Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Review Article

Free Access

2014 KLCSG-NCC Korea Practice Guidelines for the Management of Hepatocellular Carcinoma: HCC Diagnostic Algorithm

Lee J.M.a, b · Park J.-W.c · Choi B.I.a, b

Author affiliations

aDepartment of Radiology, Seoul National University Hospital, and bInstitute of Radiation Medicine, Seoul National University College of Medicine, Seoul, and cCenter for Liver Cancer, National Cancer Center, Koyang, Korea

Corresponding Author

Byung Ihn Choi, MD

Department of Radiology and Institute of Radiation Medicine

Seoul National University College of Medicine

101 Daehak-ro, Jongno-gu, Seoul 110-744 (Korea)

E-Mail bichoi@snu.ac.kr

Related Articles for ""

Dig Dis 2014;32:764-777

Abstract

Hepatocellular carcinoma (HCC) is the fifth most commonly occurring cancer in Korea and typically has a poor prognosis with a 5-year survival rate of only 28.6%. Therefore, it is of paramount importance to achieve the earliest possible diagnosis of HCC and to recommend the most up-to-date optimal treatment strategy in order to increase the survival rate of patients who develop this disease. After the establishment of the Korean Liver Cancer Study Group (KLCSG) and the National Cancer Center (NCC), Korea jointly produced for the first time the Clinical Practice Guidelines for HCC in 2003, revised them in 2009, and published the newest revision of the guidelines in 2014, including changes in the diagnostic criteria of HCC and incorporating the most recent medical advances over the past 5 years. In this review, we will address the noninvasive diagnostic criteria and diagnostic algorithm of HCC included in the newly established KLCSG-NCC guidelines in 2014, and review the differences in the criteria for a diagnosis of HCC between the KLCSG-NCC guidelines and the most recent imaging guidelines endorsed by the European Organisation for Research and Treatment of Cancer (EORTC), the Liver Imaging Reporting and Data System (LI-RADS), the Organ Procurement and Transplantation Network (OPTN) system, the Asian Pacific Association for the Study of the Liver (APASL) and the Japan Society of Hepatology (JSH).

© 2014 S. Karger AG, Basel


Introduction

Hepatocellular carcinoma (HCC) is the sixth most commonly occurring cancer in the world and the third most common cause of cancer-related mortality [1]. The incidence of HCC is particularly high in Asia [2,3]. Although the diagnoses of cancers are generally established via invasive methods such as biopsy, the diagnosis of HCC can also be made through noninvasive methods such as imaging studies or tumor markers [4]. This unique feature of the diagnostic workup of HCC is related to the drawbacks of percutaneous biopsy, including bleeding due to liver dysfunction in patients with liver cirrhosis, difficulties in tumor targeting and track seeding [5], as well as reports of the characteristic imaging features of HCC shown as arterial enhancement and wash-out on portal/delayed phase on dynamic imaging [6,7]. Currently, contrast-enhanced multidetector computed tomography (MDCT) and dynamic magnetic resonance imaging (MRI) are the two most commonly used diagnostic imaging modalities for the noninvasive diagnosis of HCC [8,9,10,11,12,13]. Since the European Association for the Study of the Liver (EASL) working group proposed the imaging criteria for the diagnosis of HCC in its guidelines in 2000 [14], many guidelines, including those of the European Organisation for Research and Treatment of Cancer (EORTC) [15], the Liver Imaging Reporting and Data System (LI-RADS) [16], the Organ Procurement and Transplantation Network (OPTN) system [17] from Europe and the USA, the Asian Pacific Association for the Study of the Liver (APASL) [18], the Japan Society of Hepatology (JSH) [19], the Korean Liver Cancer Study Group (KLCSG) and the National Cancer Center (NCC) [20], have been published worldwide. These guidelines have been widely used for the surveillance, diagnosis and management of HCCs [21,22,23,24], and they all allow a noninvasive diagnosis of HCC through imaging studies, with biopsy often reserved for atypically enhancing nodules which do not satisfy the noninvasive imaging criteria for HCC reported in previous guidelines [15,25].

Most guidelines, at present, recommend four-phase MDCT or contrast-enhanced dynamic MRI using extracellular contrast agents as the primary examination for the diagnosis of HCCs in patients with cirrhosis [15,16,17,18,19,20,25]. The diagnostic criteria advocated by most guidelines focus mainly on hemodynamic alteration of the nodules, i.e. arterioportal imbalance, which results in arterial enhancement and wash-out on the portal/delayed phase of dynamic CT or MRI [6,7]. However, despite the similarities in the diagnostic criteria of HCC, there are some discrepancies among the guidelines. These include the use of tumor markers such as alpha-fetoprotein (AFP), size criteria, inclusion of subcentimeter nodules and the use of contrast-enhanced ultrasonography (CEUS) and/or tissue-specific MRI contrast media [26]. As an example, many guidelines from Western societies recommend biopsy if a nodule between 1 and 2 cm does not show typical imaging features of HCC. Conversely, the APASL and JSH guidelines include liver-specific contrast media-enhanced MRI, such as superparamagnetic iron oxide or gadoxetic acid (Primovist; Bayer Healthcare, Berlin, Germany), or CEUS as well as biopsy when initial diagnostic tests show atypical imaging features of the lesion.

The first Evidence-Based Clinical Practice Guidelines of HCC, which were published in 2003 [27] and updated in 2009 [20], have been adopted for liver cancer treatment by many centers throughout Korea. Since then, however, owing to technological advances in cross-sectional imaging modalities including CEUS, MDCT and MRI as well as the development of new contrast agents over the past 5 years, the diagnosis of HCC has changed considerably [4,28,29,30,31]. Therefore, the KLCSG and the NCC of Korea recently revised the Clinical Practice Guidelines for HCC.

This article addresses the role of imaging in the diagnosis of HCCs as well as the noninvasive diagnostic criteria of HCCs included in the management guidelines endorsed by the KLCSG and the NCC in 2014, and reviews the differences in criteria between the KLCSG-NCC guidelines and other recent imaging guidelines of the EASL-EORTC, the American Association for the Study of Liver Diseases (AASLD), the LI-RADS and the United Network for Organ Sharing (UNOS). In addition, the use of these diagnostic criteria in the management of patients with HCCs as well as future directions will be discussed.

Basic Concepts for the Noninvasive Diagnosis of HCC

For the diagnosis of HCC, not only biopsy but also imaging can be used. In fact, many treatments such as surgical treatments or local ablation treatments could be started without a pathologic diagnosis, contrasting it from most cancers for which tissue sampling is required prior to therapy. This unique feature of HCC is attributed to the fact that in cirrhotic patients with a well-defined high risk for developing HCC, the characteristic imaging features on dynamic imaging modalities such as CT or MRI allow the diagnosis of HCC with a positive predictive value of nearly 100% as well as the ability for staging, whereas percutaneous needle biopsy may result in frequent false-negative results in small HCCs and may not be used for multiple lesions [21,32].

The noninvasive diagnosis of HCC is based on three key factors, including the background liver disease with high risk for developing HCC, tumor markers and imaging diagnosis. The first key factor is the background liver disease with high risk for the development of HCC such as hepatitis B virus infection, hepatitis C virus infection and cirrhosis. Several previous studies have demonstrated the cost-effectiveness and survival benefit of detecting HCC at an early stage through a surveillance program using abdominal US and serum AFP [33,34,35]. The second key factor is tumor markers. Among several tumor markers for HCC, serum AFP is the most widely used tumor marker. Although serum AFP levels can be normal in up to 35% of small HCCs and can be nonspecifically elevated in patients with active hepatitis or active hepatocyte regeneration, if the serum AFP level steadily increases over time, particularly in hepatitis B patients with fully suppressed viral activity, the development of HCC should be suspected and detailed imaging study is strongly recommended [18,19,36]. Last but not least, imaging diagnosis plays a major role in the diagnosis of HCC by showing key pathologic features of its malignant changes during the process of hepatocarcinogenesis, including increased arterial flow, decreased portal flow, increased cellular density, decreased Kupffer cell number and/or function and decreased function of organic anion transporter 8 (OATP8) of hepatocytes [6,37,38,39,40,41,42,43]. Today, dynamic CT and MRI can effectively demonstrate the hemodynamic alterations of HCC (increased arterial flow and decreased portal flow), which can be shown as wash-in (arterial hyperenhancement) and wash-out (hypoenhancement on portal or delayed phase). The essential task of imaging studies is the differentiation of HCC from nonmalignant cirrhotic nodules such as dysplastic nodules, benign lesions (e.g. small hemangioma, confluent fibrosis) or pseudolesions (arterioportal shunt), which are commonly found in the cirrhotic liver, as well as differentiation of HCCs from nonhepatocellular malignancies such as cholangiocarcinomas [8,24,44,45,46,47,48,49]. Also important is the radiological staging which represents the determination of the number and size of the HCCs, the presence of tumor thrombosis in the major branches of the portal vein or hepatic vein, and extrahepatic metastases. In fact, the clinical decision-making and selection of optimal treatment strategies for patients with HCCs are often based on this radiological staging [17,25,50]. According to the OPTN policy, only nodules that satisfy the imaging criteria for definite HCC or those that are proven by biopsy to be HCC contribute to the staging [51], and nodules that are suspicious but not diagnostic for HCC usually are ignored for staging purposes.

Imaging Modalities and Their Diagnostic Performance

Among the diverse imaging modalities, dynamic contrast-enhanced CT and dynamic contrast-enhanced MRI are two of the most commonly used imaging studies for the evaluation of the hemodynamic alteration of HCC, and are recommended as the initial diagnostic tests for the noninvasive diagnosis of HCC in many guidelines [15,16,17,18,20,25,52,53]. These dynamic examinations should include precontrast, late arterial, portal venous, and delayed phase (3-5 min after contrast administration) acquisitions. Several previous studies have demonstrated that the optimal detection of hypervascular HCCs on CT or MRI requires careful timing of the image acquisition so as to take place during the late arterial phase of contrast enhancement, as early arterial images provide strong enhancement of the hepatic artery but do not provide strong enhancement of the tumors [54,55,56]. As the imaging diagnosis of HCC plays an important role in the clinical care and decision-making of patients with HCC, it is crucial that imaging tests be performed in the optimal setting [8]. CT or MRI studies should also be performed according to proven multiphasic imaging protocols using high-quality scanners and appropriate the correct amount and rate of contrast given, with precise individualized timing of the image acquisitions in relation to contrast injection and image reconstruction with a suitable minimum slice thickness (tables 1, 2) [8,17]. The panels of the KLCSG and the NCC of Korea guideline committee agreed that a four-slice MDCT scanner and a 1.5-T MRI unit would be the minimum acceptable machine type affording dynamic imaging at an acceptable reconstructed image resolution. Bolus tracking techniques for the acquisition of late arterial phase imaging are also recommended to maximize HCC detection with both CT and MRI. Recent studies [58,59] demonstrated improved diagnostic values of combined use of low tube voltage and iterative reconstruction technique for detection of hypervascular HCC at lower radiation dose, and therefore, if possible, these techniques are also recommended.

Table 1

Technical specifications for liver MRI with extracellular contrast media or gadoxetic acid

http://www.karger.com/WebMaterial/ShowPic/160689

Table 2

Recommended minimum technical specifications for dynamic contrast-enhanced CT of the liver

http://www.karger.com/WebMaterial/ShowPic/160688

As the noninvasive diagnosis of HCC mostly depends on imaging studies, the sensitivity and specificity of the imaging modalities are particularly important for an accurate diagnosis of HCC. Several previous single-center studies have reported better performance with dynamic MRI than multiphasic CT [9,57]; the per-lesion sensitivity of MRI for HCC was reported to range from 77 to 100%, while that of CT is in the range of 68-91% [9,10,11,60,61]. However, tumor size can significantly affect the sensitivity of CT or MRI for the detection of HCC; the per-lesion sensitivities for nodular HCCs >2 cm are 100% for both modalities, but 44-47% (MRI) and 40-44% (CT) for HCCs measuring 1-2 cm [9,57,60]. According to previous comparative studies in patients undergoing liver transplantation, the diagnostic sensitivity of dynamic CT was 75.0%, and that of dynamic MRI was 100% for HCCs ≥2 cm in diameter but only 52% for HCCs <2 cm in diameter [62,63,64]. However, according to studies using the explanted liver as a standard of reference, sensitivity values of both CT and MRI for small HCCs <1 cm were reported to range from 29 to 43% (MRI) and from 10 to 33% (CT) [10,57,60]. Therefore, both imaging modalities have shown poor sensitivity for HCCs <1 cm, though it is not yet clear which modality is superior for the detection of HCC. Each modality has its own advantages and disadvantages. As an example, MDCT has been shown to be more rapid, robust, less expensive and more widely available than MRI. On the other hand, MDCT has disadvantages of radiation exposure as well as relatively low soft tissue contrast compared with MRI having higher soft tissue contrast. However, MRI is more prone to artifacts. Therefore, depending on the availability and expertise of the radiologist at each center, either CT or MRI can be used for the diagnosis of HCC.

Recently, CEUS including SonoVue®, Definity® or Sonazoid™ has been shown to be useful for the assessment of tumor vascularity because these agents can be used in continuous bubble imaging at a low mechanical index [4,65,66,67,68,69]. With CEUS, typical findings related to HCC are hypervascularity of the lesion relative to the liver parenchyma in the arterial phase and wash-out in the portal venous or equilibrium phase, similar to those obtained with CT and MRI [4,66,67]. Unfortunately, US contrast agents are not widely available in many countries, including the United States. Furthermore, US is operator-dependent and the limited field of view does not permit single contrast phase whole-organ imaging [8]. Therefore, despite the definite advantage of the high temporal resolution of CEUS for revealing hypervascularity of nodules and therefore characterization of liver nodules, CEUS is seemingly limited for the noninvasive diagnosis of HCCs, as nonhepatocellular malignancies such as cholangiocarcinoma or metastases also display the hallmark signs of HCC, i.e. homogeneous contrast uptake at US contrast followed by wash-out [49,70]. CEUS does, however, have a definite role for guiding invasive procedures such as radiofrequency ablation for the treatment of HCC [71]. Based on previous reports regarding the value of CEUS in revealing arterial hypervascularity, Sonazoid-enhanced US was included in the previous JSH guideline as a second-line imaging modality for the evaluation of indeterminate nodules. However, as stated above, although CEUS may play a role in characterizing liver nodules in cirrhosis in some countries, its role as a primary diagnostic test for the diagnosis and staging of HCC remains quite limited as of now [15,71], and contrast-enhanced CT and MRI are the two most important and widely used techniques for the noninvasive diagnosis of HCC. Another modality that has been investigated in this regard, positron emission tomography CT, is not recommended as a primary diagnostic imaging owing to its relatively low diagnostic accuracy, especially in patients with small HCCs [72].

Although MRI with hepatocyte-specific contrast agents (gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid; Gd-EOB-DTPA) is not yet integrated into most clinical practice guidelines except for the JSH guidelines [19], several previous studies have demonstrated that MRI using hepatocyte-specific contrast agents (Gd-EOB-DTPA) can provide better diagnostic performance than dynamic CT for the detection and characterization of HCCs in cirrhotic livers [30,65,73,74,75,76,77,78,79,80,81] or dynamic MRI using extracellular agents [82]. In addition, several other studies have also suggested that MRI with gadoxetic acid may be the most sensitive method not only for the detection of small progressed HCCs but also for the detection of early HCCs or premalignant lesions such as high-grade dysplastic nodules [13,78,83,84,85,86,87,88,89,90]. Owing to these results, gadoxetic acid-enhanced liver MRI is currently emerging worldwide as a leading method for the diagnosis and staging of HCC [44,65,91]. Therefore, in the newest revision, dynamic CT or dynamic MRI using gadolinium-based extracellular contrast media and/or Gd-EOB-DTPA-enhanced MRI is preferentially recommended by the KLCSG and the NCC if HCC is suspected during a surveillance program.

Diagnostic Criteria

If the hallmark imaging features of HCC (arterial phase hyperenhancement with wash-out in the portal or delayed phases) are identified in the imaging techniques mentioned above, a nodule 1 cm or larger in size can be diagnosed as HCC (fig. 1). Arterial phase hyperenhancement is caused by increased intranodular arterial supply, and is nonspecific as it can be seen in small hemangiomas, small perfusion abnormalities such as arterioportal shunts, focal nodular hyperplasias, some atypical dysplastic nodules or small cholangiocarcinomas [49,92,93,94]. In addition, ‘wash-out' is defined as hypoenhancement relative to the surrounding liver in portal venous or delayed phases [95]. This ‘wash-out' by itself is also not specific for HCC as this feature may be observed in dysplastic nodules. Although the individual ‘arterial hyperenhancement or wash-in' or ‘wash-out' features may be nonspecific, the combination of arterial phase hyperenhancement and wash-out on portal venous/delayed phase is highly specific for HCC in patients with cirrhosis or other risk factors for HCC such as chronic hepatis B or C [21,96,97,98,99]. Furthermore, when antecedent US visibility (a detected nodule on surveillance US) is added to the diagnostic criteria of arterial hyperenhancement and wash-out, the positive predictive value becomes nearly 100% [21,60,96,100]. However, this enhancement pattern (wash-in and wash-out enhancement pattern) could be seen in patients with hypervascular metastases and other benign lesions such as hepatocellular adenomas, angiomyolipomas or eosinophilic abscess, and therefore, it should be regarded as being not specific for the diagnosis of HCC in the general population. Rather, this diagnostic criterion should be applied for the noninvasive diagnosis of HCCs in a population with a high risk of HCC development including liver cirrhosis, chronic hepatitis B and chronic hepatitis C.

Fig. 1

Diagnostic algorithm for suspected HCC of the new KLCSG-NCC guideline. CHB = Chronic hepatitis B; CHC = chronic hepatitis C; LC = liver cirrhosis.

http://www.karger.com/WebMaterial/ShowPic/160687

There are several ancillary imaging features which are frequently identified in progressed HCC and therefore reported as suggestive signs of HCC [16,101,102,103,104]. These include mild to moderate signal intensity in the T2-weighted image, intralesional fat, iron sparing in an iron-overloaded liver, corona enhancement, nodule-in-nodule or ‘mosaic' appearance, capsule appearance or pseudocapsule at equilibrium phase imaging, low signal intensity in the hepatobiliary phase of gadoxetic acid-enhanced MRI and high signal intensity in diffusion-weighted imaging (DWI), suggesting restricted or impeded diffusion [16,104]. However, according to a recent prospective single-center study, conclusive noninvasive diagnosis of HCC in cirrhosis was made with a sensitivity and specificity of 58.3 and 96.4%, respectively, based on the contrast enhancement pattern, but other ancillary features such as intralesional fat or capsule did not increase the diagnostic accuracy beyond the dynamic criteria [97].

Until now, accumulating evidence has demonstrated that gadoxetic acid-enhanced MRI may provide better detection and characterization of HCCs compared with MDCT by permitting simultaneous evaluation of tumor vascularity as well as hepatocellular function [29,65,78,81,82,105,106,107,108,109,110]. Since OATP expression declines during hepatocarcinogenesis, approximately 88-95% of HCCs have low or no OATP8 expression and do not take up gadoxetic acid and therefore show hypointensity on hepatobiliary phase imaging [111,112]. Furthermore, during hepatobiliary phase imaging, the liver parenchyma shows strong enhancement whereas most HCCs show hypointensity [113], and so hepatobiliary phase imaging can increase HCC conspicuity and delineation. The additional benefit of hepatobiliary phase imaging is in the differentiation of hypervascular HCCs from hypervascular pseudolesions such as arterioportal shunts [81,114], which are the most common source of diagnostic confusion on dynamic CT or dynamic MRI using extracellular contrast agents. Consequently, hepatobiliary phase imaging of gadoxetic acid-enhanced MRI may provide additional diagnostic value in the detection and characterization of hepatocellular nodules in the cirrhotic liver compared with dynamic imaging [4,6,19,44,76,91,92,115,116,117]. According to previous studies, the per-lesion sensitivity for the diagnosis of HCC could be improved by 6-15% with gadoxetate disodium after adding hepatobiliary phase images to the dynamic image set [28,74,118]. However, although the hypointensity of nodules on hepatobiliary phase images of gadoxetic acid-enhanced MRI has been suggested as an additional important imaging finding implying the diagnosis of HCC in the characterization of hypervascular lesions on arterial phase imaging [77,102,119,120,121,122], other nonhepatocellular lesions such as hemangiomas, cholangiocarcinomas or inflammatory lesions showing arterial hyperenhancement may show these ancillary findings. Therefore, hepatobiliary phase hypointensity is not a specific sign of HCC, and further prospective validation studies are warranted to provide confirmatory evidence of the role of such findings. Furthermore, gadoxetic acid-enhanced MRI does not provide a conventional equilibrium or late dynamic phase, and instead provides a transitional phase with mixed features of the late dynamic and hepatobiliary phase. Thus, the interpretation of hypointensity on this transitional phase may require great caution from radiologists, as hemangioma or cholangiocarcinomas may show pseudo-wash-out during the transitional phase, owing to the relatively stronger enhancement of the liver parenchyma related with intracellular uptake of the contrast medium [44,46,123,124,125,126,127]. Most nodules with arterial phase hyperintensity, portal venous phase isointensity and transitional phase hypointensity probably are HCCs, but the specificity of this pattern for HCC remains to be determined [29]. For these reasons, the dynamic phases and hepatobiliary phase of gadoxetic acid-enhanced MRI must be evaluated in conjunction with other phases and sequences - such a T1-weighted dual-echo, T2-weighted or DWI - to differentiate HCC from other entities that may appear hypointense in the hepatobiliary phase. With moderately and heavily T2-weighted image sequences as well as DWI, flash-enhancing hemangiomas can be differentiated from HCCs, as hemangiomas show hyperintensity on both moderately and heavily T2-weighted images, and less diffusion restriction than HCC on DWI [75,128,129]. Although a retrospective study [125] reported that DWI is indeed helpful for the characterization of intrahepatic cholangiocarcinoma from HCC on gadoxetic acid-enhanced MRI by demonstrating the ‘target' sign on DWI, it remains to be validated in further studies with a larger study population.

In addition, not only progressed hypervascular HCCs, but also many early HCCs and some high-grade dysplastic nodules show decreased enhancement in hepatobiliary phase imaging [85,87,105,115,116,130,131,132], whereas low-risk nodules including regenerative nodules and low-grade dysplastic nodules, some high-grade dysplastic nodules (<50%) and approximately 10% of HCCs are isointense or hyperintense due to preserved expression [6]. Although there are some overlaps between early HCCs and high-grade dysplastic nodules, hepatobiliary phase imaging of gadoxetic acid-enhanced MRI helps identify early HCCs which are not easily detected with dynamic CT or MRI with extracellular agents due to their incomplete arterial hypervascularity [132]. However, as this finding is not specific for early HCC and as the differential diagnosis for nonhypervascular, hepatobiliary phase hypointense nodules may include high-grade dysplastic nodules [118,133] and other benign cirrhotic nodules [125], US-guided biopsy or close follow-up with cross-sectional imaging studies at 3-6 months should be considered. The rationale behind the necessity of close follow-up is as follows. Regardless of the pathologic nature of such nonhypervascular hepatobiliary phase hypointensity nodules, approximately 10-35% of nonhypervascular hepatobiliary phase hypointense nodules will progress to hypervascular HCC over 12 months [84,85,86,87,88,134]. Although several imaging features have been suggested as potential predictors of the development of hypervascular HCCs, including nodule size (>1 cm) [87,88], the degree of hepatobiliary phase hypointensity [85], hyperintensity on DWI [85], hyperintensity on T2-weighted imaging [84,85] and intralesional fat [84], none of these findings seems to be very specific for early HCC. Therefore, the optimal management of these nodules has not yet been determined.

The accuracy of noninvasive diagnostic criteria with CT or MRI largely depends on the size of the nodules as described above [10,59,60,62,63,64]. In general, HCCs >2 cm frequently show the typical hallmark of HCC, i.e. hypervascularity in the arterial phase with wash-out in the portal or delayed phases owing to a gradual increase of the tumor artery and regression of portal flow [135,136], but small HCCs (<2 cm) or well-differentiated HCCs show a tendency of having an atypical enhancement pattern [137,138,139]. With the most recent progress in imaging technology and contrast media as well as more active use of surveillance programs, however, an increasing number of small nodules <1 cm in diameter are being more frequently detected [15,105,140,141]. Although the diagnostic performance of dynamic CT, dynamic MRI, or gadoxetic acid-enhanced MRI for small HCCs <1 cm is still low, when these subcentimeter lesions show typical arterial hypervascularization with wash-out in cirrhosis, the probability of progressing to a typical hypervascular HCC >1 cm is higher than 95% [105]. Many guidelines form Asia, including the JSH guideline and the APASL guidelines, allow for the noninvasive diagnosis of HCC using CT or MRI for these small nodules <1 cm [18,19,20].

According to the new KLCSG-NCC guideline in 2014, noninvasive diagnosis should be based on the identification of the typical hallmark of HCC (hypervascular in the arterial phase and wash-out in the portal or 3-min-delayed phase) for liver nodules ≥1 cm on one or more imaging techniques among the three first-line diagnostic tests (dynamic CT, dynamic MRI and gadoxetic acid-enhanced MRI) [19,20,142] (fig. 1). However, depending on the technical specifications of CT or MRI, two or more techniques are required in suboptimal settings where the imaging technology is not at an adequate level (high-end level) for nodules sized 1-2 cm, similar to the recent EASL guideline [15]. Furthermore, considering that the evaluation of the enhancement pattern of small nodules <1 cm on dynamic phase imaging is difficult, stricter criteria are warranted for the diagnosis of HCC for nodules <1 cm. We believe that the diagnosis should be based on the combination of the identification of the typical hallmark features of HCCs in two or more imaging modalities as well as increased serum AFP levels with a rising trend over time for liver nodules <1 cm in patients with suppressed hepatitis activity [77]. As for biopsy, it should be considered for atypical nodules not fulfilling the noninvasive criteria, and any changes in size or characteristics of nodules and serum tumor markers should be monitored if a noninvasive or pathologic diagnosis is not feasible for liver nodules in high-risk patients. Although the new KLCSG-NCC guidelines in 2014 did not specify the follow-up imaging modalities or interval, recent OPTN guidelines included the criterion of a rapidly growing nodule by 50% or more documented on serial CT or MRI obtained ≤6 months apart as a criterion of HCC [17].

Features of the New KLCSG-NCC Guidelines in Comparison with Other Imaging Guidelines for HCC Diagnosis

With the rapid technological development of diagnostic imaging modalities and contrast media, the AASLD (2010), the EASL-EORTC (2012) and the APASL (2010) published new guidelines for the diagnosis of HCC since 2009. Recently, the JSH and the KLCSG also revised their guidelines. Although the diagnostic criteria for HCC across the various guidelines have some imaging features in common - for example, arterial phase hyperenhancement and venous or delayed phase hypoenhancement (wash-out) [5,9,10,15] - the criteria diverge in other features such as lesion size and growth as well as in the number of required imaging modalities [24].

The diagnostic criteria of the new KLCSG-NCC guidelines in 2014 present several differences compared with the criteria of other guidelines.

First, the definition of a high-risk group of HCC, in whom a noninvasive imaging diagnosis can be made, is different. In the new KLCSG-NCC guidelines, chronic hepatitis B, chronic hepatitis C and liver cirrhosis are included in the high-risk group of HCC, and a noninvasive imaging diagnosis can be made if nodules with antecedent US visibility show the hallmark signs of HCC on CT or MRI. Several previous studies [21,96,97,98,99] have demonstrated that the combination of arterial phase hyperenhancement and wash-out on the portal venous/delayed phase can be highly specific for HCC in patients with cirrhosis or other risk factors for HCC such as chronic hepatitis B or C. However, according to the guidelines proposed by both the AASLD and the EASL-EORTC, only liver cirrhosis patients are defined as a high-risk population, and noninvasive diagnosis can only be applicable in cirrhotic patients, while the APASL also included chronic liver disease (chronic hepatitis B or C) as well as liver cirrhosis. This difference may represent the high prevalence of HCC and hepatitis B or C viral infections in Asia.

Second, a noninvasive imaging diagnosis of HCC can be made for subcentimeter nodules if a subcentimeter nodule shows the typical hallmark signs of HCC in two or more imaging modalities, with increased serum AFP levels with a rising trend over time in patients with suppressed hepatitis activity [77]. Once again, according to the guidelines proposed by both the AASLD and the EASL-EORTC from Western countries, noninvasive diagnosis may be applicable only for nodules >1 cm in cirrhotic patients, whereas the APASL and the JSH from Asia also allow the noninvasive diagnosis of subcentimeter nodules based on the hallmark imaging features of HCC in patients with chronic liver disease or liver cirrhosis. This difference could be attributed to the difference in the prevalence of HCC across regions as well as in the policy for liver transplantation allocation. As an example, the UNOS assigns a Model for End-Stage Liver Disease (MELD) exception score for patients with HCC in order to increase the priority for candidates with HCC that are within the Milan criteria. Therefore, the noninvasive diagnostic criteria of HCC proposed by the AASLD, the EASL-EORTC, the OPTN and the LI-RADS (category 5) were intentionally not optimized to achieve maximum sensitivity for HCC detection, but rather to raise the specificity of an HCC diagnosis [15,17,25]. Conversely in Asia, including Japan and Korea, liver transplantation is mainly used as a salvage operation after applying many treatments such as surgical resection, radiofrequency ablation and transarterial chemoembolization, and more than 70% of liver transplantations in Asia are living donor liver transplantations [143].

Third, the new KLCSG-NCC guidelines include gadoxetic acid-enhanced MRI as well as dynamic CT or MRI with extracellular contrast media as primary diagnostic tests for the noninvasive diagnosis of HCC. Gadoxetic acid-enhanced MRI was included as a secondary diagnostic test in the JSH guideline in 2009 and is included as a primary diagnostic test in the new JSH guideline in 2014 [19]. However, gadoxetic acid-enhanced MRI is not yet used as a primary diagnostic test for the noninvasive diagnosis of HCC in the guidelines of the AASLD, the EASL-EORTC, the OPTN and the LI-RADS. This difference in the respective guidelines may have been caused by the preference toward higher sensitivities and specificities of the imaging modalities for HCC. Although the per-lesion sensitivity for the diagnosis of HCC could be improved by 6-15% for gadoxetate disodium after adding hepatobiliary phase images to dynamic image sets using hypointensity on hepatobiliary phase images as an alternative criterion to wash-out for the diagnosis of HCC [4,6,19,28,44,74,76,77,91,92,102,115,116,117,118,119,120,121,122], other nonhepatocellular lesions such as arterially enhancing hemangiomas or cholangiocarcinomas may show hepatobiliary phase hypointensity. Therefore, there is concern that although gadoxetic acid could contribute to increased sensitivity, this could be at a cost of losing specificity. In addition, both the APASL [18] and the JSH guidelines [19] used Sonazoid-enhanced US as a secondary diagnostic test when a nodule showed no ‘wash-out' appearance or no arterial hypervascularity on CT and/or MRI. However, CEUS was not included in the diagnostic algorithm of the new KLCSG-NCC guidelines.

Last but not least, in terms of the policy for indeterminate nodules not fulfilling specific imaging criteria, the new KLCSG-NCC guidelines recommend either biopsy or follow-up with imaging if percutaneous biopsy is not feasible for liver nodules in high-risk patients.

On the other hand, the AASLD and the EASL-EORTC guidelines recommend that all US-visible nodules >10 mm not fulfilling HCC diagnostic criteria on CT or MRI should either be biopsied or evaluated by a second exam and, if the second exam is also inconclusive, be biopsied [15,25]. However, biopsy may have several potential problems, including high interobserver variability among pathologists, substantial risk of both false-positive and false-negative tissue diagnosis [21,144], and a risk of complications such as bleeding or track seeding [145]. Furthermore, until now, no outcome studies have been done to show that survival is prolonged by performing a biopsy of indeterminate nodules >10 mm rather than following them closely for growth [16].

Consensus Statements

(1) HCC is diagnosed on the basis of either pathology or clinical criteria in patients belonging to the high-risk group (chronic hepatitis B/C or cirrhosis) (A1).

(2) When HCC is suspected during surveillance in the high-risk group, dynamic contrast-enhanced CT/MRI or MRI with liver-specific contrast agents should be performed for diagnosis (B1).

(3) In the high-risk group, HCC can be diagnosed for nodules ≥1 cm in diameter if one or two of the above-mentioned imaging techniques show typical features of HCC (for the diagnosis of nodules 1-2 cm in diameter, two or more imaging modalities are required if a suboptimal imaging technique is used). Typical features of HCC include arterial phase enhancement with wash-out in the portal or delayed phase (B1).

(4) Nodules <1 cm in diameter can be diagnosed as HCC in the high-risk group when all of the following conditions are met: typical features of HCC in two or more of the above-mentioned imaging modalities and continuously rising serum AFP levels with hepatitis activity under control (C1).

(5) Pathologic diagnosis should be considered if the clinical criteria are not met or typical features of HCC are not shown. Indeterminate nodules despite imaging workups or pathologic examination need to be followed up with repeated imaging and serum tumor marker analysis (B1).


References

  1. El-Serag HB: Hepatocellular carcinoma. N Engl J Med 2011;365:1118-1127.
  2. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-2917.
  3. Kim DY, Han KH: Epidemiology and surveillance of hepatocellular carcinoma. Liver Cancer 2012;1:2-14.
  4. Kudo M: Diagnostic imaging of hepatocellular carcinoma: recent progress. Oncology 2011;81(suppl 1):73-85.
  5. Stigliano R, Marelli L, Yu D, Davies N, Patch D, Burroughs AK: Seeding following percutaneous diagnostic and therapeutic approaches for hepatocellular carcinoma. What is the risk and the outcome? Seeding risk for percutaneous approach of HCC. Cancer Treat Rev 2007;33:437-447.
  6. Kudo M: Multistep human hepatocarcinogenesis: correlation of imaging with pathology. J Gastroenterol 2009;44(suppl 19):112-118.
  7. Matsui O, Kobayashi S, Sanada J, Kouda W, Ryu Y, Kozaka K, Kitao A, Nakamura K, Gabata T: Hepatocellular nodules in liver cirrhosis: hemodynamic evaluation (angiography-assisted CT) with special reference to multi-step hepatocarcinogenesis. Abdom Imaging 2011;36:264-272.
  8. Lee JM, Trevisani F, Vilgrain V, Wald C: Imaging diagnosis and staging of hepatocellular carcinoma. Liver Transpl 2011;17(suppl 2):S34-S43.
  9. Burrel M, Llovet JM, Ayuso C, Iglesias C, Sala M, Miquel R, Caralt T, Ayuso JR, Solé M, Sanchez M, Brú C, Bruix J; Barcelona Clinic Liver Cancer Group: MRI angiography is superior to helical CT for detection of HCC prior to liver transplantation: an explant correlation. Hepatology 2003;38:1034-1042.
  10. Krinsky GA, Lee VS, Theise ND, Weinreb JC, Rofsky NM, Diflo T, Teperman LW: Hepatocellular carcinoma and dysplastic nodules in patients with cirrhosis: prospective diagnosis with MR imaging and explantation correlation. Radiology 2001;219:445-454.
  11. Kim YK, Kim CS, Chung GH, Han YM, Lee SY, Chon SB, Lee JM: Comparison of gadobenate dimeglumine-enhanced dynamic MRI and 16-MDCT for the detection of hepatocellular carcinoma. AJR Am J Roentgenol 2006;186:149-157.
  12. Lee JM, Yoon JH, Joo I, Woo HS: Recent advances in CT and MR imaging for evaluation of hepatocellular carcinoma. Liver Cancer 2012;1:22-40.
  13. Kudo M: Early hepatocellular carcinoma: definition and diagnosis. Liver Cancer 2013;2:69-72.
  14. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, Pagliaro L, Colombo M, Rodes J: Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001;35:421-430.
  15. European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer: EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908-943.
    External Resources
  16. Mitchell DG, Bruix J, Sherman M, Sirlin CB: LI-RADS (Liver Imaging Reporting and Data System): Summary, discussion, consensus of the LI-RADS Management Working Group and future directions. Hepatology 2014, Epub ahead of print.
  17. 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;266:376-382.
  18. Omata M, Lesmana LA, Tateishi R, Chen PJ, Lin SM, Yoshida H, Kudo M, Lee JM, Choi BI, Poon RT, Shiina S, Cheng AL, Jia JD, Obi S, Han KH, Jafri W, Chow P, Lim SG, Chawla YK, Budihusodo U, Gani RA, Lesmana CR, Putranto TA, Liaw YF, Sarin SK: Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. Hepatol Int 2010;4:439-474.
  19. Kudo M, Izumi N, Kokudo N, Matsui O, Sakamoto M, Nakashima O, Kojiro M, Makuuchi M; 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;29:339-364.
  20. Korean Liver Cancer Study Group and National Cancer Center, Korea: Practice guidelines for management of hepatocellular carcinoma 2009 (in Korean). Korean J Hepatol 2009;15:391-423.
  21. Forner A, Vilana R, Ayuso C, Bianchi L, Sole M, Ayuso JR, Boix L, Sala M, Varela M, Llovet JM, Bru C, Bruix J: Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology 2008;47:97-104.
  22. Lin MT, Chang KC, Tseng PL, Yen YH, Wang CC, Tsai MC, Cheng YF, Eng HL, Wu CK, Hu TH: The validation of 2010 AASLD guideline for the diagnosis of hepatocellular carcinoma in an endemic area. J Gastroenterol Hepatol 2014, Epub ahead of print.
  23. Minagawa M, Ikai I, Matsuyama Y, Yamaoka Y, Makuuchi M: Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan. Ann Surg 2007;245:909-922.
  24. Tang A, Cruite I, Sirlin CB: Toward a standardized system for hepatocellular carcinoma diagnosis using computed tomography and MRI. Expert Rev Gastroenterol Hepatol 2013;7:269-279.
  25. Bruix J, Sherman M: Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020-1022.
  26. Song do S, Bae SH: Changes of guidelines diagnosing hepatocellular carcinoma during the last ten-year period. Clin Mol Hepatol 2012;18:258-267.
  27. Park JW; Korean Liver Cancer Study Group and National Cancer Center: Practice guideline for diagnosis and treatment of hepatocellular carcinoma (in Korean). Korean J Hepatol 2004;10:88-98.
    External Resources
  28. Ahn SS, Kim MJ, Lim JS, Hong HS, Chung YE, Choi JY: Added value of gadoxetic acid-enhanced hepatobiliary phase MR imaging in the diagnosis of hepatocellular carcinoma. Radiology 2010;255:459-466.
  29. Choi JW, Lee JM, Kim SJ, Yoon JH, Baek JH, Han JK, Choi BI: Hepatocellular carcinoma: imaging patterns on gadoxetic acid-enhanced MR images and their value as an imaging biomarker. Radiology 2013;267:776-786.
  30. Choi JY, Lee JM, Sirlin CB: CT and MR imaging diagnosis and staging of hepatocellular carcinoma: part II. Extracellular agents, hepatobiliary agents, and ancillary imaging features. Radiology 2014;273:30-50.
  31. Sugimoto K, Moriyasu F, Saito K, Taira J, Saguchi T, Yoshimura N, Oshiro H, Imai Y, Shiraishi J: Comparison of Kupffer-phase Sonazoid-enhanced sonography and hepatobiliary-phase gadoxetic acid-enhanced magnetic resonance imaging of hepatocellular carcinoma and correlation with histologic grading. J Ultrasound Med 2012;31:529-538.
    External Resources
  32. Hatfield MK, Beres RA, Sane SS, Zaleski GX: Percutaneous imaging-guided solid organ core needle biopsy: coaxial versus noncoaxial method. AJR Am J Roentgenol 2008;190:413-417.
  33. Singal A, Volk ML, Waljee A, Salgia R, Higgins P, Rogers MA, Marrero JA: Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther 2009;30:37-47.
  34. 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;6:1418-1424.
  35. Zhang BH, Yang BH, Tang ZY: Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;130:417-422.
  36. Wong GL, Chan HL, Tse YK, Chan HY, Tse CH, Lo AO, Wong VW: On-treatment alpha-fetoprotein is a specific tumor marker for hepatocellular carcinoma in patients with chronic hepatitis B receiving entecavir. Hepatology 2014;59:986-995.
  37. Bartolozzi C, Crocetti L, Lencioni R, Cioni D, Della Pina C, Campani D: Biliary and reticuloendothelial impairment in hepatocarcinogenesis: the diagnostic role of tissue-specific MR contrast media. Eur Radiol 2007;17:2519-2530.
  38. Coleman WB: Mechanisms of human hepatocarcinogenesis. Curr Mol Med 2003;3:573-588.
  39. Effendi K, Sakamoto M: Molecular pathology in early hepatocarcinogenesis. Oncology 2010;78:157-160.
  40. Efremidis SC, Hytiroglou P: The multistep process of hepatocarcinogenesis in cirrhosis with imaging correlation. Eur Radiol 2002;12:753-764.
  41. Kitao A, Matsui O, Yoneda N, Kozaka K, Shinmura R, Koda W, Kobayashi S, Gabata T, Zen Y, Yamashita T: The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging. Eur Radiol 2011;21:2056-2066.
  42. Kitao A, Zen Y, Matsui O, Gabata T, Nakanuma Y: Hepatocarcinogenesis: multistep changes of drainage vessels at CT during arterial portography and hepatic arteriography - radiologic-pathologic correlation. Radiology 2009;252:605-614.
  43. Park YN, Kim MJ: Hepatocarcinogenesis: imaging-pathologic correlation. Abdom Imaging 2011;36:232-243.
  44. Lee JM, Zech CJ, Bolondi L, Jonas E, Kim MJ, Matsui O, Merkle EM, Sakamoto M, Choi BI: Consensus report of the 4th International Forum for Gadolinium-Ethoxybenzyl-Diethylenetriamine Pentaacetic Acid Magnetic Resonance Imaging. Korean J Radiol 2011;12:403-415.
  45. Ito K, Honjo K, Fujita T, Awaya H, Matsumoto T, Matsunaga N, Higuchi M, Kada T, Mattrey RF: Liver neoplasms: diagnostic pitfalls in cross-sectional imaging. Radiographics 1996;16:273-293.
  46. Kang Y, Lee JM, Kim SH, Han JK, Choi BI: Intrahepatic mass-forming cholangiocarcinoma: enhancement patterns on gadoxetic acid-enhanced MR images. Radiology 2012;264:751-760.
  47. Kim SA, Lee JM, Lee KB, Kim SH, Yoon SH, Han JK, Choi BI: Intrahepatic mass-forming cholangiocarcinomas: enhancement patterns at multiphasic CT, with special emphasis on arterial enhancement pattern - correlation with clinicopathologic findings. Radiology 2011;260:148-157.
  48. Kim SJ, Lee JM, Han JK, Kim KH, Lee JY, Choi BI: Peripheral mass-forming cholangiocarcinoma in cirrhotic liver. AJR Am J Roentgenol 2007;189:1428-1434.
  49. Rimola J, Forner A, Reig M, Vilana R, de Lope CR, Ayuso C, Bruix J: Cholangiocarcinoma in cirrhosis: absence of contrast washout in delayed phases by magnetic resonance imaging avoids misdiagnosis of hepatocellular carcinoma. Hepatology 2009;50:791-798.
  50. de Lope CR, Tremosini S, Forner A, Reig M, Bruix J: Management of HCC. J Hepatol 2012;56(suppl 1):S75-S87.
  51. Pomfret EA, Washburn K, Wald C, Nalesnik MA, Douglas D, Russo M, Roberts J, Reich DJ, Schwartz ME, Mieles L, Lee FT, Florman S, Yao F, Harper A, Edwards E, Freeman R, Lake J: Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl 2010;16:262-278.
  52. Ricke J, Seidensticker M, Mohnike K: Noninvasive diagnosis of hepatocellular carcinoma in cirrhotic liver: current guidelines and future prospects for radiological imaging. Liver Cancer 2012;1:51-58.
  53. Bota S, Piscaglia F, Marinelli S, Pecorelli A, Terzi E, Bolondi L: Comparison of international guidelines for noninvasive diagnosis of hepatocellular carcinoma. Liver Cancer 2012;1:190-200.
  54. Francis IR, Cohan RH, McNulty NJ, Platt JF, Korobkin M, Gebremariam A, Ragupathi KI: Multidetector CT of the liver and hepatic neoplasms: effect of multiphasic imaging on tumor conspicuity and vascular enhancement. AJR Am J Roentgenol 2003;180:1217-1224.
  55. Zhao H, Yao JL, Wang Y, Zhou KR: Detection of small hepatocellular carcinoma: comparison of dynamic enhancement magnetic resonance imaging and multiphase multirow-detector helical CT scanning. World J Gastroenterol 2007;13:1252-1256.
  56. Huang JS, Pan HB, Chou CP, Liang HL, Yeh LR, Yang TL, Liu SI: Optimizing scanning phases in detecting small (<2 cm) hepatocellular carcinoma: whole-liver dynamic study with multidetector row CT. J Comput Assist Tomogr 2008;32:341-346.
  57. Rode A, Bancel B, Douek P, Chevallier M, Vilgrain V, Picaud G, Henry L, Berger F, Bizollon T, Gaudin JL, Ducerf C: Small nodule detection in cirrhotic livers: evaluation with US, spiral CT, and MRI and correlation with pathologic examination of explanted liver. J Comput Assist Tomogr 2001;25:327-336.
  58. Yu MH, Lee JM, Yoon JH, Baek JH, Han JK, Choi BI, Flohr TG: Low tube voltage intermediate tube current liver MDCT: sinogram-affirmed iterative reconstruction algorithm for detection of hypervascular hepatocellular carcinoma. AJR Am J Roentgenol 2013;201:23-32.
  59. Hur S, Lee JM, Kim SJ, Park JH, Han JK, Choi BI: 80-kVp CT using Iterative Reconstruction in Image Space algorithm for the detection of hypervascular hepatocellular carcinoma: phantom and initial clinical experience. Korean J Radiol 2012;13:152-64.
  60. Sangiovanni A, Manini MA, Iavarone M, Romeo R, Forzenigo LV, Fraquelli M, Massironi S, Della Corte C, Ronchi G, Rumi MG, Biondetti P, Colombo M: The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 2010;59:638-644.
  61. Lim JH, Kim CK, Lee WJ, Park CK, Koh KC, Paik SW, Joh JW: Detection of hepatocellular carcinomas and dysplastic nodules in cirrhotic livers: accuracy of helical CT in transplant patients. AJR Am J Roentgenol 2000;175:693-698.
  62. Krinsky GA, Lee VS, Theise ND, Weinreb JC, Morgan GR, Diflo T, John D, Teperman LW, Goldenberg AS: Transplantation for hepatocellular carcinoma and cirrhosis: sensitivity of magnetic resonance imaging. Liver Transpl 2002;8:1156-1164.
  63. Zacherl J, Pokieser P, Wrba F, Scheuba C, Prokesch R, Zacherl M, Langle F, Berlakovich GA, Muhlbacher F, Steininger R: Accuracy of multiphasic helical computed tomography and intraoperative sonography in patients undergoing orthotopic liver transplantation for hepatoma: what is the truth? Annals Surg 2002;235:528-532.
  64. Kim SH, Choi BI, Lee JY, Kim SJ, So YH, Eun HW, Lee JM, Han JK: Diagnostic accuracy of multi-/single-detector row CT and contrast-enhanced MRI in the detection of hepatocellular carcinomas meeting the Milan criteria before liver transplantation. Intervirology 2008;51(suppl 1):52-60.
  65. Lee JM, Yoon JH, Kim KW: Diagnosis of hepatocellular carcinoma: newer radiological tools. Semin Oncol 2012;39:399-409.
  66. Mita K, Kim SR, Kudo M, Imoto S, Nakajima T, Ando K, Fukuda K, Matsuoka T, Maekawa Y, Hayashi Y: Diagnostic sensitivity of imaging modalities for hepatocellular carcinoma smaller than 2 cm. World J Gastroenterol 2010;16:4187-4192.
  67. Salvaggio G, Campisi A, Lo Greco V, Cannella I, Meloni MF, Caruso G: Evaluation of posttreatment response of hepatocellular carcinoma: comparison of ultrasonography with second-generation ultrasound contrast agent and multidetector CT. Abdom Imaging 2010;35:447-453.
  68. Donadon M, Torzilli G: Intraoperative ultrasound in patients with hepatocellular carcinoma: from daily practice to future trends. Liver Cancer 2013;2:16-24.
  69. Joo I, Choi BI: New paradigm for management of hepatocellular carcinoma by imaging. Liver Cancer 2012;1:94-109.
  70. Jang HJ, Kim TK, Wilson SR: Imaging of malignant liver masses: characterization and detection. Ultrasound Q 2006;22:19-29.
    External Resources
  71. Kim AY, Lee MW, Rhim H, Cha DI, Choi D, Kim YS, Lim HK, Cho SW: Pretreatment evaluation with contrast-enhanced ultrasonography for percutaneous radiofrequency ablation of hepatocellular carcinomas with poor conspicuity on conventional ultrasonography. Korean J Radiol 2013;14:754-763.
  72. Park JW, Kim JH, Kim SK, Kang KW, Park KW, Choi JI, Lee WJ, Kim CM, Nam BH: A prospective evaluation of 18F-FDG and 11C-acetate PET/CT for detection of primary and metastatic hepatocellular carcinoma. J Nucl Med 2008;49:1912-1921.
  73. Granito A, Galassi M, Piscaglia F, Romanini L, Lucidi V, Renzulli M, Borghi A, Grazioli L, Golfieri R, Bolondi L: Impact of gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance on the non-invasive diagnosis of small hepatocellular carcinoma: a prospective study. Aliment Pharmacol Ther 2013;37:355-363.
  74. Haradome H, Grazioli L, Tinti R, Morone M, Motosugi U, Sano K, Ichikawa T, Kwee TC, Colagrande S: Additional value of gadoxetic acid-DTPA-enhanced hepatobiliary phase MR imaging in the diagnosis of early-stage hepatocellular carcinoma: comparison with dynamic triple-phase multidetector CT imaging. J Magn Reson Imaging 2011;34:69-78.
  75. Holzapfel K, Eiber MJ, Fingerle AA, Bruegel M, Rummeny EJ, Gaa J: Detection, classification, and characterization of focal liver lesions: value of diffusion-weighted MR imaging, gadoxetic acid-enhanced MR imaging and the combination of both methods. Abdom Imaging 2012;37:74-82.
  76. Iannicelli E, Di Pietropaolo M, Marignani M, Briani C, Federici GF, Delle Fave G, David V: Gadoxetic acid-enhanced MRI for hepatocellular carcinoma and hypointense nodule observed in the hepatobiliary phase. Radiol Med 2014;119:367-376.
  77. Kim JE, Kim SH, Lee SJ, Rhim H: Hypervascular hepatocellular carcinoma 1 cm or smaller in patients with chronic liver disease: characterization with gadoxetic acid-enhanced MRI that includes diffusion-weighted imaging. AJR Am J Roentgenol 2011;196:W758-W765.
  78. Kim SH, Kim SH, Lee J, Kim MJ, Jeon YH, Park Y, Choi D, Lee WJ, Lim HK: Gadoxetic acid-enhanced MRI versus triple-phase MDCT for the preoperative detection of hepatocellular carcinoma. AJR Am J Roentgenol 2009;192:1675-1681.
  79. Kim YK, Lee MW, Lee WJ, Kim SH, Rhim H, Lim JH, Choi D, Kim YS, Jang KM, Lee SJ, Lim HK: Diagnostic accuracy and sensitivity of diffusion-weighted and of gadoxetic acid-enhanced 3-T MR imaging alone or in combination in the detection of small liver metastasis (≤ 1.5 cm in diameter). Invest Radiol 2012;47:159-166.
    External Resources
  80. Park MJ, Kim YK, Lee MH, Lee JH: Validation of diagnostic criteria using gadoxetic acid-enhanced and diffusion-weighted MR imaging for small hepatocellular carcinoma (<= 2.0 cm) in patients with hepatitis-induced liver cirrhosis. Acta Radiol 2013;54:127-136.
  81. Sun HY, Lee JM, Shin CI, Lee DH, Moon SK, Kim KW, Han JK, Choi BI: Gadoxetic acid-enhanced magnetic resonance imaging for differentiating small hepatocellular carcinomas (< or = 2 cm in diameter) from arterial enhancing pseudolesions: special emphasis on hepatobiliary phase imaging. Invest Radiol 2010;45:96-103.
  82. Park G, Kim YK, Kim CS, Yu HC, Hwang SB: Diagnostic efficacy of gadoxetic acid-enhanced MRI in the detection of hepatocellular carcinomas: comparison with gadopentetate dimeglumine. Br J Radiol 2010;83:1010-1016.
  83. Park MJ, Kim YK, Lee MW, Lee WJ, Kim YS, Kim SH, Choi D, Rhim H: Small hepatocellular carcinomas: improved sensitivity by combining gadoxetic acid-enhanced and diffusion-weighted MR imaging patterns. Radiology 2012;264:761-770.
  84. Hyodo T, Murakami T, Imai Y, Okada M, Hori M, Kagawa Y, Kogita S, Kumano S, Kudo M, Mochizuki T: Hypovascular nodules in patients with chronic liver disease: risk factors for development of hypervascular hepatocellular carcinoma. Radiology 2013;266:480-490.
  85. Kim YK, Lee WJ, Park MJ, Kim SH, Rhim H, Choi D: Hypovascular hypointense nodules on hepatobiliary phase gadoxetic acid-enhanced MR images in patients with cirrhosis: potential of DW imaging in predicting progression to hypervascular HCC. Radiology 2012;265:104-114.
  86. Kobayashi S, Matsui O, Gabata T, Koda W, Minami T, Ryu Y, Kozaka K, Kitao A: Relationship between signal intensity on hepatobiliary phase of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced MR imaging and prognosis of borderline lesions of hepatocellular carcinoma. Eur J Radiol 2012;81:3002-3009.
  87. Kumada T, Toyoda H, Tada T, Sone Y, Fujimori M, Ogawa S, Ishikawa T: Evolution of hypointense hepatocellular nodules observed only in the hepatobiliary phase of gadoxetate disodium-enhanced MRI. AJR Am J Roentgenol 2011;197:58-63.
  88. Takayama Y, Nishie A, Nakayama T, Asayama Y, Ishigami K, Kakihara D, Ushijima Y, Fujita N, Hirakawa M, Honda H: Hypovascular hepatic nodule showing hypointensity in the hepatobiliary phase of gadoxetic acid-enhanced MRI in patients with chronic liver disease: prediction of malignant transformation. Eur J Radiol 2012;81:3072-3078.
  89. Murakami T, Tsurusaki M: Hypervascular benign and malignant liver tumors that require differentiation from hepatocellular carcinoma: key points of imaging diagnosis. Liver Cancer 2014;3:85-96.
  90. Ichikawa T, Sano K, Morisaka H: Diagnosis of pathologically early HCC with EOB-MRI: experiences and current consensus. Liver Cancer 2014;3:97-107.
  91. Kudo M: Will Gd-EOB-MRI change the diagnostic algorithm in hepatocellular carcinoma? Oncology 2010;78(suppl 1):87-93.
  92. Lee JM, Choi BI: Hepatocellular nodules in liver cirrhosis: MR evaluation. Abdom Imaging 2011;36:282-289.
  93. Cruite I, Schroeder M, Merkle EM, Sirlin CB: Gadoxetate disodium-enhanced MRI of the liver: part 2, protocol optimization and lesion appearance in the cirrhotic liver. AJR Am J Roentgenol 2010;195:29-41.
  94. Hwang SH, Yu JS, Kim KW, Kim JH, Chung JJ: Small hypervascular enhancing lesions on arterial phase images of multiphase dynamic computed tomography in cirrhotic liver: fate and implications. J Comput Assist Tomogr 2008;32:39-45.
  95. Lau DT, Everhart J, Kleiner DE, Park Y, Vergalla J, Schmid P, Hoofnagle JH: Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology 1997;113:1660-1667.
  96. Kim TK, Lee KH, Jang HJ, Haider MA, Jacks LM, Menezes RJ, Park SH, Yazdi L, Sherman M, Khalili K: 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;259:730-738.
  97. Rimola J, Forner A, Tremosini S, Reig M, Vilana R, Bianchi L, Rodriguez-Lope C, Sole M, Ayuso C, Bruix J: Non-invasive diagnosis of hepatocellular carcinoma ≤ 2 cm in cirrhosis. Diagnostic accuracy assessing fat, capsule and signal intensity at dynamic MRI. J Hepatol 2012;56:1317-1323.
  98. 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;32:360-366.
  99. 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;11:281-289.
  100. 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;105:599-609.
  101. Arif-Tiwari H, Kalb B, Chundru S, Sharma P, Costello J, Guessner RW, Martin DR: MRI of hepatocellular carcinoma: an update of current practices. Diagn Interv Radiol 2014;20:209-221.
  102. Davenport MS, Khalatbari S, Liu PS, Maturen KE, Kaza RK, Wasnik AP, Al-Hawary MM, Glazer DI, Stein EB, Patel J, Somashekar DK, Viglianti BL, Hussain HK: Repeatability of diagnostic features and scoring systems for hepatocellular carcinoma by using MR imaging. Radiology 2014;272:132-142.
  103. Jha RC, Mitchell DG, Weinreb JC, Santillan CS, Yeh BM, Francois R, Sirlin CB: LI-RADS categorization of benign and likely benign findings in patients at risk of hepatocellular carcinoma: a pictorial atlas. AJR Am J Roentgenol 2014;203:W48-W69.
  104. Purysko AS, Remer EM, Coppa CP, Leao Filho HM, Thupili CR, Veniero JC: LI-RADS: a case-based review of the new categorization of liver findings in patients with end-stage liver disease. Radiographics 2012;32:1977-1995.
  105. Jang KM, Kim SH, Kim YK, Choi D: Imaging features of subcentimeter hypointense nodules on gadoxetic acid-enhanced hepatobiliary phase MR imaging that progress to hypervascular hepatocellular carcinoma in patients with chronic liver disease. Acta Radiol 2014, Epub ahead of print.
  106. Kim HS, Choi D, Kim SH, Lee MW, Lee WJ, Kim YK, Jang KM, Park MJ, Park CK: Changes in the signal- and contrast-to-noise ratios of hepatocellular carcinomas on gadoxetic acid-enhanced dynamic MR imaging. Eur J Radiol 2013;82:62-68.
  107. Simon G, Link TM, Wortler K, Doebereiner F, Schulte-Frohlinde E, Daldrup-Link H, Settles M, Rummeny EJ: Detection of hepatocellular carcinoma: comparison of Gd-DTPA- and ferumoxides-enhanced MR imaging. Eur Radiol 2005;15:895-903.
  108. Akai H, Kiryu S, Matsuda I, Satou J, Takao H, Tajima T, Watanabe Y, Imamura H, Kokudo N, Akahane M, Ohtomo K: Detection of hepatocellular carcinoma by Gd-EOB-DTPA-enhanced liver MRI: comparison with triple phase 64 detector row helical CT. Eur J Radiol 2011;80:310-315.
  109. Bashir MR, Gupta RT, Davenport MS, Allen BC, Jaffe TA, Ho LM, Boll DT, Merkle EM: Hepatocellular carcinoma in a North American population: does hepatobiliary MR imaging with Gd-EOB-DTPA improve sensitivity and confidence for diagnosis? J Magn Reson Imaging 2013;37:398-406.
  110. Kim YK, Kim CS, Han YM, Park G: Detection of small hepatocellular carcinoma: can gadoxetic acid-enhanced magnetic resonance imaging replace combining gadopentetate dimeglumine-enhanced and superparamagnetic iron oxide-enhanced magnetic resonance imaging? Invest Radiol 2010;45:740-746.
  111. Narita M, Hatano E, Arizono S, Miyagawa-Hayashino A, Isoda H, Kitamura K, Taura K, Yasuchika K, Nitta T, Ikai I, Uemoto S: Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma. J Gastroenterol 2009;44:793-798.
  112. Kitao A, Zen Y, Matsui O, Gabata T, Kobayashi S, Koda W, Kozaka K, Yoneda N, Yamashita T, Kaneko S, Nakanuma Y: Hepatocellular carcinoma: signal intensity at gadoxetic acid-enhanced MR imaging - correlation with molecular transporters and histopathologic features. Radiology 2010;256:817-826.
  113. Tanimoto A, Kuwatsuru R, Kadoya M, Ohtomo K, Hirohashi S, Murakami T, Hiramatsu K, Yoshikawa K, Katayama H: Evaluation of gadobenate dimeglumine in hepatocellular carcinoma: results from phase II and phase III clinical trials in Japan. J Magn Reson Imaging 1999;10:450-460.
  114. Marin D, Di Martino M, Guerrisi A, De Filippis G, Rossi M, Ginanni Corradini S, Masciangelo R, Catalano C, Passariello R: Hepatocellular carcinoma in patients with cirrhosis: qualitative comparison of gadobenate dimeglumine-enhanced MR imaging and multiphasic 64-section CT. Radiology 2009;251:85-95.
  115. Inoue T, Hyodo T, Murakami T, Takayama Y, Nishie A, Higaki A, Korenaga K, Sakamoto A, Osaki Y, Aikata H, Chayama K, Suda T, Takano T, Miyoshi K, Koda M, Numata K, Tanaka H, Iijima H, Ochi H, Hirooka M, Imai Y, Kudo M: Hypovascular hepatic nodules showing hypointense on the hepatobiliary-phase image of Gd-EOB-DTPA- enhanced MRI to develop a hypervascular hepatocellular carcinoma: a nationwide retrospective study on their natural course and risk factors. Dig Dis 2013;31:472-479.
  116. Motosugi U: Hypovascular hypointense nodules on hepatocyte phase gadoxetic acid-enhanced MR images: too early or too progressed to determine hypervascularity. Radiology 2013;267:317-318.
  117. Chou CT, Chen YL, Su WW, Wu HK, Chen RC: Characterization of cirrhotic nodules with gadoxetic acid-enhanced magnetic resonance imaging: the efficacy of hepatocyte-phase imaging. J Magn Reson Imaging 2010;32:895-902.
  118. Golfieri R, Renzulli M, Lucidi V, Corcioni B, Trevisani F, Bolondi L: Contribution of the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI to dynamic MRI in the detection of hypovascular small (≤ 2 cm) HCC in cirrhosis. Eur Radiol 2011;21:1233-1242.
  119. Chen WX, Min PQ, Song B, Xiao BL, Liu Y, Ge YH: Single-level dynamic spiral CT of hepatocellular carcinoma: correlation between imaging features and density of tumor microvessels. World J Gastroenterol 2004;10:67-72.
    External Resources
  120. Grazioli L, Olivetti L, Fugazzola C, Benetti A, Stanga C, Dettori E, Gallo C, Matricardi L, Giacobbe A, Chiesa A: The pseudocapsule in hepatocellular carcinoma: correlation between dynamic MR imaging and pathology. Eur Radiol 1999;9:62-67.
  121. Ishigami K, Yoshimitsu K, Nishihara Y, Irie H, Asayama Y, Tajima T, Nishie A, Hirakawa M, Ushijima Y, Okamoto D, Taketomi A, Honda H: Hepatocellular carcinoma with a pseudocapsule on gadolinium-enhanced MR images: correlation with histopathologic findings. Radiology 2009;250:435-443.
  122. Lee MH, Kim SH, Park MJ, Park CK, Rhim H: Gadoxetic acid-enhanced hepatobiliary phase MRI and high-b-value diffusion-weighted imaging to distinguish well-differentiated hepatocellular carcinomas from benign nodules in patients with chronic liver disease. AJR Am J Roentgenol 2011;197:W868-W875.
  123. Nakamura Y, Toyota N, Date S, Oda S, Namimoto T, Yamashita Y, Beppu T, Awai K: Clinical significance of the transitional phase at gadoxetate disodium-enhanced hepatic MRI for the diagnosis of hepatocellular carcinoma: preliminary results. J Comput Assist Tomogr 2011;35:723-727.
  124. Chong YS, Kim YK, Lee MW, Kim SH, Lee WJ, Rhim HC, Lee SJ: Differentiating mass-forming intrahepatic cholangiocarcinoma from atypical hepatocellular carcinoma using gadoxetic acid-enhanced MRI. Clin Radiol 2012;67:766-773.
  125. Park HJ, Kim YK, Park MJ, Lee WJ: Small intrahepatic mass-forming cholangiocarcinoma: target sign on diffusion-weighted imaging for differentiation from hepatocellular carcinoma. Abdom Imaging 2013;38:793-801.
  126. Pradella S, Lucarini S, Colagrande S: Liver lesion characterization: the wrong choice of contrast agent can mislead the diagnosis of hemangioma. AJR Am J Roentgenol 2012;199:W662.
  127. Tanimoto A, Lee JM, Murakami T, Huppertz A, Kudo M, Grazioli L: Consensus report of the 2nd International Forum for Liver MRI. Eur Radiol 2009;19(suppl 5):S975-S989.
  128. Bruegel M, Holzapfel K, Gaa J, Woertler K, Waldt S, Kiefer B, Stemmer A, Ganter C, Rummeny EJ: Characterization of focal liver lesions by ADC measurements using a respiratory triggered diffusion-weighted single-shot echo-planar MR imaging technique. Eur Radiol 2008;18:477-485.
  129. Haradome H, Grazioli L, Morone M, Gambarini S, Kwee TC, Takahara T, Colagrande S: T2-weighted and diffusion-weighted MRI for discriminating benign from malignant focal liver lesions: diagnostic abilities of single versus combined interpretations. J Magn Reson Imaging 2012;35:1388-1396.
  130. Toyoda H, Kumada T, Tada T, Niinomi T, Ito T, Sone Y, Kaneoka Y, Maeda A: Non-hypervascular hypointense nodules detected by Gd-EOB-DTPA-enhanced MRI are a risk factor for recurrence of HCC after hepatectomy. J Hepatol 2013;58:1174-1180.
  131. Yamamoto A, Ito K, Tamada T, Higaki A, Kanki A, Sato T, Tanimoto D: Newly developed hypervascular hepatocellular carcinoma during follow-up periods in patients with chronic liver disease: observation in serial gadoxetic acid-enhanced MRI. AJR Am J Roentgenol 2013;200:1254-1260.
  132. Sano K, Ichikawa T, Motosugi U, Sou H, Muhi AM, Matsuda M, Nakano M, Sakamoto M, Nakazawa T, Asakawa M, Fujii H, Kitamura T, Enomoto N, Araki T: Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid-enhanced MR imaging. Radiology 2011;261:834-844.
  133. Bartolozzi C, Battaglia V, Bargellini I, Bozzi E, Campani D, Pollina LE, Filipponi F: Contrast-enhanced magnetic resonance imaging of 102 nodules in cirrhosis: correlation with histological findings on explanted livers. Abdom Imaging 2013;38:290-296.
  134. Takechi M, Tsuda T, Yoshioka S, Murata S, Tanaka H, Hirooka M, Mochizuki T: Risk of hypervascularization in small hypovascular hepatic nodules showing hypointense in the hepatobiliary phase of gadoxetic acid-enhanced MRI in patients with chronic liver disease. Jpn J Radiol 2012;30:743-751.
  135. Matsui O: Detection and characterization of hepatocellular carcinoma by imaging. Clin Gastroenterol Hepatol 2005;3(10 suppl 2):S136-S140.
  136. Piscaglia F, Bolondi L: Recent advances in the diagnosis of hepatocellular carcinoma. Hepatol Res 2007;37(suppl 2):S178-S192.
  137. Lee J, Lee WJ, Lim HK, Lim JH, Choi N, Park MH, Kim SW, Park CK: Early hepatocellular carcinoma: three-phase helical CT features of 16 patients. Korean J Radiol 2008;9:325-332.
  138. Lee JH, Lee JM, Kim SJ, Baek JH, Yun SH, Kim KW, Han JK, Choi BI: Enhancement patterns of hepatocellular carcinomas on multiphasic multidetector row CT: comparison with pathological differentiation. Br J Radiol 2012;85:e573-e583.
  139. Yoon SH, Lee JM, So YH, Hong SH, Kim SJ, Han JK, Choi BI: Multiphasic MDCT enhancement pattern of hepatocellular carcinoma smaller than 3 cm in diameter: tumor size and cellular differentiation. AJR Am J Roentgenol 2009;193:W482-W489.
  140. Yu MH, Kim JH, Yoon JH, Kim HC, Chung JW, Han JK, Choi BI: Small (≤1-cm) hepatocellular carcinoma: diagnostic performance and imaging features at gadoxetic acid-enhanced MR imaging. Radiology 2014;271:748-760.
  141. Golfieri R, Marini E, Bazzocchi A, Fusco F, Trevisani F, Sama C, Mazzella G, Cavuto S, Piscaglia F, Bolondi L: Small (< or = 3 cm) hepatocellular carcinoma in cirrhosis: the role of double contrast agents in MR imaging versus multidetector-row CT. Radiol Med 2009;114:1239-1266.
  142. Bae SY, Choi MS, Gwak GY, Paik YH, Lee JH, Koh KC, Paik SW, Yoo BC: Comparison of usefulness of clinical diagnostic criteria for hepatocellular carcinoma in a hepatitis B endemic area. Clin Mol Hepatol 2012;18:185-194.
  143. Moon JI, Kwon CH, Joh JW, Choi GS, Jung GO, Kim JM, Shin M, Choi SJ, Kim SJ, Lee SK: Primary versus salvage living donor liver transplantation for patients with hepatocellular carcinoma: impact of microvascular invasion on survival. Transplant Proc 2012;44:487-493.
  144. Kojiro M: Pathological diagnosis at early stage: reaching international consensus. Oncology 2010;78(suppl 1):31-35.
  145. 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;57:1592-1596.

Author Contacts

Byung Ihn Choi, MD

Department of Radiology and Institute of Radiation Medicine

Seoul National University College of Medicine

101 Daehak-ro, Jongno-gu, Seoul 110-744 (Korea)

E-Mail bichoi@snu.ac.kr


Article / Publication Details

First-Page Preview
Abstract of Review Article

Published online: October 29, 2014
Issue release date: October 2014

Number of Print Pages: 14
Number of Figures: 1
Number of Tables: 2

ISSN: 0257-2753 (Print)
eISSN: 1421-9875 (Online)

For additional information: https://www.karger.com/DDI


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. El-Serag HB: Hepatocellular carcinoma. N Engl J Med 2011;365:1118-1127.
  2. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-2917.
  3. Kim DY, Han KH: Epidemiology and surveillance of hepatocellular carcinoma. Liver Cancer 2012;1:2-14.
  4. Kudo M: Diagnostic imaging of hepatocellular carcinoma: recent progress. Oncology 2011;81(suppl 1):73-85.
  5. Stigliano R, Marelli L, Yu D, Davies N, Patch D, Burroughs AK: Seeding following percutaneous diagnostic and therapeutic approaches for hepatocellular carcinoma. What is the risk and the outcome? Seeding risk for percutaneous approach of HCC. Cancer Treat Rev 2007;33:437-447.
  6. Kudo M: Multistep human hepatocarcinogenesis: correlation of imaging with pathology. J Gastroenterol 2009;44(suppl 19):112-118.
  7. Matsui O, Kobayashi S, Sanada J, Kouda W, Ryu Y, Kozaka K, Kitao A, Nakamura K, Gabata T: Hepatocellular nodules in liver cirrhosis: hemodynamic evaluation (angiography-assisted CT) with special reference to multi-step hepatocarcinogenesis. Abdom Imaging 2011;36:264-272.
  8. Lee JM, Trevisani F, Vilgrain V, Wald C: Imaging diagnosis and staging of hepatocellular carcinoma. Liver Transpl 2011;17(suppl 2):S34-S43.
  9. Burrel M, Llovet JM, Ayuso C, Iglesias C, Sala M, Miquel R, Caralt T, Ayuso JR, Solé M, Sanchez M, Brú C, Bruix J; Barcelona Clinic Liver Cancer Group: MRI angiography is superior to helical CT for detection of HCC prior to liver transplantation: an explant correlation. Hepatology 2003;38:1034-1042.
  10. Krinsky GA, Lee VS, Theise ND, Weinreb JC, Rofsky NM, Diflo T, Teperman LW: Hepatocellular carcinoma and dysplastic nodules in patients with cirrhosis: prospective diagnosis with MR imaging and explantation correlation. Radiology 2001;219:445-454.
  11. Kim YK, Kim CS, Chung GH, Han YM, Lee SY, Chon SB, Lee JM: Comparison of gadobenate dimeglumine-enhanced dynamic MRI and 16-MDCT for the detection of hepatocellular carcinoma. AJR Am J Roentgenol 2006;186:149-157.
  12. Lee JM, Yoon JH, Joo I, Woo HS: Recent advances in CT and MR imaging for evaluation of hepatocellular carcinoma. Liver Cancer 2012;1:22-40.
  13. Kudo M: Early hepatocellular carcinoma: definition and diagnosis. Liver Cancer 2013;2:69-72.
  14. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, Pagliaro L, Colombo M, Rodes J: Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001;35:421-430.
  15. European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer: EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908-943.
    External Resources
  16. Mitchell DG, Bruix J, Sherman M, Sirlin CB: LI-RADS (Liver Imaging Reporting and Data System): Summary, discussion, consensus of the LI-RADS Management Working Group and future directions. Hepatology 2014, Epub ahead of print.
  17. 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;266:376-382.
  18. Omata M, Lesmana LA, Tateishi R, Chen PJ, Lin SM, Yoshida H, Kudo M, Lee JM, Choi BI, Poon RT, Shiina S, Cheng AL, Jia JD, Obi S, Han KH, Jafri W, Chow P, Lim SG, Chawla YK, Budihusodo U, Gani RA, Lesmana CR, Putranto TA, Liaw YF, Sarin SK: Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. Hepatol Int 2010;4:439-474.
  19. Kudo M, Izumi N, Kokudo N, Matsui O, Sakamoto M, Nakashima O, Kojiro M, Makuuchi M; 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;29:339-364.
  20. Korean Liver Cancer Study Group and National Cancer Center, Korea: Practice guidelines for management of hepatocellular carcinoma 2009 (in Korean). Korean J Hepatol 2009;15:391-423.
  21. Forner A, Vilana R, Ayuso C, Bianchi L, Sole M, Ayuso JR, Boix L, Sala M, Varela M, Llovet JM, Bru C, Bruix J: Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology 2008;47:97-104.
  22. Lin MT, Chang KC, Tseng PL, Yen YH, Wang CC, Tsai MC, Cheng YF, Eng HL, Wu CK, Hu TH: The validation of 2010 AASLD guideline for the diagnosis of hepatocellular carcinoma in an endemic area. J Gastroenterol Hepatol 2014, Epub ahead of print.
  23. Minagawa M, Ikai I, Matsuyama Y, Yamaoka Y, Makuuchi M: Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan. Ann Surg 2007;245:909-922.
  24. Tang A, Cruite I, Sirlin CB: Toward a standardized system for hepatocellular carcinoma diagnosis using computed tomography and MRI. Expert Rev Gastroenterol Hepatol 2013;7:269-279.
  25. Bruix J, Sherman M: Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020-1022.
  26. Song do S, Bae SH: Changes of guidelines diagnosing hepatocellular carcinoma during the last ten-year period. Clin Mol Hepatol 2012;18:258-267.
  27. Park JW; Korean Liver Cancer Study Group and National Cancer Center: Practice guideline for diagnosis and treatment of hepatocellular carcinoma (in Korean). Korean J Hepatol 2004;10:88-98.
    External Resources
  28. Ahn SS, Kim MJ, Lim JS, Hong HS, Chung YE, Choi JY: Added value of gadoxetic acid-enhanced hepatobiliary phase MR imaging in the diagnosis of hepatocellular carcinoma. Radiology 2010;255:459-466.
  29. Choi JW, Lee JM, Kim SJ, Yoon JH, Baek JH, Han JK, Choi BI: Hepatocellular carcinoma: imaging patterns on gadoxetic acid-enhanced MR images and their value as an imaging biomarker. Radiology 2013;267:776-786.
  30. Choi JY, Lee JM, Sirlin CB: CT and MR imaging diagnosis and staging of hepatocellular carcinoma: part II. Extracellular agents, hepatobiliary agents, and ancillary imaging features. Radiology 2014;273:30-50.
  31. Sugimoto K, Moriyasu F, Saito K, Taira J, Saguchi T, Yoshimura N, Oshiro H, Imai Y, Shiraishi J: Comparison of Kupffer-phase Sonazoid-enhanced sonography and hepatobiliary-phase gadoxetic acid-enhanced magnetic resonance imaging of hepatocellular carcinoma and correlation with histologic grading. J Ultrasound Med 2012;31:529-538.
    External Resources
  32. Hatfield MK, Beres RA, Sane SS, Zaleski GX: Percutaneous imaging-guided solid organ core needle biopsy: coaxial versus noncoaxial method. AJR Am J Roentgenol 2008;190:413-417.
  33. Singal A, Volk ML, Waljee A, Salgia R, Higgins P, Rogers MA, Marrero JA: Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther 2009;30:37-47.
  34. 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;6:1418-1424.
  35. Zhang BH, Yang BH, Tang ZY: Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;130:417-422.
  36. Wong GL, Chan HL, Tse YK, Chan HY, Tse CH, Lo AO, Wong VW: On-treatment alpha-fetoprotein is a specific tumor marker for hepatocellular carcinoma in patients with chronic hepatitis B receiving entecavir. Hepatology 2014;59:986-995.
  37. Bartolozzi C, Crocetti L, Lencioni R, Cioni D, Della Pina C, Campani D: Biliary and reticuloendothelial impairment in hepatocarcinogenesis: the diagnostic role of tissue-specific MR contrast media. Eur Radiol 2007;17:2519-2530.
  38. Coleman WB: Mechanisms of human hepatocarcinogenesis. Curr Mol Med 2003;3:573-588.
  39. Effendi K, Sakamoto M: Molecular pathology in early hepatocarcinogenesis. Oncology 2010;78:157-160.
  40. Efremidis SC, Hytiroglou P: The multistep process of hepatocarcinogenesis in cirrhosis with imaging correlation. Eur Radiol 2002;12:753-764.
  41. Kitao A, Matsui O, Yoneda N, Kozaka K, Shinmura R, Koda W, Kobayashi S, Gabata T, Zen Y, Yamashita T: The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging. Eur Radiol 2011;21:2056-2066.
  42. Kitao A, Zen Y, Matsui O, Gabata T, Nakanuma Y: Hepatocarcinogenesis: multistep changes of drainage vessels at CT during arterial portography and hepatic arteriography - radiologic-pathologic correlation. Radiology 2009;252:605-614.
  43. Park YN, Kim MJ: Hepatocarcinogenesis: imaging-pathologic correlation. Abdom Imaging 2011;36:232-243.
  44. Lee JM, Zech CJ, Bolondi L, Jonas E, Kim MJ, Matsui O, Merkle EM, Sakamoto M, Choi BI: Consensus report of the 4th International Forum for Gadolinium-Ethoxybenzyl-Diethylenetriamine Pentaacetic Acid Magnetic Resonance Imaging. Korean J Radiol 2011;12:403-415.
  45. Ito K, Honjo K, Fujita T, Awaya H, Matsumoto T, Matsunaga N, Higuchi M, Kada T, Mattrey RF: Liver neoplasms: diagnostic pitfalls in cross-sectional imaging. Radiographics 1996;16:273-293.
  46. Kang Y, Lee JM, Kim SH, Han JK, Choi BI: Intrahepatic mass-forming cholangiocarcinoma: enhancement patterns on gadoxetic acid-enhanced MR images. Radiology 2012;264:751-760.
  47. Kim SA, Lee JM, Lee KB, Kim SH, Yoon SH, Han JK, Choi BI: Intrahepatic mass-forming cholangiocarcinomas: enhancement patterns at multiphasic CT, with special emphasis on arterial enhancement pattern - correlation with clinicopathologic findings. Radiology 2011;260:148-157.
  48. Kim SJ, Lee JM, Han JK, Kim KH, Lee JY, Choi BI: Peripheral mass-forming cholangiocarcinoma in cirrhotic liver. AJR Am J Roentgenol 2007;189:1428-1434.
  49. Rimola J, Forner A, Reig M, Vilana R, de Lope CR, Ayuso C, Bruix J: Cholangiocarcinoma in cirrhosis: absence of contrast washout in delayed phases by magnetic resonance imaging avoids misdiagnosis of hepatocellular carcinoma. Hepatology 2009;50:791-798.
  50. de Lope CR, Tremosini S, Forner A, Reig M, Bruix J: Management of HCC. J Hepatol 2012;56(suppl 1):S75-S87.
  51. Pomfret EA, Washburn K, Wald C, Nalesnik MA, Douglas D, Russo M, Roberts J, Reich DJ, Schwartz ME, Mieles L, Lee FT, Florman S, Yao F, Harper A, Edwards E, Freeman R, Lake J: Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl 2010;16:262-278.
  52. Ricke J, Seidensticker M, Mohnike K: Noninvasive diagnosis of hepatocellular carcinoma in cirrhotic liver: current guidelines and future prospects for radiological imaging. Liver Cancer 2012;1:51-58.
  53. Bota S, Piscaglia F, Marinelli S, Pecorelli A, Terzi E, Bolondi L: Comparison of international guidelines for noninvasive diagnosis of hepatocellular carcinoma. Liver Cancer 2012;1:190-200.
  54. Francis IR, Cohan RH, McNulty NJ, Platt JF, Korobkin M, Gebremariam A, Ragupathi KI: Multidetector CT of the liver and hepatic neoplasms: effect of multiphasic imaging on tumor conspicuity and vascular enhancement. AJR Am J Roentgenol 2003;180:1217-1224.
  55. Zhao H, Yao JL, Wang Y, Zhou KR: Detection of small hepatocellular carcinoma: comparison of dynamic enhancement magnetic resonance imaging and multiphase multirow-detector helical CT scanning. World J Gastroenterol 2007;13:1252-1256.
  56. Huang JS, Pan HB, Chou CP, Liang HL, Yeh LR, Yang TL, Liu SI: Optimizing scanning phases in detecting small (<2 cm) hepatocellular carcinoma: whole-liver dynamic study with multidetector row CT. J Comput Assist Tomogr 2008;32:341-346.
  57. Rode A, Bancel B, Douek P, Chevallier M, Vilgrain V, Picaud G, Henry L, Berger F, Bizollon T, Gaudin JL, Ducerf C: Small nodule detection in cirrhotic livers: evaluation with US, spiral CT, and MRI and correlation with pathologic examination of explanted liver. J Comput Assist Tomogr 2001;25:327-336.
  58. Yu MH, Lee JM, Yoon JH, Baek JH, Han JK, Choi BI, Flohr TG: Low tube voltage intermediate tube current liver MDCT: sinogram-affirmed iterative reconstruction algorithm for detection of hypervascular hepatocellular carcinoma. AJR Am J Roentgenol 2013;201:23-32.
  59. Hur S, Lee JM, Kim SJ, Park JH, Han JK, Choi BI: 80-kVp CT using Iterative Reconstruction in Image Space algorithm for the detection of hypervascular hepatocellular carcinoma: phantom and initial clinical experience. Korean J Radiol 2012;13:152-64.
  60. Sangiovanni A, Manini MA, Iavarone M, Romeo R, Forzenigo LV, Fraquelli M, Massironi S, Della Corte C, Ronchi G, Rumi MG, Biondetti P, Colombo M: The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 2010;59:638-644.
  61. Lim JH, Kim CK, Lee WJ, Park CK, Koh KC, Paik SW, Joh JW: Detection of hepatocellular carcinomas and dysplastic nodules in cirrhotic livers: accuracy of helical CT in transplant patients. AJR Am J Roentgenol 2000;175:693-698.
  62. Krinsky GA, Lee VS, Theise ND, Weinreb JC, Morgan GR, Diflo T, John D, Teperman LW, Goldenberg AS: Transplantation for hepatocellular carcinoma and cirrhosis: sensitivity of magnetic resonance imaging. Liver Transpl 2002;8:1156-1164.
  63. Zacherl J, Pokieser P, Wrba F, Scheuba C, Prokesch R, Zacherl M, Langle F, Berlakovich GA, Muhlbacher F, Steininger R: Accuracy of multiphasic helical computed tomography and intraoperative sonography in patients undergoing orthotopic liver transplantation for hepatoma: what is the truth? Annals Surg 2002;235:528-532.
  64. Kim SH, Choi BI, Lee JY, Kim SJ, So YH, Eun HW, Lee JM, Han JK: Diagnostic accuracy of multi-/single-detector row CT and contrast-enhanced MRI in the detection of hepatocellular carcinomas meeting the Milan criteria before liver transplantation. Intervirology 2008;51(suppl 1):52-60.
  65. Lee JM, Yoon JH, Kim KW: Diagnosis of hepatocellular carcinoma: newer radiological tools. Semin Oncol 2012;39:399-409.
  66. Mita K, Kim SR, Kudo M, Imoto S, Nakajima T, Ando K, Fukuda K, Matsuoka T, Maekawa Y, Hayashi Y: Diagnostic sensitivity of imaging modalities for hepatocellular carcinoma smaller than 2 cm. World J Gastroenterol 2010;16:4187-4192.
  67. Salvaggio G, Campisi A, Lo Greco V, Cannella I, Meloni MF, Caruso G: Evaluation of posttreatment response of hepatocellular carcinoma: comparison of ultrasonography with second-generation ultrasound contrast agent and multidetector CT. Abdom Imaging 2010;35:447-453.
  68. Donadon M, Torzilli G: Intraoperative ultrasound in patients with hepatocellular carcinoma: from daily practice to future trends. Liver Cancer 2013;2:16-24.
  69. Joo I, Choi BI: New paradigm for management of hepatocellular carcinoma by imaging. Liver Cancer 2012;1:94-109.
  70. Jang HJ, Kim TK, Wilson SR: Imaging of malignant liver masses: characterization and detection. Ultrasound Q 2006;22:19-29.
    External Resources
  71. Kim AY, Lee MW, Rhim H, Cha DI, Choi D, Kim YS, Lim HK, Cho SW: Pretreatment evaluation with contrast-enhanced ultrasonography for percutaneous radiofrequency ablation of hepatocellular carcinomas with poor conspicuity on conventional ultrasonography. Korean J Radiol 2013;14:754-763.
  72. Park JW, Kim JH, Kim SK, Kang KW, Park KW, Choi JI, Lee WJ, Kim CM, Nam BH: A prospective evaluation of 18F-FDG and 11C-acetate PET/CT for detection of primary and metastatic hepatocellular carcinoma. J Nucl Med 2008;49:1912-1921.
  73. Granito A, Galassi M, Piscaglia F, Romanini L, Lucidi V, Renzulli M, Borghi A, Grazioli L, Golfieri R, Bolondi L: Impact of gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance on the non-invasive diagnosis of small hepatocellular carcinoma: a prospective study. Aliment Pharmacol Ther 2013;37:355-363.
  74. Haradome H, Grazioli L, Tinti R, Morone M, Motosugi U, Sano K, Ichikawa T, Kwee TC, Colagrande S: Additional value of gadoxetic acid-DTPA-enhanced hepatobiliary phase MR imaging in the diagnosis of early-stage hepatocellular carcinoma: comparison with dynamic triple-phase multidetector CT imaging. J Magn Reson Imaging 2011;34:69-78.
  75. Holzapfel K, Eiber MJ, Fingerle AA, Bruegel M, Rummeny EJ, Gaa J: Detection, classification, and characterization of focal liver lesions: value of diffusion-weighted MR imaging, gadoxetic acid-enhanced MR imaging and the combination of both methods. Abdom Imaging 2012;37:74-82.
  76. Iannicelli E, Di Pietropaolo M, Marignani M, Briani C, Federici GF, Delle Fave G, David V: Gadoxetic acid-enhanced MRI for hepatocellular carcinoma and hypointense nodule observed in the hepatobiliary phase. Radiol Med 2014;119:367-376.
  77. Kim JE, Kim SH, Lee SJ, Rhim H: Hypervascular hepatocellular carcinoma 1 cm or smaller in patients with chronic liver disease: characterization with gadoxetic acid-enhanced MRI that includes diffusion-weighted imaging. AJR Am J Roentgenol 2011;196:W758-W765.
  78. Kim SH, Kim SH, Lee J, Kim MJ, Jeon YH, Park Y, Choi D, Lee WJ, Lim HK: Gadoxetic acid-enhanced MRI versus triple-phase MDCT for the preoperative detection of hepatocellular carcinoma. AJR Am J Roentgenol 2009;192:1675-1681.
  79. Kim YK, Lee MW, Lee WJ, Kim SH, Rhim H, Lim JH, Choi D, Kim YS, Jang KM, Lee SJ, Lim HK: Diagnostic accuracy and sensitivity of diffusion-weighted and of gadoxetic acid-enhanced 3-T MR imaging alone or in combination in the detection of small liver metastasis (≤ 1.5 cm in diameter). Invest Radiol 2012;47:159-166.
    External Resources
  80. Park MJ, Kim YK, Lee MH, Lee JH: Validation of diagnostic criteria using gadoxetic acid-enhanced and diffusion-weighted MR imaging for small hepatocellular carcinoma (<= 2.0 cm) in patients with hepatitis-induced liver cirrhosis. Acta Radiol 2013;54:127-136.
  81. Sun HY, Lee JM, Shin CI, Lee DH, Moon SK, Kim KW, Han JK, Choi BI: Gadoxetic acid-enhanced magnetic resonance imaging for differentiating small hepatocellular carcinomas (< or = 2 cm in diameter) from arterial enhancing pseudolesions: special emphasis on hepatobiliary phase imaging. Invest Radiol 2010;45:96-103.
  82. Park G, Kim YK, Kim CS, Yu HC, Hwang SB: Diagnostic efficacy of gadoxetic acid-enhanced MRI in the detection of hepatocellular carcinomas: comparison with gadopentetate dimeglumine. Br J Radiol 2010;83:1010-1016.
  83. Park MJ, Kim YK, Lee MW, Lee WJ, Kim YS, Kim SH, Choi D, Rhim H: Small hepatocellular carcinomas: improved sensitivity by combining gadoxetic acid-enhanced and diffusion-weighted MR imaging patterns. Radiology 2012;264:761-770.
  84. Hyodo T, Murakami T, Imai Y, Okada M, Hori M, Kagawa Y, Kogita S, Kumano S, Kudo M, Mochizuki T: Hypovascular nodules in patients with chronic liver disease: risk factors for development of hypervascular hepatocellular carcinoma. Radiology 2013;266:480-490.
  85. Kim YK, Lee WJ, Park MJ, Kim SH, Rhim H, Choi D: Hypovascular hypointense nodules on hepatobiliary phase gadoxetic acid-enhanced MR images in patients with cirrhosis: potential of DW imaging in predicting progression to hypervascular HCC. Radiology 2012;265:104-114.
  86. Kobayashi S, Matsui O, Gabata T, Koda W, Minami T, Ryu Y, Kozaka K, Kitao A: Relationship between signal intensity on hepatobiliary phase of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced MR imaging and prognosis of borderline lesions of hepatocellular carcinoma. Eur J Radiol 2012;81:3002-3009.
  87. Kumada T, Toyoda H, Tada T, Sone Y, Fujimori M, Ogawa S, Ishikawa T: Evolution of hypointense hepatocellular nodules observed only in the hepatobiliary phase of gadoxetate disodium-enhanced MRI. AJR Am J Roentgenol 2011;197:58-63.
  88. Takayama Y, Nishie A, Nakayama T, Asayama Y, Ishigami K, Kakihara D, Ushijima Y, Fujita N, Hirakawa M, Honda H: Hypovascular hepatic nodule showing hypointensity in the hepatobiliary phase of gadoxetic acid-enhanced MRI in patients with chronic liver disease: prediction of malignant transformation. Eur J Radiol 2012;81:3072-3078.
  89. Murakami T, Tsurusaki M: Hypervascular benign and malignant liver tumors that require differentiation from hepatocellular carcinoma: key points of imaging diagnosis. Liver Cancer 2014;3:85-96.
  90. Ichikawa T, Sano K, Morisaka H: Diagnosis of pathologically early HCC with EOB-MRI: experiences and current consensus. Liver Cancer 2014;3:97-107.
  91. Kudo M: Will Gd-EOB-MRI change the diagnostic algorithm in hepatocellular carcinoma? Oncology 2010;78(suppl 1):87-93.
  92. Lee JM, Choi BI: Hepatocellular nodules in liver cirrhosis: MR evaluation. Abdom Imaging 2011;36:282-289.
  93. Cruite I, Schroeder M, Merkle EM, Sirlin CB: Gadoxetate disodium-enhanced MRI of the liver: part 2, protocol optimization and lesion appearance in the cirrhotic liver. AJR Am J Roentgenol 2010;195:29-41.
  94. Hwang SH, Yu JS, Kim KW, Kim JH, Chung JJ: Small hypervascular enhancing lesions on arterial phase images of multiphase dynamic computed tomography in cirrhotic liver: fate and implications. J Comput Assist Tomogr 2008;32:39-45.
  95. Lau DT, Everhart J, Kleiner DE, Park Y, Vergalla J, Schmid P, Hoofnagle JH: Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology 1997;113:1660-1667.
  96. Kim TK, Lee KH, Jang HJ, Haider MA, Jacks LM, Menezes RJ, Park SH, Yazdi L, Sherman M, Khalili K: 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;259:730-738.
  97. Rimola J, Forner A, Tremosini S, Reig M, Vilana R, Bianchi L, Rodriguez-Lope C, Sole M, Ayuso C, Bruix J: Non-invasive diagnosis of hepatocellular carcinoma ≤ 2 cm in cirrhosis. Diagnostic accuracy assessing fat, capsule and signal intensity at dynamic MRI. J Hepatol 2012;56:1317-1323.
  98. 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;32:360-366.
  99. 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;11:281-289.
  100. 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;105:599-609.
  101. Arif-Tiwari H, Kalb B, Chundru S, Sharma P, Costello J, Guessner RW, Martin DR: MRI of hepatocellular carcinoma: an update of current practices. Diagn Interv Radiol 2014;20:209-221.
  102. Davenport MS, Khalatbari S, Liu PS, Maturen KE, Kaza RK, Wasnik AP, Al-Hawary MM, Glazer DI, Stein EB, Patel J, Somashekar DK, Viglianti BL, Hussain HK: Repeatability of diagnostic features and scoring systems for hepatocellular carcinoma by using MR imaging. Radiology 2014;272:132-142.
  103. Jha RC, Mitchell DG, Weinreb JC, Santillan CS, Yeh BM, Francois R, Sirlin CB: LI-RADS categorization of benign and likely benign findings in patients at risk of hepatocellular carcinoma: a pictorial atlas. AJR Am J Roentgenol 2014;203:W48-W69.
  104. Purysko AS, Remer EM, Coppa CP, Leao Filho HM, Thupili CR, Veniero JC: LI-RADS: a case-based review of the new categorization of liver findings in patients with end-stage liver disease. Radiographics 2012;32:1977-1995.
  105. Jang KM, Kim SH, Kim YK, Choi D: Imaging features of subcentimeter hypointense nodules on gadoxetic acid-enhanced hepatobiliary phase MR imaging that progress to hypervascular hepatocellular carcinoma in patients with chronic liver disease. Acta Radiol 2014, Epub ahead of print.
  106. Kim HS, Choi D, Kim SH, Lee MW, Lee WJ, Kim YK, Jang KM, Park MJ, Park CK: Changes in the signal- and contrast-to-noise ratios of hepatocellular carcinomas on gadoxetic acid-enhanced dynamic MR imaging. Eur J Radiol 2013;82:62-68.
  107. Simon G, Link TM, Wortler K, Doebereiner F, Schulte-Frohlinde E, Daldrup-Link H, Settles M, Rummeny EJ: Detection of hepatocellular carcinoma: comparison of Gd-DTPA- and ferumoxides-enhanced MR imaging. Eur Radiol 2005;15:895-903.
  108. Akai H, Kiryu S, Matsuda I, Satou J, Takao H, Tajima T, Watanabe Y, Imamura H, Kokudo N, Akahane M, Ohtomo K: Detection of hepatocellular carcinoma by Gd-EOB-DTPA-enhanced liver MRI: comparison with triple phase 64 detector row helical CT. Eur J Radiol 2011;80:310-315.
  109. Bashir MR, Gupta RT, Davenport MS, Allen BC, Jaffe TA, Ho LM, Boll DT, Merkle EM: Hepatocellular carcinoma in a North American population: does hepatobiliary MR imaging with Gd-EOB-DTPA improve sensitivity and confidence for diagnosis? J Magn Reson Imaging 2013;37:398-406.
  110. Kim YK, Kim CS, Han YM, Park G: Detection of small hepatocellular carcinoma: can gadoxetic acid-enhanced magnetic resonance imaging replace combining gadopentetate dimeglumine-enhanced and superparamagnetic iron oxide-enhanced magnetic resonance imaging? Invest Radiol 2010;45:740-746.
  111. Narita M, Hatano E, Arizono S, Miyagawa-Hayashino A, Isoda H, Kitamura K, Taura K, Yasuchika K, Nitta T, Ikai I, Uemoto S: Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma. J Gastroenterol 2009;44:793-798.
  112. Kitao A, Zen Y, Matsui O, Gabata T, Kobayashi S, Koda W, Kozaka K, Yoneda N, Yamashita T, Kaneko S, Nakanuma Y: Hepatocellular carcinoma: signal intensity at gadoxetic acid-enhanced MR imaging - correlation with molecular transporters and histopathologic features. Radiology 2010;256:817-826.
  113. Tanimoto A, Kuwatsuru R, Kadoya M, Ohtomo K, Hirohashi S, Murakami T, Hiramatsu K, Yoshikawa K, Katayama H: Evaluation of gadobenate dimeglumine in hepatocellular carcinoma: results from phase II and phase III clinical trials in Japan. J Magn Reson Imaging 1999;10:450-460.
  114. Marin D, Di Martino M, Guerrisi A, De Filippis G, Rossi M, Ginanni Corradini S, Masciangelo R, Catalano C, Passariello R: Hepatocellular carcinoma in patients with cirrhosis: qualitative comparison of gadobenate dimeglumine-enhanced MR imaging and multiphasic 64-section CT. Radiology 2009;251:85-95.
  115. Inoue T, Hyodo T, Murakami T, Takayama Y, Nishie A, Higaki A, Korenaga K, Sakamoto A, Osaki Y, Aikata H, Chayama K, Suda T, Takano T, Miyoshi K, Koda M, Numata K, Tanaka H, Iijima H, Ochi H, Hirooka M, Imai Y, Kudo M: Hypovascular hepatic nodules showing hypointense on the hepatobiliary-phase image of Gd-EOB-DTPA- enhanced MRI to develop a hypervascular hepatocellular carcinoma: a nationwide retrospective study on their natural course and risk factors. Dig Dis 2013;31:472-479.
  116. Motosugi U: Hypovascular hypointense nodules on hepatocyte phase gadoxetic acid-enhanced MR images: too early or too progressed to determine hypervascularity. Radiology 2013;267:317-318.
  117. Chou CT, Chen YL, Su WW, Wu HK, Chen RC: Characterization of cirrhotic nodules with gadoxetic acid-enhanced magnetic resonance imaging: the efficacy of hepatocyte-phase imaging. J Magn Reson Imaging 2010;32:895-902.
  118. Golfieri R, Renzulli M, Lucidi V, Corcioni B, Trevisani F, Bolondi L: Contribution of the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI to dynamic MRI in the detection of hypovascular small (≤ 2 cm) HCC in cirrhosis. Eur Radiol 2011;21:1233-1242.
  119. Chen WX, Min PQ, Song B, Xiao BL, Liu Y, Ge YH: Single-level dynamic spiral CT of hepatocellular carcinoma: correlation between imaging features and density of tumor microvessels. World J Gastroenterol 2004;10:67-72.
    External Resources
  120. Grazioli L, Olivetti L, Fugazzola C, Benetti A, Stanga C, Dettori E, Gallo C, Matricardi L, Giacobbe A, Chiesa A: The pseudocapsule in hepatocellular carcinoma: correlation between dynamic MR imaging and pathology. Eur Radiol 1999;9:62-67.
  121. Ishigami K, Yoshimitsu K, Nishihara Y, Irie H, Asayama Y, Tajima T, Nishie A, Hirakawa M, Ushijima Y, Okamoto D, Taketomi A, Honda H: Hepatocellular carcinoma with a pseudocapsule on gadolinium-enhanced MR images: correlation with histopathologic findings. Radiology 2009;250:435-443.
  122. Lee MH, Kim SH, Park MJ, Park CK, Rhim H: Gadoxetic acid-enhanced hepatobiliary phase MRI and high-b-value diffusion-weighted imaging to distinguish well-differentiated hepatocellular carcinomas from benign nodules in patients with chronic liver disease. AJR Am J Roentgenol 2011;197:W868-W875.
  123. Nakamura Y, Toyota N, Date S, Oda S, Namimoto T, Yamashita Y, Beppu T, Awai K: Clinical significance of the transitional phase at gadoxetate disodium-enhanced hepatic MRI for the diagnosis of hepatocellular carcinoma: preliminary results. J Comput Assist Tomogr 2011;35:723-727.
  124. Chong YS, Kim YK, Lee MW, Kim SH, Lee WJ, Rhim HC, Lee SJ: Differentiating mass-forming intrahepatic cholangiocarcinoma from atypical hepatocellular carcinoma using gadoxetic acid-enhanced MRI. Clin Radiol 2012;67:766-773.
  125. Park HJ, Kim YK, Park MJ, Lee WJ: Small intrahepatic mass-forming cholangiocarcinoma: target sign on diffusion-weighted imaging for differentiation from hepatocellular carcinoma. Abdom Imaging 2013;38:793-801.
  126. Pradella S, Lucarini S, Colagrande S: Liver lesion characterization: the wrong choice of contrast agent can mislead the diagnosis of hemangioma. AJR Am J Roentgenol 2012;199:W662.
  127. Tanimoto A, Lee JM, Murakami T, Huppertz A, Kudo M, Grazioli L: Consensus report of the 2nd International Forum for Liver MRI. Eur Radiol 2009;19(suppl 5):S975-S989.
  128. Bruegel M, Holzapfel K, Gaa J, Woertler K, Waldt S, Kiefer B, Stemmer A, Ganter C, Rummeny EJ: Characterization of focal liver lesions by ADC measurements using a respiratory triggered diffusion-weighted single-shot echo-planar MR imaging technique. Eur Radiol 2008;18:477-485.
  129. Haradome H, Grazioli L, Morone M, Gambarini S, Kwee TC, Takahara T, Colagrande S: T2-weighted and diffusion-weighted MRI for discriminating benign from malignant focal liver lesions: diagnostic abilities of single versus combined interpretations. J Magn Reson Imaging 2012;35:1388-1396.
  130. Toyoda H, Kumada T, Tada T, Niinomi T, Ito T, Sone Y, Kaneoka Y, Maeda A: Non-hypervascular hypointense nodules detected by Gd-EOB-DTPA-enhanced MRI are a risk factor for recurrence of HCC after hepatectomy. J Hepatol 2013;58:1174-1180.
  131. Yamamoto A, Ito K, Tamada T, Higaki A, Kanki A, Sato T, Tanimoto D: Newly developed hypervascular hepatocellular carcinoma during follow-up periods in patients with chronic liver disease: observation in serial gadoxetic acid-enhanced MRI. AJR Am J Roentgenol 2013;200:1254-1260.
  132. Sano K, Ichikawa T, Motosugi U, Sou H, Muhi AM, Matsuda M, Nakano M, Sakamoto M, Nakazawa T, Asakawa M, Fujii H, Kitamura T, Enomoto N, Araki T: Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid-enhanced MR imaging. Radiology 2011;261:834-844.
  133. Bartolozzi C, Battaglia V, Bargellini I, Bozzi E, Campani D, Pollina LE, Filipponi F: Contrast-enhanced magnetic resonance imaging of 102 nodules in cirrhosis: correlation with histological findings on explanted livers. Abdom Imaging 2013;38:290-296.
  134. Takechi M, Tsuda T, Yoshioka S, Murata S, Tanaka H, Hirooka M, Mochizuki T: Risk of hypervascularization in small hypovascular hepatic nodules showing hypointense in the hepatobiliary phase of gadoxetic acid-enhanced MRI in patients with chronic liver disease. Jpn J Radiol 2012;30:743-751.
  135. Matsui O: Detection and characterization of hepatocellular carcinoma by imaging. Clin Gastroenterol Hepatol 2005;3(10 suppl 2):S136-S140.
  136. Piscaglia F, Bolondi L: Recent advances in the diagnosis of hepatocellular carcinoma. Hepatol Res 2007;37(suppl 2):S178-S192.
  137. Lee J, Lee WJ, Lim HK, Lim JH, Choi N, Park MH, Kim SW, Park CK: Early hepatocellular carcinoma: three-phase helical CT features of 16 patients. Korean J Radiol 2008;9:325-332.
  138. Lee JH, Lee JM, Kim SJ, Baek JH, Yun SH, Kim KW, Han JK, Choi BI: Enhancement patterns of hepatocellular carcinomas on multiphasic multidetector row CT: comparison with pathological differentiation. Br J Radiol 2012;85:e573-e583.
  139. Yoon SH, Lee JM, So YH, Hong SH, Kim SJ, Han JK, Choi BI: Multiphasic MDCT enhancement pattern of hepatocellular carcinoma smaller than 3 cm in diameter: tumor size and cellular differentiation. AJR Am J Roentgenol 2009;193:W482-W489.
  140. Yu MH, Kim JH, Yoon JH, Kim HC, Chung JW, Han JK, Choi BI: Small (≤1-cm) hepatocellular carcinoma: diagnostic performance and imaging features at gadoxetic acid-enhanced MR imaging. Radiology 2014;271:748-760.
  141. Golfieri R, Marini E, Bazzocchi A, Fusco F, Trevisani F, Sama C, Mazzella G, Cavuto S, Piscaglia F, Bolondi L: Small (< or = 3 cm) hepatocellular carcinoma in cirrhosis: the role of double contrast agents in MR imaging versus multidetector-row CT. Radiol Med 2009;114:1239-1266.
  142. Bae SY, Choi MS, Gwak GY, Paik YH, Lee JH, Koh KC, Paik SW, Yoo BC: Comparison of usefulness of clinical diagnostic criteria for hepatocellular carcinoma in a hepatitis B endemic area. Clin Mol Hepatol 2012;18:185-194.
  143. Moon JI, Kwon CH, Joh JW, Choi GS, Jung GO, Kim JM, Shin M, Choi SJ, Kim SJ, Lee SK: Primary versus salvage living donor liver transplantation for patients with hepatocellular carcinoma: impact of microvascular invasion on survival. Transplant Proc 2012;44:487-493.
  144. Kojiro M: Pathological diagnosis at early stage: reaching international consensus. Oncology 2010;78(suppl 1):31-35.
  145. 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;57:1592-1596.
ppt logo Download Images (.pptx)


Figures
Thumbnail

Tables
Thumbnail
Thumbnail