to increase the total volume [41, 42]. Some recent evidence shows that using twice the recommended dose of gadoxetic acid (0.05 mmol/ kg) provides increased arterial enhancement [43], albeit to a lesser extent than with gadobenate dimeglumine (although gadoxetic acid provides greater enhancement in the hepatobiliary phase than gadobenate dimeglumine) [44]. However, a double dose of gado xetic acid only appears to provide additional enhancement (above that of the standard dose) during the hepatobiliary phase in patients with advanced liver disease (Child-Pugh class B) [43], and increasing the dose spectrum ( mmol/kg) did not improve the portal vein-to-liver contrast during the delayed phase [45]. Therefore, a double dose of gadoxetic acid may provide additional diagnostic confidence for some applications, but for the majority of investigations, the standard mmol/kg dose appears to be adequate. Prospective studies assessing whether doubledose gadoxetic acid enhanced MRI improves per-lesion diagnostic accuracy are needed. C Fig. 1 Gadoxetic acid enhanced MR cholangiography in three different patients. Coronal images were reconstructed from fat-suppressed 3D T1-weighted gradient-recalled echo in axial plane. A, 68-year-old man/woman with normal liver function. B, 77-year-old man/woman with total bilirubin level of 1.9 mg/dl. C, 79-year-old man/woman with abnormal liver function, with total bilirubin level of 2.2 mg/dl. Common duct, left and right hepatic ducts, and gallbladder are not visualized. A B 100 AJR:201, July 2013

5 Fifth International Forum for Liver MRI Arterial phase images should be obtained so that central k-space sampling occurs about 15 seconds after the arrival of contrast medium to the suprarenal abdominal aorta, determined by the bolus technique. Techniques that reduce acquisition time while maintaining high spatial resolution, such as partially sampled 3D techniques [46], may reduce truncation and motion artifacts and marginal high intensity. Portal venous phase images should be acquired seconds after the end of the arterial phase. Usually, late phase images are obtained 2 3 minutes after the injection of contrast medium [42], although the incremental diagnostic value of these images is not yet established scientifically. Hepatobiliary phase images should be acquired approximately minutes after contrast medium injection, depending on liver function [47, 48]. Although some institutions acquire hepatobiliary phase images with greater than 20 minutes of delay in patients with compromised hepatic function, T1 mapping on gad oxetic acid enhanced MRI has shown that there is no further reduction in hepatic parenchymal T1 relaxation values after 13 minutes in patients with or without severe liver damage [49], suggesting that additional delay may not be efficacious. However, the reduction rate of T1 relaxation time between unenhanced imaging and administration of gadoxetic acid is lower for patients with Child Pugh class B disease compared with other groups after 8 minutes (T1 relaxation time reduction rate was 38.0% [Child Pugh class B] vs 47.1% [chronic hepatitis], respectively; p < 0.05) [49]; this finding suggests that contrast-enhanced T1 relaxation time reduction can be used to estimate liver function. Indocyanine green retention rate at 15 Assign LI-RADS Category Code LI-RADS 1 LI-RADS 2 LI-RADS 3 LI-RADS 4 LI-RADS 5 Definitely benign Probably benign Intermediate probability for HCC Probably HCC Definitely HCC minutes has been shown to be a significant predictor of the SI achieved with gadoxetic acid enhanced MRI in the bile ducts [50]. This finding may reflect the status of the underlying liver function and indicates that indocyanine green could also be used as a marker. Serum bilirubin could also be used as an indicator of liver function and, thus, signal intensity on gadoxetic acid enhanced MRI (Fig. 1). Finally, it must be noted that T2-weighted imaging and DWI after gadoxetic acid injection could be used for HCC diagnosis given that there are no significant differences in signal-to-noise or contrast-to-noise ratio at any time, and MR cholangiopancreatographic images can even be obtained within 1.5 minutes after injection [51, 52]. It is hoped that ongoing refinements will be incorporated into global standards, including the Liver Imaging Reporting and Data System (LI-RADS), which is described later in this article. Consensus Statement 2.2 Emerging scientific data suggest that slower injection rates (e.g., 1 ml/s) improve the quality of gadoxetic acid enhanced arterial phase images. However, there are not yet scientific data on how slower injection rates affect diagnostic performance or later imaging phases. Saline chase of adequate volume is important (e.g., > 20 ml; 85% agreement [68/80]). Consensus Statement 2.3 Emerging scientific data suggest that T1 relaxation of the liver almost plateaus at about minutes after gadoxetic acid injection and that further delay in image acquisition does not result in a further meaningful reduction in liver T1 relaxation time. However, it is not yet known whether further delay 100% certain observation is benign Some but not all features diagnostic of benign entity Cannot classify as more likely benign or more likely HCC Some but not all features diagnostic of HCC 100% certain observation is HCC; if done, explant would confirm HCC Fig. 2 Overview of Liver Imaging Reporting and Data System (LI-RADS) categories. HCC = hepatocellular carcinoma. affects liver-to-lesion contrast (84% agreement [71/85]). Toward a Global Standard of MRI: LI-RADS LI-RADS is a functional system aimed at standardizing the interpretation and reporting of imaging (MRI and CT) data, aiding the categorization and management of liver lesions, and to assigning the probability of imaging-detected lesions being HCC. It originated from two universities in the United States (University of California, San Diego, and Thomas Jefferson University) and was refined through an independent American College of Radiology committee. Over a 3-year period, the committee refined five LI-RADS categories (LI-RADS 1 5) and developed a list of controlled terminology for evaluating the entire lesion spectrum [53] (Fig. 2). In summary, a LI-RADS category 1 observation is regarded as definitely benign (e.g., a cyst or hemangioma), and a LI-RADS category 5 observation is a definite HCC with imaging features that may warrant transplantation (if no contraindications and of appropriate stage) without biopsy. LI-RADS category 5 also includes observations associated with definite tumor in vein (macrovascular invasion), a contraindication to transplantation. LI-RADS category 2 describes features of lesions that are probably benign, and LI-RADS category 4 refers to probable HCCs, with another category (LI-RADS category 3) for intermediate probability of HCC. LI-RADS 4 and 5 criteria are based on imaging features, such as observation size, presence of arterial phase hyper- versus hypo- or isoenhancement, washout appearance, capsule appearance, and threshold growth [53] (Table 2). Refinement and testing of the LI-RADS system is ongoing. It is hoped that LI-RADS will undergo further validation from global committees and will incorporate standardized techniques for contrast-enhanced MRI, including gadoxetic acid enhanced MRI and cost considerations according to different diagnostic strategies. Update on MRI Findings of HCA Correlation Between MRI Pattern and Pathologic-Molecular Classification of HCA Distinguishing between early or borderline HCC, focal nodular hyperplasia (FNH), and HCA has been difficult using conventional imaging techniques because of the overlap of features, including fatty, necrotic, and hemorrhagic components. However, the recent iden- AJR:201, July

6 TABLE 2: Categorization of Definitely and Probably Hepatocellular Carcinoma (HCC) According to LI-RADS (Version , released January 2013) [53] LI-RADS Category Criteria 5, Definitely HCC 10- to 19- mm mass Arterial phase hyperenhancement AND two of the following: washout appearance, capsule appearance, threshold growth 20- mm mass Arterial phase hyperenhancement AND one of the following: washout appearance, capsule appearance, threshold growth 5V, Definitely HCC with tumor in vein Definite enhancing soft tissue in vein a 4, Probably HCC Arterial phase hyperenhancing < 10- mm mass Arterial phase hyperenhancement AND one of the following: washout appearance, capsule appearance, threshold growth 10- to 19- mm mass Arterial phase hyperenhancement AND exactly one of the following: washout appearance, capsule appearance, threshold growth 20- mm mass Arterial phase hyperenhancement AND none of the following: washout appearance, capsule appearance, threshold growth Arterial phase hypo- or isoenhancing < 20- mm mass Arterial phase hypo- or isoenhancement AND two of the following: washout appearance, capsule appearance, threshold growth 20- mm mass Arterial phase hypo- or isoenhancement AND one of the following: washout appearance, capsule appearance, threshold growth Note Criteria are from LI-RADS version , released January 2013 [53]. a Applies to mass of any size, even if parenchymal component of mass is not identified at imaging. The interested reader is referred to the ACR LI-RADS website ( for a review of the entire system, including the LI-RADS 1, 2, and 3 categories. tification of certain pathologic characteristics has enabled the classification of three subtypes of HCA, which are generally referred to as hepatocyte nuclear factor 1 α (HNF1α) mutated HCA, inflammatory HCA, and β-catenin mutated HCA [54 57]. A strong association between the typical characteristics observed for at least the first two main subtypes, and the resulting MRI pattern, has improved the differential diagnosis between HCA and FNH [58, 59]. Validation of the MRI criteria for HCA subtype differentiation has also been performed in a blinded retrospective study of 47 histologically defined lesions, which showed that HCA subtypes were correctly classified in 85% of cases. The agreement (sensitivity) between MRI and routine histopathologic analysis was 73.5% for inflammatory HCAs and 63.6% for HNF1α-mutated HCA [60]. The features and typical MRI pattern association with each subtype are described in the following paragraphs. The HNF1α-mutated HCA subtype, which develops as a result of mutations in the TCF1 gene, accounts for approximately 35 40% of observed HCAs [61]. These HCAs are phenotypically characterized by homogeneous diffuse steatosis with no cytologic abnormalities or inflammation [57]. The HNF1α mutation is accompanied by down-regulation of the fatty acid binding protein 1 (FABP1) gene (an HNF1α target gene) and an absence of liver FABP as observed by immunohistochemistry, compared with nontumoral liver (Figs. 3A 3C). The lack of liver FABP expression has 100% sensitivity and specificity for indicating HNF1α-mutated HCA [56] and may, therefore, be useful in the diagnosis of multiple microadenomas throughout the parenchyma. Examinations using gadolinium-enhanced MRI have shown that HNF1α-mutated HCAs appear slightly isoor hyperintense on T2-weighted images, with diffuse signal dropout on T1-weighted chemical shift sequences (positive predictive value, 100%; negative predictive value, 94.7%). Characteristically, these lesions enhance moderately in the arterial phase and, relative to liver, are isoenhancing in the portal venous and delayed phases; these lesions typically do not exhibit the persistent hyperenhancement characteristic of inflammatory HCAs [54, 58] (Table 3). However, it must be noted that MRI classification can be hindered if HNF1α-mutated HCA presents with heterogeneous steatosis. Inflammatory HCAs, which are frequently caused by somatic activating mutations of glycoprotein 130 (interleukin-6 coreceptor), account for more than 50% of HCA cases [61]. These lesions are usually present in patients with obesity, high alcohol intake, or biologic manifestations of an inflammatory syndrome [61, 62]. They are typified by areas of sinusoidal dilatation or peliosis alongside numerous thick-walled vessels and overexpression of inflammatory proteins, such as serum amyloid A and C-reactive protein, in tumor hepatocytes (Figs. 3F and 3G). Inflammatory HCAs can also hemorrhage and may have variable ductular reaction; they were often misdiagnosed in the past as telangiectatic FNH [63, 64]. If steatosis is present, it is usually focal and less frequent compared with HNF1α-mutated HCA [61, 62]. Inflammatory lesions display no signal dropout on T1-weighted chemical shift sequences, but have hyperintense T2-weighted images with delayed enhancement (positive predictive value, 88.5%; negative predictive value, 84%) [58] (Table 3). Interpretation of MRI findings can be difficult if inflammatory HCAs present with focal, rather than widespread, sinusoidal dilation. Beta-catenin mutated HCAs account for around 10 15% of lesions. They commonly exhibit cytologic abnormalities, pseudoglandular formation, and are accompanied by an up-regulation of GLUL, which codes for glutamine synthetase [61]. The combination of glutamine synthetase overexpression and nuclear β-catenin immunohistochemical staining has been shown to be a good diagnostic predictor of β-catenin mutated HCA (85% sensitivity, 100% specificity) [56] (Figs. 3D and 3E). Correct identification is essential because this subtype carries a high risk of HCC transformation [57], and it is often difficult to distinguish β-catenin mutated HCAs from 102 AJR:201, July 2013

7 Fifth International Forum for Liver MRI TABLE 3: Characteristics of Hepatocellular Adenoma (HCA) Subtypes A D F B E G Fig. 3 Immunohistochemical stainings of hepatocellular adenoma (HCA) subtypes. A C, Hepatocyte nuclear factor 1 -mutated HCA (H-HCA) liver fatty acid binding protein (LFABP) immunostaining. Photomicrographs show no expression of LFABP in steatotic H-HCA ( 200, A), normal expression of LFABP in corresponding nontumoral (NT) liver ( 100, B), and numerous microadenomas (asterisks, C) lacking LFABP contrasting with normal expression in surrounding nontumoral liver ( 20). D and E, Beta-catenin mutated HCA (b-hca) subtypes. Photomicrographs show aberrant cytoplasmic and nuclear expression of β-catenin in b-hca ( 400, D) and strong and diffuse expression of glutamine synthetase in nontumoral liver ( 20, E). F and G, Inflammatory HCA (IHCA) subtypes. Photomicrographs show serum amyloid A expression in IHCA contrasting with negativity in nontumoral liver ( 40, F) and C-reactive protein expression (asterisk) in micro-ihca ( 10, G). Subtype Frequency (%) Gadolinium-Based Contrast Medium MRI Hepatocyte nuclear factor 1 α mutated a Homogeneous intralesional steatosis defined by signal dropout on chemical shift sequences; homogeneous and iso- or slightly hyperintense on T2-weighted images; moderate enhancement on arterial phase; no persistent enhancement on delayed phase β-catenin mutated b No specific MRI pattern; imaging diagnosis remains a challenge Inflammatory c 50 Widespread sinusoidal dilatation; markedly hyperintense on T2-weighted images with high-signal peripheral ring; strong enhancement on arterial phase; persistent enhancement on delayed phase a Immunohistochemical stainings of this HCA subtype are shown in Figures 3A 3C. b Immunohistochemical stainings of this HCA subtype are shown in Figures 3D and 3E. c Immunohistochemical stainings of this HCA subtype are shown in Figures 3F and 3G. well-differentiated or borderline HCCs. Around 10% of inflammatory HCAs can also be β-catenin mutated, which increases the risk of transformation into HCC [61]. However, it must be noted that there is currently no validated MRI marker for this high-risk subtype (Table 3); this is mainly because of the small number of reported cases. Role of Gadoxetic Acid Enhanced MRI in Differential Diagnosis of HCA The added diagnostic information provided by liver-specific MRI contrast agents such as gadoxetic acid may improve the differentiation between FNH and HCA, because contrast agent is partially excreted through bile ducts that are present in FNHs but not in HCAs [65, 66]. In a study of 82 patients with 111 lesions (68 FNHs and 43 HCAs), 91.2% of FNHs appeared iso- or hyperintense to the surrounding parenchyma in the hepatobiliary phase of gadoxetic acid enhanced MRI, whereas 93% of HCAs appeared hypointense in this phase [67]. The combined diagnostic criteria for HCA of hypointensity in the hep- C AJR:201, July

8 atobiliary phase and mild-to-moderate arterial enhancement resulted in 83.7% sensitivity and 100% specificity. In addition, strong arterial enhancement and iso- or hyperintensity in the hepatobiliary phase resulted in 83.8% sensitivity and 98.5% specificity for FNH. A total of six FNHs showed atypical hypointensity in the hepatobiliary phase; four of these showed mainly hypointensity in the central parts of the lesions, whereas the peripheral cellular parts showed slight hyperintensity, similar to typical FNH, enabling an FNH diagnosis. This finding reinforces the value of a detailed analysis of the hepatobiliary phase images for cases with an atypical appearance. Three HCAs were iso- or hyperintense during the hepatobiliary phase, which was possibly related to the presence of steatosis. These findings indicate that gadoxetic acid enhanced MRI facilitates accurate differentiation of FNH from HCA and may be helpful in avoiding invasive biopsy in many cases [67]. Contrast-enhanced ultrasound also may be useful for differentiation of HCA from FNH. A recent study of 123 lesions in 89 patients described the differential diagnosis between HCA and FNH by their different perfusion and morphologic features. HCA showed typical perfusion characteristics (fast-in, slowout) with a centripetal or mixed filling pattern, but FNH showed a centrifugal filling pattern in the arterial phase. Contrast-enhanced ultrasound was useful for identifying HCA, but this contrastographic pattern is not always reproducible, and overlap has been described [68]. Comparative studies of gadoxetic acid enhanced MRI and contrast-enhanced ultrasound are needed. Consensus Statement 3.1 Gadoxetic acid enhanced MRI is an appropriate imaging modality for differentiation of HCA from FNH (84% agreement [76/91]). Consensus Statement 3.2 The additional information provided by hepatobiliary phase images of gadoxetic acid enhanced MRI is important to increase diagnostic confidence for nontypical FNH (e.g., absence of central scar, fatty component, and sinusoidal dilatation) (84% agreement [77/92]). Update on MRI in Colorectal Cancer, Including Cost Considerations For patients with colorectal cancer, the therapy strongly depends on the extent of the disease. It is known that many patients will develop pulmonary, liver, or lymph node metastases during the course of their disease. The therapeutic options for patients with liver metastases will depend on factors such as the presence or absence of extrahepatic systemic spread and the local situation in the liver. Although wholebody MRI might represent a promising and interesting tool with which to stage patients with colorectal cancer for extrahepatic disease extent, this approach depends on local expertise and suitable technical equipment; 18 F-FDG PET surely has a role for the whole-body evaluation of metastases from colorectal cancer. Nevertheless, globally, single-phase contrastenhanced CT is still done in many institutions to rule out extrahepatic disease. Consensus Statement 4.1 In patients with colorectal cancer, MDCT of the thorax and abdomen remains the firstline imaging modality for staging purposes (93% agreement [69/74]). This statement A C is intended to represent the current clinical practice in many countries and is not an evidence-based recommendation. Using single-modality imaging techniques that have been shown to be more accurate in the detection of liver metastases (as well as small HCCs) will have economic consequences in specific settings. Large prospective multicenter trials have shown the improved ability of gadoxetic acid to detect and characterize focal liver lesions compared with CT [69, 70]. Recent data from a health economic model study suggest that initially using gadoxetic acid enhanced MRI in patients with suspected liver metastases has the potential to avoid repeated diagnostic procedures by providing accurate information at an earlier stage of the diagnostic workup [71]. Considering all pretherapeutic costs, this model study determined that a diagnostic strategy starting with gadoxetic acid enhanced MRI Fig year-old man with rectal cancer. A D, Transverse sections were imaged with CT and MRI with interval of 4 days. MDCT in portovenous phase (A) shows liver metastasis (thick arrow, A D) centrally located with involvement of left liver vein. No other lesions can be identified on CT. Portal venous phase of gadoxetic acid enhanced MRI (B) and T2-weighted sequence (C) vaguely depict additional subcapsular metastasis (thin arrow, B D) in segment VIII with diameter of 7 mm, whereas hepatobiliary phase (D) clearly depicts this additional metastasis. Note also that centrally located metastasis is more conspicuous and better delineated in hepatobiliary phase. B D 104 AJR:201, July 2013

9 Fifth International Forum for Liver MRI was cost-saving against extracellular contrast enhanced MRI in Sweden, Italy, and Germany and cost-saving against MDCT in Sweden [71]. According to the expert opinion of pairs of radiologists and liver surgeons, the rate of requiring further imaging was expected to be lower with gadoxetic acid enhanced MRI (8.6%) compared with extracellular contrast enhanced MRI (18.5%) and MDCT (23.5%) [71]. The benefits and cost implications of gadoxetic acid enhanced MRI as the initial imaging modality in patients with colorectal cancer was further explored in the VALUE study [72]. That study was a prospective multicenter randomized comparison of gadoxetic acid enhanced MRI, MDCT, and extracellular contrast enhanced MRI for local hepatic staging in patients with suspected liver metastases scheduled for liver surgery in terms of surgical and patient outcomes and cost. Interim data (n = 284) showed that a therapeutic decision was reached in all patients randomized to undergo gadoxetic acid enhanced MRI, but further imaging was required in patients randomized to undergo MDCT and extracellular contrast enhanced MRI (36.3% and 15.9%, respectively). In these cases, the radiologist and surgeon selected gadoxetic acid enhanced MRI as the subsequent imaging modality in 47 of 48 cases. In fact, none of the patients randomized to undergo gadoxetic acid enhanced MRI or extracellular contrast enhanced MRI had a nondiagnostic study and needed a subsequent CT study. In addition, gadoxetic acid enhanced MRI was associated with a high or very high level of diagnostic confidence in 98% of cases (compared with 67% for MDCT and 88% for extracellular contrast enhanced MRI). Economic MRI Models in Patients With Colorectal Cancer The complete TNM staging of rectal cancer according to guidelines is currently performed using a sequential multimodal algorithm, an approach that is demanding in terms of time and logistical effort [73]. An alternative diagnostic algorithm has been designed that comprises two steps: rectoscopy followed by pelvis, abdomen, and chest MRI. The MRI protocol includes T2-weighted images of the rectum, with 3D T1-weighted arterial and delayed phase images and T2- weighted breath-hold images of the liver and HASTE images of the abdomen after a bolus injection of gadoxetic acid; the mean inroom examination time was 55 minutes [74]. The direct fixed and variable costs of pretherapeutic TNM staging of colorectal cancer using this novel strategy were compared with the costs of the classic sequential algorithm (European Union [Germany] perspective) in a study of 33 patients [74]. As expected, the technical modality costs were higher for whole-body MRI, but the personnel (i.e., physicians, nurses, technicians, and administrators) costs were lower. This resulted in a 31.3% absolute cost advantage of MRI over the sequential model ( 711 vs 1035 per patient, respectively). The potential role of gadoxetic acid enhanced MRI in imaging of rectal liver metastases is shown in Figure 4. Consensus Statement 4.2 In candidates identified by first-line imaging for liver surgery for colorectal metastases, gadoxetic acid enhanced MRI is recommended for preoperative surgical planning because of its sensitivity for detection and localization of metastases and surgical planning (85% agreement [61/72]). This statement is supported by data from a prospective randomized multicenter trial that compared the detection rate of gadoxetic acid enhanced MRI versus CT [70]. Consensus Statement 4.3 When first-line imaging identifies a nonspecific hypervascular liver lesion in patients with colorectal cancer, the recommended next diagnostic modality, if available, is gadoxetic acid enhanced MRI (88% agreement [72/82]). In the discussion for this statement, the high diagnostic performance of gadoxetic acid enhanced MRI for the diagnosis of FNH was taken into account because FNH is assumed to be a frequent cause of incidental hypervascular liver lesions in the noncirrhotic liver. Because hepatobiliary phase images do not help in the differential diagnosis of small hemangioma versus small metastases, the MRI protocol should also include T2- weighted images and, if possible, DWI. Summary There is growing evidence that gadoxetic acid enhanced MRI has high sensitivity and specificity for the diagnosis of patients with liver tumors. It provides additional imaging features in the hepatobiliary phase that can be useful in the characterization of borderline hepatocellular lesions, for the diagnosis of early HCC, and to distinguish common subtypes of HCA from FNH. The high detection rate of liver metastases seems not only to improve preoperative planning, but also may reduce the time and costs associated with further imaging. In patients with colorectal cancer, whole-body MRI can be an efficient tool for local and global staging; however, its use is currently limited to areas with special expertise. Numerous guidelines have been produced to standardize the diagnosis and management of liver lesions in patients with cirrhosis or other risk factors for HCC. Most guidelines do not yet incorporate gadoxetic acid enhanced MRI, however, and there is a need to develop standardized criteria for interpretation and reporting of gadoxetic acid enhanced MRI in patients with cirrhosis or other risk factors for HCC. Acknowledgment Editorial assistance (styling and preparation of figures) was provided by PAREXEL MMS. References 1. Schwarz JM, Carithers RL. Epidemiology and etiologic associations of hepatocellular carcinoma. Wolters Kluwer UpToDate website. Accessed April 8, Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379: Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. 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