With recent advances in treatment of hepatocellular SPECIAL ARTICLE

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1 SPECIAL ARTICLE LI-RADS (Liver Imaging Reporting and Data System): Summary, Discussion, and Consensus of the LI-RADS Management Working Group and Future Directions Donald G. Mitchell, 1 Jordi Bruix, 2 Morris Sherman, 3 and Claude B. Sirlin 4 To improve standardization and consensus regarding performance, interpreting, and reporting computed tomography (CT) and magnetic resonance imaging (MRI) examinations of the liver in patients at risk for hepatocellular carcinoma (HCC), LI-RADS (Liver Imaging Reporting and Data System) was launched in March 2011 and adopted by many clinical practices throughout the world. LI-RADS categorizes nodules recognized at CT or MRI, in patients at high risk of HCC, as definitively benign, probably benign, intermediate probability of being HCC, probably HCC, and definitively HCC (corresponding to LI-RADS categories 1-5). The LI-RADS Management Working Group, consisting of internationally recognized medical and surgical experts on HCC management, as well as radiologists involved in the development of LI-RADS, was convened to evaluate management implications related to radiological categorization of the estimated probability that a lesion will be ultimately diagnosed as HCC. In this commentary, we briefly review LI-RADS and the initial consensus of the LI-RADS Management Working Group reached during its deliberations in We then focus on initial discordance of LI-RADS with American Association for the Study of Liver Diseases and Organ Procurement Transplant Network guidelines, the basis for these differences, and how they are being addressed going forward to optimize reporting of CT and MRI findings in patients at risk for HCC and to increase consensus throughout the international community of physicians involved in the diagnosis and treatment of HCC. (HEPATOLOGY 2015;61: ) With recent advances in treatment of hepatocellular carcinoma (HCC), including surgery, tumor ablation, embolization, and hepatic transplantation, noninvasive detection as well as accurate diagnosis and staging of HCC has become increasingly important. Although ultrasound (US) is most commonly the initial imaging test used for screening and surveillance of HCC in high-risk individuals, the noninvasive diagnosis of HCC generally depends on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). The AASLD (American Association for the Study of Liver Diseases), EASL (European Association for the Study of the Liver), OPTN (Organ Procurement and Transplantation Network), Asian Pacific Association for the Study of the Liver, JSH (Japan Society of Hepatology), National Comprehensive Cancer Network, and other organizations have thereby issued guidelines for appropriate utilization of imaging for HCC diagnosis, 1-7 specifying criteria such as arterial phase hyperenhancement and washout, and some also incorporate an evaluation of nodule growth on serial exams. Though the criteria proposed by these guidelines are widely recognized as important, and the AASLD criteria in particular have been validated prospectively, 1-6 there is no established consensus regarding their exact Abbreviations: AASLD, American Association for the Study of Liver Diseases; APHE/W, arterial phase hyperenhancement and washout; CCA, cholangiocarcinoma; CT, computed tomography; EASL, European Association for the Study of the Liver; HCC, hepatocellular carcinoma; ICC, intrahepatic cholangiocarcinoma; JSH, Japan Society of Hepatology; LI-RADS, Liver Imaging Reporting and Data System; LR, LI-RADS; LT, liver transplantation; MRI, magnetic resonance imaging; OPTN, Organ Procurement Transplant Network; UNOS, United Network for Organ Sharing; US, ultrasound. From the 1 Department of Radiology, Thomas Jefferson University, Philadelphia, PA; 2 BCLC Group, Hospital Clinic, University of Barcelona, Institut d Investigacions Biome diques August Pi i Sunyer, Barcelona, Spain; 3 Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada; 4 Liver Imaging Group, Deptartment of Radiology, University of California at San Diego, San Diego, CA. Received March 31, 2014; accepted July 8,

2 HEPATOLOGY, Vol. 61, No. 3, 2015 MITCHELL ET AL definitions. For example, should arterial phase hyperenhancement rely on higher attenuation/signal on arterial phase images or calculated change in intensity/signal after versus before contrast enhancement? Should washout of a hyperenhancing nodule be determined from appearance on postcontrast images by measurements expressed on enhancement curves or subtracted images, and should it be judged compared to background liver or to non-malignant-appearing cirrhotic nodules? Is it possible that for some 1- to 2-cm nodules, dense perinodular fibrosis may create an incorrect perception of washout?. 7 What is the precise method for measuring diameter and its change over time? The lack of consensus on these fundamental issues may lead to confusion and inconsistency in the application of the diagnostic criteria both in clinical care and in research. The AASLD and other organizations generally categorize imaging diagnoses as positive, negative, or indeterminate for HCC, but in clinical practice, imaging interpretation and management decisions often are more nuanced and may vary depending on a more granular estimate of the likelihood of HCC. For example, a decision to biopsy a nodule may differ if the nodule is considered a probable hemangioma versus a probable malignancy. On the other hand, in a given patient after multidisciplinary discussion, it may occasionally be appropriate to ablate or embolize a probable HCC without biopsy proof, such as in a patient ineligible for liver transplantation (LT), if biopsy is technically difficult, or to avoid the possibility of needle track seeding 8 ; however, this would not be done if the estimated likelihood of HCC is low. One reason that existing algorithms do not provide this guidance is because radiological reports have not clearly or consistently communicated estimated likelihood of HCC. By more clearly communicating these impressions, it may be possible, through further prospective investigation, to determine the effect on management and outcome of low- versus high-probability nodules, although the optimum probability ranges for assigning categories remain speculative. To improve standardization and consensus regarding the imaging diagnosis of HCC, a panel of expert radiologists was convened in 2008, sponsored by the American College of Radiology. The goal was to develop a comprehensive system for interpreting and reporting CT and MRI examinations of the liver in patients at risk for HCC. The system would be appropriate for use in academic and nonacademic centers by expert and nonexpert radiologists alike, and it would provide precisely defined terminology, an illustrative atlas, a diagnostic algorithm, and guidance for appropriate imaging technique. LI-RADS (Liver Imaging Reporting and Data System) was officially launched in March 2011 and adopted by many clinical practices throughout the world. Since then, it has been continually expanded and updated, benefiting from input from radiologists, hepatologists, liver surgeons, and pathologists. The current version of LI-RADS, including extensive supporting information, is posted online ( LIRADS). LI-RADS is a dynamic system, developed as the product of existing data and expert radiological and clinical consensus, that will continue to be refined and updated as experience and validating data accrue and in response to actively solicited user feedback. However, prospective validation studies to establish HCC likelihood according to LI-RADS categories are not yet available. The LI-RADS Committee includes numerous working groups, each with specific responsibilities. One of these, the LI-RADS Management Working Group formed in March 2013, consists of internationally recognized medical and surgical experts on HCC management, as well as radiologists involved in the development of LI-RADS. The purpose of this working group is to evaluate management implications related to radiological categorization of the estimated probability that a lesion will be ultimately diagnosed as HCC. LI-RADS categorizes nodules recognized at CT or MRI, in patients at high risk of HCC, as definitively benign, probably benign, intermediate probability of being HCC, probably HCC, and definitively HCC (corresponding to LI-RADS categories 1-5, as explained further below). The LI-RADS Management Working Group did not address evaluation or Address reprint requests to: Donald G. Mitchell, M.D., Thomas Jefferson University, 132 South 10th Street, Suite 1094, Main Building, Philadelphia, PA donald.mitchell@jefferson.edu; fax: Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /hep Potential conflict of interest: Dr. Bruix consults, advises, and received grants from Bayer. He consults and received grants from Daiichi and Arqule. He consults and advises Biocompatibles and Novartis. He consults for Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Kowa, Lilly, and Roche. Dr. Sirlin consults and is on the speakers bureau for Bayer. He received grants from GE Healthcare.

3 1058 MITCHELL ET AL. HEPATOLOGY, March 2015 Fig. 1. Summary schematic of LI-RADS 2014 diagnostic algorithm. Text in blue represents hyperlinks to explanatory text and illustrations within the LI-RADS website (adapted from ACR LI-RADS content at: treatment of nodules with a definite diagnosis of HCC (corresponding to LI-RADS 5), because this is covered by guidelines of the AASLD and other organizations. In the course of these discussions, some discordance between LI-RADS and the AASLD guidelines became apparent, leading to modifications of LI-RADS, and these are discussed later in this commentary. Below, we briefly review LI-RADS and the initial consensus of the LI-RADS Management Working Group reached during its 2013 deliberations. We then focus on initial discordance of LI-RADS with AASLD and OPTN guidelines, the basis for these differences, and how they are being addressed going forward to optimize reporting of CT and MRI findings in patients at risk for HCC. LI-RADS Summary LI-RADS is a system for standardizing the performance and interpretation of CT and MRI for diagnosing HCC in at-risk patients. LI-RADS involves categorizing each hepatic observation (something that is visible on an image) regarding its likelihood of benignity, HCC, or other malignancy, as shown in the LI-RADS diagnostic algorithm (Fig. 1). LI-RADS should not be applied to the general population, but rather is intended only for individuals at increased risk for HCC, whether or not a nodule has previously been noted by US or other imaging. If a mass has been treated, it is categorized as LI-RADS (LR) treated. Definitely or probably benign observations are categorized, respectively, LR-1 and LR-2. If the characteristics of the mass suggest that it might be a malignancy other than HCC (e.g., cholangiocarcinoma [CCA]), it is categorized LR-M (probable malignancy, not specific for HCC). In such cases, confident diagnosis usually requires biopsy. If there is definite tumor in a vein, whether or not a primary mass is clearly visible, the observation is categorized as LR-5V. A malignant diagnosis would thus be established, but whereas intravascular tumor is most common in HCC, it can be observed in intrahepatic cholangiocarcinoma (ICC) as well. The remaining observations are categorized LR-3, LR-4, or LR-5 (as shown in the table embedded in Fig. 1), based primarily on presence or absence of major features (described below). The final category

4 HEPATOLOGY, Vol. 61, No. 3, 2015 MITCHELL ET AL may be adjusted using ancillary features and some specified decision rules. LR-5 corresponds to definite HCC the radiologist has 100% certainty that the observation is HCC. For HCC 2 cm or larger, LR-5 observations are equivalent to class 5 using the OPTN-UNOS (United Network for Organ Sharing) system 9,10 and, depending on their size and number, could be used to assign priority for LT in eligible patients. To achieve such high specificity, particularly when patients may not be prescreened by US preceding to CT or MRI, the imaging criteria for LR-5, particularly for 1- to 2-cm nodules, are more stringent than the AASLD criteria for diagnosing HCC in an US-detected nodule in the population at risk. This and other differences between LI-RADS and the AASLD and OPTN guidelines, resulting from differences in the patient populations for which these systems are intended, are discussed in the final section of this commentary. It must be emphasized that many HCCs will not meet LR-5 criteria and will be categorized LR-4 or less. LR-4 is defined as probable HCC: The observation is highly likely to be HCC, but it is supposed that there is not 100% certainty. Note that studies demonstrating the actual proportion of LR-4 and 25 observations that subsequently are proven to be HCC are needed. If there is any doubt about whether an observation can be categorized as LR-5 based on the presence of major features, a category of LR-4 is assigned; one of the goals of LI-RADS is to render false-positive imaging diagnoses of HCC as exceedingly rare. LR-4 observations should not used to assign priority for LT in the United States because, according to current OPTN policy, such assignment requires an expected 100% certainty. The criteria for assigning LI-RADS categories depend primarily on observation diameter and the presence of four specific major features that have been reported as particularly useful for diagnosing HCC: arterial phase hyperenhancement; washout appearance following hyperenhancement; capsule appearance; and threshold growth compared with previous imaging. Although these criteria have been evaluated in previous literature, none of them have been defined precisely or consistently, as discussed above in the first paragraph. In clinical practice, this ambiguity may lead to variable and unpredictable radiological interpretations, as well as difficulty in pooling results from published studies. A large, retrospective study to measure the inter-reader variability of assigning these features, using the precise definitions provided in LI-RADS, has been initiated by the LI-RADS steering committee. A complete description of the LI-RADS consensus definitions and criteria for the major and ancillary imaging features for diagnosing HCC and other hepatic nodules is beyond the scope of this commentary, but detailed descriptions and supporting illustrations are available online ( LIRADS). Although it is anticipated that adoption of LI-RADS will standardize reporting and enhance communication with clinicians, the clinical benefits of stratifying observations into categories reflecting presumed HCC probability are yet to be validated prospectively. LI-RADS Management Working Group Consensus The LI-RADS Management Working Group conferred by numerous group exchanges between March and September 2013 and physically met at the AASLD meeting in Washington, DC, on November 2, By consensus, four summary statements, concerning how LI-RADS should be considered along with other information regarding HCC diagnosis and management, were agreed upon. Several areas of potential discordance or difficulty were identified, which were discussed subsequently and described in the final section of this commentary. The four summary statements agreed upon in 2013, with some explanatory comments, are: 1. EASL and AASLD guidelines address the management of lesions that are definitely HCC by imaging criteria. LI-RADS expands the indeterminate category into probably benign, intermediate probability of HCC, and probably HCC (LI-RADS categories 2, 3, and 4). LI-RADS numerical categories apply to patients who are candidates for, or who are already enrolled in, a surveillance program for HCC and are not designed to describe incidental findings in patients at low risk for HCC. This initial statement delineates an important limitation to the scope of LI-RADS, which does not address management of patients with an established diagnosis of HCC. LI-RADS also does not prescribe the criteria or frequency for HCC surveillance, because these issues already are addressed by the EASL, AASLD, and other organizations, as applied to the population at risk and upon detection of a nodule greater than 1 cm by US. Rather, LI-RADS is meant to clarify the CT and MRI component of guidelines issued by these clinical organizations. LI-RADS categories are assigned by interpreting radiologists to each focal observation, based on a

5 1060 MITCHELL ET AL. HEPATOLOGY, March 2015 systematic judgment of the probability that the observation is HCC, using a 5-point confidence scale from 1 (definitely benign) to 5 (definite HCC). The previous category of indeterminate is expanded to clarify whether an observation is probably benign, probably HCC, or has intermediate probability of being HCC. LI-RADS is only intended for individuals in a surveillance program for HCC or who are otherwise considered at greater risk of HCC than the general population. Regarding the definition for this atrisk population, LI-RADS defers to the HCC clinical practice guidelines endorsed by the AASLD, EASL, and other clinical organizations, although, in practice, the radiologist is not always aware of whether these specified criteria for risk have been satisfied. 2. LI-RADS categories are based on contrast-enhanced CT or MRI findings in patients at risk for HCC, without regard to other clinical or imaging information that may or may not be available to the radiologists. However, for observations without a definite diagnosis by imaging (LI-RADS 2, 3, and 4), a clinician s estimated probability of HCC depends not only on the LI-RADS category, but also on factors such as biomarkers and the patient s previous probability of developing or having HCC. The LI-RADS category assigned in the MRI or CT report should be considered by a clinician, along with other available clinical information, to inform this physician s judgment as to whether a patient is likely to have HCC. For example, as discussed earlier in this commentary, if a clinician knows that a 1- to 2-cm LR-4 nodule with arterial phase hyperenhancement and washout (APHE/W) was initially detected by surveillance US, the nodule can legitimately be considered diagnostic of HCC as stated in the AASLD and EASL guidelines. Such criteria have been prospectively validated. 1-6 Subsequent to the 2013 LI-RADS Management Working Group discussions, as described later in this commentary, LI-RADS has been modified so that if a radiologist is aware that a 1- to 2-cm nodule with APHE/W was initially detected by surveillance US, the radiologist can assign a subcategory of LR-5, indicating definite HCC. 3. Decisions between accelerated follow-up (shorter than standard surveillance interval), alternative imaging, biopsy, or treatment without biopsy do not follow directly from the LI-RADS category or from a clinician s estimated probability of HCC, but rather from a clinical assessment that integrates all available medical information, including patient comorbidities and patient preference. Not only does the likelihood that an observation is HCC depend on factors other than the imaging interpretation, but the decision regarding the next step in a patient s management also depends on factors other than the likelihood of HCC, such as patient comorbidities or technical difficulty of biopsy. However, the LI-RADS category may facilitate management decisions by clearly communicating the contribution of imaging toward determining the likelihood of HCC. Note that LI-RADS does not provide a specific interval for accelerated follow-up, because this will depend on variable institutional and financial considerations, and the literature does not provide data for such over-riding specific recommendations. 4. A LI-RADS category of 2, 3, or 4 should be issued along with a diagnostic recommendation to help reach greater diagnostic certainty. This recommendation may include to: continue routine surveillance; repeat imaging at shorter than routine interval (accelerated follow-up) or repeat imaging using a different method (alternative imaging); and/or engage in multidisciplinary discussion. A recommendation for biopsy or treatment should not follow directly from an imaging interpretation, but should be the result of multidisciplinary discussion. Diagnostic options are listed in Table 1. Although the next step in patient management does not follow directly from a LI-RADS category, a diagnostic recommendation should be issued along with a LI-RADS category of 2 (probably benign), 3 (intermediate probability), or 4 (probable HCC). The radiologist recommendation should be restricted to potentially needed imaging studies. The issue of biopsy can be raised for potential multidisciplinary discussion, but management or invasive procedures should not be direct recommendations of an imaging report. Discordance With AASLD and Other Guidelines As mentioned earlier, some aspects of LI-RADS differ from the imaging component of AASLD and other guidelines for management of HCC. Some of these differences arise from the more robust consideration of observations that are neither definitely benign or

6 HEPATOLOGY, Vol. 61, No. 3, 2015 MITCHELL ET AL Table 1. LI-RADS Options for Diagnostic Recommendations* Diagnostic Option Continue standard surveillance Accelerated follow-up (shorter than standard surveillance interval) Alternative imaging method Multidisciplinary discussion, preferably at a liver center of excellence with access to LT and expertise in managing HCC Comments This option usually is appropriate for observations without a substantially increased risk of developing HCC during the surveillance interval (e.g., LR1 and most LR2). Unnecessary overimaging may be avoided. Multidisciplinary discussion is usually not necessary. This option usually is appropriate for observations considered at increased risk of developing HCC during the standard surveillance interval based on clinical assessment that integrates all available information including the LI-RADS category. This option usually is appropriate for observations considered at increased risk of developing HCC during the surveillance interval and for which an alternative imaging method has a possible diagnostic advantage, compared with the most recent imaging method. The timing of the alternative depends on clinical assessment that integrates all available information including the LI-RADS category. This option is appropriate for observations in which factors other than imaging categorization are important. Diagnostic and treatment recommendations resulting from multidisciplinary discussion may include continued routine surveillance, accelerated surveillance, alternative imaging, or biopsy. Treatment without biopsy may also be considered, depending on relative risks and benefits of biopsy, treatment, and delay in treatment. *Adapted from: ACR LI-RADS content at Most observations for which these options are appropriate will be LR3 and LR4. Some will be LR2, especially those >1 cm. definitely malignant; by expanding beyond indeterminate, to consider observations with low, intermediate, or high probability of HCC (categories 2, 3, and 4), some diagnostic decisions may be facilitated. Additionally, LI-RADS categories are assigned to observations on MRI or CT exams whether or not there has been antecedent US and whether or not a patient is a candidate for LT. Finally, the versions of LI-RADS categorize small nodules based on the number of specific major features that are present, without considering that some major features may carry more weight than others. As described below, LI- RADS 2014 has been modified with regard to diagnosis of 1- to 2-cm HCC in certain scenarios. We will briefly review the basis for some specific differences between LI-RADS and the imaging component of the AASLD and OPTN guidelines. 1. The AASLD guideline advocates that HCC may be diagnosed by biopsy or imaging techniques if specific imaging criteria are met. According to this guideline, all nodules >10 mm detected by US and interpreted as indeterminate by CT or MRI should either be biopsied or evaluated by a second exam and, if the second exam is also not conclusive, be biopsied. 11 The 10-mm cutoff was selected because for sonographically detected nodules larger than this, the probability of HCC is high. The 10-mm cutoff also helps to avoid unnecessary diagnostic interventions in smaller nodules that may not have clinical relevance. Because radiological reports have not consistently indicated which indeterminate nodules were more or less likely to be HCC, all indeterminate nodules >10 mm are considered as one category by the AASLD guideline.to our knowledge, no outcomes study has yet been done to show that survival is prolonged by performing a biopsy of indeterminate nodules >10 mm rather than following closely for growth. Potential problems include high interobserver variability among pathologists for interpreting biopsy of small hepatic nodules in patients with cirrhosis and substantial risk of both false-positive and -negative tissue diagnosis. 2,12 This may occasionally require multiple biopsies to achieve a correct diagnosis, which may increase costs as well as patient anxiety and risk. 2 Although needle track seeding is uncommon, a recent meta-analysis (including small or large tumors, located deep in the liver or in its surface, using different types of needles and techniques) noted an overall prevalence of 2.7% and an annual rate of 0.9% after biopsy of HCC. 8 LI-RADS offers more guidance than has been available in the past to radiologists and clinicians, providing criteria and language so that low- and highprobability nodules can potentially be managed differently. For example, some small low-probability nodules can be further evaluated by serial imaging at appropriate intervals, obviating duplicative exams and biopsy while taking care that, in the event of malignancy, growth beyond curability does not occur. By thus stratifying the indeterminate category in a more granular fashion, it is hoped that LI-RADS can help inform clinical decision making and restricting biopsy to those patients who would most benefit from it. However, no data are yet available about the validity of stratifying indeterminate nodules selected for further imaging evaluation and/or biopsy.

7 1062 MITCHELL ET AL. HEPATOLOGY, March 2015 Overview Target population Intended users Categorization of observations Imaging methods addressed Imaging features addressed Table 2. Summary of Differences Between AASLD, OPTN, and LI-RADS* AASLD 2011 OPTN 2014 LI-RADS 2014 Comprehensive management system for HCC OPTN policy for LT candidates with HCC (in United States). Comprehensive imaging diagnosis-system for HCC Includes algorithm for US-based surveillance and CT-/MRI-based diagnosis of HCC Includes CT and MRI criteria for HCC to determine eligibility and priority for LT Patients at risk for HCC in a surveillance Patients with HCC considered for LT All patients at risk for HCC program Radiologists with expertise in liver Radiologists at LT centers All radiologists imaging HCC Untreated definite HCC Untreated observations Indeterminate Class 5A: mm LR-1: definitely benign Benign Class 5B: mm LR-2: probably benign Class 5X: >50 mm or tumor in LR-3: intermediate probability vein Treated definite HCC LR-4: probably HCC Class 5T (treated) LR-5: definitely HCC Nondiagnostic exam LR-5V: tumor in vein Class 0 LR-M: probably malignant, not specific for HCC Treated observations: LR treated US for surveillance; CT and MRI with CT and MRI with extracellular CT and MRI with extracellular extracellular agents for diagnosis agents agents; provides guidance for use of MRI with hepatobiliary agents, although these have not been validated prospectively for primary diagnosis of HCC Arterial phase hyperenhancement Arterial phase hyperenhancement Arterial phase hyperenhancement Washout appearance Washout appearance Washout appearance Diameter Capsule appearance Capsule appearance These features apply only to 10 mm Diameter Diameter observations detected at surveillance US. Diameter increase over time Diameter increase over time Visibility at surveillance US Multiple ancillary features Imaging criteria for No No Yes tumor in vein provided Lexicon and atlas No No Yes Reporting templates No Yes Yes Prospective validation Prospective single-center European studies show that nodules 10 mm detected by surveillance US, with APHE/W, are 100% specific for HCC. Large, prospective, multicenter study in progress Pending *Adapted from: ACR LI-RADS content at 2. The AASLD guidelines, grounded in previous literature, specify that imaging surveillance for HCC be based on serial US. However, for various reasons, serial dynamic multiphasic CT or MRI are frequently used for primary surveillance, particularly in candidates for LT. Additionally, the JSH recommends CT or MRI surveillance every 6-12 months in super-high-risk patients (those with cirrhosis resulting from hepatitis B virus or hepatitis C virus) and in patients in whom US is limited because of cirrhosis or obesity. 13 However, cost-effectiveness using CT or MRI for surveillance of nontransplant candidates has not yet been validated, and modeling by Andersson et al. calculated an incremental costeffectiveness ratio for annual CT exceeding $50,000 per quality-adjusted life-year unless the sensitivity and specificity of US were less than 65% and 60%, respectively. 14 LI-RADS does not challenge the AASLD recommendation for use of US for primary surveillance, but provides guidance for interpretation and reporting of CT or MRI whether or not there has been previous detection of a nodule by US.

8 HEPATOLOGY, Vol. 61, No. 3, 2015 MITCHELL ET AL Table 3. Categorization of Arterial Phase HyperEnhancing Nodules Evaluated With CT or MRI and Without Features Suggestive of a Benign Entity or of Non-HCC Malignancy AASLD 2010 OPTN LI-RADS 2014 Detected as 10-mm nodule at antecedent surveillance US mm with washout HCC Not categorized HCC both washout and capsule HCC (OPTN 5A) (LR-5us) capsule Indeterminate Defer to LI-RADS Probably HCC (LR-4) 50% diameter increase in 6 months HCC (OPTN 5A-g) HCC (LR-5g) 20 mm with washout HCC HCC HCC both washout and capsule capsule Indeterminate (OPTN 5B or 5X) (LR-5) 50% diameter increase in 6 months HCC (OPTN 5A-g) HCC (LR-5g) Not detected as 10-mm nodule at antecedent surveillance US <10 mm with washout only Not applicable Defer to LI-RADS Probably HCC (LR-4) both washout and capsule capsule only mm with washout (nodule not detected at surveillance US) Not applicable Defer to LI-RADS Probably HCC (LR-4) both washout and capsule (nodule not detected HCC (OPTN 5A) HCC (LR-5us) capsule at surveillance US) Defer to LI-RADS Probably HCC (LR-4) 50% diameter increase in 6 months HCC (OPTN 5A-g) HCC (LR-5g) 20 mm with washout Not applicable HCC HCC both washout and capsule capsule 50% diameter increase in 6 months (nodule not detected at surveillance US) (OPTN 5B or 5X) HCC (OPTN 5A-g) (LR-5) HCC (LR-5g) Enhancing soft tissue within lumen of vein HCC (OPTN 5X) HCC with tumor in vein (LR-5V) HCC indicates that a nodule with the referenced features may be categorized as HCC based on strict application of the criteria within the corresponding diagnostic system. Defer to LI-RADS 5 UNOS-OPTN system defers to LI-RADS the categorization of observations that do not meet OPTN criteria for HCC (with exception of LR-5us). *Adapted from: ACR LI-RADS content at 3. According to AASLD guidelines, a 1- to 2-cm nodule initially detected by surveillance US, with APHE/W appearance on CT or MRI, satisfies criteria for HCC. 11 Diagnosis of HCC smaller than 2 cm is particularly important, because these nodules are most amenable to potentially curative treatment. However, though prospective studies have validated the AASLD and EASL criteria in the population at risk for whom they were devised, 2-6 retrospective studies that did not restrict their population to at-risk patients or to those with nodules initially detected by surveillance US have shown that, in the absence of antecedent US visibility, the combination of APHE/W provides only 87%-95% specificity for diagnosis of HCC, with differential diagnoses including high-grade dysplastic nodule and CCA. 2,7,15,16 The presence of antecedent US visibility, which both raises earlier probability of HCC in this population and also serves as an additional important imaging feature, raises the positive predictive value to nearly 100%. 2-6 To minimize the frequency of false-positive interpretations for 1- to 2-cm nodules detected by MRI or CT, regardless of whether US has been performed, both LI-RADS and the OPTN classification established by UNOS require more-stringent CT and MRI criteria for 1- to 2-cm nodules than AASLD criteria. Thus, a 1- to 2-cm nodule with APHE/W on CT or MRI would be categorized by the versions of LI- RADS from as LR-4, potentially interfering with diagnosis of small HCC initially detected by US by the already validated AASLD criteria. 1-6 To rectify this important discordance, the 2014 version of LI-RADS (LI-RADS 2014) has been modified so that if a radiologist knows that such a nodule was initially detected by surveillance US, a category of LR-5us (us 5 ultrasound) can be assigned, indicating a definite imaging diagnosis of HCC according to AASLD criteria. In effect, this revision in LI-RADS 2014 considers antecedent US as a major feature and recognizes the strength of the combination of APHE/W as stronger than either by themselves, and compared with the less well-validated major feature of capsule. It is reasonable

9 1064 MITCHELL ET AL. HEPATOLOGY, March 2015 to speculate that a confirmatory US subsequent to CT or MRI demonstration of APHE/W might enable noninvasive diagnosis of HCC, but this has not yet been validated. To similarly achieve greater concordance between LI-RADS and the OPTN system introduced by UNOS, 10 LI-RADS 2014 includes a subcategory of LR-5g, allowing diagnosis of arterially hyperenhancing HCC with threshold growth, defined as greater than 50% in 6 months or less. Note that LR-5us, corresponding to the diagnosis of 1- to 2-cm HCC by AASLD criteria, does not satisfy criteria of OPTN 5 to receive Model of End-Stage Liver Disease exception points for transplant. A general comparison between the AASLD, OPTN, and LI-RADS systems is presented in Table 2, and specific differences regarding characterizing nodules are detailed in Table 3. Comparison with other HCC categorization systems is difficult because of variable or incomplete definitions of diagnostic criteria, as addressed in depth by Cruite et al. 17 LI-RADS 2014 includes several improvements over the initial LI-RADS introduced in 2011, but its development and expansion continues, particularly with regard to some important remaining challenges. A more robust consideration of CCA and mixed hepatobiliary tumors arising in patients at risk for HCC is one goal, as is greater guidance for diagnosing diffuse or infiltrative HCC in the absence of definite tumor within portal vein branches. Consideration of satellite nodules adjacent to a dominant HCC tumor have been a challenge to consider systematically; a nodule that might be otherwise considered indeterminate will have more-ominous implications when it is one of many, adjacent to a LI-RADS 5 definite HCC. A related issue is whether to adjust the probability that a nodule is HCC whether or not there is a definite HCC elsewhere in the liver. LI-RADS 2014 introduces guidance for the use of hepatobiliary agents, but we note that use of these agents to improve diagnosis of HCC has not been validated prospectively. LI-RADS should be expanded to improve evaluation of response to treatment of HCC. Prospective validation of LI-RADS, including measurement of inter-reader variability, verification by tissue confirmation that LI-RADS categories can meaningfully predict the likelihood of HCC, are needed. An initial analysis of a categorization system similar to LI-RADS showed that prospective assignment of HCC probability category corresponded with prevalence of HCC (categories 1 and 2 negative predictive value 100%, category 5 PPV 100%, and categories 3 and 4 with intermediate predictive values), and inter-reader agreement was high (ICC ). 18 A prospective, multicenter trial comparing CT and MRI for HCC surveillance, using explant validation, has been initiated utilizing the similar UNOS OPTN standardized categorization system (Contrast-Enhanced CT and MRI in Diagnosing and Staging Liver Cancer Using UNOS Policy [ACRIN 6690]; ClinicalTrials.gov Identifier: NCT ). In conclusion, imaging is but one component of diagnosing and managing HCC. LI-RADS establishes standards for CT and MRI utilization for diagnosing HCC. This includes standards for performing these exams, as well as criteria for assigning a category to clearly communicate the estimated probability that a given imaging observation is HCC. LI-RADS is the product of expert review of previous literature in the context of clinical practice and is continually evolving based on experience, consensus, and additions to the peer-reviewed literature. An important goal of LI- RADS is unification of HCC categorization systems. An important step in this direction is establishment of common language and definitions, which will facilitate more-meaningful dialogue and research. Acknowledgment: All members of the LI-RADS Management Working Group contributed substantively to the material included in this commentary. In addition to the authors, this Group consists of: William Chapman (Washington University); Richard Freeman (Geisel School of Medicine at Dartmouth University); Robert Gish (Stanford University); Gregory Gores (Mayo Clinic, Rochester, MN); Jay Heiken (Washington University); Julie Heimbach (Mayo Clinic, Rochester, MN); Alan Hemming (University of California at San Diego); Ryo Hirose (University of California at San Fransisco); Steven Herrine (Thomas Jefferson University); Hero Hussain (University of Michigan); Reena Jha (Georgetown Universiy); Jorge Marrero (University of Texas, Southwestern); David Mulligan (Yale University); Arun Sanyal (Medical College of Virginia); Michael Schilsky (Yale University); Christoph Wald (Lahey Clinic, Boston, MA); Jeffrey Weinreb (Yale University); and Benjamin Yeh (University of California at San Fransisco). References 1. Serste T, Barrau V, Ozenne V, Vullierme MP, Bedossa P, Farges O, et al. Accuracy and disagreement of computed tomography and magnetic resonance imaging for the diagnosis of small hepatocellular carcinoma and dysplastic nodules: role of biopsy. HEPATOLOGY 2012;55: Forner A, Vilana R, Ayuso C, Bianchi L, Sole M, Ayuso JR, et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective

10 HEPATOLOGY, Vol. 61, No. 3, 2015 MITCHELL ET AL validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. HEPATOLOGY 2008;47: Erratum in: Hepatology 2008;47: Kim TK, Lee KH, Jang HJ, Haider MA, Jacks LM, Menezes RJ, 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: Jang HJ, Kim TK, Khalili K, Yazdi L, Menezes R, Park SH, Sherman M. Characterization of 1-to 2-cm liver nodules detected on hcc surveillance ultrasound according to the criteria of the American Association for the Study of Liver Disease: is quadriphasic CT necessary? AJR Am J Roentgenol 2013;201: Sangiovanni A, Manini MA, Iavarone M, Romeo R, Forzenigo LV, Fraquelli M, et al. The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 2010;59: Leoni S, Piscaglia F, Golfieri R, Camaggi V, Vidili G, Pini P, Bolondi L. The impact of vascular and nonvascular findings on the noninvasive diagnosis of small hepatocellular carcinoma based on the EASL and AASLD criteria. Am J Gastroenterol 2010;105: Khan AS, Hussain HK, Johnson TD, Weadock WJ, Pelletier SJ, Marrero JA. Value of delayed hypointensity and delayed enhancing rim in magnetic resonance imaging diagnosis of small hepatocellular carcinoma in the cirrhotic liver. J Magn Reson Imaging 2010;32: Silva MA, Hegab B, Hyde C, Guo B, Buckels JA, Mirza DF. Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis. Gut 2008;57: Pomfret EA, Washburn K, Wald C, Nalesnik MA, Douglas D, Russo M, et al. Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl 2010; 16: Wald C, Russo MW, Heimbach JK, Hussain HK, Pomfret EA, Bruix J. New OPTN/UNOS policy for liver transplant allocation: standardization of liver imaging, diagnosis, classification, and reporting of hepatocellular carcinoma. Radiology 2013;266: Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. HEPATOLOGY 2011;53: Kojiro M. Pathological diagnosis at early stage: reaching international consensus. Oncology 2010;78(Suppl. 1): Kudo M, Izumi N, Kokudo N, Matsui O, Sakamoto M, Nakashima O, et al.; HCC Expert Panel of Japan Society of Hepatology. Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Dig Dis 2011;29: Andersson KL, Salomon JA, Goldie SJ, Chung RT. Cost effectiveness of alternative surveillance strategies for hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol 2008;6: Yu JS, Lee JH, Chung JJ, Kim JH, Kim KW. Small hypervascular hepatocellular carcinoma: limited value of portal and delayed phases on dynamic magnetic resonance imaging. Acta Radiol 2008;49: Marrero JA, Hussain HK, Nghiem HV, Umar R, Fontana RJ, Lok AS. Improving the prediction of hepatocellular carcinoma in cirrhotic patients with an arterially-enhancing liver mass. Liver Transpl 2005;11: Cruite I, Tang A, Sirlin CB. Imaging-based diagnostic systems for hepatocellular carcinoma. AJR Am J Roentgenol 2013;201: Petruzzi N, Mitchell D, Guglielmo F, O Kane P, Deshmukh S, Roth C, et al. Hepatocellular carcinoma likelihood on MRI exams: evaluation of a standardized categorization system. Acad Radiol 2013;20: Author names in bold designate shared co-first authorship.