Imaging-Based Diagnostic Systems for Hepatocellular Carcinoma

Transcription

1 Gastrointestinal Imaging Review Cruite et al. Imaging-Based Diagnosis of Hepatocellular Carcinoma Gastrointestinal Imaging Review FOCUS ON: Irene Cruite 1 An Tang 2 Claude B. Sirlin 3 Cruite I, Tang A, Sirlin CB Keywords: hepatocellular carcinoma, imaging-based diagnostic systems DOI: /AJR Received January 1, 2013; accepted after revision February 20, I. Cruite, A. Tang, and C. B. Sirlin are members of the American College of Radiology supported LI-RADS Committee. 1 Department of Radiology, University of Washington Medical Center, Seattle, WA. 2 Department of Radiology, University of Montreal, Hôpital Saint-Luc, Montreal, QC, Canada. 3 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 2013; 201: X/13/ American Roentgen Ray Society Imaging-Based Diagnostic Systems for Hepatocellular Carcinoma OBJECTIVE. Noninvasive imaging plays critical roles in the treatment of patients with cirrhosis or other risk factors for the development of hepatocellular carcinoma. In recognition of the critical roles played by imaging, numerous international scientific organizations and societies have, in the past 12 years, proposed diagnostic systems for the interpretation of liver imaging examinations performed of at-risk patients. CONCLUSION. Although these imaging-based diagnostic systems represent important advances, they have limitations and they are not perfectly consistent with each other. The limitations and inconsistencies potentially cause confusion and may impair the integration of the systems into clinical practice as well as their utilization in research studies. The purpose of this article is to synthesize and critically appraise the current published imaging-based diagnostic systems endorsed by major societies for the noninvasive diagnosis and staging of hepatocellular carcinoma and to propose future directions that we hope may be helpful in further advancing the field. N oninvasive imaging plays critical roles in the treatment of patients with cirrhosis or other risk factors for the development of hepatocellular carcinoma () [1 4]. In addition to screening and surveillance of the at-risk population, imaging is used to noninvasively establish the diagnosis and stage of, inform prognosis and treatment decision making, assess treatment response, evaluate the severity of the underlying liver disease, and help determine eligibility and priority for liver transplantation [1 10]. In recognition of the critical roles played by imaging, numerous scientific organizations and societies have, in the past 12 years, proposed diagnostic systems for the interpretation of liver imaging examinations performed in at-risk patients. These imaging-based diagnostic systems represent important advances, but they have limitations and they are not perfectly consistent with each other. The limitations and inconsistencies potentially cause confusion and may impair the integration of the systems into clinical practice as well as their utilization in research studies. The purpose of this article is to synthesize and critically appraise the current published imaging-based diagnostic systems endorsed by major societies for the noninvasive diag- nosis and staging of and to propose future directions that we hope may be helpful in further advancing the field. Materials and Methods In 2012, Song et al. [11] reviewed management guidelines published worldwide. The review identified 17 guidelines in the PubMed database published between 2001 and 2010 [5, 11 25]. Eleven of these guidelines included an imaging-based diagnostic system for and are published in the English literature. Since 2010, an additional two guidelines that include imaging-based diagnostic systems for have been published in scientific journals or have been made publicly available online [26 28]. Of the 13 guidelines either identified by Song et al. or published after the time period addressed by Song et al., three were published by organizations from Europe, five by organizations from Asia, four by organizations from the United States, and one by a global organization. Six of the 13 guidelines have had one update between 2001 and 2013: two updates from Asia, one update from Europe, and three updates from the United States. Thus, a total of 19 diagnostic systems including updates have been published in the English literature or have been made publicly available between 2001 and A timeline is provided in Figure 1. We summarized the imaging criteria provided by the diagnostic systems in Appendix 1. AJR:201, July

2 Cruite et al. Asia 2005 J SGA 2008 J AOS 2010 APASL Europe 2001 EASL United States BASL As shown in Appendix 1, the diagnostic systems over time have become increasingly sophisticated and rigorous, largely reflecting advances in technology and radiologic knowledge. For example, the earliest systems relied exclusively on the presence of arterial phase hyperenhancement to establish the noninvasive diagnosis of without taking into account imaging features during later phases. As it became evident that arterial phase hyperenhancement is not specific for but could be seen in vascular pseudolesions and benign nodules [29 32], societies inserted into their criteria other features, such as washout appearance [17, 27, 28], corona enhancement [27, 33], capsule appearance, and threshold growth [26 28]. Also, the earliest systems often integrated serum biomarkers such as α-fetoprotein (AFP) level thresholds into the diagnostic criteria; later systems developed criteria based only on imaging. Because the systems have evolved over time, we decided to focus our review on the most current ones. Accordingly, we critically reviewed, compared, and contrasted the six imaging-based diagnostic systems released or published in 2010 or later because they represent the currently applicable guidelines in various geographic regions and better reflect the latest understanding of imaging. These systems are those currently endorsed by the 2005 AASLD 2005 NCCN 2007 JSH 2008 ESMO 2009 NCCN Developing countries 2009 WGO Japan Society of Hepatology, Asian Pacific Association for the Study of the Liver, European Association for the Study of the Liver (EASL) and European Organization for Research and Treatment of Cancer (EORTC), American Association for the Study of Liver Diseases, and the United Network for Organ Sharing and Organ Procurement and Transplantation Network (UNOS-OPTN), as well as the Liver Imaging Reporting and Data System (LI-RADS) endorsed by the American College of Radiology. Many of the diagnostic systems are displayed in the source publications or websites in an algorithmic format. To facilitate comparison of the diagnostic criteria included within each system, we converted the display format from algorithm-based to listbased, while respecting and maintaining the original content, and we displayed the resulting lists in corresponding tables (Tables 1 3). We also integrated into the tables additional information provided in the accompanying text of the source documents. The various systems differ in terminology and some use terminology inconsistently. The differences in terminology between systems and the inconsistencies within systems obscured comparison of the systems. To facilitate content-based comparison of the systems, the three authors in consensus applied standardized terminology for this article; this required 2010 JSH 2010 AASLD 2011 UNOS-OPTN 2011 LI-RADS 2012 EASL-EORTC 2013 LI-RADS Fig. 1 Timeline of hepatocellular carcinoma () imaging systems available in English. Boxed systems are reviewed in detail in this article. AASLD = American Association for the Study of Liver Diseases, AOS = Asian Oncology Summit, APASL = Asian Pacific Association for the Study of the Liver, BASL = British Association for the Study of the Liver, EASL = European Association for the Study of the Liver, EORTC = European Organization for Research and Treatment of Cancer, ESMO = European Society for Medical Oncology, J- = Japanese guidelines, JSH = Japan Society of Hepatology, LI-RADS = Liver Imaging Reporting and Data System, SGA = Saudi Gastroenterology Association, UNOS-OPTN = United Network for Organ Sharing and Organ Procurement and Transplantation Network, WGO = World Gastroenterology Organisation. the language in the source documents to be paraphrased while preserving the original meaning. Current Systems Here, we summarize the six current imaging-based diagnostic systems, organized by geographic region. Asia Japan Society of Hepatology update 2010 In 2005, the Japanese Ministry of Health, Labor, and Welfare published clinical practice guidelines for, which were updated in 2008 [34, 35]. Excerpts of these guidelines were published in English in 2006 and 2010 [33, 35 37]. The Japan Society of Hepatology modified the Japanese guidelines on the basis of consensus of a panel of experts. The Japan Society of Hepatology guidelines were published in Japanese in 2007 [38] and updated in 2010 [39]; the 2010 update may be considered as the current state of the most advanced treatment practices in Japan [33]. An English version of the 2010 guidelines was published in 2011 [33]. The Japan Society of Hepatology 2010 diagnostic system is summarized in Table AJR:201, July 2013

3 Imaging-Based Diagnosis of Hepatocellular Carcinoma TABLE 1: Summary of Diagnostic Systems for Hepatocellular Carcinoma () in Asia Endorsing Organizations Japan Society of Hepatology [33] Screening and surveillance Target population: screening and surveillance Screening and surveillance tests Imaging-based diagnosis and staging Target population for diagnostic imaging Diagnostic imaging modalities and techniques Super-high-risk population HBV-related liver cirrhosis HCV-related liver cirrhosis High-risk population Chronic HBV Chronic HCV Liver cirrhosis due to causes other than HBV or HCV (i.e., nonalcoholic steatohepatitis, alcoholic liver disease, primary biliary cirrhosis, and autoimmune hepatitis) Super-high-risk population Ultrasound and AFP/protein induced by vitamin K absence or antagonist II/AFP lectin fraction measurements every 3 4 mo Dynamic CT or dynamic MRI/gadoxetate-enhanced MRI every 6 12 mo in patients with very rough background liver parenchyma because of cirrhosis and obesity with difficulty for ultrasound evaluation High-risk population Ultrasound and AFP/protein induced by vitamin K absence or antagonist II/AFP lectin fraction measurements every 6 mo Patients at risk for with positive screening or surveillance test First-line imaging modalities or techniques c Dynamic CT: imaging technique is not specified Dynamic MRI imaging technique is not specified Second-line imaging modalities or techniques d Gadoxetate-enhanced a MRI Contrast-enhanced ultrasound with perflubutane CTHA/CTAP b Imaging centers Not specified Not specified Imaging criteria for arterial phase hyperenhancing Imaging criteria for arterial phase hypo- or isoenhancing Regardless of size Arterial phase hyperenhancement on dynamic CT, MRI, or vascular phase of contrast-enhanced ultrasound AND Washout appearance on CT, MRI, or vascular phase of contrast-enhanced ultrasound OR Corona enhancement on CT or MRI OR Reduced uptake in hepatobiliary phase of gadoxetateenhanced c MRI OR Reduced uptake in Kupffer phase of perflubutane-enhanced ultrasound OR Hyperenhancement on CTHA with hypoenhancement on CTAP Regardless of size Arterial phase hypo- or isoenhancement on dynamic CT, MRI, or contrast-enhanced ultrasound AND Reduced uptake on hepatobiliary phase of gadoxetateenhanced c MRI and Kupffer phase of perflubutaneenhanced ultrasound Asian Pacific Association for the Study of the Liver [19] Cirrhotic patients with HBV Cirrhotic patients with HCV Imaging criteria for tumor in vein None specified None specified Ancillary features None specified None specified Diagnostic scope Arterial phase hyperenhancing, arterial phase hypo- or isoenhancing All at-risk patients Ultrasound and AFP measurements every 6 mo More frequent examinations, including new tumor markers (such as protein induced by vitamin K absence or antagonist II or AFP lectin fraction) and CT/MRI should be considered according to the medical circumstances of each country Patients at risk for with positive screening/ surveillance test or clinical suspicion of e First-line imaging modalities of techniques f Dynamic CT: three-phase helical CT Dynamic MRI: three-phase dynamic contrastenhanced MRI Second-line imaging modalities or techniques d SPIO-enhanced MRI: Kupffer phase Contrast-enhanced ultrasound: perflubutane/ galactose-based microbubble-enhanced vascular and Kupffer phases Regardless of size Arterial phase hyperenhancement on dynamic CT, MRI, or vascular phase of contrast-enhanced ultrasound AND Washout appearance on CT, MRI, or vascular phase of contrast-enhanced ultrasound OR Reduced uptake in Kupffer phase of contrastenhanced ultrasound OR Reduced uptake in Kupffer phase of SPIOenhanced MRI Regardless of size Arterial phase hypo- or isoenhancement on dynamic CT, MRI, or vascular phase of contrast-enhanced ultrasound AND Reduced uptake in Kupffer phase of SPIOenhanced MRI OR Reduced uptake in Kupffer phase of contrastenhanced ultrasound Addresses arterial phase hyperenhancing and arterial phase hypo- or isoenhancing Note HBV = hepatitis B virus, HBC = hepatitis C virus, AFP = α-fetoprotein, CTHA = CT hepatic arteriography, CTAP = CT arterial portography, SPIO = superparamagnetic iron oxide. a The term EOB in the original has been replaced with gadoxetate. b CTHA and CTAP are recommended only at available institutions. c First-line imaging modalities are recommended if at least one screening or surveillance test is abnormal. d Second-line imaging modalities are recommended if evaluation with first-line modalities is inconclusive. e APASL does not specify what constitutes clinical suspicion of. f First-line imaging modalities are recommended if a screening or surveillance test is positive or if there is a clinical suspicion of. AJR:201, July

4 Cruite et al. TABLE 2: Summary of Diagnostic System for Hepatocellular Carcinoma () in Europe Endorsing Organization Screening and surveillance Target population: screening and surveillance Screening and surveillance tests Imaging-based diagnosis and staging Target population: diagnostic imaging Diagnostic imaging modalities and techniques Imaging centers Imaging criteria for arterial phase hyperenhancing Imaging criteria for arterial phase hypo- or isoenhancing Imaging criteria for tumor in vein Ancillary imaging features Diagnostic scope Note HBV = hepatitis B virus. a Frequency of CT or MRI surveillance examinations is not specified. b Only one modality is required if criteria are met. c Both modalities are required. The system applies to patients at risk for with a positive screening or surveillance test and who subsequently undergo further imaging for more definitive diagnosis and staging. For screening or surveillance, the Japan Society of Hepatology recommends periodic unenhanced ultrasound and serum biomarkers (e.g., AFP, protein induced by vitamin K absence or antagonist II, and AFP lectin fraction). In patients considered to be at super high risk for development of (i.e., those with cirrhosis due to hepatitis B or C virus) in whom ultrasound evaluation is limited by a very rough background liver parenchyma because of cirrhosis and obesity [33], the Japan Society of Hepatology endorses the use of dynamic CT or MRI for screening or surveillance. Endorsed Jointly by European Association for the Study of the Liver (EASL) and European Organization for Research and Treatment of Cancer (EORTC) [40] Cirrhotic patients Noncirrhotic HBV carriers with active hepatitis or family history of Noncirrhotic patients with chronic HBC and advanced liver fibrosis Patients on the waiting list for liver transplantation Ultrasound every 6 mo in all at-risk patients Ultrasound every 3-4 mo when a nodule of < 1 cm has been detected and in the follow-up strategy after resection or locoregional therapies CT or MRI a for patients on waiting list for liver transplantation and when obesity, intestinal gas, and chest wall deformity prevent adequate ultrasound assessment Patients at risk for with 1-cm nodule on screening or surveillance ultrasound Dynamic CT: four-phase multidetector CT Dynamic MRI: four-phase dynamic contrast-enhanced MRI Distinction is made between centers of excellence with high-end radiologic equipment and centers in which the technology at disposal or the local skills are not at the high-end level Centers of excellence Diameter > 1 cm On CT or MRI b Arterial phase hyperenhancement AND Washout appearance Centers in which the technology at disposal or the local skills are not at the high-end level Diameter 1 2 cm On CT and MRI c Arterial phase hyperenhancement AND Washout appearance Diameter > 2 cm On CT or MRI Arterial phase hyperenhancement AND Washout appearance None specified None specified None specified Arterial-phase hyperenhancing Regardless of the screening or surveillance method, for patients with a positive screening or surveillance test, dynamic CT and MRI are recommended as first-line imaging modalities for diagnosis and staging. Hepatobiliary phase MRI with gadoxetate, contrast-enhanced ultrasound, and, depending on institutional availability, CT hepatic arteriography (CTHA) and CT arterial portography (CTAP) are recommended as second-line modalities if evaluation with the first-line modalities is inconclusive [33]. With regard to contrast-enhanced ultrasound, Japan Society of Hepatology emphasizes the use of perflubutane (Sonazoid, Daiichi Sankyo) an agent that provides both vascular phase and stable Kupffer phase imaging. Other ultrasound agents, such as galactosebased microbubbles (Levovist, Bayer Schering Pharma), phospholipid-stabilized microbubbles (SonoVue, Bracco), and perflutren lipid microspheres (Definity, Lantheus Medical Imaging), provide vascular imaging but do not provide a stable Kupffer cell phase and so are not recommended by the guidelines. Technical requirements for the first- and second-line imaging modalities are not included in the guidelines. Imaging criteria are provided for both hypervascular (i.e., arterial phase hyperenhancing) and hypovascular (i.e., arterial phase hypo- or isoenhancing) s. Depending on the imaging features, the diagnosis may be established from a single imaging modality, or, if evaluation with first-line modalities is inconclusive, by integrating the information 44 AJR:201, July 2013

5 Imaging-Based Diagnosis of Hepatocellular Carcinoma TABLE 3: Summary of Diagnostic Systems for Hepatocellular Carcinoma () in the United States Endorsing Organization American Association for the Study of Liver Diseases [41] United Network for Organ Sharing (UNOS) and Organ Procurement and Transplantation Network (OPTN) [26] American College of Radiology (ACR) Liver Imaging Reporting and Data System (LI-RADS) [27] Screening and surveillance Target population: screening and surveillance HBV carriers (Asian men 40 y; Asian women 50 y; all cirrhotic HBV carriers; family history of ; African/North American blacks) Non-HBV cirrhosis (hepatitis C; stage 4 primary biliary cirrhosis; genetic hemochromatosis; α1-antitrypsin deficiency; other cirrhosis) Patients on liver transplantation waiting list Not applicable the system does not address surveillance Not applicable the system does not address surveillance Screening and surveillance tests All at-risk patients Ultrasound every 6 mo Not applicable the system does not address surveillance Not applicable the system does not address surveillance Imaging-based diagnosis and staging Target population: diagnostic imaging Patients at risk for with 1 cm nodule on screening or surveillance ultrasound Liver transplant candidates with Any patient at risk for (e.g., cirrhosis of any cause, chronic HBV, and those with history of ) a Diagnostic imaging modalities and techniques Dynamic CT: four-phase, MDCT Dynamic contrast-enhanced MRI CT: Late arterial phase, portal venous phase, and delayed phase are mandatory MRI: Unenhanced, late arterial phase, portal venous phase, and delayed phase are mandatory Unenhanced T1-weighted opposed-phase and in-phase are required T2-weighted (with and without fat saturation) are required CT: Arterial phase and portal venous phase CT: Arterial phase and portal venous phase imaging are required Late arterial phase strongly preferred over early arterial phase Unenhanced imaging suggested Delayed phase imaging suggested Multiplanar reformations suggested MRI: Unenhanced, arterial phase, portal venous phase, and delayed phase required Late arterial phase strongly preferred over early arterial phase Unenhanced T1-weighted opposed-phase and in-phase required T2-weighted fast-spin echo or T2-weighted single-shot-fast-spin echo required Diffusion-weighted imaging suggested Multiplanar acquisitions or reformations suggested Imaging centers Examinations should be conducted using state of the art equipment and read by radiologists with extensive expertise in liver radiology Examinations must be interpreted by a radiologist at an OPTN approved transplant center All centers. Imaging criteria for arterial phase hyperenhancing On CT or MRI a Diameter > 1 cm Arterial phase hyperenhancement AND Washout appearance On CT or MRI a 5A: Diameter 1 cm and < 2 cm Arterial phase hyperenhancement AND both of the following: Washout appearance, capsule appearance 5A-g: Diameter 1 cm and < 2 cm Arterial phase hyperenhancement AND threshold growth b 5B: Diameter 2cm and 5 cm Arterial phase hyperenhancement AND one or more of the following: Washout appearance, capsule appearance, threshold growth b 5X: Diameter 5 cm Arterial phase hyperenhancement AND one or more of the following: Washout appearance, capsule appearance On CT or MRI a 5A: Diameter 10 and 19 mm Mass with arterial phase hyperenhancement AND two or more of the following: Washout appearance, capsule appearance, threshold growth d 5B: Diameter 20 mm Mass with arterial phase hyperenhancement AND one or more of the following: Washout appearance, capsule appearance, threshold growth c (Table 3 continues on next page) AJR:201, July

6 Cruite et al. TABLE 3: Summary of Diagnostic Systems for Hepatocellular Carcinoma () in the United States (continued) American College of Radiology (ACR) Liver Imaging Reporting and Data System (LI-RADS) [27] United Network for Organ Sharing (UNOS) and Organ Procurement and Transplantation Network (OPTN) [26] American Association for the Study of Liver Diseases [41] Category None specified None specified None specified Imaging criteria for arterial phase hypoor isoenhancing None specified None specified On CT or MRI b 4A: Diameter < 20 mm Mass with arterial phase hypo- or isoenhancement AND two or more of following: Washout appearance, capsule appearance, threshold growth d 4B: Diameter 20 mm Mass with arterial phase hypo- or isoenhancement AND one or more of following: Washout appearance, capsule appearance, threshold growth c Imaging criteria for arterial phase hypoor isoenhancing probable Imaging criteria for tumor in vein None specified None specified On CT or MRI a 5V: Tumor in vein Regardless of size Definite enhancing soft tissue in vein Ancillary features None specified None specified Specifies ancillary features on CT and MRI that may favor or benignity; See Table 4 for list of ancillary features Addresses full spectrum of lesions and pseudolesions encountered on imaging in patients at risk for from benign to malignant, including non- malignancy d Diagnostic scope Addresses arterial phase hyperenhancing Addresses arterial phase hyperenhancing ; defers to LI-RADS the interpretation and categorization of lesions and pseudolesions that do not meet UNOS-OPTN criteria for Note HBV = hepatitis B virus. a Only one modality required if criteria are met. There is no requirement that patient has nodule on screening or surveillance ultrasound. b Threshold growth is defined by the UNOS-OPTN 2011 system as growth (maximum diameter increase) by 50% or more documented on serial MRI or CT performed < 6 months apart. c Threshold growth is defined as diameter increase of a mass by minimum of 5 mm and, depending on time interval between examinations by the following amounts: for time interval of 6 months, growth 50%; for time interval > 6 months, growth 100%. A new 10-mm mass also represents threshold growth, regardless of time interval. d Categorization of observations that do not meet LI-RADS criteria for definite or probable are described on the LI-RADS website. from two or more imaging modalities. Nodule diameter is not considered relevant; the diagnosis of s of any diameter may be made noninvasively so long as the required imaging features are present. Although diameter does not affect the diagnostic interpretation in the Japan Society of Hepatology system, diameter may affect the decision to perform a biopsy or follow-up imaging. In particular, arterial phase hypo- or isoenhancing nodules without reduced uptake in the hepatobiliary phase of gadoxetate-enhanced MRI or in the Kupffer phase of perflubutane-enhanced ultrasound may be followed if s are smaller than 1.5 cm but should be biopsied if they are 1.5 cm or larger. Ancillary features that may modulate the likelihood of are not used. Criteria for tumor in vein are not provided. Asian Pacific Association for the Study of the Liver, published in the English literature in 2010 The Asian Pacific Association for the Study of the Liver convened an international working party on the management of in The multidisciplinary working party, composed of hepatologists, hepatobiliary surgeons, radiologists, and oncologists from the Asian-Pacific region, published their consensus recommendations in the English literature in 2010 [19]. The recommendations were based on a comprehensive review of literature. According to the report, The quality of existing evidence and strength of recommendations were ranked according to the Oxford system of evidence-based approach for developing the consensus statements [19]. The Asian Pacific Association for the Study of the Liver diagnostic system is summarized in Table 1. The system applies to patients at risk for with either a positive screening or surveillance test or clinical suspicion of [19] and who subsequently undergo further imaging for more definitive diagnosis and staging. For screening or surveillance, the Asian Pacific Association for the Study of the Liver recommends, as a minimum requirement, periodic unenhanced ultrasound and serum AFP levels, additional tests such as protein induced by vitamin K absence or antagonist II and AFP lectin fraction, and CT or MRI should be considered according to the medical circumstances of each country [19]. The Asian Pacific Association for the Study of the Liver system does not specify what constitutes clinical suspicion of [19]. Regardless of the screening or surveillance method, for patients with a positive screening or surveillance test or with clinical suspi- 46 AJR:201, July 2013

7 Imaging-Based Diagnosis of Hepatocellular Carcinoma cion of, dynamic CT and MRI are recommended by the Asian Pacific Association for the Study of the Liver as first-line imaging modalities for diagnosis and staging. Superparamagnetic iron oxide (SPIO) enhanced MRI and contrast-enhanced ultrasound are recommended as second-line modalities if evaluation with the first-line modalities is inconclusive [19]. Unlike Japan Society of Hepatology, Asian Pacific Association for the Study of the Liver does not recommend CTHA and CTAP because these modalities are uncommonly used in the majority of Asia-Pacific region countries. Also, with regard to contrast-enhanced ultrasound, Asian Pacific Association for the Study of the Liver does not distinguish between perflubutane and galactose-based microbubble contrast agents; in the Asian Pacific Association for the Study of the Liver system, both agents may be used for vascular phase as well as Kupffer phase imaging. Technical requirements for the first- and second-line imaging modalities are not included. Imaging criteria are provided for both hypervascular (i.e., arterial phase hyperenhancing) and hypovascular (i.e., arterial phase hypo- or isoenhancing). Depending on the imaging features, diagnosis may be established from a single imaging modality, or, if evaluation with first-line modalities is inconclusive, by integrating the information from two or more imaging modalities. Nodule diameter is not considered relevant, and the diagnosis of of any diameter may be made noninvasively so long as the required imaging features are present. Ancillary features that may modulate the likelihood of are not used. Criteria for tumor in vein are not provided. Europe: European Association for the Study of the Liver and European Organization for Research and Treatment of Cancer 2012 The EASL held a monothematic conference on clinical management of in During the meeting, a panel of international experts met to prepare clinical management guidelines. These guidelines were published in 2001 [5]. As a European joint effort, the EASL and the EORTC published updated guidelines for the management of in 2012 [40]. The updates were based on the level of evidence and the strength of published data. The EASL-EORTC 2012 diagnostic system is summarized in Table 2. The system applies to patients at risk for with one or more nodules 1 cm or larger detected at screening or surveillance ultrasound and who subsequently undergo further imaging for more definitive diagnosis and staging. Dynamic CT and MRI are the recommended imaging modalities for diagnosis and staging of at-risk patients with ultrasound-detected nodules; these modalities also should be considered for screening or surveillance when obesity, intestinal gas, and chest wall deformity prevent an adequate ultrasound assessment [40]. Distinction is made between centers of excellence with high-end radiological equipment and centers in which the technology at disposal or the local skills are not at the high-end level [40]. For nodules 1 2 cm in diameter, one imaging modality only is recommended in centers of excellence [40] if imaging criteria diagnostic for are met. Two coincidental imaging modalities are recommended for other centers. Contrast-enhanced ultrasound, which was included in the 2001 EASL guidelines, was dropped from the EASL-EORTC 2012 guidelines because of its controversial role and its inability to compete with CT and MRI in terms of accuracy for detection of lesions [40]. Second-line modalities, such as hepatobiliary phase MRI with gadoxetate, SPIO-enhanced MRI, and CTHA and CTAP, are not considered. The EASL-EORTC system specifies that 4-phase multidetector CT/dynamic contrast-enhanced MRI [40] should be performed. Additional technical requirements are not provided. According to the EASL-EORTC 2012 system [40], the diagnosis of is made if a nodule larger than 1 cm shows arterial phase hyperenhancement and portal venous or delayed phase washout appearance on one modality (CT or MRI). As mentioned already, for examinations performed at centers that are not at the high end, the diagnosis of 1- to 2-cm s requires concordant findings at two modalities (CT and MRI). Regardless of imaging center, the diagnosis of cannot be made noninvasively for nodules smaller than 1 cm or for hypovascular (i.e., arterial phase hypo- or isoenhancing) nodules. Ancillary features that may modulate the likelihood of are not used. Criteria for tumor in vein are not provided. United States American Association for the Study of Liver Diseases 2010 The American Association for the Study of Liver Diseases published practice guidelines for the management of in 2005 [17]. The recommendations were based on literature review, guideline policies, and experience of the authors. They also included a level of evidence category reported with each recommendation. An update based on interim scientific evidence was published in 2010 [41]. The American Association for the Study of Liver Diseases 2010 diagnostic system is summarized in Table 3. The system applies to patients at risk for with one or more nodules 1 cm or larger detected at screening or surveillance ultrasound and who subsequently undergo further imaging for more definitive diagnosis and staging. Dynamic CT and MRI are the recommended imaging modalities for more definitive diagnosis and staging of such patients. These examinations should be conducted using state of the art equipment and read by radiologists with extensive expertise in liver radiology [41]. Although two modalities were required in 2005 for 1- to 2-cm lesions, the current American Association for the Study of Liver Diseases 2010 update guidelines require only one modality (CT or MRI) for any nodule 1 cm or larger if diagnostic imaging criteria for are met. If diagnostic imaging criteria for are not met on one modality, the second imaging modality (CT or MRI) should be performed. The guidelines specify that four-phase MDCT or dynamic contrast-enhanced MRI examinations should be performed. Additional technical requirements are not provided. Contrast-enhanced ultrasound was recommended in the 2005 American Association for the Study of Liver Diseases guidelines as part of the diagnostic algorithm [17]. This imaging modality was dropped in the 2010 update because it is not available in the United States and, hence, is not entirely applicable to a North American population and may offer false positive diagnosis in patients with cholangiocarcinoma [41]. Second-line modalities, such as hepatobiliary phase MRI with gadoxetate, SPIO-enhanced MRI, and CTHA and CTAP, are not considered. According to the American Association for the Study of Liver Diseases 2010 system [41], the diagnosis of is made if a nodule larger than 1 cm shows arterial phase hyperenhancement and portal venous or delayed phase washout appearance on one modality (CT or MRI). The diagnosis of cannot be made noninvasively for nodules smaller than 1 cm or for hypovascular (i.e., arterial phase hypo- or isoenhancing) nodules. Ancillary features that may modulate the likelihood of are not used. Criteria for tumor in vein are not provided. AJR:201, July

8 Cruite et al. United Network for Organ Sharing and Organ Procurement and Transplantation Network 2011 The United Network for Organ Sharing (UNOS), which operates the Organ Procurement and Transplantation Network (OPTN) in the United States, held a multidisciplinary Consensus Conference in November 2008 to make specific recommendations regarding the appropriate imaging criteria to properly determine staging. These imaging criteria were developed by an imaging work group composed of radiologists, transplant surgeons, and hepatologists. The discussions evolved from the results of an online survey conducted before the conference and the need to reduce the falsepositive rate of imaging-based diagnosis. The recommended imaging criteria were based on expert consensus and review of published evidence. These imaging criteria were approved in 2011 and published in UNOS-OPTN policy [26]. The UNOS-OPTN diagnostic system is summarized in Table 3. The system applies to liver transplantation candidates with. Patients with extrahepatic spread and/or macrovascular involvement (i.e., portal or hepatic veins) [26] are not considered eligible for liver transplantation and so are not addressed by the policy. Dynamic CT and MRI are the imaging modalities recommended by UNOS-OPTN system. Second-line modalities are not considered. The system specifies the minimum recommended technical and imaging protocol requirements for CT and MRI. These requirements are detailed in the policy document [26]. Examinations must be interpreted by a radiologist at an OPTN approved transplant center [26]. The imaging criteria were designed to have high specificity for the diagnosis of on imaging and for determining eligibility for exception points. The imaging diagnosis of requires the presence of arterial phase hyperenhancement and, depending on nodule size, various combinations of the following features: washout appearance, capsule appearance, and threshold growth, which is defined as maximum diameter increase by 50% or more documented on serial MRI or CT obtained < 6 months apart [26]. To achieve high specificity, more stringent criteria are required for 1- to 2-cm nodules than for nodules 2 cm or larger. The noninvasive diagnosis of is not allowed for nodules smaller than 1 cm and for those without arterial phase hyperenhancement. Ancillary features that may modulate the likelihood of are not used. Criteria for tumor in vein are not provided. Because the UNOS-OPTN system is designed to identify patients with suitable for liver transplantation, it does not attempt to classify nodules that do not meet its imaging criteria for. Accordingly, the UNOS-OPTN system defers to LI-RADS (discussed in the next section) the categorization of nodules that do not meet its imaging criteria for the diagnosis of. Liver Imaging Reporting and Data System 2013 In 2008, the American College of Radiology convened a committee of radiologists to develop a system for standardized interpretation, reporting, and data collection for CT and MRI examinations in patients at risk for. Version 1.0 of the resulting Liver Imaging Reporting and Data System (LI-RADS) was released online by the American College of Radiology in 2011 [28]. An update, version 2013, which includes a lexicon and an imaging atlas, was announced in January 2013 [27]. LI-RADS development was based on expert opinion; rounds of testing and iteration; feedback from radiologists, surgeons, hepatologists, and pathologists; and the need for congruence with other U.S. diagnostic systems. LI-RADS addresses the full spectrum of lesions and pseudolesions encountered on imaging of patients at risk for. The spectrum ranges from benign to malignant and includes non- malignancies, such as cholangiocellular carcinoma. Accordingly, LI-RADS categorizes observations as LR 1 (definitely benign), LR 2 (probably benign), LR 3 (intermediate probability for ), LR 4 (probably ), or LR 5 (definitely ). Observations with high probability of being malignancies other than are categorized as other malignancy. The LR 4 and LR 5 criteria are summarized in Tables 3 and 4 and are discussed in this article. The LR 1, LR 2, LR 3, and other malignancy categories are beyond the scope of this article. The LR 4 and LR 5 criteria apply to all patients at risk for, such as those with cirrhosis of any cause, those with chronic hepatitis B, and those with history of. There is no requirement for the patient to have a positive screening or surveillance test or be under consideration for liver transplantation. Dynamic CT and MRI with extracellular agents are the imaging modalities recommended. The current version of LI-RADS does not address second-line modalities, such as hepatobiliary phase MRI with gadoxetate, contrast-enhanced ultrasound, SPIO-enhanced MRI, and CTHA and CTAP [27]. LI-RADS provides guidance on CT and MRI technique, as detailed on the American College of Radiology website [27]. Discussion of this technical guidance is beyond the scope of this article. LI-RADS is applicable to all imaging centers, regardless of whether they are transplant centers, centers of excellence, or community centers. Arterial phase hyperenhancing masses may be categorized as LR 4 or LR 5, depending on the diameter of the mass and the number of the following features: washout appearance, capsule appearance, and threshold growth. Threshold growth is defined as a diameter increase of a mass by a minimum of 5 mm and, depending on the time interval between exam- TABLE 4: Nonvascular Ancillary Features of Hepatocellular Carcinoma () Specified by Liver Imaging Reporting and Data System (LI-RADS) 2013 System Ancillary Features That May Favor Ancillary Features That May Favor Benignity Mild-to-moderate T2 hyperintensity Homogeneous marked T2 hyperintensity Restricted diffusion Homogeneous marked T2 or T2* hypointensity Corona enhancement Undistorted vessels Mosaic architecture Parallels blood pool enhancement Nodule-in-nodule architecture Diameter reduction Intralesional fat Diameter stability 2 years Lesional iron sparing Lesional fat sparing Blood products Diameter increase less than threshold growth Note According to LI-RADS 2013 system, Ancillary imaging features modify likelihood of. In isolation, these features do not permit reliable categorization of observations and hence are considered ancillary [27]. Radiologists may at their discretion apply ancillary features that may favor to upgrade category (up to LR 4) or apply ancillary feat ures that may favor benignity to downgrade category. The ancillary features listed above are described in the LI-RADS website. 48 AJR:201, July 2013

9 Imaging-Based Diagnosis of Hepatocellular Carcinoma inations, by the following percentages: time interval 6 months or less and growth 50% or more, or time interval more than 6 months and growth of 100% or more. A new mass 10 mm or larger also represents threshold growth, regardless of the time interval. More stringent criteria are required for LR 5 than for LR 4 categories and, within a category, for smaller masses. Masses smaller than 1 cm cannot be categorized LR 5. Arterial phase hypo- or isoenhancing masses may be categorized as LR 4 if the criteria listed in Table 3 are met; such masses cannot be categorized as LR 5. LI-RADS incorporates ancillary imaging features (Table 4) that modulate the likelihood of. Radiologists may, at their discretion, apply ancillary features that may favor to upgrade the category by one or more categories (up to but not beyond LR 4) or apply ancillary features that may favor benignity to downgrade the category by one or more categories. LI-RADS provides a criterion for tumor in vein: definite enhancing soft tissue in vein [27]. Comparison of Most Current Systems Target Population All current diagnostic systems apply only to patients with cirrhosis or who are at risk for. The systems are not applicable to patients without cirrhosis or other risk factors for. Slight differences exist among the systems with regard to the exact target population, as delineated in Tables 1 3. Four diagnostic systems (Japan Society of Hepatology, Asian Pacific Association for the Study of the Liver, EASL-EORTC, and American Association for the Study of Liver Diseases) are intended for patients with a positive screening or surveillance test and who then are further evaluated with diagnostic examinations, such as dynamic CT, MRI, or contrast-enhanced ultrasound; in two of these systems (Japan Society of Hepatology and Asian Pacific Association for the Study of the Liver), standard screening or surveillance consists of periodic ultrasound in conjunction with one or more serum biomarkers, whereas in the other two systems (EASL-EORTC and American Association for the Study of Liver Diseases), it consists of only periodic ultrasound. One system (Asian Pacific Association for the Study of the Liver) also applies to patients with clinical suspicion of [19]. One system (UNOS-OPTN) applies only to liver transplant candidates; by definition, this system does not apply to patients with metastatic or macro-vasculoinvasive. One system (LI-RADS) applies to all at-risk patients undergoing liver CT or MRI regardless of any prior screening or surveillance findings and regardless of liver transplantation eligibility. Imaging Modalities and Techniques All current systems recommend multiphasic CT or MRI, with an emphasis mainly on extracellular contrast agents, as first-line modalities for diagnosis of. Additionally, for nodules with classic features of, all current systems allow a noninvasive diagnosis of to be made on the basis of a single imaging modality, except for the EASL- EORTC criteria, which require for 1- to 2-cm nodules in patients imaged in centers where the technology at disposal or the local skills are not at the high-end level [5], concordant imaging findings on two imaging modalities. For nodules without classic features, two systems (Japan Society of Hepatology and Asian Pacific Association for the Study of the Liver) recommend the use of second-line modalities, including contrast-enhanced ultrasound (Japan Society of Hepatology and Asian Pacific Association for the Study of the Liver), SPIO-enhanced MRI (Asian Pacific Association for the Study of the Liver), hepatobiliary phase MRI with gadoxetate (Japan Society of Hepatology), and CTHA and CTAP (Japan Society of Hepatology), and permit the diagnosis of to be made by integrating imaging features across modalities [19, 33]. Technical and Diagnostic Expertise The systems differ in their requirements for technical and diagnostic expertise. The American Association for the Study of Liver Diseases system specifies that examinations should be conducted using state of the art equipment and read by radiologists with extensive expertise in liver radiology [41]. The UNOS-OPTN system specifies that examinations must be interpreted by a radiologist at an OPTN approved transplant center [26]. The EASL-EORTC system makes a distinction between centers of excellence with high-end radiological equipment and centers in which the technology at disposal or the local skills are not at the high-end level [40]. Unlike these systems, LI-RADS explicitly makes no distinction between imaging centers or interpreting radiologists, and the system may be used by community and academic radiologists [27]. Japan Society of Hepatology and Asian Pacific Association for the Study of the Liver similarly do not stipulate requirements for technical or diagnostic expertise [19, 33]. Diagnostic Scope The systems differ in diagnostic scope. Two systems (EASL-EORTC and American Association for the Study of Liver Diseases) address only arterial phase hyperenhancing, and two systems (Japan Society of Hepatology and Asian Pacific Association for the Study of the Liver) address arterial phase hypo- or isoenhancing in addition to arterial phase hyperenhancing. One system (LI-RADS) addresses the entire spectrum of nodules and pseudolesions in patients at risk, although in this system, only arterial phase hyperenhancing masses can be categorized unequivocally as. The UNOS-OPTN system indirectly addresses the entire spectrum of lesions and pseudolesions by deferring to LI-RADS the categorization of nodules that do not meet its criteria for. Terminology The current systems differ substantially in terminology, and some of the source documents use terms inconsistently. A full discussion of the terminology differences is beyond the scope of this article. Some differences are summarized in Table 5. As mentioned already, the differences and inconsistencies in terminology complicate comparison of the various systems; to facilitate content comparison, we applied standardized terminology for this article. Major Imaging Features All current systems emphasize the same vascular enhancement pattern for imaging-based diagnosis of : arterial phase hyperenhancement with subsequent washout appearance. The systems differ in other imaging features, however, as discussed in the following sections. Diameter Four systems (EASL-EORTC, American Association for the Study of Liver Diseases, UNOS-OPTN, and LI-RADS) include nodule diameter as an imaging feature. These four systems require a minimum nodule diameter of 1 cm for a definitive diagnosis of. In addition, EASL-EORTC, UNOS-OPTN, and LI-RADS stratify nodules into diameter-based subsets and require more stringent criteria for smaller nodules. The other two systems (Japan Society of Hepatology and Asian Pacific Association for the Study of the Liver) do not include diameter as an imaging feature. In these systems, nodules of any diameter may be diagnosed as so long as the required imaging features are pres- AJR:201, July

10 Cruite et al. TABLE 5: Terminology Used by the Current Systems for Vascular Phases and for Key Imaging Features on Vascular Phases of CT and MRI Liver Imaging Reporting and Data System 2013 United Network for Organ Sharing and Organ Procurement and Transplantation Network 2011 American Association for the Study of Liver Diseases 2010 European Association for the Study of the Liver and European Organization for Research and Treatment of Cancer 2012 Asian Pacific Association for the Study of the Liver 2010 Japan Society of Hepatology 2010 Category Vascular phases Arterial phase: early arterial phase and late arterial phase Arterial phase Arterial phase Arterial phase Late arterial phase; late hepatic arterial phase Arterial phase terminology Arterial phase; arterial dominant phase; late arterial phase Portal venous phase Portal venous phase Portal venous phase Venous phase Portal venous phase; portal phase; later contrast phase Portal equilibrium phase; portal phase; venous phase; portal venous dominant phase Portal venous phase terminology Delayed phase Delayed phase; late phase Delayed phase Delayed phase; later contrast phase Delayed phase terminology Equilibrium phase; parenchymal phase Hyperenhancement Hypervascular Increased contrast enhancement; hyperenhancing Hypervascular Hypervascular Hypervascular; contrast uptake in the arterial phase Enhancement in the arterial phase that is greater than that of background liver Hypo- or isoenhancement Hypovascular Hypovascular; isovascular Enhancement in the arterial phase that is not greater than that of background liver Washout Washout Washout Washout Washout Washout appearance Visually observed temporal reduction in enhancement from arterial to portal venous or delayed phase Corona enhancement Corona enhancement; corona-shaped enhancement Peripheral rim enhancement in the arterial and early portal venous phase Capsule/pseudocapsule Capsule appearance Peripheral rim enhancement in the portal venous and delayed phases Note Blank cells indicate that the category is not addressed or no terminology is provided. Except for Liver Imaging Reporting and Data System, none of the systems provides precise definitions of the terms they use to describe vascular phases and imaging features. To facilitate comparison of the systems, the three authors in consensus classified corresponding terms in each system under standardized headings as shown. ent; moreover, diameter does not affect the stringency with which such features are applied. For some arterial phase hypo- or isoenhancing nodules, however, Japan Society of Hepatology does use diameter (< 1.5 vs 1.5 cm) to guide the decision for followup or biopsy, as discussed already in this article. Threshold growth Two systems (UNOS-OPTN and LI-RADS) include threshold growth as a feature of. In the UNOS-OPTN system, threshold growth is applicable only in patients who undergo imaging at intervals of 6 months or less; in LI-RADS, threshold growth is applicable regardless of imaging intervals. The other systems do not include threshold growth as a diagnostic feature of. Capsule appearance Two systems (UNOS-OPTN and LI-RADS) include capsule appearance as a feature of. Other systems do not include capsule appearance as a diagnostic feature of. Corona enhancement One system (Japan Society of Hepatology) includes corona enhancement as a feature of. In LI-RADS, corona enhancement is included as an ancillary rather than as a major feature of. Other systems do not include corona enhancement as a diagnostic feature of. Kupffer cell uptake Two systems (Japan Society of Hepatology and Asian Pacific Association for the Study of the Liver) include reduced Kupffer cell uptake, for imaging examinations in which Kupffer cell agents are administered, as an imaging feature of. Other systems do not address Kupffer cell uptake. Hepatocellular uptake One system (Japan Society of Hepatology) includes reduced hepatocellular uptake for MRI examinations in which gadoxetate is administered as an imaging feature of. Other systems do not address hepatocellular uptake. Ancillary Imaging Features One system, LI-RADS, incorporates ancillary features to modulate the likelihood of. Other systems do not address ancillary features. 50 AJR:201, July 2013